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Sickle Cell Disease Research

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The National Institutes of Health (NIH) has supported research on sickle cell disease — also called sickle cell anemia — since before the NHLBI’s founding in 1948. With each passing decade, the NHLBI has kept a focus on advancing the understanding of sickle cell disease and improving clinical care for people who have it. The Institute leads and supports research and programs on sickle cell disease in the United States and around the world.  For example, it has strongly supported the development of  gene therapies to treat and cure the disease. Two gene-based cures were approved by the U.S. Food and Drug Administration (FDA) in December 2023.

We are committed to building upon this legacy of research excellence to develop even more new treatments, find cures, and personalize care for the approximately 100,000 Americans and more than  8 million people worldwide living with sickle cell disease . In the United States, 9 of 10 people who have been diagnosed with this painful, life-shortening disease are of African ancestry or identify as Black.

NHLBI research that really made a difference

NHLBI-funded scientists found an effective sickle cell treatment in 1995. Results from the  NHLBI Multicenter Study of Hydroxyurea showed that hydroxyurea reduced the number of pain crises by 50% in adults with severe sickle cell disease. 

Three years later, the FDA approved hydroxyurea to treat sickle cell disease in adults. Research to improve the use of hydroxyurea continued over the next decade. In 2011, results from an NHLBI-funded study called  BABY HUG  found hydroxyurea to be safe for young children who have sickle cell disease.

Milestones in Sickle Cell Disease Research 

Learn about the history of sickle cell disease in the United States and the NHLBI research that has made a difference. 

Current research funded by the NHLBI

Find  funding opportunities  and  program contacts  for sickle cell disease research. 

Current research on sickle cell disease treatment

Many NHLBI-supported studies are looking at gene therapies and blood and marrow transplants (BMT) as transformative therapies for people with sickle cell disease.

In December 2023, the FDA approved two gene therapies for some people with sickle cell disease. Everyone’s experience is different, but people treated with gene therapy tend to have less anemia, fewer health problems related to sickle cell, and better health-related quality of life. This important advance was built upon years of NHLBI-funded discoveries about the genes that cause sickle cell disease and affect disease severity and how best to perform gene therapy. 

• Speeding progress on cures:  The Cure Sickle Cell Initiative (CureSCi) is an NHLBI-led collaborative research effort to speed the development of gene therapies to treat sickle cell disease. CureSCi clinical trials focus on altering genes in patients’ own hematopoietic (blood-forming) stem cells so that the red blood cells do not sickle. Results from the first 10 participants in a phase 1  CureSCi clinical trial showed that a type of gene therapy was safe and effective for reducing pain crises. Based on that early success, a  phase 2 trial of the same therapy began in 2024. 
• Developing medicines to help the blood work better: The NHLBI’s Sickle Cell Branch scientists conducted an early-stage study of a medicine called mitapivat in people with sickle cell disease. The study showed that mitapivat decreased red blood cell sickling and breakdown and could be safely used to improve hemoglobin levels. Based on the promising results, other research groups carried out longer studies with more participants. Those studies showed that participants who took mitapivat for a year had fewer pain crises, in addition to improved hemoglobin levels and less sickling of red blood cells.
• Making blood transfusions safer : Many patients with sickle cell disease often receive blood transfusions to treat and prevent certain complications. NHLBI-funded researchers are exploring how to optimize  safety and benefits of blood transfusions   for people living with the disease. 
• Evaluating monthly exchange red blood cell transfusions:  As people with sickle cell disease become adults, they may develop heart and lung diseases that can cause early death. Blood and heart ultrasound tests can identify patients at risk for these complications. The  Sickle Cell Disease and Cardiovascular Risk — Red Cell Exchange (SCD–CARRE) trial is testing monthly automated exchange transfusions as a strategy to reduce serious complications of sickle cell disease, improve symptoms, and prevent hospitalization and death. Exchange transfusions remove a person’s blood and replace it with red blood cells from a donor.
• Improving access to BMTs: The NHLBI collaborates with the National Cancer Institute in funding efforts to improve access to BMT through the  BMT Clinical Trials Network . Several studies are exploring options for people with sickle cell disease who don’t have a well-matched donor who is a family member. For example,  one study is comparing treatment of severe sickle cell disease with BMTs using cells from either an unrelated immune-matched donor or from a mismatched donor.

Find more NHLBI-funded studies on  sickle cell disease treatment at NIH RePORTER. Information on  NHLBI-supported sickle cell disease treatment clinical trials is also available.

Current research on managing sickle cell pain

• Exploring new ways to reduce the pain crises: Pain crises — also called sickle cell crises or vaso-occlusive crises — affect nearly all people with sickle cell disease. These crises are the leading cause of emergency department visits and hospitalizations for people with the disease. An  NHLBI-funded study found that treating children with arginine could lower inflammation linked with sickle cell pain crises and lower the amount of opioid medicine needed to manage pain. 
• Promoting guideline-based care for sickle cell pain: Too often, healthcare providers in emergency departments do not follow guidelines for treating pain. This leads to delays in treatment, more pain, and more hospitalizations. In addition, racism may be a barrier to care. An NHLBI-supported  study is testing a care pathway to promote guideline-based care for children being treated in emergency departments for pain crises. 
• Innovating approaches to reduce sickling:  Through its Small Business Innovation Research program, the NHLBI is supporting the development of a  nanoparticle-based therapy for sickle cell disease. Heparin is a medicine that shows some potential benefits for sickle cell disease, but it can raise the chance of bleeding. This project is testing a nanoparticle version of heparin in animal models and lab tests to learn whether the compound can lower sickling of red blood cells without unwanted side effects. If the  project succeeds, the nanoparticle version of heparin will be readied for first-in-human studies. 
• Studying the role of gut bacteria in pain of sickle cell disease: NHLBI-funded scientists are studying the gut microbiome — microbes living in the intestines — of people with sickle cell disease. This is  the first study of the role the microbiome may play in causing sickle cell pain crises and long-term pain. Other studies have shown that an out-of-balance microbiome can worsen the pain of some inflammatory diseases such as rheumatoid arthritis. 

Find more NHLBI-funded studies on  pain management in sickle cell disease at NIH RePORTER.  Information on  NHLBI-supported sickle cell disease pain related clinical trials is also available.

Current research into sickle cell trait

People with sickle cell disease have two genes for hemoglobin S. In contrast, people with sickle cell trait have one gene for hemoglobin S and another gene for normal hemoglobin A. Though most people who have sickle cell trait don’t have any symptoms, some may experience symptoms in rare situations. The NHLBI is supporting research to better understand health concerns that people who have sickle cell trait might face. 

• Studying health risks linked with sickle cell trait:  Two NHLBI scientists  reviewed evidence of links between sickle cell trait and various health problems. People with sickle cell trait live as long as people who don’t have the trait. The review included findings of a study of nearly 48,000 Black soldiers that showed that soldiers with sickle cell trait did not have higher rates of sudden death compared to soldiers without the trait. Sickle cell trait slightly raised the chance of rhabdomyolysis (muscle damage) with extreme exertion. Studies also suggest that sickle cell trait raises the chance of kidney disease and  venous thromboembolism .
• Detecting early signs of dangerous blood clots: An  NHLBI clinical trial is studying blood clotting and markers of inflammation in people with sickle cell trait or sickle cell disease to identify risk factors for venous thromboembolism. The researchers are comparing data from people who have had venous thromboembolism and people who do not have the condition to find possible links with sickle cell disease or trait. 

Current research to improve access to care for sickle cell disease 

Despite their extensive healthcare needs, many people living with sickle cell disease have difficulty getting appropriate care. People often report feeling stigmatized and having their symptoms dismissed when they do seek care. The NHLBI is committed to research that will help lower the barriers patients face when seeking sickle cell disease treatment and trying to stick with their treatment plan. 

• Understanding transitions in care for sickle cell disease: NHLBI-funded researchers looked at health records of 472 young people between 18 and 24 years old who received care for sickle cell disease at an Alabama clinic. The scientists checked to see how many engaged with adult care for sickle cell disease after receiving care in a pediatric clinic. The scientists found that less than half of the participants successfully transferred to adult care. Factors that led to successful transfers included engaging with pediatric and adult care at the same hospital, and being treated with hydroxyurea or blood transfusions. Many of those who did not transfer to adult clinics had dropped out of care by 15 years old.  Read more about the study.
• Finding ways to help children continue hydroxyurea treatment: In 2014, the NHLBI published treatment guidelines that recommended offering hydroxyurea to all children and youth over 9 months old who have sickle cell disease. However,  a study in New York State and Michigan found that only 1 in 3 children were taking this important medicine as prescribed. The scientists suggested that education programs for healthcare providers and families might help more children stick with this lifesaving treatment.
• Overcoming barriers to lowering stroke risk in children with sickle cell disease: Sickle cell disease greatly increases the risk of stroke in children, but regular screenings and treatments can reduce stroke risk by more than 90%. The NHLBI-funded Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) study aimed to improve access to stroke screening for children with sickle cell disease.  DISPLACE researchers identified factors that are barriers to effective stroke screening, such as challenges in scheduling ultrasound scans, a need for appointment reminders, and a lack of information and education about stroke screening.  Only about half of children received recommended ultrasound scans. The scientists also noted the  need to improve training of healthcare providers who perform and interpret the scans. The DISPLACE results are important for ensuring more consistent use of guideline-directed screening and treatment.
• Promoting education about genetic therapies for sickle cell disease: As part of the National Institutes of Health (NIH), the NHLBI supports efforts to help people understand the basics of hemoglobin disorders as well as transformative treatments. The NIH’s  Sickle Cell Disease Gene Therapy Education Project provides educational materials to help people understand gene therapies so they can make informed decisions. The materials reflect the input of patients, parents of patients, healthcare providers, community-based organizations, advocacy groups, industry leaders, government representatives, and researchers. The website includes  a set of FAQs that can help guide discussions between people with sickle cell disease and their providers.

Find NHLBI-funded studies on  health disparities and sickle cell disease at NIH RePORTER. Explore  health disparities sickle cell disease trials .

Sickle cell disease research labs at the NHLBI

Researchers from the NHLBI Division of Intramural Research , which includes investigators in our Sickle Cell Branch , are focused on developing new treatments for sickle cell disease. The  Sickle Cell Genetics and Pathophysiology Lab studies the genetic and biological factors underlying the variability of sickle cell disease symptoms and complications.

• NHLBI scientists are using the ReFRAME Drug Repurposing Library, which lists medicines that are approved by the FDA and have the potential to treat or prevent sickle cell pain crises at lower cost. By screening the medicines in the library, scientists discovered 106 compounds that stop sickling of hemoglobin. Further analysis showed that 21 compounds could be potential treatments to prevent pain crises. 
• The NHLBI set up the  Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) in 2008. BioLINCC has since expanded to include samples and data from more than 580,000 people participating in more than 180 studies. With the addition of the Cure Sickle Cell Hematopoietic Stem Cell Collection study in 2022,  samples of stem cells and  study data from people with sickle cell disease became available to support research. 

Read more about these projects and  ongoing clinical trials .

Related sickle cell disease programs

The NHLBI leads and supports many programs and initiatives around the nation and the world as we search for a cure and work to improve the lives of people with sickle cell disease.

The NHLBI Hosted 2023 Conference on Sickle Cell Disease

The 16th annual  2023 Sickle Cell in Focus (SCiF) conference was held in October 2023 and co-hosted by the NHLBI and the University of West Indies. View video recordings of the 2023 conference: 

• Day 1, October 10:  https://videocast.nih.gov/watch=52475  
• Day 2, October 11:  https://videocast.nih.gov/watch=52477
• The   Recipient Epidemiology and Donor Evaluation Study Program tests transfusion therapies and improves their safety and success. The program also works to address potential emerging threats to the United States’ blood supply and serves as a resource for work in transfusion research.
• The NHLBI has taken a lead role in managing the  Regenerative Medicine Innovation Project under the  21st Century Cures Act . Beginning in 2017, the Act authorized the investment of $30 million in clinical research with adult stem cells to treat diseases, including sickle cell disease.
• The Sickle Pan-African Research Consortium demonstrated that widespread newborn screening for sickle cell disease is possible is sub-Saharan Africa.
• The SickleGenAfrica Network developed an ethics framework and presented findings from community engagement in Ghana, Nigeria, and Tanzania.
• REACH researchers found that hydroxyurea treatment is linked with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa .  

NHLBI Annual Conference Highlights Recent Advances in Sickle Cell Disease Research and Care  

The yearly  NHLBI Sickle Cell Disease Research Meeting is a forum for scientists and healthcare providers to learn about ongoing research in the scientific and clinical aspects of the disease. View recordings of the 3-day, 2024 meeting:

• Day 1, August 12:  https://videocast.nih.gov/watch=54991  
• Day 2, August 13:  https://videocast.nih.gov/watch=54992  
• Day 3, August 14:  https://videocast.nih.gov/watch=54993   

Explore more NHLBI research on sickle cell disease

The sections above give you the highlights of NHLBI-supported research on sickle cell disease. You can explore the full list of NHLBI-funded  clinical studies on  NIH RePORTER .

To find more studies using NIH RePORTER:

• Type your search words into the Quick Search box and press enter. 
• Check Active Projects if you want current research.
• Select the Agencies arrow, then the NIH arrow, then check NHLBI.

If you want to sort the projects by budget size — from the biggest to the smallest — click on the FY Total Cost by IC column heading.

• Open access
• Published: 03 March 2022

Advances in the diagnosis and treatment of sickle cell disease

• A. M. Brandow 1 &
• R. I. Liem   ORCID: orcid.org/0000-0003-2057-3749 2  

Journal of Hematology & Oncology volume  15 , Article number:  20 ( 2022 ) Cite this article

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Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of l -glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.

Introduction

Sickle cell disease (SCD), a group of inherited hemoglobinopathies characterized by mutations that affect the β-globin chain of hemoglobin, affects approximately 100,000 people in the USA and more than 3 million people worldwide [ 1 , 2 ]. SCD is characterized by chronic hemolytic anemia, severe acute and chronic pain as well as end-organ damage that occurs across the lifespan. SCD is associated with premature mortality with a median age of death of 43 years (IQR 31.5–55 years) [ 3 ]. Treatment requires early diagnosis, prevention of complications and management of end-organ damage. In this review, we discuss recent advances in the diagnosis and management of four major complications in SCD: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. Updates in disease-modifying and curative therapies for SCD are also discussed.

Molecular basis and pathophysiology

Hemoglobin S (HbS) results from the replacement of glutamic acid by valine in the sixth position of the β-globin chain of hemoglobin (Fig.  1 ). Severe forms of SCD include hemoglobin SS due to homozygous inheritance of HbS and S/β 0 thalassemia due to co-inheritance of HbS with the β 0 thalassemia mutation. Other forms include co-inheritance of HbS with other β-globin gene mutations such as hemoglobin C, hemoglobin D-Los Angeles/Punjab or β + thalassemia. Hb S has reduced solubility and increased polymerization, which cause red blood cell sickling, hemolysis and vaso-occlusion (Table 1 ) that subsequently lead to pain episodes and end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease (Table 2 ).

Genetic and molecular basis of sickle cell disease. SCD is caused by mutations in the β globin gene, located on the β globin locus found on the short arm of chromosome 11. The homozygous inheritance of Hb S or co-inheritance of Hb S with the β 0 thalassemia mutation results in the most common forms of severe SCD. Co-inheritance of Hb S with other variants such as Hb C, Hb D-Los Angeles/Punjab, Hb O-Arab or β + thalassemia also leads to clinically significant sickling syndromes (LCR, locus control region; HS, hypersensitivity site)

Acute and chronic pain

Severe intermittent acute pain is the most common SCD complication and accounts for over 70% of acute care visits for individuals with SCD [ 4 ]. Chronic daily pain increases with older age, occurring in 30–40% of adolescents and adults with SCD [ 5 , 6 ]. Acute pain is largely related to vaso-occlusion of sickled red blood cells with ischemia–reperfusion injury and tissue infarction and presents in one isolated anatomic location (e.g., arm, leg, back) or multiple locations. Chronic pain can be caused by sensitization of the central and/or peripheral nervous system and is often diffuse with neuropathic pain features [ 7 , 8 ]. A consensus definition for chronic pain includes “Reports of ongoing pain on most days over the past 6 months either in a single location or multiple locations” [ 9 ]. Disease complications such as avascular necrosis (hip, shoulder) and leg ulcers also cause chronic pain [ 9 ].

Diagnosis of acute and chronic pain

The gold standard for pain assessment and diagnosis is patient self-report. There are no reliable diagnostic tests to confirm the presence of acute or chronic pain in individuals with SCD except when there are identifiable causes like avascular necrosis on imaging or leg ulcers on exam. The effects of pain on individuals’ function are assessed using patient-reported outcome measures (PROs) that determine to what extent pain interferes with individuals’ daily function. Tools shown to be valid, reliable and responsive can be used in clinical practice to track patients’ pain-related function over time to determine additional treatment needs and to compare to population norms [ 10 ]. There are currently no plasma pain biomarkers that improve assessment and management of SCD acute or chronic pain.

Depression and anxiety as co-morbid conditions in SCD can contribute to increased pain, more pain-related distress/interference and poor coping [ 11 ]. The prevalence of depression and anxiety range from 26–33% and 6.5–36%, respectively, in adults with SCD [ 11 , 12 , 13 ]. Adults with SCD have an 11% higher prevalence of depression compared to Black American adults without SCD [ 14 ]. Depression and anxiety can be assessed using self-reported validated screening tools (e.g., Depression: Patient Health Questionnaire (PHQ-9) [ 15 ] for adults, Center for Epidemiologic Studies Depression Scale for Children (CES-DC) [ 16 ], PROMIS assessments for adults and children; Anxiety: Generalized Anxiety Disorder 7-item (GAD-7) scale for adults, State-Trait Anxiety Inventory for Children (STAIC) [ 17 ], PROMIS assessments for adults and children). Individuals who screen positive using these tools should be referred for evaluation by a psychologist/psychiatrist.

Management of acute and chronic pain

The goal of acute pain management is to provide sufficient analgesia to return patients to their usual function, which may mean complete resolution of pain for some or return to baseline chronic pain for others. The goal of chronic pain management is to optimize individuals’ function, which may not mean being pain free. When there is an identifiable cause of chronic pain, treatment of the underlying issue (e.g., joint replacement for avascular necrosis, leg ulcer treatment) is important. Opioids, oral for outpatient management and intravenous for inpatient management, are first line therapy for acute SCD pain. In the acute care setting, analgesics should be initiated within 30–60 min of triage [ 18 ]. Ketamine, a non-opioid analgesic, can be prescribed at sub-anesthetic (analgesic) intravenous doses (0.1–0.3 mg/kg per h, maximum 1 mg/kg per h) as adjuvant treatment for acute SCD pain refractory to opioids [ 18 , 19 ]. In an uncontrolled observational study of 85 patients with SCD receiving ketamine infusions for acute pain, ketamine was associated with a decrease in mean opioid consumption by oral morphine equivalents (3.1 vs. 2.2 mg/kg/day, p  < 0.001) and reductions in mean pain scores (0–10 scale) from baseline until discontinuation of the infusion (7.81 vs. 5.44, p  < 0.001) [ 20 ]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely used as adjuvant therapy for acute pain treatment [ 18 ]. In a RCT ( n  = 20) of hospitalized patients with acute pain, ketorolac was associated with lower total dose of meperidine required (1866.7 ± 12.4 vs. 2804.5 ± 795.1 mg, p  < 0.05) and shorter hospitalization (median 3.3 vs. 7.2 days, p  = 0.027) [ 21 ]. In a case series of children treated for 70 acute pain events in the ED, 53% of events resolved with ketorolac and hydration alone with reduction in 100 mm visual analog scale (VAS) pain score from 60 to 13 ( p  < 0.001) [ 22 ]. Patients at risk for NSAID toxicity (e.g., renal impairment, on anticoagulation) should be identified.

Despite paucity of data, chronic opioid therapy (COT) can be considered after assessing benefits versus harms [ 23 ] and the functional status of patients with SCD who have chronic pain. Harms of COT seen in patient populations other than SCD are dose dependent and include myocardial infarction, bone fracture, increased risk of motor vehicle collisions, sexual dysfunction and mortality [ 23 ]. There are few published studies investigating non-opioid analgesics for chronic SCD pain [ 24 , 25 , 26 ]. In a randomized trial of 39 participants, those who received Vitamin D experienced a range of 6–10 pain days over 24 weeks while those who received placebo experienced 10–16 pain days, which was not significantly different [ 26 ]. In a phase 1, uncontrolled trial of 18 participants taking trifluoperazine, an antipsychotic drug, 8 participants showed a 50% reduction in the VAS (10 cm horizontal line) pain score from baseline on at least 3 assessments over 24 h without severe sedation or supplemental opioid analgesics, 7 participants showed pain reduction on 1 assessment, and the remaining 3 participants showed no reduction [ 24 ]. Although published data are not available for serotonin and norepinephrine reuptake inhibitors (SNRIs), gabapentinoids and tricyclic antidepressants (TCAs) in individuals with SCD, evidence supports their use in fibromyalgia, a chronic pain condition similar to SCD chronic pain in mechanism. A Cochrane Review that included 10 RCTs ( n  = 6038) showed that the SNRIs milnacipran and duloxetine, compared to placebo, were associated with a reduction in pain [ 27 ]. A systematic review and meta-analysis of 9 studies ( n  = 520) showed the TCA amitriptyline improved pain intensity and function [ 28 ]. Finally, a meta-analysis of 5 RCTs ( n  = 1874) of the gabapentinoid pregabalin showed a reduction in pain intensity [ 29 ]. Collectively, the indirect evidence from fibromyalgia supports the conditional recommendation in current SCD practice guidelines to consider these 3 drug classes for chronic SCD pain treatment [ 18 ]. Standard formulary dosing recommendations should be followed and reported adverse effects considered.

Non-pharmacologic therapies (e.g., integrative, psychological-based therapies) are important components of SCD pain treatment. In a case–control study of 101 children with SCD and chronic pain referred for cognitive behavioral therapy (CBT) (57 CBT, 44 no CBT) [ 30 ], CBT was associated with more rapid decrease in pain hospitalizations (estimate − 0.63, p  < 0.05) and faster reduction in hospital days over time (estimate − 5.50, p  < 0.05). Among 18 children who received CBT and completed PROs pre- and 12 months posttreatment, improvements were seen in mean pain intensity (5.47 vs. 3.76, p  = 0.009; 0–10 numeric rating pain scale), functional disability (26.24 vs. 15.18, p  < 0.001; 0–60 score range) and pain coping (8.00 vs. 9.65, p  = 0.03; 3–15 score range) post treatment [ 30 ]. In 2 uncontrolled clinical trials, acupuncture was associated with a significant reduction in pain scores by 2.1 points (0–10 numeric pain scale) in 24 participants immediately after treatment [ 31 ] or a significant mean difference in pre-post pain scores of 0.9333 (0–10 numeric pain scale) ( p  < 0.000) after 33 acupuncture sessions [ 32 ].

Cardiopulmonary disease

Cardiopulmonary disease is associated with increased morbidity and mortality in individuals with SCD. Pulmonary hypertension (PH), most commonly pulmonary arterial hypertension (PAH), is present based on right-heart catheterization in up to 10% of adults with SCD [ 33 ]. Chronic intravascular hemolysis represents the biggest risk factor for development of PAH in SCD and leads to pulmonary arteriole vasoconstriction and smooth muscle proliferation. Based on pulmonary function testing (PFT), obstructive lung disease may be observed in 16% of children and 8% of adults with SCD, while restrictive lung disease may be seen in up to 28% of adults and only 7% of children with SCD [ 34 , 35 ]. Sleep-disordered breathing, which can manifest as obstructive sleep apnea or nocturnal hypoxemia, occurs in up to 42% of children and 46% of adults with SCD [ 36 , 37 ]. Cardiopulmonary disease, including PH or restrictive lung disease, presents with dyspnea with or without exertion, chest pain, hypoxemia or exercise intolerance that is unexplained or increased from baseline. Obstructive lung disease can also present with wheezing.

Diagnosis of cardiopulmonary disease

The confirmation of PH in patients with SCD requires right-heart catheterization. Recently, the mean pulmonary artery pressure threshold used to define PH in the general population was lowered from ≥ 25 to ≥ 20 mm Hg [ 38 ]. Elevated peak tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s on Doppler echocardiogram (ECHO) is associated with early mortality in adults with SCD and may suggest elevated pulmonary artery pressures, especially when other signs of PH (e.g., right-heart strain, septal flattening) or left ventricular diastolic dysfunction, which may contribute to PH, are present [ 39 ]. However, the positive predictive value (PPV) of peak TRJV alone for identifying PH in adults with SCD is only 25% [ 40 ]. Increasing the peak TRJV threshold to at least 2.9 m/s has been shown to increase the PPV to 64%. For a peak TRJV of 2.5–2.8 m/s, an increased N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 164.5 pg/mL or a reduced 6-min walk distance (6MWD) < 333 m can also improve the PPV to 62% with a false negative rate of 7% [ 33 , 40 , 41 ].

PFT, which includes spirometry and measurement of lung volumes and diffusion capacity, is standard for diagnosing obstructive and restrictive lung disease in patients with SCD. Emerging modalities include impulse oscillometry, a non-invasive method using forced sound waves to detect changes in lower airway mechanics in individuals unable to perform spirometry [ 42 ], and airway provocation studies using cold air or methacholine to reveal latent airway hyperreactivity [ 43 ]. Formal in-lab, sleep study/polysomnography remains the gold standard to evaluate for sleep-disordered breathing, which may include nocturnal hypoxemia, apnea/hypopnea events and other causes of sleep disruption. Nocturnal hypoxemia may increase red blood cell sickling, cellular adhesion and endothelial dysfunction. In 47 children with SCD, mean overnight oxygen saturation was higher in those with grade 0 compared to grade 2 or 3 cerebral arteriopathy (97 ± 1.6 vs. 93.9 ± 3.7 vs. 93.5 ± 3.0%, p  < 0.01) on magnetic resonance angiography and lower overnight oxygen saturation was independently associated with mild, moderate or severe cerebral arteriopathy after adjusting for reticulocytosis (OR 0.50, 95% CI 0.26–0.96, p  < 0.05) [ 44 ].

Management of cardiopulmonary disease

Patients with SCD who have symptoms suggestive of cardiopulmonary disease, such as worsening dyspnea, hypoxemia or reduced exercise tolerance, should be evaluated with a diagnostic ECHO and PFT. The presence of snoring, witnessed apnea, respiratory pauses or hypoxemia during sleep, daytime somnolence or nocturnal enuresis in older children and adults is sufficient for a diagnostic sleep study.

Without treatment, the mortality rate in SCD patients with PH is high compared to those without (5-year, all-cause mortality rate of 32 vs. 16%, p  < 0.001) [ 33 ]. PAH-targeted therapies should be considered for SCD patients with PAH confirmed by right-heart catheterization. However, the only RCT ( n  = 6) in individuals with SCD and PAH confirmed by right-heart catheterization (bosentan versus placebo) was stopped early for poor accrual with no efficacy endpoints analyzed [ 45 ]. In SCD patients with elevated peak TRJV, a randomized controlled trial ( n  = 74) of sildenafil, a phosphodiesterase-5 inhibitor, was discontinued early due to increased pain events in the sildenafil versus placebo arm (35 vs. 14%, p  = 0.029) with no treatment benefit [ 46 ]. Despite absence of clinical trial data, patients with SCD and confirmed PH should be considered for hydroxyurea or monthly red blood cell transfusions given their disease-modifying benefits. In a retrospective analysis of 13 adults with SCD and PAH, 77% of patients starting at a New York Heart Association (NYHA) functional capacity class III or IV achieved class I/II after a median of 4 exchange transfusions with improvement in median pulmonary vascular resistance (3.7 vs. 2.8 Wood units, p  = 0.01) [ 47 ].

Approximately 28% of children with SCD have asthma, which is associated with increased pain episodes that may result from impaired oxygenation leading to sickling and vaso-occlusion as well as with acute chest syndrome and higher mortality [ 48 , 49 , 50 ]. First line therapies include standard beta-adrenergic bronchodilators and supplemental oxygen as needed. When corticosteroids are indicated, courses should be tapered over several days given the risk of rebound SCD pain from abrupt discontinuation. Inhaled corticosteroids such as fluticasone proprionate or beclomethasone diproprionate are reserved for patients with recurrent asthma exacerbations, but their anti-inflammatory effects and impact on preventing pain episodes in patients with SCD who do not have asthma is under investigation [ 51 ]. Finally, management of sleep-disordered breathing is tailored to findings on formal sleep study in consultation with a sleep/pulmonary specialist.

Central nervous system (CNS) complications

CNS complications, such as overt and silent cerebral infarcts, cause significant morbidity in individuals with SCD. Eleven percent of patients with HbSS disease by age 20 years and 24% by age 45 years will have had an overt stroke [ 52 ]. Silent cerebral infarcts occur in 39% by 18 years and in > 50% by 30 years [ 53 , 54 ]. Patients with either type of stroke are at increased risk of recurrent stroke [ 55 ]. Overt stroke involves large-arteries, including middle cerebral arteries and intracranial internal carotid arteries, while silent cerebral infarcts involve penetrating arteries. The pathophysiology of overt stroke includes vasculopathy, increased sickled red blood cell adherence, and hemolysis-induced endothelial activation and altered vasomotor tone [ 56 ]. Overt strokes present as weakness or paresis, dysarthria or aphasia, seizures, sensory deficits, headache or altered level of consciousness, while silent cerebral infarcts are associated with cognitive deficits, including lower IQ and impaired academic performance.

Diagnosis of CNS complications in SCD

Overt stroke is diagnosed by evidence of acute infarct on brain MRI diffusion-weighted imaging and focal deficit on neurologic exam. A silent cerebral infarct is defined by a brain “MRI signal abnormality at least 3 mm in one dimension and visible in 2 planes on fluid-attenuated inversion recovery (FLAIR) T2-weighted images” and no deficit on neurologic exam [ 57 ]. Since silent cerebral infarcts cannot be detected clinically, a screening baseline brain MRI is recommended in school-aged children with SCD [ 58 ]. Recent SCD clinical practice guidelines also suggest a screening brain MRI in adults with SCD to facilitate rehabilitation services, patient and family understanding of cognitive deficits and further needs assessment [ 58 ]. An MRA should be added to screening/diagnostic MRIs to evaluate for cerebral vasculopathy (e.g., moyamoya), which may increase risk for recurrent stroke or hemorrhage [ 59 ].

Annual screening for increased stroke risk by transcranial doppler (TCD) ultrasound is recommended by the American Society of Hematology for children 2–16 years old with HbSS or HbS/β° thalassemia [ 58 ]. Increased stroke risk on non-imaging TCD is indicated by abnormally elevated cerebral blood flow velocity, defined as ≥ 200 cm/s (time-averaged mean of the maximum velocity) on 2 occasions or a single velocity of > 220 cm/s in the distal internal carotid or proximal middle cerebral artery [ 60 ]. Many centers rely on imaging TCD, which results in velocities 10–15% lower than values obtained by non-imaging protocols and therefore, require adjustments to cut-offs for abnormal velocities. Data supporting stroke risk assessment using TCD are lacking for adults with SCD and standard recommendations do not exist.

Neurocognitive deficits occur in over 30% of children and adults with severe SCD [ 61 , 62 ]. These occur as a result of overt and/or silent cerebral infarcts but in some patients, the etiology is unknown. The Bright Futures Guidelines for Health Supervision of Infants, Children and Adolescents or the Cognitive Assessment Toolkit for adults are commonly used tools to screen for developmental delays or neurocognitive impairment [ 58 ]. Abnormal results should prompt referral for formal neuropsychological evaluation, which directs the need for brain imaging to evaluate for silent cerebral infarcts and facilitate educational/vocational accommodations.

Management of CNS complications

Monthly chronic red blood cell transfusions to suppress HbS < 30% are standard of care for primary stroke prevention in children with an abnormal TCD. In an RCT of 130 children, chronic transfusions, compared to no transfusions, were associated with a difference in stroke risk of 92% (1 vs. 10 strokes, p  < 0.001) [ 60 ]. However, children with abnormal TCD and no MRI/MRA evidence of cerebral vasculopathy can safely transition to hydroxyurea after 1 year of transfusions [ 63 ]. Lifelong transfusions to maintain HbS < 30% remain standard of care for secondary stroke prevention in individuals with overt stroke [ 64 ]. Chronic monthly red blood cell transfusions should also be considered for children with silent cerebral infarct [ 58 ]. In a randomized controlled trial ( n  = 196), monthly transfusions, compared to observation without hydroxyurea, reduced risk of overt stroke, new silent cerebral infarct or enlarging silent cerebral infarct in children with HbSS or HbS/β 0 thalassemia and an existing silent cerebral infarct (2 vs. 4.8 events, incidence rate ratio of 0.41, 95% CI 0.12–0.99, p  = 0.04) [ 57 ].

Acute stroke treatment requires transfusion therapy to increase cerebral oxygen delivery. Red blood cell exchange transfusion, defined as replacement of patients’ red blood cells with donor red blood cells, to rapidly reduce HbS to < 30% is the recommended treatment as simple transfusion alone is shown to have a fivefold greater relative risk (57 vs. 21% with recurrent stroke, RR = 5.0; 95% CI 1.3–18.6) of subsequent stroke compared to exchange transfusion [ 65 ]. However, a simple transfusion is often given urgently while preparing for exchange transfusion [ 58 ]. Tissue plasminogen activator (tPA) is not recommended for children with SCD who have an acute stroke since the pathophysiology of SCD stroke is less likely to be thromboembolic in origin and there is risk for harm. Since the benefits and risks of tPA in adults with SCD and overt stroke are not clear, its use depends on co-morbidities, risk factors and stroke protocols but should not delay or replace prompt transfusion therapy.

Data guiding treatment of SCD cerebral vasculopathy (e.g., moyamoya) are limited, and only nonrandomized, low-quality evidence exists for neurosurgical interventions (e.g., encephaloduroarteriosynangiosis) [ 66 ]. Consultation with a neurosurgeon to discuss surgical options in patients with moyamoya and history of stroke or transient ischemic attack should be considered [ 58 ].

Kidney disease

Glomerulopathy, characterized by hyperfiltration leading to albuminuria, is an early asymptomatic manifestation of SCD nephropathy and worsens with age. Hyperfiltration, defined by an absolute increase in glomerular filtration rate, may be seen in 43% of children with SCD [ 67 ]. Albuminuria, defined by the presence of urine albumin ≥ 30 mg/g over 24 h, has been observed in 32% of adults with SCD [ 68 ]. Glomerulopathy results from intravascular hemolysis and endothelial dysfunction in the renal cortex. Medullary hypoperfusion and ischemia also contribute to kidney disease in SCD, causing hematuria, urine concentrating defects and distal tubular dysfunction [ 69 ]. Approximately 20–40% of adults with SCD develop chronic kidney disease (CKD) and are at risk of developing end-stage renal disease (ESRD), with rapid declines in estimated glomerular filtration rate (eGFR) > 3 mL/min/1.73 m 2 associated with increased mortality (HR 2.4, 95% CI 1.31–4.42, p  = 0.005) [ 68 ].

Diagnosis of kidney disease in SCD

The diagnosis of sickle cell nephropathy is made by detecting abnormalities such as albuminuria, hematuria or CKD rather than by distinct diagnostic criteria in SCD, which have not been developed. Traditional markers of kidney function such as serum creatinine and eGFR should be interpreted with caution in individuals with SCD because renal hyperfiltration affects their accuracy by increasing both. Practical considerations preclude directly measuring GFR by urine or plasma clearance techniques, which achieves the most accurate results. The accuracy of eGFR, however, may be improved by equations that incorporate serum cystatin C [ 70 ].

Since microalbuminuria/proteinuria precedes CKD in SCD, annual screening for urine microalbumin/protein is recommended beginning at age 10 years [ 71 ]. When evaluating urine for microalbumin concentration, samples from first morning rather than random voids are preferable to exclude orthostatic proteinuria. Recent studies suggest HMOX1 and APOL1 gene variants may be associated with CKD in individuals with SCD [ 72 ]. Potential novel predictors of acute kidney injury in individuals with SCD include urine biomarkers kidney injury molecule 1 (KIM-1) [ 73 ], monocyte chemotactic protein 1 (MCP-1) [ 74 ] and neutrophil gelatinase-associated lipocalin (NGAL) [ 75 ]. Their contribution to chronic kidney disease and interaction with other causes of kidney injury in SCD (e.g., inflammation, hemolysis) are not clear.

Management of kidney disease

Managing kidney complications in SCD should focus on mitigating risk factors for acute and chronic kidney injury such as medication toxicity, reduced kidney perfusion from hypotension and dehydration, and general disease progression, as well as early screening and treatment of microalbuminuria/proteinuria. Acute kidney injury, either an increase in serum creatinine ≥ 0.3 mg/dL or a 50% increase in serum creatinine from baseline, is associated with ketorolac use in children with SCD hospitalized for pain [ 76 ]. Increasing intravenous fluids to maintain urine output > 0.5 to 1 mL/kg/h and limiting NSAIDs and antibiotics associated with nephrotoxicity in this setting are important. Despite absence of controlled clinical trials, hydroxyurea may be associated with improvements in glomerular hyperfiltration and urine concentrating ability in children with SCD [ 77 , 78 ]. Hydroxyurea is also associated with a lower prevalence (34.7 vs. 55.4%, p  = 0.01) and likelihood of albuminuria (OR 0.28, 95% CI 0.11–0.75, p  = 0.01) in adults with SCD after adjusting for age, angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin receptor blockade (ARB) use and major disease risk factors [ 79 ].

ACE-I or ARB therapy reduces microalbuminuria in patients with SCD. In a phase 2 trial of 36 children and adults, a ≥ 25% reduction in urine albumin-to-creatinine ratio was observed in 83% ( p  < 0.0001) and 58% ( p  < 0.0001) of patients with macroalbuminuria (> 300 mg/g creatinine) and microalbuminuria (30–300 mg/g creatinine), respectively, after 6 months of treatment with losartan at a dose of 0.7 mg/kg/day (max of 50 mg) in children and 50 mg daily in adults [ 80 ]. However, ACE-I or ARB therapy has not been shown to improve kidney function or prevent CKD. Hemodialysis is associated with a 1-year mortality rate of 26.3% after starting hemodialysis and an increase risk of death in SCD patients with ESRD compared to non-SCD patients with ESRD (44.6 vs. 34.5% deaths, mortality hazard ratio of 2.8, 95% CI 2.31–3.38) [ 81 ]. Renal transplant should be considered for individuals with SCD and ESRD because of recent improvements in renal graft survival and post-transplant mortality [ 82 ].

Disease-modifying therapies in SCD

Since publication of its landmark trial in 1995, hydroxyurea continues to represent a mainstay of disease-modifying therapy for SCD. Hydroxyurea induces fetal hemoglobin production through stress erythropoiesis, reduces inflammation, increases nitric oxide and decreases cell adhesion. The FDA approved hydroxyurea in 1998 for adults with SCD. Subsequently, hydroxyurea was FDA approved for children in 2017 to reduce the frequency pain events and need for blood transfusions in children ≥ 2 years of age [ 63 ]. The landscape of disease-modifying therapies, however, has improved with the recent FDA approval of 3 other treatments— l -glutamine and crizanlizumab for reducing acute complications (e.g., pain), and voxelotor for improving anemia (Table 3 ) [ 83 , 84 , 85 ]. Other therapies in current development focus on inducing fetal hemoglobin, reducing anti-sickling or cellular adhesion, or activating pyruvate kinase-R.

l -glutamine

Glutamine is required for the synthesis of glutathione, nicotinamide adenine dinucleotide and arginine. The essential amino acid protects red blood cells against oxidative damage, which forms the basis for its proposed utility in SCD. The exact mechanism of benefit in SCD, however, remains unclear. In a phase 3 RCT of 230 participants (hemoglobin SS or S/β 0 thalassemia), l -glutamine compared to placebo was associated with fewer pain events (median 3 vs. 4, p  = 0.005) and hospitalizations for pain (median 2 vs. 3, p  = 0.005) over the 48-week treatment period [ 84 ]. The percentage of patients who had at least 1 episode of acute chest syndrome, defined as presence of chest wall pain with fever and a new pulmonary infiltrate, was lower in the l -glutamine group (8.6 vs. 23.1%, p  = 0.003). There were no significant between-group differences in hemoglobin, hematocrit or reticulocyte count. Common side effects of l -glutamine include GI upset (constipation, nausea, vomiting and abdominal pain) and headaches.

Crizanlizumab

P-selectin expression, triggered by inflammation, promotes adhesion of neutrophils, activated platelets and sickle red blood cells to the endothelial surface and to each other, which promotes vaso-occlusion in SCD. Crizanlizumab, given as a monthly intravenous infusion, is a humanized monoclonal antibody that binds P-selectin and blocks the adhesion molecule’s interaction with its ligand, P-selectin glycoprotein ligand 1. FDA approval for crizanlizumab was based on a phase 2 RCT ( n  = 198, all genotypes), in which the median rate of pain events (primary endpoint) was lower (1.63 vs. 2.68, p  = 0.01) and time to first pain event (secondary endpoint) was longer (4.07 vs. 1.38 months, p  = 0.001) for patients on high-dose crizanlizumab (5 mg/kg/dose) compared to placebo treated for 52 weeks (14 doses total) [ 83 ]. In this trial, patients with SCD on chronic transfusion therapy were excluded, but those on stable hydroxyurea dosing were not. Adverse events were uncommon but included headache, back pain, nausea, arthralgia and pain in the extremity.

Polymerization of Hb S in the deoxygenated state represents the initial step in red blood cell sickling, which leads to reduced red blood cell deformability and increased hemolysis. Voxelotor is a first-in-class allosteric modifier of Hb S that increases oxygen affinity. The primary endpoint for the phase 3 RCT of voxelotor ( n  = 274, all genotypes) that led to FDA approval was an increase in hemoglobin of at least 1 g/dL after 24 weeks of treatment [ 85 ]. More participants receiving 1500 mg daily of oral voxelotor versus placebo had a hemoglobin response of at least 1 g/dL (51%, 95% CI 41–61 vs. 7%, 95% CI 1–12, p < 0.001). Approximately 2/3 of the participants in these trials were on hydroxyurea, with treatment benefits observed regardless of hydroxyurea status. Despite improvements associated with voxelotor in biomarkers of hemolysis (reticulocyte count, indirect bilirubin and lactate dehydrogenase), annualized incidence rate of vaso-occlusive crisis was not significantly different among treatment groups. Adverse events included headaches, GI symptoms, arthralgia, fatigue and rash.

Curative therapies in SCD

For individuals with SCD undergoing hematopoietic stem cell transplantation (HSCT) using HLA-matched sibling donors and either myeloablative or reduced-intensity conditioning regimens, the five-year event-free and overall survival is high at 91% and 93%, respectively [ 86 ]. Limited availability of HLA-matched sibling donors in this population requires alternative donors or the promise of autologous strategies such as gene-based therapies (i.e. gene addition, transfer or editing) (Table 4 ). Matched unrelated donors have not been used routinely due to increased risk of graft-versus-host disease (GVHD) as high as 19% (95% CI 12–28) in the first 100 days for acute GVHD and 29% (95% CI 21–38) over 3 years for chronic GVHD [ 87 ]. Haplo-identical HSCT, using biological parents or siblings as donors, that incorporate post-transplant cyclophosphamide demonstrates acceptable engraftment rates, transplant-related morbidity and overall mortality [ 88 ]. Regardless of allogeneic HSCT type, older age is associated with lower event-free (102/418 vs. 72/491 events, HR 1.74, 95% CI 1.24–2.45) and overall survival (54/418 vs. 22/491 events, HR 3.15, 95% CI 1.86–5.34) in patients ≥ 13 years old compared to < 12 years old undergoing HSCT [ 87 ].

Advancing research in SCD

Despite progress to date, additional high-quality, longitudinal data are needed to better understand the natural history of the disease and to inform optimal screening for SCD-related complications. In the era of multiple FDA-approved therapies with disease-modifying potential, clinical trials to evaluate additional indications and test them in combination with or compared to each other are needed. Dissemination and implementation studies are also needed to identify barriers and facilitators related to treatment in everyday life, which can be incorporated into decision aids and treatment algorithms for patients and their providers [ 89 ]. Lastly, continued efforts should acknowledge social determinants of health and other factors that affect access and disease-related outcomes such as the role of third-party payers, provider and patient education, health literacy and patient trust. Establishing evidence-derived quality of care metrics can also drive public policy changes required to ensure care optimization for this population.

Conclusions

SCD is associated with complications that include acute and chronic pain as well as end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease that result in increased morbidity and mortality. Several well-designed clinical trials have resulted in key advances in management of SCD in the past decade. Data from these trials have led to FDA approval of 3 new drugs, l -glutamine, crizanlizumab and voxelotor, which prevent acute pain and improve chronic anemia. Moderate to high-quality data support recommendations for managing SCD cerebrovascular disease and early kidney disease. However, further research is needed to determine the best treatment for chronic pain and cardiopulmonary disease in SCD. Comparative effectiveness research, dissemination and implementation studies and a continued focus on social determinants of health are also essential.

Availability of data and materials

Not applicable.

Abbreviations

Six-minute walk distance

Angiotensin-converting enzyme inhibitor

Angiotensin receptor blockade

Cognitive behavioral therapy

Chronic kidney disease

Chronic opioid therapy

Echocardiogram

End stage renal disease

Fluid-attenuated inversion recovery

Glomerular filtration rate

Graft-versus-host disease

Hemoglobin S

Hematopoietic stem cell transplant

Nonsteroidal anti-inflammatory drugs

N-terminal pro-brain natriuretic peptide

New York Heart Association

Pulmonary arterial hypertension

Pulmonary function test

Pulmonary hypertension

Positive predictive value

Patient-reported outcomes

Randomized controlled trial

• Sickle cell disease

Serotonin and norepinephrine reuptake inhibitors

Tricyclic antidepressants

Transcranial Doppler

Tissue plasminogen activator

Tricuspid regurgitant jet velocity

Visual Analog Scale

Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013;381(9861):142–51.

Article   PubMed   PubMed Central   Google Scholar  

Brousseau DC, Panepinto JA, Nimmer M, Hoffmann RG. The number of people with sickle-cell disease in the United States: national and state estimates. Am J Hematol. 2010;85(1):77–8.

PubMed   Google Scholar  

Payne AB, Mehal JM, Chapman C, Haberling DL, Richardson LC, Bean CJ, et al. Trends in sickle cell disease-related mortality in the United States, 1979 to 2017. Ann Emerg Med. 2020;76(3S):S28–36.

Article   PubMed   Google Scholar  

Brousseau DC, Owens PL, Mosso AL, Panepinto JA, Steiner CA. Acute care utilization and rehospitalizations for sickle cell disease. JAMA. 2010;303(13):1288–94.

Article   CAS   PubMed   Google Scholar  

Sil S, Cohen LL, Dampier C. Psychosocial and functional outcomes in youth with chronic sickle cell pain. Clin J Pain. 2016;32(6):527–33.

Smith WR, Penberthy LT, Bovbjerg VE, McClish DK, Roberts JD, Dahman B, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008;148(2):94–101.

Ballas SK, Darbari DS. Neuropathy, neuropathic pain, and sickle cell disease. Am J Hematol. 2013;88(11):927–9.

Sharma D, Brandow AM. Neuropathic pain in individuals with sickle cell disease. Neurosci Lett. 2020;714:134445.

Dampier C, Palermo TM, Darbari DS, Hassell K, Smith W, Zempsky W. AAPT diagnostic criteria for chronic sickle cell disease pain. J Pain. 2017;18(5):490–8.

Darbari DS, Hampson JP, Ichesco E, Kadom N, Vezina G, Evangelou I, et al. Frequency of hospitalizations for pain and association with altered brain network connectivity in sickle cell disease. J Pain. 2015;16(11):1077–86.

Levenson JL, Mcclish DK, Dahman BA, Bovbjerg VE, Penberthy LT, et al. Depression and anxiety in adults with sickle cell disease: the PiSCES project. Psychosom Med. 2008;70(2):192–6.

Treadwell MJBB, Kaur K, Gildengorin G. Emotional distress, barriers to care, and health-related quality of life in sickle cell disease. J Clin Outcomes Manag. 2015;22:10.

Google Scholar  

Jonassaint CR, Jones VL, Leong S, Frierson GM. A systematic review of the association between depression and health care utilization in children and adults with sickle cell disease. Br J Haematol. 2016;174(1):136–47.

Laurence B, George D, Woods D. Association between elevated depressive symptoms and clinical disease severity in African-American adults with sickle cell disease. J Natl Med Assoc. 2006;98(3):365–9.

PubMed   PubMed Central   Google Scholar  

Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606–13.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Faulstich ME, Carey MP, Ruggiero L, Enyart P, Gresham F. Assessment of depression in childhood and adolescence: an evaluation of the Center for Epidemiological Studies Depression Scale for Children (CES-DC). Am J Psychiatry. 1986;143(8):1024–7.

Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA. Manual for the state-trait anxiety inventory. Palo Alto: Consulting Psychologists Press; 1983.

Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656–701.

Lubega FA, DeSilva MS, Munube D, Nkwine R, Tumukunde J, Agaba PK, et al. Low dose ketamine versus morphine for acute severe vaso occlusive pain in children: a randomized controlled trial. Scand J Pain. 2018;18(1):19–27.

Nobrega R, Sheehy KA, Lippold C, Rice AL, Finkel JC, Quezado ZMN. Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease. Pediatr Res. 2018;83(2):445–54.

Perlin E, Finke H, Castro O, Rana S, Pittman J, Burt R, et al. Enhancement of pain control with ketorolac tromethamine in patients with sickle cell vaso-occlusive crisis. Am J Hematol. 1994;46(1):43–7.

Beiter JL Jr, Simon HK, Chambliss CR, Adamkiewicz T, Sullivan K. Intravenous ketorolac in the emergency department management of sickle cell pain and predictors of its effectiveness. Arch Pediatr Adolesc Med. 2001;155(4):496–500.

Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162(4):276–86.

Molokie RE, Wilkie DJ, Wittert H, Suarez ML, Yao Y, Zhao Z, et al. Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease. Eur J Pharmacol. 2014;723:419–24.

Schlaeger JM, Molokie RE, Yao Y, Suarez ML, Golembiewski J, Wilkie DJ, et al. Management of sickle cell pain using pregabalin: a pilot study. Pain Manag Nurs. 2017;18(6):391–400.

Osunkwo I, Ziegler TR, Alvarez J, McCracken C, Cherry K, Osunkwo CE, et al. High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study. Br J Haematol. 2012;159(2):211–5.

Hauser W, Urrutia G, Tort S, Uceyler N, Walitt B. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome. Cochrane Database Syst Rev. 2013;1:CD010292.

Hauser W, Wolfe F, Tolle T, Uceyler N, Sommer C. The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis. CNS Drugs. 2012;26(4):297–307.

Derry S, Cording M, Wiffen PJ, Law S, Phillips T, Moore RA. Pregabalin for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2016;9:CD011790.

Sil S, Lai K, Lee JL, Gilleland Marchak J, Thompson B, Cohen L, et al. Preliminary evaluation of the clinical implementation of cognitive-behavioral therapy for chronic pain management in pediatric sickle cell disease. Complement Ther Med. 2020;49:102348.

Lu K, Cheng MC, Ge X, Berger A, Xu D, Kato GJ, et al. A retrospective review of acupuncture use for the treatment of pain in sickle cell disease patients: descriptive analysis from a single institution. Clin J Pain. 2014;30(9):825–30.

Mahmood LA, Reece-Stremtan S, Idiokitas R, Martin B, Margulies S, Hardy SJ, et al. Acupuncture for pain management in children with sickle cell disease. Complement Ther Med. 2020;49:102287.

Mehari A, Alam S, Tian X, Cuttica MJ, Barnett CF, Miles G, et al. Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med. 2013;187(8):840–7.

Cohen RT, Strunk RC, Rodeghier M, Rosen CL, Kirkham FJ, Kirkby J, et al. Pattern of lung function is not associated with prior or future morbidity in children with sickle cell anemia. Ann Am Thorac Soc. 2016;13(8):1314–23.

Kassim AA, Payne AB, Rodeghier M, Macklin EA, Strunk RC, DeBaun MR. Low forced expiratory volume is associated with earlier death in sickle cell anemia. Blood. 2015;126(13):1544–50.

Sharma S, Efird JT, Knupp C, Kadali R, Liles D, Shiue K, et al. Sleep disorders in adult sickle cell patients. J Clin Sleep Med. 2015;11(3):219–23.

Rosen CL, Debaun MR, Strunk RC, Redline S, Seicean S, Craven DI, et al. Obstructive sleep apnea and sickle cell anemia. Pediatrics. 2014;134(2):273–81.

Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1).

Chaturvedi S, Labib Ghafuri D, Kassim A, Rodeghier M, DeBaun MR. Elevated tricuspid regurgitant jet velocity, reduced forced expiratory volume in 1 second, and mortality in adults with sickle cell disease. Am J Hematol. 2017;92(2):125–30.

Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;365(1):44–53.

Machado RF, Anthi A, Steinberg MH, Bonds D, Sachdev V, Kato GJ, et al. N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA. 2006;296(3):310–8.

Mondal P, Yirinec A, Midya V, Sankoorikal BJ, Smink G, Khokhar A, et al. Diagnostic value of spirometry vs impulse oscillometry: a comparative study in children with sickle cell disease. Pediatr Pulmonol. 2019;54(9):1422–30.

Field JJ, Stocks J, Kirkham FJ, Rosen CL, Dietzen DJ, Semon T, et al. Airway hyperresponsiveness in children with sickle cell anemia. Chest. 2011;139(3):563–8.

Dlamini N, Saunders DE, Bynevelt M, Trompeter S, Cox TC, Bucks RS, et al. Nocturnal oxyhemoglobin desaturation and arteriopathy in a pediatric sickle cell disease cohort. Neurology. 2017;89(24):2406–12.

Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, et al. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. Br J Haematol. 2010;149(3):426–35.

Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato GJ, Gordeuk VR, et al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood. 2011;118(4):855–64.

Turpin M, Chantalat-Auger C, Parent F, Driss F, Lionnet F, Habibi A, et al. Chronic blood exchange transfusions in the management of pre-capillary pulmonary hypertension complicating sickle cell disease. European Respiratory Journal. 2018;52(4).

Knight-Madden JM, Barton-Gooden A, Weaver SR, Reid M, Greenough A. Mortality, asthma, smoking and acute chest syndrome in young adults with sickle cell disease. Lung. 2013;191(1):95–100.

Strunk RC, Cohen RT, Cooper BP, Rodeghier M, Kirkham FJ, Warner JO, et al. Wheezing symptoms and parental asthma are associated with a physician diagnosis of asthma in children with sickle cell anemia. J Pediatr. 2014;164(4):821-6e1.

Article   Google Scholar  

Takahashi T, Okubo Y, Handa A. Acute chest syndrome among children hospitalized with vaso-occlusive crisis: a nationwide study in the United States. Pediatr Blood Cancer. 2018;65(3):e26885.

Glassberg J, Minnitti C, Cromwell C, Cytryn L, Kraus T, Skloot GS, et al. Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: a triple-blind, randomized trial. Am J Hematol. 2017;92(7):622–31.

Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288–94.

CAS   PubMed   Google Scholar  

Bernaudin F, Verlhac S, Arnaud C, Kamdem A, Vasile M, Kasbi F, et al. Chronic and acute anemia and extracranial internal carotid stenosis are risk factors for silent cerebral infarcts in sickle cell anemia. Blood. 2015;125(10):1653–61.

Kassim AA, Pruthi S, Day M, Rodeghier M, Gindville MC, Brodsky MA, et al. Silent cerebral infarcts and cerebral aneurysms are prevalent in adults with sickle cell anemia. Blood. 2016;127(16):2038–40.

Powars D, Wilson B, Imbus C, Pegelow C, Allen J. The natural history of stroke in sickle cell disease. Am J Med. 1978;65(3):461–71.

Switzer JA, Hess DC, Nichols FT, Adams RJ. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 2006;5(6):501–12.

DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014;371(8):699–710.

DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020;4(8):1554–88.

Dobson SR, Holden KR, Nietert PJ, Cure JK, Laver JH, Disco D, et al. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood. 2002;99(9):3144–50.

Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5–11.

Vichinsky EP, Neumayr LD, Gold JI, Weiner MW, Rule RR, Truran D, et al. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA. 2010;303(18):1823–31.

Hijmans CT, Fijnvandraat K, Grootenhuis MA, van Geloven N, Heijboer H, Peters M, et al. Neurocognitive deficits in children with sickle cell disease: a comprehensive profile. Pediatr Blood Cancer. 2011;56(5):783–8.

Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016;387(10019):661–70.

Scothorn DJ, Price C, Schwartz D, Terrill C, Buchanan GR, Shurney W, et al. Risk of recurrent stroke in children with sickle cell disease receiving blood transfusion therapy for at least five years after initial stroke. J Pediatr. 2002;140(3):348–54.

Hulbert ML, Scothorn DJ, Panepinto JA, Scott JP, Buchanan GR, Sarnaik S, et al. Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. J Pediatr. 2006;149(5):710–2.

Hall EM, Leonard J, Smith JL, Guilliams KP, Binkley M, Fallon RJ, et al. Reduction in overt and silent stroke recurrence rate following cerebral revascularization surgery in children with sickle cell disease and severe cerebral vasculopathy. Pediatr Blood Cancer. 2016;63(8):1431–7.

Lebensburger JD, Aban I, Pernell B, Kasztan M, Feig DI, Hilliard LM, et al. Hyperfiltration during early childhood precedes albuminuria in pediatric sickle cell nephropathy. Am J Hematol. 2019;94(4):417–23.

Niss O, Lane A, Asnani MR, Yee ME, Raj A, Creary S, et al. Progression of albuminuria in patients with sickle cell anemia: a multicenter, longitudinal study. Blood Adv. 2020;4(7):1501–11.

Cazenave M, Audard V, Bertocchio JP, Habibi A, Baron S, Prot-Bertoye C, et al. Tubular acidification defect in adults with sickle cell disease. Clin J Am Soc Nephrol. 2020;15(1):16–24.

Yee MEM, Lane PA, Archer DR, Joiner CH, Eckman JR, Guasch A. Estimation of glomerular filtration rate using serum cystatin C and creatinine in adults with sickle cell anemia. Am J Hematol. 2017;92(10):E598–9.

Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033–48.

Saraf SL, Zhang X, Shah B, Kanias T, Gudehithlu KP, Kittles R, et al. Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy. Haematologica. 2015;100(10):1275–84.

Hamideh D, Raj V, Harrington T, Li H, Margolles E, Amole F, et al. Albuminuria correlates with hemolysis and NAG and KIM-1 in patients with sickle cell anemia. Pediatr Nephrol. 2014;29(10):1997–2003.

dos Santos TE, Goncalves RP, Barbosa MC, da Silva GB, Jr., Daher Ede F. Monocyte chemoatractant protein-1: a potential biomarker of renal lesion and its relation with oxidative status in sickle cell disease. Blood Cells Mol Dis. 2015;54(3):297–301.

Audard V, Moutereau S, Vandemelebrouck G, Habibi A, Khellaf M, Grimbert P, et al. First evidence of subclinical renal tubular injury during sickle-cell crisis. Orphanet J Rare Dis. 2014;9:67.

Baddam S, Aban I, Hilliard L, Howard T, Askenazi D, Lebensburger JD. Acute kidney injury during a pediatric sickle cell vaso-occlusive pain crisis. Pediatr Nephrol. 2017;32(8):1451–6.

Zahr RS, Hankins JS, Kang G, Li C, Wang WC, Lebensburger J, et al. Hydroxyurea prevents onset and progression of albuminuria in children with sickle cell anemia. Am J Hematol. 2019;94(1):E27–9.

Alvarez O, Miller ST, Wang WC, Luo Z, McCarville MB, Schwartz GJ, et al. Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer. 2012;59(4):668–74.

Laurin LP, Nachman PH, Desai PC, Ataga KI, Derebail VK. Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease. Nephrol Dial Transplant. 2014;29(6):1211–8.

Quinn CT, Saraf SL, Gordeuk VR, Fitzhugh CD, Creary SE, Bodas P, et al. Losartan for the nephropathy of sickle cell anemia: a phase-2, multicenter trial. Am J Hematol. 2017;92(9):E520–8.

McClellan AC, Luthi JC, Lynch JR, Soucie JM, Kulkarni R, Guasch A, et al. High one year mortality in adults with sickle cell disease and end-stage renal disease. Br J Haematol. 2012;159(3):360–7.

Gérardin C, Moktefi A, Couchoud C, Duquesne A, Ouali N, Gataut P, et al. Survival and specific outcome of sickle cell disease patients after renal transplantation. Br J Haematol. 2019;187(5):676–80.

Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429–39.

Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, et al. A phase 3 trial of l -glutamine in sickle cell disease. N Engl J Med. 2018;379(3):226–35.

Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509–19.

Gluckman E, Cappelli B, Bernaudin F, Labopin M, Volt F, Carreras J, et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood. 2017;129(11):1548–56.

Eapen M, Brazauskas R, Walters MC, Bernaudin F, Bo-Subait K, Fitzhugh CD, et al. Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study. Lancet Haematol. 2019;6(11):e585–96.

Bolanos-Meade J, Cooke KR, Gamper CJ, Ali SA, Ambinder RF, Borrello IM, et al. Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial. Lancet Haematol. 2019;6(4):e183–93.

Krishnamurti L, Ross D, Sinha C, Leong T, Bakshi N, Mittal N, et al. Comparative effectiveness of a web-based patient decision aid for therapeutic options for sickle cell disease: randomized controlled trial. J Med Internet Res. 2019;21(12):e14462.

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• Published: 15 March 2018
• Sickle cell disease
• Gregory J. Kato 1 ,
• Frédéric B. Piel 2 ,
• Clarice D. Reid 3 ,
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• Kwaku Ohene-Frempong 5 ,
• Lakshmanan Krishnamurti 6 ,
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• Elliott P. Vichinsky 11  

Nature Reviews Disease Primers volume  4 , Article number:  18010 ( 2018 ) Cite this article

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• Genetic predisposition to disease
• Genetic testing

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB , which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

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Introduction.

Sickle cell disease (SCD) is an umbrella term that defines a group of inherited diseases (including sickle cell anaemia (SCA), HbSC and HbSβ-thalassaemia, see below) characterized by mutations in the gene encoding the haemoglobin subunit β ( HBB ) ( Fig. 1 ). Haemoglobin (Hb) is a tetrameric protein composed of different combinations of globin subunits; each globin subunit is associated with the cofactor haem, which can carry a molecule of oxygen. Hb is expressed by red blood cells, both reticulocytes (immature red blood cells) and erythrocytes (mature red blood cells). Several genes encode different types of globin proteins, and their various tetrameric combinations generate multiple types of Hb, which are normally expressed at different stages of life — embryonic, fetal and adult. Hb A (HbA), the most abundant (>90%) form of adult Hb, comprises two α-globin subunits (encoded by the duplicated HBA1 and HBA2 genes) and two β-globin subunits. A single nucleotide substitution in HBB results in the sickle Hb (HbS) allele β S ; the mutant protein generated from the β S allele is the sickle β-globin subunit and has an amino acid substitution. Under conditions of deoxygenation (that is, when the Hb is not bound to oxygen), Hb tetramers that include two of these mutant sickle β-globin subunits (that is, HbS) can polymerize and cause the erythrocytes to assume a crescent or sickled shape from which the disease takes its name. Hb tetramers with one sickle β-globin subunit can also polymerize, albeit not as efficiently as HbS. Sickle erythrocytes can lead to recurrent vaso-occlusive episodes that are the hallmark of SCD.

Normal haemoglobin A (HbA) is formed by two α-globin subunits and two β-globin subunits, the latter of which are encoded by HBB . The sickle Hb (HbS) allele, β S , is an HBB allele in which an adenine-to-thymine substitution results in the replacement of glutamic acid with valine at position 6 in the mature β-globin chain. Sickle cell disease (SCD) occurs when both HBB alleles are mutated and at least one of them is the β S allele. Deoxygenated (not bound to oxygen) HbS can polymerize, and HbS polymers can stiffen the erythrocyte. Individuals with one β S allele have the sickle cell trait (HbAS) but not SCD; individuals with sickle cell anaemia (SCA), the most common SCD genotype, have two β S alleles (β S /β S ). Other relatively common SCD genotypes are possible. Individuals with the HbSC genotype have one β S allele and one HBB allele with a different nucleotide substitution ( HBB Glu6Lys, or β C allele) that generates another structural variant of Hb, HbC. The β C allele is mostly prevalent in West Africa or in individuals with ancestry from this region 16 . HbSC disease is a condition with generally milder haemolytic anaemia and less frequent acute and chronic complications than SCA, although retinopathy and osteonecrosis (also known as bone infarction, in which bone tissue is lost owing to interruption of the blood flow) are common occurrences 259 . The β S allele combined with a null HBB allele (Hbβ 0 ) that results in no protein translation causes HbSβ 0 -thalassaemia, a clinical syndrome indistinguishable from SCA except for the presence of microcytosis (a condition in which erythrocytes are abnormally small) 260 . The β S allele combined with a hypomorphic HBB allele (Hbβ + ; with a decreased amount of normal β-globin protein) results in HbSβ + -thalassaemia, a clinical syndrome generally milder than SCA owing to low-level expression of normal HbA. Severe and moderate forms of HbSβ-thalassaemia are most prevalent in the eastern Mediterranean region and parts of India, whereas mild forms are common in populations of African ancestry. Rarely seen compound heterozygous SCD genotypes include HbS combined with HbD, HbE, HbO Arab or Hb Lepore (not shown) 261 .

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SCD is inherited as an autosomal codominant trait 1 ; individuals who are heterozygous for the β S allele carry the sickle cell trait (HbAS) but do not have SCD, whereas individuals who are homozygous for the β S allele have SCA. SCA, the most common form of SCD, is a lifelong disease characterized by chronic haemolytic anaemia, unpredictable episodes of pain and widespread organ damage. There is a wide variability in the clinical severity of SCA, as well as in the life expectancy 2 . Genetic and genome-wide association studies have consistently found that high levels of fetal Hb (HbF; the heterodimeric combination of two α-globin proteins and two γ-globin proteins (encoded by HBG1 and HBG2 )) 3 and the co-inheritance of α-thalassaemia (which is caused by mutations in HBA1 and HBA2 ) are associated, on average, with milder SCD phenotypes 2 . However, these two biomarkers explain only a small fraction of the observed phenotypic variability.

Since the 1980s, a rapidly expanding body of knowledge has promoted a better understanding of SCD, particularly in high-income countries 4 , 5 . In the United States, research funding increased exponentially, awareness and education programmes expanded, counselling programmes were improved and universal newborn screening programmes now ensure early diagnosis and intervention. Specific research and training programmes led to a cadre of knowledgeable health professionals working in this field, improved patient management, prevention of complications and extension of life expectancy.

In this Primer, we focus on SCA and aim to balance such remarkable advances with the key major challenges remaining worldwide to improve the prevention and management of this chronic disease and ultimately to discover an affordable cure.

Epidemiology

Natural history.

There is rather little information on the natural history of SCD (which is relevant for SCD prevention and control), especially in areas of high prevalence. The main sources of information are the Jamaican Cohort Study of Sickle Cell Disease, which was initiated in 1973 and followed up all individuals with SCD detected among 100,000 consecutive deliveries in Kingston, Jamaica 6 , and, in the United States, the Cooperative Study of Sickle Cell Disease (CSSCD; 1978–1998), which gathered data on growth and development, disease complications, clinical studies and epidemiology on >3,000 individuals with SCD 7 . Since the discontinuation of the CSSCD, the ongoing natural history of SCD in the United States can be gleaned from a few single-institution ongoing registries, screening populations of clinical trial cohorts and administrative health data sets.

Several cohort studies in high-income and middle-income countries have demonstrated that the clinical course of SCD has substantially changed since the 1970s in both children and adults. Survival similar to that of healthy children has been reported in children with SCA in the United States and the United Kingdom 8 . Adults with SCD in high-income countries can now expect to live well into their sixties, and a median survival of 67 years has been reported for patients with SCD at one London hospital 9 ; nevertheless, survival is still much lower than that of the general population of London. As childhood mortality of SCD has fallen, the transition from paediatric to adult patterns of lifestyle and medical care delivery is increasingly important. For example, in the United States, there is a declining workforce of adult haematologists who are trained specifically in SCD, which means that adults with SCD are treated by primary care physicians or by haematologists–oncologists who are minimally experienced in SCD. There are limited data available about the survival of individuals with SCD in sub-Saharan Africa and India. Data from African studies indicate a childhood SCA mortality (before 5 years of age) of 50–90% 10 .

Distribution

The geographical distribution of the β S allele is mainly driven by two factors: the endemicity of malaria and population movements. The overlap between the geographical distribution of the β S allele and malaria endemicity in sub-Saharan Africa led in the 1950s to the hypothesis that individuals with HbAS might be protected against Plasmodium falciparum malaria 11 . There is now clear evidence that HbAS provides a remarkable protection against severe P. falciparum malaria 12 (in fact, individuals with HbAS are 90% less likely to experience severe malaria than individuals with only normal Hb), which explains the high frequencies of the β S allele observed across sub-Saharan Africa and parts of the Mediterranean, the Middle East and India 13 . Population movements, including the slave trade, have led to a much wider distribution of the β S allele, particularly in North America and Western Europe 14 . Detailed mapping of the β S allele frequency has highlighted that geographical heterogeneities in the prevalence of inherited Hb disorders can occur over short distances 15 .

Prevalence and incidence

The incidence of births with SCA in sub-Saharan Africa was estimated to be ∼ 230,000 in 2010, which corresponds to ∼ 75% of births with SCA worldwide 14 ( Fig. 2 ). In addition, West Africa has the highest incidence of HbSC disease, the second most common type of SCD 16 ( Fig. 1 ). Over the next 40 years, these numbers are predicted to increase, particularly in sub-Saharan Africa 17 . The 2010 estimates reported that there were >3.5 million newborn infants with HbAS in sub-Saharan Africa, who could benefit from a potent protection from severe P. falciparum malaria and its associated mortality 13 . To date, no African country has implemented a national screening programme for SCD 18 . Even in countries where universal screening programmes have been in place for >10 years (for example, the United Kingdom), estimating the prevalence, incidence and burden of disease remains challenging 19 , 20 . In the past 20 years, ∼ 40,000 confirmed cases of SCD were identified in 76 million newborn babies, with >1.1 million newborn babies with the HbAS genotype in the United States 21 . Thus, 1 in every 1,941 neonates had SCD, and 1 in every 67 was heterozygous for the β S allele.

Estimated numbers of births with sickle cell anaemia per 100,000 births per country in 2015. Estimates are derived from prevalence data published in Ref. 14 . Birth data for 2015–2020 were extracted from the 2017 Revision of the United Nations World Population Prospects database . NA, not applicable.

The incidence of SCD varies by state, race and ethnicity 22 , 23 . Among African Americans, ∼ 1 in 360 newborn babies has SCD. Substantial demographical changes have resulted in a more-diverse population at risk and a high prevalence of SCD in immigrant populations. Newborn screening studies for SCD in the state of New York document the marked effect of immigration on the frequency of neonates with SCD 24 , as most of them have foreign-born mothers.

The incidence of SCD in newborn babies varies substantially among the states in Brazil, reflecting the ethnic heterogeneity of the Brazilian population. In 2014, the incidence of SCD was ∼ 1 in 650 newborn babies screened in the state of Bahia, 1 in 1,300 in the state of Rio de Janeiro and 1 in 13,500 in the state of Santa Catarina 25 . Nationwide, in 2016, 1,071 newborn babies had SCD and >60,000 were heterozygous for the β S allele (F.F.C., unpublished observations). There are an estimated 30,000 individuals with SCD in the whole country. The prevalence of the β S allele in Brazil varies from 1.2% to 10.9%, depending on the region, whereas the prevalence of the β C allele is reported to be between 0.15% and 7.4% 25 – 30 . The number of all-age individuals affected by SCA globally is currently unknown and cannot be estimated reliably owing to the paucity of epidemiological data, in particular mortality data, in areas of high prevalence.

Disease severity

The variability in the clinical severity of SCA can partly be explained by genetic modifiers, including factors that affect HbF level and co-inheritance of α-thalassaemia (see below) 31 , 32 . For example, the Arab–India haplotype (a haplotype is a set of DNA polymorphisms that are inherited together), which is found in an area extending from the eastern coast of Saudi Arabia and East Africa to India, is considered to be associated with a phenotype milder than that associated with the four African haplotypes (Benin, Bantu, Cameroon and Senegal haplotypes), and, within India, this phenotype could be milder in the tribal populations than in the non-tribal populations 33 owing to a higher level of HbF 32 . However, evidence suggests that the range of severity of SCD in India is wider than previously thought 34 . Environmental factors (such as the home environment, socio-economic status, nutrition and access to care) also influence the severity of the disease; however, apart from malaria, their role has rarely been investigated 35 , 36 . Although some complications are more frequent in some regions than in others (for example, leg ulcers are common in tropical regions but are relatively rare in temperate climates 37 , whereas priapism (persistent and painful erection) is common in patients of African ancestry but rarer in those of Indian ancestry 38 ), these geographical differences have never been comprehensively and rigorously documented.

Disease burden

It has been estimated that 50–90% of children with SCA who live in sub-Saharan Africa die by 5 years of age 10 . Most of these children die from infections, including invasive pneumococcal disease and malaria 39 , 40 . Owing to the limited data across most areas of high prevalence, it is difficult to precisely assess the future health and economic burden of SCD. As low-income and middle-income countries go through epidemiological transition (that is, changing patterns of population age distributions, mortality, fertility, life expectancy and causes of death, largely driven by public health improvements), which involves substantial reductions in infant mortality that enable SCA diagnoses and treatment, and international migrations contribute to further expand the distribution of the β S allele, the health burden of this disease will increase 41 . Demographical projections estimated that the annual number of newborn babies with SCA worldwide will exceed 400,000 by 2050 (Ref. 17 ).

Mechanisms/pathophysiology

The landmark complication associated with SCA is the vaso-occlusive pain crisis. Although vaso-occlusion is a complex phenomenon, HbS polymerization is the essential pathophysiological occurrence in SCA 42 – 44 . HbS polymerization changes the shape and physical properties of erythrocytes, resulting in haemolytic anaemia and blockage of blood flow, particularly in small (and some large) vessels, which can damage any organ. HbS polymerization can also occur in reticulocytes, which account for ∼ 20% of the red blood cells in individuals with SCA. Direct and indirect consequences of haemolysis play a part in modifying the course and complications of SCD. Furthermore, HbS polymers lead to other abnormalities at the cellular level that contribute to the overall pathophysiological mechanism of SCD. The several variant genotypes of SCD (double heterozygous states or SCA with modifying genes) share a common pathophysiology as described in this section. The variants provide nuanced phenotypic differences or reduced severity ( Fig. 1 ).

Erythrocyte morphology

HbS oxygen affinity and polymerization . HbS has reduced oxygen affinity compared with HbA. Reduced HbS oxygen affinity exacerbates HbS polymerization, which in turn further reduces HbS oxygen affinity 45 ( Fig. 3 ). HbS oxygen affinity is further reduced by 2,3-diphosphoglycerate (2,3-DPG), which is a glycolytic intermediate that is physiologically present at very high levels in sickle erythrocytes and, through interaction with deoxygenated β-globin subunits, reduces Hb oxygen affinity 46 . At any partial pressure of oxygen (pO 2 ), low HbS oxygen affinity kinetically favours an increase in the fraction of deoxygenated HbS (which is the tense conformation (T-state) that readily polymerizes), which in turn promotes HbS polymerization and the formation of sickle erythrocytes. Initial reports indicate that sickle erythrocytes have increased sphingosine kinase activity, leading to high levels of sphingosine-1-phosphate, which also decreases HbS oxygen affinity 47 . Sphingosine kinase is activated by increased levels of plasma adenosine (resulting from the hydrolysis of adenosine nucleotides that are released from erythrocytes during haemolysis) via the erythrocyte adenosine receptor A2b 48 , 49 .

Long polymers of sickle haemoglobin (HbS) align into fibres, which then align into parallel rods. The polymer has a helical structure with 14 HbS molecules in each section 42 , 55 , 262 . The polymerization of HbS depends on many factors, including the HbS concentration, partial pressure of oxygen (pO 2 ), temperature, pH, 2,3-diphosphoglycerate (2,3-DPG) concentration and the presence of different Hb molecules 263 – 265 . The basic concept of HbS polymerization kinetics is the double nucleation mechanism. Before any polymer is detected, there is a latency period (delay time) in which deoxygenated HbS molecules form a small nucleus, which is followed by rapid polymer growth and formation 266 , 267 . Free cytoplasmic haem can increase the attraction of the HbS molecules and the speed of nucleation and polymer formation 268 . Cation homeostasis is abnormal in sickle erythrocytes, leading to the dehydration of cells. Potassium loss occurs via the intermediate conductance calcium-activated potassium channel protein 4 (also known as the putative Gardos channel) and K–Cl cotransporter 1 (KCC1), KCC3 and/or KCC4 (Refs 269 , 270 ). Plasma adenosine can also reprogramme the metabolism of the erythrocyte, altering sphingosine-1-phosphate (S1P). ADORA2B, adenosine receptor A2b; AE1, band 3 anion transport protein; HbA, haemoglobin A; HbF, fetal haemoglobin.

HbS polymerization correlates exponentially with the concentration of HbS within the erythrocyte and also with the composition of other haemoglobins that variably participate in polymers 50 . In α-thalassaemia, reduced production of α-globin subunits favours the formation of unstable β S tetramers (formed by four sickle β-globin subunits), which are proteolyzed, leaving a lower HbS concentration that slows HbS polymerization and haemolysis. Abnormal cation homeostasis (described in the following section) in sickle erythrocytes leads to cell dehydration, which results in increased HbS concentration and polymerization ( Fig. 3 ). As the polymer fibres extend, they deform the erythrocytes and interfere with their flexibility and rheological properties (that is, how they flow), eventually resulting in vaso-occlusion 51 . This impaired blood flow rheology is worsened by erythrocyte aggregation, especially in individuals with SCD and high haematocrit (the percentage of blood volume composed of erythrocytes) 51 . Repeated episodes of HbS polymerization and erythrocyte sickling in conditions of low pO 2 and unsickling in conditions of high pO 2 can lead to severe alterations in the membrane structure and function (see below) and abnormal calcium compartmentalization. Membrane deformation and erythrocyte dehydration eventually result in the formation of an irreversibly sickled cell — a sickle erythrocyte that can no longer revert to its natural shape 52 – 55 .

Altered erythrocyte membrane biology . HbS polymerization directly or indirectly alters the typical lipid bilayer and proteins of the erythrocyte membrane, which leads to reduced cellular hydration, increased haemolysis and abnormal interactions with other blood cells and contributes to early erythrocyte apoptosis 55 – 58 ( Fig. 4 ). Several membrane ion channels are dysfunctional, including the erythroid K–Cl cotransporter 1 (KCC1; encoded by SLC12A4 ), KCC3 (encoded by SLC12A6 ) and KCC4 (encoded by SLC12A7 ), the putative Gardos channel (encoded by KCNN4 ) and P sickle , the polymerization-induced membrane permeability, most likely mediated by piezo-type mechanosensitive ion channel component 1 (PIEZO1), resulting in reduced cellular hydration. In a subpopulation of sickle erythrocytes, phosphatidylserine (which is usually confined to the inner layer of the membrane) is exposed on the erythrocyte surface. Circulating phosphatidylserine-exposing erythrocytes have a role in many important pathophysiological events, including increased haemolysis, endothelial activation, interaction between erythrocytes, white blood cells and platelets and activation of coagulation pathways 59 , 60 . HbS polymers and HbS oxidation (see below) also affect membrane proteins that have structural functions, especially the band 3 anion transport protein, and these changes lead to membrane microvesiculation and the release of erythrocyte microparticles 61 , 62 . These submicron, unilamellar vesicles are shed from the plasma membrane under cellular stress to the membrane and cytoskeleton. In SCD, they are derived in large numbers from erythrocytes 63 but also from platelets, monocytes and endothelial cells. Microvesicles possess cell-surface markers, cytoplasmic proteins and microRNAs derived from their cell of origin and can affect coagulation, adhesion, inflammation and endothelial function 64 , 65 . By contrast, exosomes originate from the endosomal system 66 and have been less studied in SCD.

Damage and dysfunction of the erythrocyte membrane caused by sickle haemoglobin (HbS) polymerization lead to haemolysis. Oxidized membrane proteins reveal antigens that bind to existing antibodies, and membranes expose phosphatidylserine; both mechanisms promote phagocytosis of erythrocytes by macrophages, a pathway of extravascular haemolysis. Intravascular haemolysis releases the contents of erythrocytes into the plasma. Hb scavenges nitric oxide (NO), arginase 1 depletes the ʟ-arginine substrate of NO synthase (NOS), and asymmetric dimethylarginine (ADMA) inhibits NOS. Reactive oxygen species (ROS) further deplete NO, leading to vasoconstriction and vascular remodelling, especially in the lung. Adenine nucleotides and NO deficiency promote platelet activation and activation of blood clotting proteins. Haem and other danger-associated molecular pattern (DAMP) molecules activate the innate immune system. Ligand-bound Toll-like receptor 4 (TLR4) and TLR2 activate monocytes and macrophages to release inflammatory cytokines, which promote an inflammatory state and activation of endothelial cells. TLR4 activation on platelets promotes their adhesion to neutrophils, which in turn release DNA to form neutrophil extracellular traps (NETs). Circulating blood cells adhere to each other and to the activated endothelium, contributing and potentially even initiating vaso-occlusion. In postcapillary venules, activated endothelial cells that express P-selectin and E-selectin can bind rolling neutrophils. Activated platelets and adhesive sickle erythrocytes can adhere to circulating or endothelium-bound neutrophils and form aggregates. Sickle erythrocytes might also bind directly to the activated endothelium. The figure shows only some examples of the complex and redundant receptor–ligand interactions involved in the adhesion of circulating cells to the damaged endothelium and exposed subendothelium. AE1, band 3 anion transport protein; BCAM, basal cell adhesion molecule; GSH, glutathione; HMGB1, high mobility group protein B1; ICAM1, intercellular adhesion molecule 1; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; PGE 2 , prostaglandin E2; PGF, placenta growth factor; TNF, tumour necrosis factor; VCAM1, vascular cell adhesion protein 1; VEGFR1, vascular endothelial growth factor receptor 1.

Sickle erythrocytes are highly unstable, with a lifespan that is reduced by ≥75% 65 , 67 . Haemolysis is thought to occur principally via extravascular phagocytosis by macrophages, but a substantial fraction (roughly one-third) occurs through intravascular haemolysis 68 ( Fig. 4 ). It has been hypothesized that the rate of intravascular haemolysis in SCD is insufficient to produce a clinical phenotype, including pulmonary hypertension 69 , the most serious consequence of intravascular haemolysis. However, the epidemiological, biochemical, genetic and physiological data supporting a link between intravascular haemolysis and vasculopathy continue to expand 70 .

Oxidative stress . Haemolysis is both a cause and an effect of oxidative stress. The substantial levels of oxidative stress in sickle erythrocytes enhance HbS auto-oxidation, which could contribute to the damage of the cell membrane, premature erythrocyte ageing and haemolysis 65 . In addition to the accelerated auto-oxidation of HbS, oxygen radicals result from increased expression of oxidases, especially xanthine dehydrogenase and xanthine oxidase, and reduced NADPH oxidase 71 , 72 , extracellular haem and Hb in plasma and probably also from recurrent ischaemia–reperfusion of tissues. Cytoskeletal proteins and membrane lipids become oxidized, and this chronic severe oxidative stress in sickle erythrocytes depletes the levels of catalytic antioxidants 65 such as superoxide dismutase, peroxiredoxin 2 and peroxiredoxin 4 (Refs 46 , 73 ). This issue is worsened by depletion of the endogenous reductant glutathione 46 , 74 ; impaired antioxidant capacity probably contributes to haemolysis.

Free plasma Hb and haem . Extracellular Hb (in plasma or in microparticles 64 , 65 ) and haem in plasma promote severe oxidative stress, especially to blood vessels and blood cells 65 . Continuous auto-oxidation of extracellular Hb produces superoxide, which dismutates into hydrogen peroxide (H 2 O 2 ), a source for additional potent oxidative species, including the ferryl ion, which promotes vasoconstriction 65 . Extracellular Hb scavenges nitric oxide (NO; which is generated by NO synthase (NOS) in endothelial cells and promotes vasodilation) ∼ 1,000-fold more rapidly than cytoplasmic Hb, thereby decreasing NO bioavailability 75 . This decreased bioavailability of NO results in vascular dysfunction, indicated by impaired vasodilatory response to NO donors, activation of endothelial cells (producing cell-surface expression of endothelial adhesion molecules and detected by elaboration of soluble ectodomains of the adhesion molecules into plasma) and haemostatic activation of platelets, indicated by cell-surface expression of P-selectin (which mediates the interaction between activated platelets and leukocytes) and activated αIIbβ3 integrin 70 . Markers of haemolytic severity (such as low Hb or high serum lactate dehydrogenase) predict the clinical risk of developing vascular disease complications (see below).

Disruption of arginine metabolism . Intravascular haemolysis releases two factors that interfere with NOS activity. The enzyme arginase 1 competes with NOS for L -arginine, the substrate required for NO production by NOS 76 . Arginase 1 converts L -arginine into ornithine, which fuels the synthesis of polyamines, which in turn facilitate cell proliferation 77 , potentially of vascular cells, probably promoting vascular remodelling. Asymmetric dimethylarginine (ADMA) is an endogenous NOS inhibitor and a proteolytic product of proteins methylated on arginine; ADMA is abundant in erythrocytes and is also released during haemolysis 78 . Both ADMA and depletion of L -arginine by arginase 1 could contribute to uncoupling of NOS, which then produces reactive oxygen species (ROS) instead of NO 79 , 80 .

Plasma lipids . Individuals with SCA often have a form of dyslipidaemia that is associated with vasculopathy: triglyceride levels are high and correlate with haemolytic severity 81 . Although total cholesterol levels are generally low in individuals with SCA, the levels of apolipoprotein A-I (which promotes hepatic cholesterol catabolism and NOS activity) are particularly low, especially during vaso-occlusive pain crises and in association with markers of pulmonary hypertension and endothelial dysfunction 82 . Genetic variants of apolipoprotein L1 have been associated with renal disease in SCA 83 .

Innate immune system activation

Plasma haem and Hb act as danger-associated molecular patterns (DAMPs) to activate the innate immune system and heighten the adhesiveness of circulating blood cells to each other and to the endothelium, thereby triggering vaso-occlusion 70 ( Fig. 4 ). Haem activates neutrophils to release DNA as neutrophil extracellular traps (NETs) that increase platelet activation and thrombosis and promote pulmonary vaso-occlusion 84 and release of placenta growth factor (PGF) from erythroblasts (nucleated precursors of erythrocytes). PGF is a ligand for vascular endothelial growth factor receptor 1 on endothelial cells and macrophages, promoting release of endothelin 1 (a vasoconstrictor), which contributes to pulmonary hypertension 85 . Toll-like receptor 4 (TLR4) is highly expressed in immune cells in SCD, and tissue damage and platelet activation release high mobility group protein B1 (HMGB1), a high-affinity TLR4 ligand. TLR4 also binds lipopolysaccharide (LPS) derived from Gram-negative bacteria, which could explain why infections promote vaso-occlusive crises in individuals with SCA. TLR4 ligands activate monocytes and macrophages to release inflammatory cytokines, which promote an inflammatory state and activate the adhesiveness of neutrophils, platelets and endothelial cells. Finally, increased intracellular iron from turnover of haemolyzed and transfused erythrocytes is associated with markedly increased expression in the peripheral blood mononuclear cells of several components of the inflammasome pathway 86 .

Cell adhesion and vaso-occlusion

Endothelium activation . Vaso-occlusion in SCA is a complex phenomenon in which interactions between erythrocytes and endothelial cells, leukocytes and platelets play a central part ( Fig. 4 ). Endothelial cells are probably activated by direct contact of sickle erythrocytes, free haem and Hb and hypoxia-induced ROS 87 . Reduced NO bioavailability could induce the expression of adhesion molecules and production of endothelin 1. The increased expression of endothelial adhesion molecules (such as vascular cell adhesion protein 1 (VCAM1) 88 , 89 , intercellular adhesion molecule 1 (ICAM1) 90 , P-selectin, E-selectin, leukocyte surface antigen CD47 and αVβ3 integrin) and exposed heparin sulfate proteoglycans and phosphatidylserine are responsible for erythrocyte and leukocyte adhesion 89 . Activated endothelial cells also produce inflammatory mediators, such as IL-1β, IL-6 and tumour necrosis factor (TNF), which lead to a chronic inflammatory state.

Erythrocytes . Sickle erythrocytes are more adhesive to endothelial cells than normal erythrocytes 87 , 91 . Many adhesion molecules (the most important include α4β1 integrin (also known as very late antigen 4 (VLA4), which is reticulocyte-specific), platelet glycoprotein 4 (also known as CD36) and basal cell adhesion molecule (BCAM)) are overexpressed by sickle red blood cells and mediate the adhesion to the endothelium 92 . Interestingly, reticulocytes and deformable erythrocytes (that is, erythrocytes that have not become permanently sickled) are substantially more adhesive than the irreversible and dense sickle erythrocytes 93 .

Leukocytes . High baseline leukocyte numbers are associated with increased morbidity and mortality in SCA 94 , 95 . Many studies in mouse models of SCA indicate that neutrophils have an important role in vaso-occlusion; neutrophils adhere to the endothelium and sickle erythrocytes could bind to these cells, thereby reducing blood flow and promoting vaso-occlusion 96 . Indeed, neutrophils are in an activated state in SCA and have increased expression of αMβ2 integrin with enhanced adhesion to endothelial and subendothelial proteins (such as fibronectin) 97 . Selectins produced by activated endothelium have an important role in the initial binding of neutrophils to the vascular wall 96 .

Platelets . Platelets play an important part in the pathophysiology of SCA and are in an activated state 96 , with high levels of P-selectin and activated αIIbβ3 integrin. Moreover, several biological markers of activated platelets are increased in SCA (for example, platelet microparticles 64 , thrombospondin 93 , platelet factor 4 (also known as CXC-chemokine ligand 4 (CXCL4)) and β-thromboglobulin). Platelets are found in the circulating heterocellular aggregates of neutrophils and red blood cells (mainly reticulocytes) in the blood from individuals with SCA, and their adhesion to these aggregates is mediated in part through P-selectin 98 . These data strongly suggest that platelets have a role in the formation of these aggregates. Platelets could also act as accessory cells of the innate immune system by releasing cytokines 99 .

Diagnosis, screening and prevention

Diagnostic opportunities.

The goals and methods of diagnosis of SCD vary with the age of the person. In general, there are four overlapping testing periods: preconception, prenatal, neonatal and post-neonatal. Preconception testing is designed to identify asymptomatic potential parents whose offspring would be at risk of SCD. Laboratory techniques used for preconception testing are routine basic methods of protein chemistry that enable separation of Hb species according to their protein structure, including Hb electrophoresis, high-performance liquid chromatography (HPLC) and isoelectric focusing 100 . Prenatal diagnosis is a generally safe but invasive procedure and is offered during early pregnancy to couples who tested positive at preconception screening. It requires fetal DNA samples obtained from chorionic villus analysis performed at 9 weeks of gestation 100 . Non-invasive prenatal diagnosis techniques are being developed but are still investigational. These new techniques can detect fetal DNA in maternal circulation by as early as 4 weeks of gestation. Some couples who test positive at preconception screening might opt for in vitro fertilization with pre-implantation genetic diagnosis, if available, to genetically identify at-risk embryos before embryo transfer occurs 101 .

Newborn screening . Newborn screening for SCD is performed at birth before symptoms occur, using Hb protein analysis methodologies. Two types of newborn screening programmes have been used: selective screening of infants of high-risk parents (targeted screening) and universal screening. Universal screening is generally more cost-effective, identifies more newborn babies with disease and prevents more deaths 17 , 102 . In areas without newborn screening programmes, the initial diagnosis of SCD occurs at approximately 21 months of age 103 . For many individuals with SCD, the initial presentation is a fatal infection or acute splenic sequestration crisis 103 . Early diagnosis accompanied by penicillin prophylaxis and family education reduces the mortality in the first 5 years of life from 25% to <3% 103 , 104 . Similar positive results are found in low-income countries 105 , 106 .

Post-neonatal testing . The requirement of post-neonatal testing for SCD is influenced by several factors that affect the general population's knowledge of their SCD status. These factors include the regional success of neonatal screening programmes, immigration of at-risk patients not previously tested and access to neonatal results in older patients 107 . HbAS is a benign condition and not a disease, but it is also a risk factor for uncommon serious complications 107 . Thus, knowledge of one's own HbAS status is important in the prevention of rare serious complications and in family planning.

HbAS can also be detected by newborn screening programmes; however, HbAS detection is not the primary objective, and many programmes do not provide this information or offer associated counselling. Individuals who wish to have children should be screened to discover heterozygous genotypes that could be important in genetic counselling. HbAS screening enables informed decisions concerning preconception counselling and prenatal diagnosis.

Routine fitness training does not increase the risk of mortality for individuals with HbAS. However, there is a concern of increased risk of rhabdomyolysis (rapid destruction of skeletal muscle) and sudden death during intense, prolonged physical activity; this risk can be mitigated by proper training 108 . In some regions, these observations have resulted in voluntary or mandatory screening of athletes for HbAS 107 . There are rare and specific complications of HbAS that should prompt HbAS testing. These include haematuria (blood in the urine), hyphema (blood inside the eye's anterior chamber) and renal medullary carcinoma, a rare malignancy. HbAS could be a risk factor for chronic kidney disease and pulmonary embolism 109 .

Newborn screening programmes

Newborn screening programmes for SCD are now in place in several European countries, the United States ( Box 1 ), India, Africa ( Box 2 ) and Brazil ( Box 3 ).

Screening in Europe . Newborn screening programmes for SCD in the United Kingdom became universal in 2006 (Ref. 110 ); the primary aim of the programme is to diagnose SCD, but if a baby has HbAS, the parents are provided with specific informational materials. In France, screening for SCD has been in place since 2000 but is restricted to newborn babies whose parents both originate from SCD-endemic regions 111 . In Spain, universal screening has been recommended for regions with a high annual birth rate and SCD prevalence (for example, Catalonia and Madrid), whereas targeted screening is recommended for regions with a low annual birth rate and SCD prevalence 112 . Screening programmes are also present in Italy 113 and Germany 114 .

Screening in the United States . In the United States, statewide newborn screening originated in New York state in 1975 ( Box 1 ), and by 2007, all states had universal screening programmes 21 . In the United States, HPLC and isoelectric focusing are the predominant screening methods 21 , 100 . Confirmation of the diagnosis by DNA analyses to detect Hb variants is commonly used but is not standardized among states. A major gap in these programmes is the lack of follow-up and the variability of statewide education programmes 115 . The identification of substantial clinical morbidity occasionally associated with individuals with HbAS has not yet resulted in routine counselling and genetic testing of family members of newborn babies with HbAS 107 .

Screening in India . The population of India consists of >2,000 different ethnic groups, most of which have practised endogamy (the custom of marrying only within the limits of the local community) over centuries. Thus, although the β S allele has been detected in many ethnic groups, its prevalence has been enriched in some. The at-risk population consists of several hundreds of millions of individuals, predominantly belonging to historically disadvantaged groups 116 . Screening efforts have focused on groups with a high prevalence of the β S allele and areas with large numbers of these at-risk populations. Screening typically consists of an Hb solubility test (a screening test that does not distinguish HbAS from disease) at the point of care with further testing of initial positive samples by HPLC analysis at a reference centre. Screening programmes also include education, testing and genetic counselling. In many hospitals, such services are also offered to the relatives of patients diagnosed with SCD and in the prenatal setting to mothers either previously diagnosed with HbAS or belonging to an at-risk ethnic group. Pilot projects of newborn screening programmes for SCD have been implemented in the states of Gujarat, Maharashtra and Chhattisgarh 105 , 106 , 117 – 120 , which resulted in detailed data on the prevalence of HbAS in various populations, with ranges of 2–40%. There is considerable regional variation in the implementation of follow-up approaches such as comprehensive care, penicillin prophylaxis and immunization against pneumococcus.

Screening in Africa . No country in sub-Saharan Africa has implemented a universal newborn screening programme for any disease 121 . However, a few countries in sub-Saharan Africa have developed pilot newborn screening programmes for SCD. Among these, Ghana's National Newborn Screening Programme for SCD, launched in 2010 following a 15-year pilot study, is the most developed 122 ( Box 2 ). Other countries in Africa where small-scale or pilot newborn screening programmes for SCD have been conducted or are ongoing include Angola 123 , Benin 124 , Burkina Faso 125 , Burundi 126 , Democratic Republic of the Congo 127 , Nigeria 128 , Rwanda 126 , Senegal 129 , Tanzania 130 and Uganda 131 . Screening followed by penicillin prophylaxis can reduce early mortality from pneumococcal bacteraemia 103 , 104 . Nevertheless, current and future numbers of individuals with SCA or HbAS make the scalability of the interventions implemented in high-income, low-burden countries (such as universal newborn screening programmes) in low-resource settings challenging. There is no mandatory or large-scale preconception screening programme for adults who wish to have children in any African country. However, several churches require couples to be screened for SCD-related conditions as a prerequisite for marriage approval. Such screening often involves inexpensive but inconclusive ‘sickling’ and solubility tests, which cannot identify individuals with the β C allele or β-thalassaemia, conditions that, although not characterized by the presence of HbS, are of genetic counselling relevance. There are very few much-needed certified genetic counsellors to support the screening programmes. The Sickle Cell Foundation of Ghana launched the first Sickle Cell Genetic Counsellor Training and Certification Programme in June 2015 ( Box 2 ).

Box 1: Roadmap to screening programmes in the United States

The National Sickle Cell Anemia Control Act (Public Law 92–294) was signed into law in 1972 in response to a presidential initiative and congressional mandate 257 . The act provided for voluntary sickle cell disease (SCD) screening and counselling, education programmes for health professionals and the public and research and training in the diagnosis and treatment of SCD. Because of this legislation, a national broad-based programme of basic and clinical research was established at the NIH and was coordinated across federal agencies. The Comprehensive Sickle Cell Centers were the major component of this programme; ten centres were established in hospitals and universities located in geographical areas with large at-risk populations. These centres provided an integrated programme of research and care for individuals with SCD and emphasized prevention, education, early diagnosis and counselling programmes supported by the NIH. The establishment of treatment guidelines and protocols standardized treatment across the country. The centres gradually shifted towards basic and clinical research, and the NIH Comprehensive Sickle Cell Center programme was disassembled in 2008.

Box 2: Screening in Ghana

The screening programme in Ghana is designed to be universal and includes screening for neonates born at both public and private birth facilities as well as screening at ‘well-baby’, free immunization clinics (that is, public health clinics where babies are brought to receive free immunizations) for babies who were not screened at birth or who were referred from facilities where screening is not available 122 . Babies with possible sickle cell disease (SCD) are referred to a treatment centre, where a second sample is obtained to confirm the initial screening results. Babies with SCD are enrolled in a comprehensive care programme that includes penicillin and antimalarial prophylaxis, folic acid supplementation and parental education about management of SCD. Ghana's National Health Insurance Authority funds newborn screening programmes as part of the mandated free care for children of <5 years of age. By the end of 2015, >400,000 newborn babies were screened for SCD and related conditions. Of the 6,941 newborn babies who were diagnosed with SCD, 80% had been successfully followed up, and 70% of them registered at the Kumasi Centre for SCD, which was established for the pilot screening programme (K.O.-F., unpublished observations). However, follow-up is challenging, as 80% of mothers of babies with SCD initially failed to return for results and had to be reached at their homes, and irregular government funding can cause intermittent shortages of laboratory supplies. Limited funding has stalled the national scale-up of the free screening programme, which currently reaches only 4.2% of the 850,000 annual neonates.

Box 3: Screening in Brazil

The Newborn Screening Program in Brazil was implemented as an official programme of the federal government in 2001, but a few statewide programmes were already in place. As of 2017, the National Program for Newborn Screening (PNTN) is available to all 26 states of the country, although the coverage is highly variable (for example, in 2016, it was ∼ 100% of hospitals in the state of Minas Gerais and ∼ 55% of hospitals in the state of Amapa) (F.F.C., unpublished observations).

The newborn screening programmes enabled the analysis of the survival of children with sickle cell disease (SCD). In the state of Minas Gerais, 3.6 million newborn babies were screened between 1998 and 2012, and 2,500 children were diagnosed with SCD. During the 14-year study period, the mortality was 7.4%. The main causes were infection (45%) and acute splenic sequestration (14%) 258 . In another study in the state of Rio de Janeiro, >1.2 million newborn babies were screened between 2000 and 2010, and 912 had SCD. The mortality was 4.2% during the 10-year period, and the main causes were acute chest syndrome (36.8%), sepsis (31.6%) and splenic sequestration (21.1%) 27 .

Phenotypes in sickle cell disease

There is great phenotypic variability among individuals with SCD. Some variability shows a specific geographical distribution and is associated with known or suspected genetic variants 132 . However, some complications cluster together epidemiologically in subphenotypes, at times united by a common biomarker that suggests a mechanism, such as a particularly low Hb level with a high reticulocyte count or high serum lactate dehydrogenase level, implying more-intense haemolysis. These phenotypes are not mutually exclusive, exist often as a spectrum, can overlap, are probably due to independent genetic modifiers of the underlying mechanisms and might change with ageing.

Vaso-occlusive subphenotype . This SCA subphenotype is characterized by a higher haematocrit than that observed in individuals with other SCA phenotypes; a higher haematocrit promotes higher blood viscosity. Individuals with this phenotype are predisposed to frequent vaso-occlusive pain crises, acute chest syndrome (that is, a vaso-occlusive crisis of the pulmonary vasculature) and osteonecrosis. Co-inheritance of α-thalassaemia reduces haemolysis (by reducing the intracellular concentration of HbS, which slows HbS polymerization and haemolysis) but promotes higher haematocrit 133 .

Haemolysis and vasculopathy subphenotype . This phenotype is characterized by a lower haematocrit than that found in individuals with the vaso-occlusive subphenotype accompanied by higher levels of serum lactate dehydrogenase and bilirubin, which indicate more-severe haemolytic anaemia. Individuals in this group are at risk of ischaemic stroke, pulmonary hypertension, leg ulceration, gallstones, priapism and possibly nephropathy 134 . Decreased NO bioavailability, haem exposure and haem turnover are associated with these vasculopathic complications. The severe anaemia also promotes high cardiac output as a compensatory mechanism, and this excessive blood flow has been suggested to promote vasculopathy in the kidney and potentially in other organs.

High HbF subphenotype . Persistent expression of HbF in the range of 10–25% of total Hb owing to genetic variants generally reduces the clinical severity of SCA 3 , 135 . However, not all individuals with the common, uneven cellular distribution of HbF (heterocellular distribution) have a mild phenotype. Expression levels of 25–50% of HbF in every erythrocyte (pancellular distribution) lead to nearly complete amelioration of SCA, with rare clinical symptoms and no anaemia 136 , a finding that could prompt the development of drugs that can induce ‘globin switching’ (that is, the preferential expression of HBG1 and HBG2 ).

Pain subphenotypes . Individuals with pain-sensitive or pain-protective phenotypes experience pain differently, potentially owing to altered neurophysiology of pain sensation pathways. One example of a genetic modifier of pain is GCH1 , which is associated with pain sensitivity in healthy individuals, and a variant of GCH1 is associated with frequency of severe pain in SCA 137 . Quantitative sensory testing of pain sensitivity is being used to functionally characterize these phenotypes in SCA 138 .

SCD is a complex, multisystem condition characterized by acute and chronic complications ( Fig. 5 ). Advances in general medical care, early diagnosis and comprehensive treatment have led to substantial improvements in the life expectancy of individuals with SCA in high-income countries 8 , 9 as almost all patients survive beyond 18 years of age 139 . However, even with the best of care, life expectancy is still reduced by ∼ 30 years, routine and emergency care for individuals with SCD have great financial costs, the quality of life often deteriorates during adulthood and the social and psychological effects of SCD on affected individuals and their families remain underappreciated 140 . Furthermore, most of these advances have not reached low-income countries 141 .

Acute complications bring the individual with sickle cell disease (SCD) to immediate medical attention; pain is the most common acute complication. As individuals with SCD age, chronic complications produce organ dysfunction that can contribute to earlier death. Complications of pregnancy include pre-eclampsia, intrauterine growth restriction, preterm delivery and perinatal mortality.

Three therapies modify the disease course of SCA: hydroxycarbamide, erythrocyte transfusion and haematopoietic stem cell transplantation 142 .

Hydroxycarbamide . Hydroxycarbamide (alternatively known in some countries as hydroxyurea), a ribonucleotide reductase inhibitor, has multiple physiological effects, including increasing HbF expression (in most individuals with SCA 143 ) and decreasing leukocyte count. It was approved by the US FDA in 1998 and by the European Medicines Agency (EMA) in 2007 for the treatment of SCD. The drug significantly reduces the incidence of SCA vaso-occlusive crises, hospitalizations and mortality in high-income countries (with studies ongoing in low-resource countries) with an excellent safety profile 144 , although some patients do not have a beneficial response, usually because of limitations of adherence to treatment 145 but possibly sometimes for pharmacogenomic reasons 146 . Hydroxycarbamide is underutilized because of health-care infrastructure deficiencies in both low-resource and high-resource countries and disproportionate perceptions of carcinogenicity, teratogenicity and reduced fertility, which have not been problems thus far in follow-up studies 143 , 147 , 148 ; however, hydroxycarbamide use is increasing. Snapshots from various cohorts over the years show that in high-resource countries, at specialized SCD clinics, up to 63% of patients with SCA may be on hydroxycarbamide 149 , but the percentage is near zero in most African countries 150 . Because of very favourable clinical trial results in infants and toddlers 151 , hydroxycarbamide is prescribed with increasing frequency to children with SCA — up to 45% in multinational SCD centres 152 . Although there is still limited evidence on whether hydroxycarbamide improves survival and prevents SCD complications in low-income countries 153 , various studies, including the Realizing Effectiveness Across Continents with Hydroxyurea (REACH) trial, are currently underway and should address knowledge gaps about treatment options for SCA in sub-Saharan Africa 150 .

Erythrocyte transfusion . This therapy improves microvascular flow by decreasing the number of circulating sickle erythrocytes and is associated with decreased endothelial injury and inflammatory damage 154 , 155 . Chronic transfusion therapy, prescribed in high-resource countries primarily to the roughly 10% of patients with SCA at high risk of stroke, can ameliorate and prevent stroke and vaso-occlusive crises 156 ; however, several potential adverse effects, including iron overload, alloimmunization (an immune response to foreign antigens that are present in the donor's blood) and haemolytic transfusion reactions, limit its potential benefits. The availability of oral iron-chelating drugs since 2005 has reduced the adverse effects of iron overload. In countries with limited testing of blood products for infectious agents, there are substantial risks of transmission of blood-borne infections, such as hepatitis B, hepatitis C, HIV infection, West Nile virus infection and others. Transfusion protocols with extended erythrocyte matching that includes the erythrocyte antigens Kell, C, E and Jkb and iron-chelation therapy guidelines improve the safety of this therapy 156 . Systematic genotyping of blood groups for the patient has been proposed to reduce alloimmunization 157 .

Haematopoietic stem cell transplantation . Haematopoietic stem cell transplantation in SCA is curative and should be considered in symptomatic patients with a human leukocyte antigen (HLA)-matched family donor. Worldwide, it is estimated that nearly 2,000 individuals with SCA have undergone allogeneic haematopoietic stem cell transplantation; the survival exceeds 90% in US and European studies 158 , 159 . In pooled registry data, the average rate of both acute and chronic graft-versus-host disease has been 14% and is generally lower with newer approaches 158 , and the rate of graft failure has been 2% 159 . Early results with experimental reduced-intensity conditioning regimens (pretransplantation chemotherapy to ablate or suppress the recipient's bone marrow) are very encouraging 160 . However, most patients do not have an HLA-matched related donor. Experimental use of expanded donor pools (haploidentical donors (who share 50% of the HLA antigens with the recipient) and unrelated HLA-matched donors) can increase the probability of cure but also increase the rate of graft rejection and mortality, which seem to improve with ongoing research 161 . Although haematopoietic stem cell transplantation from the bone marrow of a healthy HLA-matched donor can cure SCA, this therapy is limited by the paucity of suitable donors and is available only in high-income countries 162 .

Management of acute complications

The principles of management of acute complications in SCA ( Fig. 5 ) include the need for early diagnosis, consideration of other non-SCD-related causes and rapid initiation of treatment. The use of standardized protocols for common complications improves outcomes.

Acute pain . Acute pain events usually affecting the extremities, chest and back are the most common cause of hospitalization for individuals with SCA. However, the majority of such events are managed at home with NSAIDs or non-prescription oral opioid analgesics without the involvement of the health care provider. The pathophysiology and natural history of acute pain events are complex, and treatment is suboptimal 163 . Individual personalized protocols for outpatient and inpatient pain management improve quality of life and decrease hospital admissions 164 – 166 . The treatment is guided by the severity of pain, which is generally self-reported using pain severity scales. When home management with oral analgesics, hydration and rest is ineffective, rapid triage with timely administration of opioids is recommended. Initial treatment in a day unit compared with an emergency room drastically decreases hospitalization 167 . Initiation of treatment for emergency room patients with SCD is often markedly delayed, with patients with SCD waiting 25–50% longer than patients without SCD with similar pain acuity 168 . In some programmes, innovative emergency room treatment protocols for patients with SCD using standardized time-specific dosing protocols and intranasal fentanyl (an opioid) have substantially reduced time to treatment; similar approaches should be adopted universally 164 , 165 . Once an individual is hospitalized, a standardized protocol using patient-controlled analgesia devices is indicated. These intravenous infusion pumps enable patient self-medication and, in general, result in improved analgesic control and less analgesic use 169 . Incentive spirometry, a simple device that prevents atelectasis (the complete or partial collapse of a lung), with close monitoring of the patient's levels of sedation, hydration and oxygenation improves outcomes. Although intensive analgesia is important for effective medical management of pain in SCD, in some countries, opioids are unavailable owing to resource limitations or are not prescribed or consumed owing to stigma 170 . Vaso-occlusive crises can sometimes result in sudden unexpected death 3 , 171 . The precise aetiology of sudden death in such cases is unclear, although autopsy often shows histopathological evidence of pulmonary arterial hypertension 171 .

Acute chest syndrome . Acute chest syndrome is the second most frequent reason for hospitalization and a leading cause of death in individuals with SCD — it is often linked to and follows an acute pain event 172 . The severity of acute chest syndrome increases with age. In adults, >10% of cases are fatal or complicated by neurological events and multi-organ failure 173 . The initial pulmonary injury is multifactorial, including infection, pulmonary fat embolism, pulmonary infarction and pulmonary embolism 174 . The presence of underlying, often undetected bronchoreactive lung disease can increase the frequency and severity of acute chest syndrome events 175 . Early chest X-ray imaging tests and oxygen monitoring of patients with any pulmonary symptoms are necessary. Hospitalization with broad-spectrum antibiotics, bronchodilators, oxygen supplementation and red cell transfusions is often indicated 176 . Exchange transfusions (in which the patient's blood is replaced by donor blood) and steroids, which decrease acute inflammation, could modify a severe or rapidly deteriorating event 176 , 177 . Exchange transfusion is the most effective method of lowering the level of HbS below 30% of the total Hb without raising the total Hb level above 10 g dl −1 (Ref. 178 ). However, delayed transfusion reactions can complicate transfusion therapy and present as a hyperhaemolytic episode in which the transfused cells and the patient's own red blood cells are destroyed 179 . Steroids often provide benefit but are associated with an ∼ 25% risk of mild or severe complications (in particular, there is a high rate of recurrence of acute chest syndrome once the steroids are stopped); thus, their use is usually limited to life-threatening acute chest syndrome events 180 .

Acute stroke . An acute stroke, including ischaemic and haemorrhagic events, is a medical emergency. Children with SCA have a 300-fold higher risk of acute stroke than other children without SCD, and by 45 years of age, one in four adults with SCA has had a stroke 181 . In the United States, 25% of individuals with SCA develop an overt stroke, and another 35% have non-focal central nervous system injury 181 – 183 . Ischaemic stroke is usually caused by occlusion of a large cerebral artery and can occur as a complication of acute chest syndrome (defined above) or independently, and can manifest with transient ischaemic attack, sudden weakness or loss of consciousness. Prompt evaluation (including MRI of patients with subtler presentations) is indicated. Rapid exchange transfusion is the standard treatment. In addition, chronic transfusion decreases secondary stroke recurrence 178 . The importance of subsequent monthly chronic transfusion to prevent secondary stroke has been re-affirmed by the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) study 184 .

Intracranial haemorrhage or haemorrhagic stroke account for 3–30% of acute neurological events and have a 25–50% acute mortality 185 . Clinically, these patients present with severe headache or loss of consciousness without hemiparesis. Imaging with angiography could reveal a surgically treatable aneurysm. Individuals with moyamoya vasculopathy, which is a prominent collateral circulation around occluded arteries of the circle of Willis that is frequent in individuals with SCD, are at high risk of intracranial bleeding. When this pathology is electively detected, indirect revascularization using encephaloduroarteriosynangiosis (a surgical procedure that implants the superficial temporal artery to the brain surface, increasing blood flow to the ischaemic area) is often considered to decrease bleeding risk and improve oxygenation 186 , 187 .

Acute anaemic events . Over half of patients with SCD will experience an acute anaemic event, which can be fatal, at some point in their life. The most common types of anaemic events are splenic sequestration crisis, aplastic crisis (temporary absence of erythropoiesis) and hyperhaemolytic crisis. Acute splenic sequestration crisis is characterized by rapid swelling of the spleen and hypovolemia with a sudden fall in Hb levels. As many as 30% of young children experience acute sequestration events, which are a leading cause of infant mortality. Early detection is crucial, and transfusion followed by elective splenectomy is usually required 188 . Nonsurgical supportive care can be successful, and, when necessary, transfusion with extended red blood cell antigen-matched erythrocyte units and selective use of immunosuppressive therapy are indicated.

Cholelithiasis . Cholelithiasis (gallstones) results from the chronic accelerated rate of erythrocyte destruction in individuals with SCD. Haem is metabolized to bilirubin, which in the bile can form insoluble calcium bilirubinate, which in turn precipitates as a pigment and forms gallstones. Of note, a variant of UGT1A1 (which encodes a protein involved in bilirubin processing) increases bilirubin metabolism and, therefore, the formation of gallstones in individuals with SCD 189 . By adulthood ( Fig. 6 ), 20% of patients with SCD have acute complications from gallstones, which can promote cholecystitis (inflammation of the gall bladder) and often necessitate cholecystectomy (surgical removal of the gallbladder) 190 . By contrast, individuals with SCD who also inherit α-thalassemia have reduced haemolysis, bilirubin production and gallstone formation 189 .

Development of clinical complications in 5,100 individuals with sickle cell disease (SCD) identified in the California Hemoglobinopathy Surveillance Program 271 . ACS, acute chest syndrome.

Long-term management

Improved management of acute complications is associated with a longer survival. As individuals with SCD age, chronic problems resulting from cumulative organ injury can lead to severe morbidity 191 ( Figs 5 , 6 ). Chronic pain is common; the Pain in Sickle Cell Epidemiology Study (PiSCES) found that adults with SCD have pain on 55% of days 192 , and pain, in general, is a poorly managed complication of SCD 193 . Individuals with SCD and recurrent pain have altered brain network connectivity, which affects their response to treatment 194 . Chronic pain requires a multidisciplinary team familiar with neuropathic pain tolerance, withdrawal symptoms and hyperanalgesia syndrome 193 . Hydroxycarbamide, selective use of chronic transfusions in severe cases and long-acting opioids are useful components of a multidisciplinary pain management approach.

Avascular necrosis of the hip is a common cause of chronic pain that eventually develops in many individuals with SCD 195 ; in >20% of hospitalizations, symptoms are related to avascular necrosis. Although core decompression (in which a small core of bone is removed from the damaged area, lowering the bone marrow pressure and stimulating healthy bone regrowth), physiatry (rehabilitation) therapy and analgesics are temporarily helpful, total hip replacement is often required.

Chronic kidney disease is relatively common in older individuals with SCD and is thought to have a poor prognosis in these individuals compared with individuals without SCD 196 . This worse outcome could in part be due to delayed access to dialysis and renal transplant for individuals with SCD, as they might not be considered good candidates for these therapies. Of note, individuals with SCD who receive a timely renal transplantation have an outcome comparable with that of individuals without SCD who receive a transplant 197 , 198 .

Although screening for brain injury with annual transcranial Doppler (TCD) screening and/or MRI and chronic transfusion therapy for high-risk patients decrease the frequency and severity of stroke complications, patients continue to have progressive neurocognitive injury and require close observation and long-term therapy 182 . In addition, implementation of multidisciplinary plans for management of other common chronic complications of SCD (for example, cardiopulmonary dysfunction, priapism and leg ulcers) improves the quality of life of these patients as they age 199 , 200 .

Prevention of complications

Preventive strategies have changed the long-term outcome in SCD more than any other approach. Prevention of life-threatening infections and stroke has drastically reduced childhood mortality in SCD; generalized screening of individuals with SCD for risk factors and early evidence of disease enable the implementation of treatment that can reduce morbidity. Screening for pulmonary, renal and systemic hypertension, retinopathy and damage to other organs is indicated 201 . Detailed generalized screening recommendations for SCD are available 202 , 203 .

Prevention of infection . Until the 1990s, in the United States, up to 30% of young children with SCA died from infections, predominantly due to encapsulated bacteria 104 , owing to a common childhood deficiency of immune response to polysaccharide antigens 204 and exacerbated in SCA by impaired clearance of blood-borne bacteria as a result of functional asplenia 104 . The introduction of prophylactic penicillin treatment decreased the incidence of pneumococcal bacteraemia associated with impaired splenic function by 85% 104 . Prophylactic penicillin has remained safe and beneficial in patients up to at least 5 years of age. The universal use of pneumococcal and other standard vaccinations has further lowered infectious disease mortality. The first conjugated pneumococcal vaccine decreased the rate of pneumococcal bacteraemia in children of <3 years of age by 93.4% and added protection to the large cohort of individuals with SCD who have suboptimal compliance with prophylactic penicillin therapy 205 . Long-term penicillin prophylaxis has raised concerns about the development of penicillin-resistant pneumococcal colonization and disease 206 , especially in low-income countries, although the benefit-to-risk ratio of prophylaxis is still high. The pneumococcal conjugate vaccine PCV13 and pneumococcal polysaccharide vaccine PPSV23 (Ref. 207 ) can prevent infection by most, but not all, serotypes.

Prevention of central nervous system injury . Cerebral vascular injury and neuro-ischaemic damage are a leading cause of death and morbidity in children and adults with SCA. The complications of these events are largely irreversible and mandate universal prevention and screening policies. TCD screening to detect increased vascular velocity can contribute to identifying children at high risk of stroke, which can be largely prevented by initiating transfusion therapy 208 . The landmark Stroke Prevention Trial in Sickle Cell Anaemia (STOP) study demonstrated that neurologically healthy children with elevated TCD measurements (vascular velocity >200 cm s −1 ) are at high risk of stroke, and chronic monthly transfusions reduced the rate of strokes from ∼ 11% to 1% 208 . These findings suggest that all children with SCA should be screened annually with TCD. The STOP II study found that discontinuing these preventive transfusions was not safe and that transfusion therapy for an indefinite period of time might be necessary 209 .

Nevertheless, chronic transfusion therapy for primary stroke prevention is associated with substantial complications and is not available in many low-income countries. Hydroxycarbamide therapy has been associated with decreased TCD vascular velocity 210 . The TCD With Transfusions Changing to Hydroxyurea (TWiTCH) trial determined that hydroxycarbamide therapy at maximum dosing was non-inferior to blood transfusions for primary stroke prevention in children with non-severe vasculopathy on MRI findings and who had been receiving transfusions for ≥1 year 211 . The Stroke Prevention Study in Nigeria (SPIN) provided pilot evidence that TCD screening followed by fixed-dose hydroxycarbamide therapy is feasible and has the potential to prevent strokes in low-resource areas 212 . Global TCD screening of all children with SCA is a major public health priority.

TCD screening does not detect silent infarction involving small-vessel disease, which is a major cause of neurocognitive impairment in SCD. The Silent Cerebral Infarct Transfusion Multi-Centre Clinical Trial (SIT) used MRI to screen children who had normal TCD measurements and no neurological symptoms 213 . Children with small non-focal cerebral infarctions (detected by MRI) were randomly assigned to receive transfusion or observation. Children in the transfusion group had a 59% relative risk reduction for stroke. Whether all children should be screened with MRI remains debated. However, all individuals with soft (subtle) neurological signs or neurocognitive changes (such as sudden unexplained decline in school or work performance) should undergo MRI screening, and those with silent infarction should be offered transfusion therapy. Neurocognitive testing, where available, is a useful tool in identifying individuals who have non-focal ischaemic cerebral injury, which can progress with age and is common in adults with no neurological symptoms 182 .

Prevention of pulmonary complications . Pulmonary disease is a leading cause of morbidity and mortality in individuals with SCD 3 , 191 , 214 . Asthma is an independent predictor of mortality in this population 215 , 216 . Unrecognized bronchoreactive lung disease is common in paediatric patients and increases the severity and frequency of acute chest syndrome events. Many adults have undetected, restrictive chronic lung disease, which is a risk factor of pulmonary failure and myocardial injury 217 . Incorporating respiratory symptom questionnaires and routine spirometry into outpatient management is indicated. Pulmonary hypertension or an elevation in the tricuspid regurgitant jet velocity (TRV), which is a marker of pulmonary hypertension, are also independent predictors of mortality. Individuals with TRV of ≥3 cm s −1 have a tenfold increased mortality compared with individuals with normal TRV 214 . The American Thoracic Society recommends that all adults with SCA undergo serial echocardiography every 1–3 years to detect pulmonary hypertension 203 .

Prevention of renal complications . One-third of individuals with SCA develop chronic kidney disease, and up to 18% of individuals with SCA require dialysis or renal transplantation 218 . Proteinuria is strongly associated with progressive disease; serial urinary screening for proteinuria accompanied with treatment with angiotensin-converting enzyme inhibitors (which correct the proteinuria) could lower the risk of chronic kidney disease 201 . Mild systemic hypertension (120–139/80–90 mmHg) increases the risk of stroke, pulmonary hypertension, nephropathy, mortality and hospitalization in SCD 219 , 220 , and early diagnosis and treatment are beneficial 220 , 221 . Asymptomatic proliferative retinopathy can occur in up to 43% of individuals with HbSC disease and in 14% of individuals with SCA 222 ; if untreated, asymptomatic proliferative retinopathy results in loss of visual acuity 223 .

Comorbidities

Individuals with SCD are prone to other unrelated diseases that can modify each individual's clinical course. Very common (in at least one-third of individuals with SCD) comorbidities identified using screening questionnaires are depression and anxiety 224 , 225 . Depression and anxiety are associated with greater sensitivity to pain 226 and greater health care utilization 227 . Depression is also linked to sleep disturbance 228 and, in general, might be under-recognized and undertreated in individuals with SCD. Asthma is common: it occurs in at least 25% of children with SCD and is associated with an increased incidence of acute pain events, acute chest syndrome and early death 175 , 215 , 216 . Venous thrombosis has been reported in up to 25% of individuals with SCD and could be due to the commonly observed activation of the haemostatic system 229 .

Quality of life

Generic health-related quality-of-life (HRQOL) instruments (for example, the 36-Item Short Form Health Survey (SF-36) for adults and the Pediatric Quality of Life Inventory (PedsQL) for children) 230 , 231 measure physical, emotional and social functioning and enable the comparison of individuals with SCD with healthy individuals. Disease-specific measures, such as the PedsQL Sickle Cell Disease module for children with SCD, have better specificity for detecting differences within a population of individuals with SCD and are designed to detect changes in HRQOL over time 232 .

Both adults and children with SCD have substantially impaired baseline HRQOL 199 , 233 ( Fig. 7 ). Compared with healthy individuals, individuals with SCD have impaired HRQOL in nearly every domain, especially within the areas of pain, fatigue and physical functioning 234 , 235 . Adolescents and adults report poor sleep quality, moderate levels of fatigue and that sleep quality mediates the relationship between pain and fatigue 236 . The baseline physical functioning HRQOL domain of many individuals with SCD is worse than or comparable with that of individuals with other chronic diseases, such as cancer, cystic fibrosis or obesity 237 .

Physical functioning scores measured using the 36-Item Short Form Health Survey (SF-36) and the Pediatric Quality of Life Inventory (PedsQL) generic core scales in healthy individuals and individuals with chronic disease 237 , 272 . Scores range from 100, representing the best health-related quality of life (HRQOL), to 0. Specific areas represented in physical functioning scores include the ability to perform all types of physical activities, such as running, walking for a short distance, lifting heavy objects and bathing without help.

Acute complications, such as an acute vaso-occlusive pain crisis, are significantly associated with worse HRQOL than at baseline 238 . Children with SCD report substantial problems with physical functioning, pain and sleep during and immediately following vaso-occlusive crises 239 . Daily pain can affect the ability to attend school or work 240 , 241 and is predictive of worse HRQOL in adults with SCD 242 . Nearly one-third of adults with SCD report pain almost every day, and over half of the individuals with SCD have pain 50% of the time 241 .

Effect of treatment on health-related quality of life

Adults with SCD who had a favourable response to hydroxycarbamide had better general health and reduced pain than those who received placebo or who had a low response to treatment 243 . Similar results were observed in children with SCD who received hydroxycarbamide 244 or chronic red blood cell transfusion therapy 245 . As more experimental drugs for individuals with SCD are tested in clinical trials, it is imperative to measure the effect of these new therapies on individuals’ HRQOL.

The wide implementation of affordable interventions, including neonatal diagnosis, penicillin prophylaxis and vaccination (which led to substantial reductions in mortality among children with SCA of <5 years of age in high-income countries), could prolong the lives of ∼ 5 million newborn babies with SCA by 2050 (Ref. 17 ). Similarly, large-scale screening and treatment programmes could save the lives of up to 10 million newborn babies with SCA globally, most of them in sub-Saharan Africa 17 , 40 .

Screening for SCD and related conditions is essential in Africa, where the incidence is highest. However, the implementation of universal newborn screening programmes remains a major economical and public health challenge. African communities and governments should also develop culturally acceptable programmes for screening adults for family planning purposes. The development of new, accurate and affordable rapid diagnostic tests would offer a long-awaited point-of-care screening option for low-income and middle-income countries. Clinical validation of such tests showed that they can reliably detect the β S and β C alleles with high specificity and sensitivity 246 . These tests could be used as a large-scale first screening step before confirmation of diagnosis by HPLC or isoelectric focusing, which will be necessary to identify individuals who also have thalassaemia or other Hb variants.

In the short term, the identification of ways to enhance the use of proven therapies, such as hydroxycarbamide and haematopoietic stem cell transplantation, is the quickest route to improve management. Nevertheless, questions remain about the long-term effectiveness of hydroxycarbamide, ways to improve adherence to hydroxycarbamide therapy and possible development of antibacterial resistance in children with SCD under long-term penicillin prophylaxis. Owing to the complexity of SCD and the range of possible complications, a multidrug approach will probably be used by health care providers. However, drug development is a time-consuming process; thus, multidrug treatments will probably be available only in the mid-term or long term. Future work to understand the HRQOL of individuals with SCD over time and outside of the medical system and the effect of therapy on HRQOL is needed to provide tailored care and maximize HRQOL 247 .

Gene therapy has been considered a promising cure for SCD since the mid-1990s. Lentiviral vectors have been developed to insert γ-globin or modified β-globin genes that have been engineered to reduce sickling into haematopoietic stem cells; these vectors are now in clinical trials 248 and have yielded a promising initial result 249 . Newer gene editing approaches based on zinc-finger nucleases and transcription activator-like effector nucleases have been designed and tested for proof of principle in SCD 250 . The development of CRISPR techniques, which enable the precise replacement of a specific region of DNA, is another promising gene therapy approach for SCD, currently tested only in mice 251 and cultured human cells 252 until the multiyear regulatory process is cleared for human trials. However, many ethical issues need to be resolved before these techniques can be used in humans: long-term follow-up trials will be needed to confirm the safety and sustainability of these techniques, and the accessibility of gene therapy in high-burden, low-income areas needs to be addressed. Although some of these current gene therapy strategies are potentially curative, many of them only aim to ameliorate disease severity.

New drugs . In the United States, the decision of the FDA Division of Hematology Products to consider the development of new SCD treatments as a top priority and grant orphan drug status or ‘fast-track’ designation to several drugs and biological products has facilitated investments from pharmaceutical companies. Many products that target one or more of the mechanisms that contribute to the disease process (for example, by boosting HbF levels or countering oxidative stress) are currently in phase II or phase III trials 253 ( Table 1 ). A large clinical trial of an anti-platelet agent, prasugrel, failed to significantly reduce vaso-occlusive crisis episodes in children with SCA 152 , but P-selectin blocking approaches are promising to prevent 149 and to reduce the duration and severity 254 of vaso-occlusive crisis episodes. Enrolment in SCD trials remains challenging: a systematic review of 174 SCD interventional trials closed to enrolment showed that 57% of them terminated owing to low enrolment 255 . However, the recent completion of a series of large, multicentre, multinational clinical trials demonstrates that the community of patients with SCD and health care providers is eager to collaborate with the pharmaceutical industry to find effective new treatments 149 , 150 , 152 , 254 , 256 . The prospects for new treatments in SCD have never looked better.

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How to cite this Primer

Kato, G. J. et al. Sickle cell disease. Nat. Rev. Dis. Primers 4 , 18010 (2018).

Related links

United Nations World Population Prospects database

Neel, J. V. The inheritance of sickle cell anemia. Science 110 , 64–66 (1949).

CAS   PubMed   Google Scholar  

Steinberg, M. H. & Sebastiani, P. Genetic modifiers of sickle cell disease. Am. J. Hematol. 87 , 795–803 (2012).

CAS   PubMed   PubMed Central   Google Scholar  

Platt, O. S. et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N. Engl. J. Med. 330 , 1639–1644 (1994). This landmark natural history study established life expectancy and risk factors for mortality for SCD in the United States.

Piel, F. B., Steinberg, M. H. & Rees, D. C. Sickle cell disease. N. Engl. J. Med. 376 , 1561–1573 (2017).

Ware, R. E., de Montalembert, M., Tshilolo, L. & Abboud, M. R. Sickle cell disease. Lancet 390 , 311–323 (2017).

PubMed   Google Scholar  

Serjeant, G. R. & Serjeant, B. E. Management of sickle cell disease; lessons from the Jamaican Cohort Study. Blood Rev. 7 , 137–145 (1993).

Bonds, D. R. Three decades of innovation in the management of sickle cell disease: the road to understanding the sickle cell disease clinical phenotype. Blood Rev. 19 , 99–110 (2005).

Quinn, C. T., Rogers, Z. R., McCavit, T. L. & Buchanan, G. R. Improved survival of children and adolescents with sickle cell disease. Blood 115 , 3447–3452 (2010).

Gardner, K. et al. Survival in adults with sickle cell disease in a high-income setting. Blood 128 , 1436–1438 (2016).

Grosse, S. D. et al. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am. J. Prev. Med. 41 , S398–405 (2011).

PubMed   PubMed Central   Google Scholar  

Allison, A. C. Protection afforded by sickle-cell trait against subtertian malarial infection. BMJ 1 , 290–294 (1954).

Luzzatto, L. Sickle cell anaemia and malaria. Mediterr. J. Hematol. Infect. Dis. 4 , e2012065 (2012).

Piel, F. B. et al. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat. Commun. 1 , 104 (2010).

Piel, F. B. et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 381 , 142–151 (2013).

Weatherall, D. J. The importance of micromapping the gene frequencies for the common inherited disorders of haemoglobin. Br. J. Haematol. 149 , 635–637 (2010).

Piel, F. B. et al. The distribution of haemoglobin C and its prevalence in newborns in Africa. Sci. Rep. 3 , 1671 (2013).

Piel, F. B., Hay, S. I., Gupta, S., Weatherall, D. J. & Williams, T. N. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 10 , e1001484 (2013). This study places the disease burden of SCA into a global perspective.

Diallo, D. A. & Guindo, A. Sickle cell disease in sub-Saharan Africa: stakes and strategies for control of the disease. Curr. Opin. Hematol. 21 , 210–214 (2014).

Therrell, B. L. Jr., Lloyd-Puryear, M. A., Eckman, J. R. & Mann, M. Y. Newborn screening for sickle cell diseases in the United States: a review of data spanning 2 decades. Semin. Perinatol. 39 , 238–251 (2015).

Charlton, M. NHS Sickle Cell and Thalassaemia Screening Programme Data Report 2015/16: Trends and Performance Analysis (Public Health England, 2017).

Google Scholar  

Benson, J. M. & Therrell, B. L. Jr. History and current status of newborn screening for hemoglobinopathies. Semin. Perinatol. 34 , 134–144 (2010).

Feuchtbaum, L., Carter, J., Dowray, S., Currier, R. J. & Lorey, F. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 14 , 937–945 (2012).

Ojodu, J. et al. Incidence of sickle cell trait — United States, 2010. MMWR Morb. Mortal. Wkly Rep. 63 , 1155–1158 (2014).

Wang, Y. et al. Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity. Genet. Med. 15 , 222–228 (2013).

Ministry of Health Brazil. Sickle Cell disease: what you should know about genetic inheritance, 2014 [Portuguese]. Ministério da Saúde http://bvsms.saude.gov.br/bvs/publicacoes/doenca_falciforme_deve_saber_sobre_heranca.pdf (2014).

Silva, W. S. et al. Screening for structural hemoglobin variants in Bahia, Brazil. Int. J. Environ. Res. Publ. Health 13 , 225 (2016).

Lobo, C. L. et al. Newborn screening program for hemoglobinopathies in Rio de Janeiro, Brazil. Pediatr. Blood Cancer 61 , 34–39 (2014).

Braga, J. A., Verissimo, M. P., Saad, S. T., Cancado, R. D. & Loggetto, S. R. Guidelines on neonatal screening and painful vaso-occlusive crisis in sickle cell disease: Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular: Project guidelines: Associacao Medica Brasileira - 2016. Rev. Bras. Hematol. Hemoter. 38 , 147–157 (2016).

Lervolino, L. G. et al. Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies. Rev. Bras. Hematol. Hemoter. 33 , 49–54 (2011).

Brandelise, S. et al. Newborn screening for sickle cell disease in Brazil: the Campinas experience. Clin. Lab. Haematol. 26 , 15–19 (2004).

Steinberg, M. H. Predicting clinical severity in sickle cell anaemia. Br. J. Haematol. 129 , 465–481 (2005).

Ngo, D. et al. Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype. Blood Cells Mol. Dis. 51 , 22–26 (2013).

Italia, K. et al. Variable phenotypes of sickle cell disease in India with the Arab-Indian haplotype. Br. J. Haematol. 168 , 156–159 (2015).

Mukherjee, M. B. et al. Clinical, hematologic and molecular variability of sickle cell-beta thalassemia in western India. Indian J. Hum. Genet. 16 , 154–158 (2010).

Jones, S. et al. Windy weather and low humidity are associated with an increased number of hospital admissions for acute pain and sickle cell disease in an urban environment with a maritime temperate climate. Br. J. Haematol. 131 , 530–533 (2005).

Tewari, S., Brousse, V., Piel, F. B., Menzel, S. & Rees, D. C. Environmental determinants of severity in sickle cell disease. Haematologica 100 , 1108–1116 (2015).

Minniti, C. P., Eckman, J., Sebastiani, P., Steinberg, M. H. & Ballas, S. K. Leg ulcers in sickle cell disease. Am. J. Hematol. 85 , 831–833 (2010).

Dash, B. P. & Kar, B. C. Priapism is rare in sickle cell disease in India. J. Assoc. Physicians India 48 , 255 (2000).

McAuley, C. F. et al. High mortality from Plasmodium falciparum malaria in children living with sickle cell anemia on the coast of Kenya. Blood 116 , 1663–1668 (2010).

Williams, T. N. et al. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 374 , 1364–1370 (2009).

Weatherall, D. J. The inherited diseases of hemoglobin are an emerging global health burden. Blood 115 , 4331–4336 (2010).

Steinberg, M. H. Pathophysiology of sickle cell disease. Baillieres Clin. Haematol. 11 , 163–184 (1998).

Pawliuk, R. et al. Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 294 , 2368–2371 (2001).

Vekilov, P. G. Sickle-cell haemoglobin polymerization: is it the primary pathogenic event of sickle-cell anaemia? Br. J. Haematol. 139 , 173–184 (2007).

Seakins, M., Gibbs, W. N., Milner, P. F. & Bertles, J. F. Erythrocyte Hb-S concentration. An important factor in the low oxygen affinity of blood in sickle cell anemia. J. Clin. Invest. 52 , 422–432 (1973).

Rogers, S. C. et al. Sickle hemoglobin disturbs normal coupling among erythrocyte O2 content, glycolysis, and antioxidant capacity. Blood 121 , 1651–1662 (2013).

Zhang, Y. et al. Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression. J. Clin. Invest. 124 , 2750–2761 (2014).

Sun, K. et al. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia. Nat. Commun. 7 , 12086 (2016).

Sun, K. et al. Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity. Blood 125 , 1643–1652 (2015).

Noguchi, C. T. & Schechter, A. N. Sickle haemoglobin polymerization in solution and in cells. Annu. Rev. Biophys. Biophys. Chem. 14 , 239–263 (1985)

Connes, P. et al. The role of blood rheology in sickle cell disease. Blood Rev. 30 , 111–118 (2016).

Smith, C. M., Krivit, W. & White, J. G. The irreversibly sickled cell. Am. J. Pediatr. Hematol. Oncol. 4 , 307–315 (1982).

Evans, E. A. & Mohandas, N. Membrane-associated sickle hemoglobin: a major determinant of sickle erythrocyte rigidity. Blood 70 , 1443–1449 (1987).

Nash, G. B., Johnson, C. S. & Meiselman, H. J. Rheologic impairment of sickle RBCs induced by repetitive cycles of deoxygenation-reoxygenation. Blood 72 , 539–545 (1988).

Kuypers, F. A. Hemoglobin s polymerization and red cell membrane changes. Hematol. Oncol. Clin. North Am. 28 , 155–179 (2014).

Allan, D. & Raval, P. Some morphological consequences of uncoupling the lipid bilayer from the plasma membrane skeleton in intact erythrocytes. Biomed. Biochim. Acta 42 , S11–16 (1983).

Blumenfeld, N., Zachowski, A., Galacteros, F., Beuzard, Y. & Devaux, P. F. Transmembrane mobility of phospholipids in sickle erythrocytes: effect of deoxygenation on diffusion and asymmetry. Blood 77 , 849–854 (1991).

Fadok, V. A., de Cathelineau, A., Daleke, D. L., Henson, P. M. & Bratton, D. L. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. J. Biol. Chem. 276 , 1071–1077 (2001).

Kuypers, F. A. Membrane lipid alterations in hemoglobinopathies. Hematol. Am. Soc. Hematol. Educ. Program 2007 , 68–73 (2007).

Kuypers, F. A. & de Jong, K. The role of phosphatidylserine in recognition and removal of erythrocytes. Cell. Mol. Biol. 50 , 147–158 (2004).

Piccin, A., Murphy, W. G. & Smith, O. P. Circulating microparticles: pathophysiology and clinical implications. Blood Rev. 21 , 157–171 (2007).

Westerman, M. et al. Microvesicles in haemoglobinopathies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy. Br. J. Haematol. 142 , 126–135 (2008).

Westerman, M. & Porter, J. B. Red blood cell-derived microparticles: an overview. Blood Cells Mol. Dis. 59 , 134–139 (2016).

Hebbel, R. P. & Key, N. S. Microparticles in sickle cell anaemia: promise and pitfalls. Br. J. Haematol. 174 , 16–29 (2016).

Alayash, A. I. Oxidative pathways in the sickle cell and beyond. Blood Cells Mol. Dis. https://doi.org/10.1016/j.bcmd.2017.05.009 (2017).

van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/nrm.2017.125 (2018).

Quinn, C. T. et al. Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia. Am. J. Hematol. 91 , 1195–1201 (2016).

Crosby, W. H. The metabolism of hemoglobin and bile pigment in hemolytic disease. Am. J. Med. 18 , 112–122 (1955).

Bunn, H. F. et al. Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 116 , 687–692 (2010).

Kato, G. J., Steinberg, M. H. & Gladwin, M. T. Intravascular hemolysis and the pathophysiology of sickle cell disease. J. Clin. Invest. 127 , 750–760 (2017). This is a comprehensive review of the contribution of haemolysis to SCD pathophysiology.

Wood, K. C. & Granger, D. N. Sickle cell disease: role of reactive oxygen and nitrogen metabolites. Clin. Exp. Pharmacol. Physiol. 34 , 926–932 (2007).

Aslan, M. & Freeman, B. A. Redox-dependent impairment of vascular function in sickle cell disease. Free Radic. Biol. Med. 43 , 1469–1483 (2007).

Cho, C. S. et al. Hydroxyurea-induced expression of glutathione peroxidase 1 in red blood cells of individuals with sickle cell anemia. Antioxid. Redox Signal. 13 , 1–11 (2010).

Morris, C. R. et al. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 111 , 402–410 (2008).

Reiter, C. D. et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat. Med. 8 , 1383–1389 (2002).

Morris, C. R. et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294 , 81–90 (2005).

Miller-Fleming, L., Olin-Sandoval, V., Campbell, K. & Ralser, M. Remaining mysteries of molecular biology: the role of polyamines in the cell. J. Mol. Biol. 427 , 3389–3406 (2015).

Landburg, P. P. et al. Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype. Blood Cells Mol. Dis. 44 , 229–232 (2010).

Antoniades, C. et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur. Heart J. 30 , 1142–1150 (2009).

Luo, S., Lei, H., Qin, H. & Xia, Y. Molecular mechanisms of endothelial NO synthase uncoupling. Curr. Pharm. Des. 20 , 3548–3553 (2014).

Zorca, S. et al. Lipid levels in sickle-cell disease associated with haemolytic severity, vascular dysfunction and pulmonary hypertension. Br. J. Haematol. 149 , 436–445 (2010).

Tumblin, A. et al. Apolipoprotein A-I and serum amyloid A plasma levels are biomarkers of acute painful episodes in patients with sickle cell disease. Haematologica 95 , 1467–1472 (2010).

Saraf, S. L. et al. APOL1, alpha-thalassemia, and BCL11A variants as a genetic risk profile for progression of chronic kidney disease in sickle cell anemia. Haematologica 102 , e1–e6 (2017).

Gladwin, M. T. & Ofori-Acquah, S. F. Erythroid DAMPs drive inflammation in SCD. Blood 123 , 3689–3690 (2014).

Wang, X. et al. Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Kruppel-like factor. Blood 124 , 946–954 (2014).

van Beers, E. J. et al. Iron, inflammation, and early death in adults with sickle cell disease. Circ. Res. 116 , 298–306 (2015).

Hebbel, R. P. Adhesive interactions of sickle erythrocytes with endothelium. J. Clin. Invest. 100 , S83–86 (1997).

Kaul, D. K. et al. Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood 95 , 368–374 (2000).

Setty, B. N. & Stuart, M. J. Vascular cell adhesion molecule-1 is involved in mediating hypoxia-induced sickle red blood cell adherence to endothelium: potential role in sickle cell disease. Blood 88 , 2311–2320 (1996).

Hines, P. C. et al. Novel epinephrine and cyclic AMP-mediated activation of BCAM/Lu-dependent sickle (SS) RBC adhesion. Blood 101 , 3281–3287 (2003).

Wagner, M. C., Eckman, J. R. & Wick, T. M. Sickle cell adhesion depends on hemodynamics and endothelial activation. J. Lab Clin. Med. 144 , 260–268 (2004).

Murphy, M. M. et al. Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU. Blood 105 , 3322–3329 (2005).

Sugihara, K., Sugihara, T., Mohandas, N. & Hebbel, R. P. Thrombospondin mediates adherence of CD36+ sickle reticulocytes to endothelial cells. Blood 80 , 2634–2642 (1992).

Miller, S. T. et al. Prediction of adverse outcomes in children with sickle cell disease. N. Engl. J. Med. 342 , 83–89 (2000).

Elmariah, H. et al. Factors associated with survival in a contemporary adult sickle cell disease cohort. Am. J. Hematol. 89 , 530–535 (2014).

Zhang, D., Xu, C., Manwani, D. & Frenette, P. S. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood 127 , 801–809 (2016). This is an updated review of the principal adhesive pathways involved in SCD vaso-occlusion.

Canalli, A. A. et al. Participation of Mac-1, LFA-1 and VLA-4 integrins in the in vitro adhesion of sickle cell disease neutrophils to endothelial layers, and reversal of adhesion by simvastatin. Haematologica 96 , 526–533 (2011).

Dominical, V. M. et al. Prominent role of platelets in the formation of circulating neutrophil-red cell heterocellular aggregates in sickle cell anemia. Haematologica 99 , e214–e217 (2014).

Davila, J. et al. A novel inflammatory role for platelets in sickle cell disease. Platelets 26 , 726–729 (2015).

Hoppe, C. C. Prenatal and newborn screening for hemoglobinopathies. Int. J. Lab. Hematol. 35 , 297–305 (2013).

Traeger-Synodinos, J. Pre-implantation genetic diagnosis. Best Pract. Res. Clin. Obstet. Gynaecol. 39 , 74–88 (2017).

Robitaille, N., Delvin, E. E. & Hume, H. A. Newborn screening for sickle cell disease: A 1988–2003 Quebec experience. Paediatr. Child Health 11 , 223–227 (2006).

Vichinsky, E., Hurst, D., Earles, A., Kleman, K. & Lubin, B. Newborn screening for sickle cell disease: effect on mortality. Pediatrics 81 , 749–755 (1988).

Gaston, M. H. et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N. Engl. J. Med. 314 , 1593–1599 (1986). This study provides proof that penicillin prophylaxis reduces mortality, which marked a turning point for life expectancy in SCA.

Kate, S. & Lingojwar, D. Epidemiology of sickle cell disorder in the state of Maharashtra. Int. J. Hum. Genet. 2 , 161–167 (2002).

Patra, P. K., Khodiar, P. K., Hambleton, I. R. & Serjeant, G. R. The Chhattisgarh state screening programme for the sickle cell gene: a cost-effective approach to a public health problem. J. Commun. Genet. 6 , 361–368 (2015).

CAS   Google Scholar  

Naik, R. P. & Haywood, C. Jr. Sickle cell trait diagnosis: clinical and social implications. Hematol. Am. Soc. Hematol. Educ. Program 2015 , 160–167 (2015).

Nelson, D. A. et al. Sickle cell trait, rhabdomyolysis, and mortality among U. S. army soldiers. N. Engl. J. Med. 375 , 435–442 (2016).

Key, N. S., Connes, P. & Derebail, V. K. Negative health implications of sickle cell trait in high income countries: from the football field to the laboratory. Br. J. Haematol. 170 , 5–14 (2015).

Streetly, A., Latinovic, R. & Henthorn, J. Positive screening and carrier results for the England-wide universal newborn sickle cell screening programme by ethnicity and area for 2005–2007. J. Clin. Pathol. 63 , 626–629 (2010).

Thuret, I. et al. Neonatal screening for sickle cell disease in France: evaluation of the selective process. J. Clin. Pathol. 63 , 548–551 (2010).

Manu Pereira, M. & Corrons, J. L. Neonatal haemoglobinopathy screening in Spain. J. Clin. Pathol. 62 , 22–25 (2009).

Colombatti, R. et al. Organizing national responses for rare blood disorders: the Italian experience with sickle cell disease in childhood. Orphanet J. Rare Dis. 8 , 169 (2013).

Kunz, J. B. et al. Significant prevalence of sickle cell disease in Southwest Germany: results from a birth cohort study indicate the necessity for newborn screening. Ann. Hematol. 95 , 397–402 (2016).

Minkovitz, C. S., Grason, H., Ruderman, M. & Casella, J. F. Newborn screening programs and sickle cell disease: a public health services and systems approach. Am. J. Prev. Med. 51 , S39–S47 (2016).

Colah, R. B., Mukherjee, M. B., Martin, S. & Ghosh, K. Sickle cell disease in tribal populations in India. Indian J. Med. Res. 141 , 509–515 (2015).

Chandrashekar, V. & Soni, M. Hemoglobin disorders in South India. ISRN Hematol. 2011 , 748939 (2011).

Italia, K. et al. Hydroxyurea in sickle cell disease — a study of clinico-pharmacological efficacy in the Indian haplotype. Blood Cells Mol. Dis. 42 , 25–31 (2009).

Kamble, M. & Chatruvedi, P. Epidemiology of sickle cell disease in a rural hospital of central India. Indian Pediatr. 37 , 391–396 (2000).

Shukla, R. N. & Solanki, B. R. Sickle-cell trait in Central India. Lancet 1 , 297–298 (1958).

Therrell, B. L. et al. Current status of newborn screening worldwide: 2015. Semin. Perinatol. 39 , 171–187 (2015).

Ohene-Frempong, K., Oduro, J., Tetteh, H. & Nkrumah, F. Screening newborns for sickle cell disease in Ghana. Pediatrics 121 (Suppl. 2), S120–S121(2008).

McGann, P. T. et al. A prospective newborn screening and treatment program for sickle cell anemia in Luanda, Angola. Am. J. Hematol. 88 , 984–989 (2013).

Rahimy, M. C., Gangbo, A., Ahouignan, G. & Alihonou, E. Newborn screening for sickle cell disease in the Republic of Benin. J. Clin. Pathol. 62 , 46–48 (2009).

Kafando, E. et al. Neonatal haemoglobinopathy screening in Burkina Faso. J. Clin. Pathol. 62 , 39–41 (2009).

Mutesa, L. et al. Neonatal screening for sickle cell disease in Central Africa: a study of 1825 newborns with a new enzyme-linked immunosorbent assay test. J. Med. Screen. 14 , 113–116 (2007).

Tshilolo, L. et al. Neonatal screening for sickle cell anaemia in the Democratic Republic of the Congo: experience from a pioneer project on 31 204 newborns. J. Clin. Pathol. 62 , 35–38 (2009).

Odunvbun, M. E., Okolo, A. A. & Rahimy, C. M. Newborn screening for sickle cell disease in a Nigerian hospital. Publ. Health 122 , 1111–1116 (2008).

Mbodj, M. et al. Sickle cell disease neonatal screening. First evaluation [French]. Dakar Med. 48 , 202–205 (2003).

Makani, J. et al. Health policy for sickle cell disease in Africa: experience from Tanzania on interventions to reduce under-five mortality. Trop. Med. Int. Health 20 , 184–187 (2015).

Ndeezi, G. et al. Burden of sickle cell trait and disease in the Uganda Sickle Surveillance Study (US3): a cross-sectional study. Lancet Global Health 4 , e195–e200 (2016).

Serjeant, G. R. The natural history of sickle cell disease. Cold Spring Harb. Perspect. Med. 3 , a011783 (2013).

Fertrin, K. Y. & Costa, F. F. Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment. Expert Rev. Hematol. 3 , 443–458 (2010).

Kato, G. J., Gladwin, M. T. & Steinberg, M. H. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 21 , 37–47 (2007).

Lettre, G. & Bauer, D. E. Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies. Lancet 387 , 2554–2564 (2016).

Steinberg, M. H., Chui, D. H., Dover, G. J., Sebastiani, P. & Alsultan, A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 123 , 481–485 (2014).

Belfer, I. et al. A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia. Am. J. Hematol. 89 , 187–193 (2014).

Brandow, A. M., Stucky, C. L., Hillery, C. A., Hoffmann, R. G. & Panepinto, J. A. Patients with sickle cell disease have increased sensitivity to cold and heat. Am. J. Hematol. 88 , 37–43 (2013).

Quinn, C. T., Rogers, Z. R. & Buchanan, G. R. Survival of children with sickle cell disease. Blood 103 , 4023–4027 (2004).

Anie, K. A. Psychological complications in sickle cell disease. Br. J. Haematol. 129 , 723–729 (2005).

Weatherall, D. J. The challenge of haemoglobinopathies in resource-poor countries. Br. J. Haematol. 154 , 736–744 (2011).

Kassim, A. A. & DeBaun, M. R. The case for and against initiating either hydroxyurea therapy, blood transfusion therapy or hematopoietic stem cell transplant in asymptomatic children with sickle cell disease. Expert Opin. Pharmacother. 15 , 325–336 (2014).

McGann, P. T. & Ware, R. E. Hydroxyurea therapy for sickle cell anemia. Expert Opin. Drug Saf. 14 , 1749–1758 (2015).

Charache, S. et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N. Engl. J. Med. 332 , 1317–1322 (1995). This landmark trial proved that hydroxycarbamide reduces the frequency of pain episodes in SCA, leading to the approval of this drug.

Walsh, K. E. et al. Medication adherence among pediatric patients with sickle cell disease: a systematic review. Pediatrics 134 , 1175–1183 (2014).

Husain, M., Hartman, A. D. & Desai, P. Pharmacogenomics of sickle cell disease: steps toward personalized medicine. Pharmgenom. Pers. Med. 10 , 261–265 (2017).

Wong, T. E., Brandow, A. M., Lim, W. & Lottenberg, R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood 124 , 3850–3857 (2014).

DeBaun, M. R. Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review. Expert Rev. Hematol. 7 , 767–773 (2014).

Ataga, K. I. et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N. Engl. J. Med. 376 , 429–439 (2017).

McGann, P. T. et al. Hydroxyurea therapy for children with sickle cell anemia in sub-Saharan Africa: rationale and design of the REACH trial. Pediatr. Blood Cancer 63 , 98–104 (2016).

Wang, W. C. et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 377 , 1663–1672 (2011). This article presents evidence that hydroxycarbamide is effective in infants and toddlers with SCA.

Heeney, M. M. et al. A multinational trial of Prasugrel for sickle cell vaso-occlusive events. N. Engl. J. Med. 374 , 625–635 (2016).

Mulaku, M. et al. Evidence review of hydroxyurea for the prevention of sickle cell complications in low-income countries. Arch. Dis. Child. 98 , 908–914 (2013).

Hyacinth, H. I., Adams, R. J., Voeks, J. H., Hibbert, J. M. & Gee, B. E. Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk. Am. J. Hematol. 89 , 47–51 (2014).

Hyacinth, H. I. et al. Effect of chronic blood transfusion on biomarkers of coagulation activation and thrombin generation in sickle cell patients at risk for stroke. PLoS ONE 10 , e0134193 (2015).

Quirolo, K. & Vichinsky, E. in Rossi's Principles of Transfusion Medicine (eds Simon T. L. et al.) (Wiley-Blackwell, 2016).

Fasano, R. M. & Chou, S. T. Red blood cell antigen genotyping for sickle cell disease, thalassemia, and other transfusion complications. Transfus. Med. Rev. 30 , 197–201 (2016).

Walters, M. C. et al. Indications and results of HLA-identical sibling hematopoietic cell transplantation for sickle cell disease. Biol. Blood Marrow Transplant. 22 , 207–211 (2016).

Gluckman, E. et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood 129 , 1548–1556 (2017).

Hsieh, M. M. et al. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA 312 , 48–56 (2014).

Saraf, S. L. et al. Nonmyeloablative stem cell transplantation with alemtuzumab/low-dose irradiation to cure and improve the quality of life of adults with sickle cell disease. Biol. Blood Marrow Transplant. 22 , 441–448 (2016).

Gluckman, E. Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease. Hematol. Am. Soc. Hematol. Educ. Program 2013 , 370–376 (2013).

Ballas, S. K., Gupta, K. & Adams-Graves, P. Sickle cell pain: a critical reappraisal. Blood 120 , 3647–3656 (2012).

Treadwell, M. J. et al. A quality improvement initiative to improve emergency department care for pediatric patients with sickle cell disease. J. Clin. Outcomes Manag. 21 , 62–70 (2014).

Kavanagh, P. L. et al. Improving the management of vaso-occlusive episodes in the pediatric emergency department. Pediatrics 136 , e1016–1025 (2015).

Tanabe, P. et al. A randomized controlled trial comparing two vaso-occlusive episode (VOE) protocols in sickle cell disease (SCD). Am. J. Hematol. 93 , 159–168 (2018).

Lanzkron, S. et al. Impact of a dedicated infusion clinic for acute management of adults with sickle cell pain crisis. Am. J. Hematol. 90 , 376–380 (2015).

Haywood, C. et al. The impact of race and disease on sickle cell patient wait times in the emergency department. Am. J. Emerg. Med. 31 , 651–656 (2013).

van Beers, E. J. et al. Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial. Am. J. Hematol. 82 , 955–960 (2007).

Makani, J., Ofori-Acquah, S. F., Nnodu, O., Wonkam, A. & Ohene-Frempong, K. Sickle cell disease: new opportunities and challenges in Africa. Sci. World J. 2013 , 193252 (2013).

Manci, E. A. et al. Causes of death in sickle cell disease: an autopsy study. Br. J. Haematol. 123 , 359–365 (2003).

Novelli, E. M. & Gladwin, M. T. Crises in sickle cell disease. Chest 149 , 1082–1093 (2016).

Vichinsky, E. P. et al. Acute chest syndrome in sickle cell disease: clinical presentation and course. Blood 89 , 1787–1792 (1997).

Vichinsky, E. P. et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. N. Engl. J. Med. 342 , 1855–1865 (2000). This study comprehensively establishes the causes and outcomes of acute chest syndrome.

DeBaun, M. R. & Strunk, R. C. The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia. Lancet 387 , 2545–2553 (2016).

Howard, J. et al. Guideline on the management of acute chest syndrome in sickle cell disease. Br. J. Haematol. 169 , 492–505 (2015).

Bernini, J. C. et al. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Blood 92 , 3082–3089 (1998).

Kassim, A. A., Galadanci, N. A., Pruthi, S. & DeBaun, M. R. How I treat and manage strokes in sickle cell disease. Blood 125 , 3401–3410 (2015).

Gardner, K., Hoppe, C., Mijovic, A. & Thein, S. L. How we treat delayed haemolytic transfusion reactions in patients with sickle cell disease. Br. J. Haematol. 170 , 745–756 (2015).

Ogunlesi, F., Heeney, M. M. & Koumbourlis, A. C. Systemic corticosteroids in acute chest syndrome: friend or foe? Paediatr. Respir. Rev. 15 , 24–27 (2014).

Ohene-Frempong, K. et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 91 , 288–294 (1998).

Vichinsky, E. P. et al. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA 303 , 1823–1831 (2010).

DeBaun, M. R. et al. Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. Blood 119 , 4587–4596 (2012).

Ware, R. E. & Helms, R. W. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood 119 , 3925–3932 (2012).

Strouse, J. J., Hulbert, M. L., DeBaun, M. R., Jordan, L. C. & Casella, J. F. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics 118 , 1916–1924 (2006).

Scott, R. M. & Smith, E. R. Moyamoya disease and moyamoya syndrome. N. Engl. J. Med. 360 , 1226–1237 (2009).

Kennedy, B. C. et al. Pial synangiosis for moyamoya syndrome in children with sickle cell anemia: a comprehensive review of reported cases. Neurosurg. Focus 36 , E12 (2014).

Brousse, V. et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br. J. Haematol. 156 , 643–648 (2012).

Vasavda, N. et al. The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease. Br. J. Haematol. 138 , 263–270 (2007).

Leake, P. A., Reid, M. & Plummer, J. A case series of cholecystectomy in Jamaican sickle cell disease patients — the need for a new strategy. Ann. Med. Surg. 15 , 37–42 (2017).

Powars, D. R., Chan, L. S., Hiti, A., Ramicone, E. & Johnson, C. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine 84 , 363–376 (2005).

McClish, D. K. et al. Pain site frequency and location in sickle cell disease: the PiSCES project. Pain 145 , 246–251 (2009).

Ballas, S. K. Update on pain management in sickle cell disease. Hemoglobin 35 , 520–529 (2011).

Darbari, D. S. et al. Frequency of hospitalizations for pain and association with altered brain network connectivity in sickle cell disease. J. Pain 16 , 1077–1086 (2015).

Neumayr, L. D. et al. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment. J. Bone Joint Surg. Am. 88 , 2573–2582 (2006).

McClellan, A. C. et al. High one year mortality in adults with sickle cell disease and end-stage renal disease. Br. J. Haematol. 159 , 360–367 (2012).

Abbott, K. C., Hypolite, I. O. & Agodoa, L. Y. Sickle cell nephropathy at end-stage renal disease in the United States: patient characteristics and survival. Clin. Nephrol. 58 , 9–15 (2002).

Huang, E. et al. Improved survival among sickle cell kidney transplant recipients in the recent era. Nephrol. Dial. Transplant. 28 , 1039–1046 (2013).

Dampier, C. et al. Health-related quality of life in adults with sickle cell disease (SCD): a report from the comprehensive sickle cell centers clinical trial consortium. Am. J. Hematol. 86 , 203–205 (2011).

Chaturvedi, S. & DeBaun, M. R. Evolution of sickle cell disease from a life-threatening disease of children to a chronic disease of adults: the last 40 years. Am. J. Hematol. 91 , 5–14 (2016).

Yawn, B. P. et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 312 , 1033–1048 (2014).

Buchanan, G. et al. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report 2014 (National Heart Lung and Blood Institute, 2014). This article presents detailed evidence-based guidelines for the clinical management of individuals with SCD.

Klings, E. S. et al. An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. Am. J. Respir. Crit. Care Med. 189 , 727–740 (2014).

Butler, J. C., Breiman, R. F., Lipman, H. B., Hofmann, J. & Facklam, R. R. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978-1994: implications for development of a conjugate vaccine. J. Infect. Dis. 171 , 885–889 (1995).

Halasa, N. B. et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin. Infect. Dis. 44 , 1428–1433 (2007).

Cober, M. P. & Phelps, S. J. Penicillin prophylaxis in children with sickle cell disease. J. Pediatr. Pharmacol. Ther. 15 , 152–159 (2010).

Obaro, S. K. & Iroh Tam, P. Y. Preventing infections in sickle cell disease: the unfinished business. Pediatr. Blood Cancer 63 , 781–785 (2016).

Adams, R. J. et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N. Engl. J. Med. 339 , 5–11 (1998). This study shows that ischaemic stroke can be prevented by chronic transfusion in children identified at high risk by non-invasive ultrasonography screening.

Adams, R. J., Brambilla, D. & Investigators, S. T. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N. Engl. J. Med. 353 , 2769–2778 (2005).

Zimmerman, S. A., Schultz, W. H., Burgett, S., Mortier, N. A. & Ware, R. E. Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia. Blood 110 , 1043–1047 (2007).

Ware, R. E. et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 387 , 661–670 (2016).

Galadanci, N. A. et al. Primary stroke prevention in Nigerian children with sickle cell disease (SPIN): challenges of conducting a feasibility trial. Pediatr. Blood Cancer 62 , 395–401 (2015).

DeBaun, M. R. et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N. Engl. J. Med. 371 , 699–710 (2014).

Gladwin, M. T. et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N. Engl. J. Med. 350 , 886–895 (2004).

Boyd, J. H., Macklin, E. A., Strunk, R. C. & DeBaun, M. R. Asthma is associated with Increased mortality in individuals with sickle cell anemia. Haematologica 92 , 1115–1118 (2007).

Glassberg, J. A. et al. Wheezing and asthma are independent risk factors for increased sickle cell disease morbidity. Br. J. Haematol. 159 , 472–479 (2012).

Powars, D., Weidman, J. A., Odom-Maryon, T., Niland, J. C. & Johnson, C. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine 67 , 66–76 (1988).

Falk, R. J. et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N. Engl. J. Med. 326 , 910–915 (1992).

Gordeuk, V. R. et al. Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency. Am. J. Hematol. 83 , 15–18 (2008).

Pegelow, C. H. et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am. J. Med. 102 , 171–177 (1997).

Rodgers, G. P., Walker, E. C. & Podgor, M. J. Is “relative” hypertension a risk factor for vaso-occlusive complications in sickle cell disease? Am. J. Med. Sci. 305 , 150–156 (1993).

Downes, S. M. et al. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmology 112 , 1869–1875 (2005).

Moriarty, B. J., Acheson, R. W., Condon, P. I. & Serjeant, G. R. Patterns of visual loss in untreated sickle cell retinopathy. Eye 2 , 330–335 (1988).

Adam, S. S. et al. Depression, quality of life, and medical resource utilization in sickle cell disease. Blood Adv. 1 , 1983–1992 (2017).

McClish, D. K. et al. Comorbidity, pain, utilization, and psychosocial outcomes in older versus younger sickle cell adults: the PiSCES project. Biomed. Res. Int. 2017 , 4070547 (2017).

Bakshi, N., Lukombo, I., Shnol, H., Belfer, I. & Krishnamurti, L. Psychological characteristics and pain frequency are associated with experimental pain sensitivity in pediatric patients with sickle cell disease. J. Pain 18 , 1216–1228 (2017).

Jonassaint, C. R., Jones, V. L., Leong, S. & Frierson, G. M. A systematic review of the association between depression and health care utilization in children and adults with sickle cell disease. Br. J. Haematol. 174 , 136–147 (2016).

Wallen, G. R. et al. Sleep disturbance, depression and pain in adults with sickle cell disease. BMC Psychiatry 14 , 207 (2014).

Noubouossie, D., Key, N. S. & Ataga, K. I. Coagulation abnormalities of sickle cell disease: relationship with clinical outcomes and the effect of disease modifying therapies. Blood Rev. 30 , 245–256 (2016).

Ware, J. E. Jr & Sherbourne, C. D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 30 , 473–483 (1992).

Varni, J. The PedsQL TM 4.0 Measurement Model for the Pediatric Quality of Life Inventory TM Version 4.0: Administration Guidelines. PedsQL TM http://www.pedsql.org/pedsqladmin.html (2004).

Panepinto, J. A. et al. Determining the longitudinal validity and meaningful differences in HRQL of the PedsQL Sickle Cell Disease Module. Health Qual. Life Outcomes 15 , 124 (2017).

Panepinto, J. A. & Bonner, M. Health-related quality of life in sickle cell disease: past, present, and future. Pediatr. Blood Cancer 59 , 377–385 (2012).

Keller, S. D., Yang, M., Treadwell, M. J., Werner, E. M. & Hassell, K. L. Patient reports of health outcome for adults living with sickle cell disease: development and testing of the ASCQ-Me item banks. Health Qual. Life Outcomes 12 , 125 (2014).

Panepinto, J. A. et al. PedsQL sickle cell disease module: feasibility, reliability, and validity. Pediatr. Blood Cancer 60 , 1338–1344 (2013).

Ameringer, S., Elswick, R. K. Jr & Smith, W. Fatigue in adolescents and young adults with sickle cell disease: biological and behavioral correlates and health-related quality of life. J. Pediatr. Oncol. Nurs. 31 , 6–17 (2014).

McClish, D. K. et al. Health related quality of life in sickle cell patients: the PiSCES project. Health Qual. Life Outcomes 3 , 50 (2005).

Brandow, A. M., Brousseau, D. C., Pajewski, N. M. & Panepinto, J. A. Vaso-occlusive painful events in sickle cell disease: impact on child well-being. Pediatr. Blood Cancer 54 , 92–97 (2010).

Brandow, A. M., Brousseau, D. C. & Panepinto, J. A. Postdischarge pain, functional limitations and impact on caregivers of children with sickle cell disease treated for painful events. Br. J. Haematol. 144 , 782–788 (2009).

Dampier, C., Ely, E., Brodecki, D. & O’Neal, P. Home management of pain in sickle cell disease: a daily diary study in children and adolescents. J. Pediatr. Hematol. Oncol. 24 , 643–647 (2002).

Smith, W. R. et al. Daily assessment of pain in adults with sickle cell disease. Ann. Intern. Med. 148 , 94–101 (2008).

Smith, W. R. et al. Understanding pain and improving management of sickle cell disease: the PiSCES study. J. Natl Med. Assoc. 97 , 183–193 (2005).

Ballas, S. K. et al. Hydroxyurea and sickle cell anemia: effect on quality of life. Health Qual. Life Outcomes 4 , 59 (2006).

Thornburg, C. D., Calatroni, A. & Panepinto, J. A. Differences in health-related quality of life in children with sickle cell disease receiving hydroxyurea. J. Pediatr. Hematol. Oncol. 33 , 251–254 (2011).

Beverung, L. M. et al. Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy. Am. J. Hematol. 90 , 139–143 (2015).

Kanter, J. et al. Validation of a novel point of care testing device for sickle cell disease. BMC Med. 13 , 225 (2015).

Beverung, L. M., Varni, J. W. & Panepinto, J. A. Clinically meaningful interpretation of pediatric health-related quality of life in sickle cell disease. J. Pediatr. Hematol. Oncol. 37 , 128–133 (2015).

Hoban, M. D., Orkin, S. H. & Bauer, D. E. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood 127 , 839–848 (2016).

Ribeil, J. A. et al. Gene therapy in a patient with sickle cell disease. N. Engl. J. Med. 376 , 848–855 (2017).

Tasan, I., Jain, S. & Zhao, H. Use of genome-editing tools to treat sickle cell disease. Hum. Genet. 135 , 1011–1028 (2016).

Traxler, E. A. et al. A genome-editing strategy to treat beta-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med. 22 , 987–990 (2016).

Dever, D. P. et al. CRISPR/Cas9 beta-globin gene targeting in human haematopoietic stem cells. Nature 539 , 384–389 (2016).

Telen, M. J. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Blood 127 , 810–819 (2016).

Telen, M. J. et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood 125 , 2656–2664 (2015).

Lebensburger, J. D. et al. Systematic review of interventional sickle cell trials registered in ClinicalTrials.gov. Clin. Trials 12 , 575–583 (2015).

Niihara, Y. et al. Phase 3 study of L-glutamine therapy in sickle cell anemia and sickle β 0 -thalassemia subgroup analyses show consistent clinical improvement. Blood 128 , 1318–1318 (2016).

Pace, B. Renaissance of Sickle Cell Disease Research in the Genome Era (Imperial College Press, 2007).

Sabarense, A. P., Lima, G. O., Silva, L. M. & Viana, M. B. Survival of children with sickle cell disease in the comprehensive newborn screening programme in Minas Gerais, Brazil. Paediatr. Int. Child Health 35 , 329–332 (2015).

Gualandro, S. F., Fonseca, G. H., Yokomizo, I. K., Gualandro, D. M. & Suganuma, L. M. Cohort study of adult patients with haemoglobin SC disease: clinical characteristics and predictors of mortality. Br. J. Haematol. 171 , 631–637 (2015).

Figueiredo, M. S. The compound state: Hb S/beta-thalassemia. Rev. Bras. Hematol. Hemoter. 37 , 150–152 (2015).

Steinberg, M. H. in Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management (eds Steinberg, M. H., Forget, B. G., Higgs, D. R. & Weatherall, D. J. ) 786–810 (Cambridge Univ. Press, 2009).

Harrington, D. J., Adachi, K. & Royer, W. E. Jr. The high resolution crystal structure of deoxyhemoglobin S. J. Mol. Biol. 272 , 398–407 (1997).

Eaton, W. A. & Hofrichter, J. Sickle cell hemoglobin polymerization. Adv. Protein Chem. 40 , 63–279 (1990).

Briehl, R. W. & Ewert, S. Effects of pH, 2,3-diphosphoglycerate and salts on gelation of sickle cell deoxyhemoglobin. J. Mol. Biol. 80 , 445–458 (1973).

Bookchin, R. M., Balazs, T. & Landau, L. C. Determinants of red cell sickling. Effects of varying pH and of increasing intracellular hemoglobin concentration by osmotic shrinkage. J. Lab Clin. Med. 87 , 597–616 (1976).

Eaton, W. A., Hofrichter, J. & Ross, P. D. Editorial: Delay time of gelation: a possible determinant of clinical severity in sickle cell disease. Blood 47 , 621–627 (1976).

Ferrone, F. A. The delay time in sickle cell disease after 40 years: a paradigm assessed. Am. J. Hematol. 90 , 438–445 (2015).

Uzunova, V. V., Pan, W., Galkin, O. & Vekilov, P. G. Free heme and the polymerization of sickle cell hemoglobin. Biophys. J. 99 , 1976–1985 (2010).

Hebbel, R. P., Boogaerts, M. A., Eaton, J. W. & Steinberg, M. H. Erythrocyte adherence to endothelium in sickle-cell anemia. A possible determinant of disease severity. N. Engl. J. Med. 302 , 992–995 (1980).

Brugnara, C., de Franceschi, L. & Alper, S. L. Inhibition of Ca 2+ -dependent K + transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives. J. Clin. Invest. 92 , 520–526 (1993).

Centers for Disease Control and Prevention. Registry and Surveillance System for Hemoglobinopathies (RuSH). CDC https://www.cdc.gov/ncbddd/hemoglobinopathies/rush.html (2017).

Panepinto, J. A., Pajewski, N. M., Foerster, L. M. & Hoffmann, R. G. The performance of the PedsQL generic core scales in children with sickle cell disease. J. Pediatr. Hematol. Oncol. 30 , 666–673 (2008).

[No authors listed.] FDA Briefing Document, Oncologic Drugs Advisory Committee Meeting, NDA 208587, L-glutamine, Applicant: Emmaus Medical, Inc. U.S. Food and Drug Administration https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM559734.pdf (2017).

Hoppe, C. C. et al. Design of the DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) trial: a global phase 3 double-blind, randomized, placebo-controlled, multicenter study of the efficacy and safety of prasugrel in pediatric patients with sickle cell anemia utilizing a dose titration strategy. Pediatr. Blood Cancer 63 , 299–305 (2016).

Gibbs, W. J. & Hagemann, T. M. Purified poloxamer 188 for sickle cell vaso-occlusive crisis. Ann. Pharmacother. 38 , 320–324 (2004).

Morris, C. R. et al. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica 98 , 1375–1382 (2013).

Du, E., Mendelsohn, L., Nichols, J. S., Dao, M. & Kato, G. J. Quantification of anti-sickling effect of Aes-103 in sickle cell disease using an in vitro microfluidic assay. Blood 124 , 2699–2699 (2014).

Sins, J. W. R. et al. Effect of N-acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial. Br. J. Haematol. https://doi.org/10.1111/bjh.14809 (2017).

Brousseau, D. C. et al. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood 126 , 1651–1657 (2015).

Ware, R. E., Helms, R. W. & Investigators, S. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood 119 , 3925–3932 (2012).

Metcalf, B. et al. Discovery of GBT440, an orally bioavailable R-state stabilizer of sickle cell hemoglobin. ACS Med. Chem. Lett. 8 , 321–326 (2017).

Gladwin, M. T. et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 305 , 893–902 (2011).

Machado, R. F. et al. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood 118 , 855–864 (2011).

Misra, H. et al. A Phase Ib open label, randomized, safety study of SANGUINATE in patients with sickle cell anemia. Rev. Bras. Hematol. Hemoter 39 , 20–27 (2017).

Telen, M. J. et al. Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion. Br. J. Haematol. 175 , 935–948 (2016).

Moutouh-de Parseval, L. A. et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J. Clin. Invest. 118 , 248–258 (2008).

McArthur, J. G. et al. A novel, highly potent and selective PDE9 inhibitor for the treatment of sickle cell disease. Blood 128 , 268–268 (2016).

Wambebe, C. et al. Double-blind, placebo-controlled, randomised cross-over clinical trial of NIPRISAN in patients with Sickle Cell Disorder. Phytomedicine 8 , 252–261 (2001).

Conran, N. Prospects for early investigational therapies for sickle cell disease. Expert Opin. Investig. Drugs 24 , 595–602 (2015).

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Gregory J. Kato

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Introduction (M.H.G. and C.D.R.); Epidemiology (D.J.W. and F.B.P.); Mechanisms/pathophysiology (G.J.K. and F.F.C.); Diagnosis, screening and prevention (K.O.-F., E.P.V. and L.K.); Management (G.J.K., E.P.V. and F.B.P.); Quality of life (W.R.S. and J.A.P.); Outlook (G.J.K., F.B.P. and E.P.V.); Overview of Primer (G.J.K., F.B.P. and E.P.V.).

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G.J.K. is listed as a co-inventor on a patent application by the US NIH for the formulation of topical sodium nitrite (PCT/US2015/060015), receives research support from Bayer Pharmaceuticals and has received research support from AesRx and personal consulting fees (honoraria) from Novartis and Bioverativ outside the submitted work. The University of Pittsburgh received support for G.J.K.'s salary to serve on the steering committee for a clinical trial by Mast Therapeutics. F.B.P. reports personal fees (honoraria) from Novartis outside the submitted work. L.K., W.R.S., J.A.P., D.J.W., F.F.C. and E.V.P. declare no competing interests. Editor's note: all other authors have chosen not to declare any competing interests.

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Kato, G., Piel, F., Reid, C. et al. Sickle cell disease. Nat Rev Dis Primers 4 , 18010 (2018). https://doi.org/10.1038/nrdp.2018.10

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• 1 Case Western Reserve University
• 2 Allama Iqbal Medical College
• 3 Maulana Azad Medical College, New Delhi, India
• PMID: 29489205
• Bookshelf ID: NBK482164

Sickle cell disease (SCD) refers to a group of hemoglobinopathies that include mutations in the gene encoding the beta subunit of hemoglobin. The first description of SCA 'like' disorder was provided by Dr. Africanus Horton in his book The Disease of Tropical Climates and their Treatment (1872). However, it was not until 1910 when Dr. James B Herrick and Dr. Ernest Irons reported noticing 'sickle-shaped' red cells in a dental student (Walter Clement Noel from Grenada). In 1949, independent reports from Dr. James V Neel and Col. E. A. Beet described the patterns of inheritance in patients with SCD. In the same year, Dr. Linus Pauling described the molecular nature of sickle hemoglobin (HbS) in his paper 'Sickle Cell Anemia Hemoglobin.' Ingram Vernon, in 1956, used a fingerprinting technique to describe the replacement of negatively charged glutamine with neutral valine and validated the findings of Linus Pauling.

Within the umbrella of SCD, many subgroups exist, namely sickle cell anemia (SCA), hemoglobin SC disease (HbSC), and hemoglobin sickle-beta-thalassemia (beta-thalassemia positive or beta-thalassemia negative). Several other minor variants within the group of SCDs also, albeit not as common as the varieties mentioned above. Lastly, it is essential to mention the sickle cell trait (HbAS), which carries a heterozygous mutation and seldom presents clinical signs or symptoms. Sickle cell anemia is the most common form of SCD, with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage.

Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. In 1984, Platt et al. first reported the use of hydroxyurea in increasing the levels of HbF. Since then, the treatment of sickle cell has taken to new heights by introducing several new agents (voxelotor, crizanlizumab, L-glutamine) and, most recently, gene therapy.

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Disclosure: Ankit Mangla declares no relevant financial relationships with ineligible companies.

Disclosure: Moavia Ehsan declares no relevant financial relationships with ineligible companies.

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• Histopathology
• History and Physical
• Treatment / Management
• Differential Diagnosis
• Medical Oncology
• Complications
• Deterrence and Patient Education
• Enhancing Healthcare Team Outcomes
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• Volume 100, Issue 1
• Sickle cell disease: a neglected chronic disease of increasing global health importance
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• Subarna Chakravorty 1 ,
• Thomas N Williams 1 , 2
• 1 Department of Medicine , Imperial College , London , UK
• 2 KEMRI-Wellcome Trust Research Programme , Kilifi , Kenya
• Correspondence to Thomas N Williams, KEMRI-Wellcome Trust Research Programme, PO Box 230 Kilifi 80108, Kenya; [email protected]

Sickle cell disease (SCD) is a single gene disorder causing a debilitating systemic syndrome characterised by chronic anaemia, acute painful episodes, organ infarction and chronic organ damage and by a significant reduction in life expectancy. The origin of SCD lies in the malarial regions of the tropics where carriers are protected against death from malaria and hence enjoy an evolutionary advantage. More recently, population migration has meant that SCD now has a worldwide distribution and that a substantial number of children are born with the condition in higher-income areas, including large parts of Europe and North and South America. Newborn screening, systematic clinical follow-up and prevention of sepsis and organ damage have led to an increased life expectancy among people with SCD in many such countries; however, in resource-limited settings where the majority continue to be born, most affected children continue to die in early childhood, usually undiagnosed, due to the lack of effective programmes for its early detection and treatment. As new therapies emerge, potentially leading to disease amelioration or cure, it is of paramount importance that the significant burden of SCD in resource-poor countries is properly recognised.

• Haematology
• sickle cell disease

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Introduction

Sickle haemoglobin (HbS) is a structural variant of normal adult haemoglobin (HbA) caused by a mutation in the HBB gene that leads to the substitution of valine for glutamic acid at position 6 of the β-globin subunit (β S ) of the haemoglobin molecule. 1 The term ‘sickle cell disease’ (SCD) refers to any condition in which the production of HbS leads to pathophysiological consequences. The most common form (>70% of SCD worldwide) 2 results from the homozygous inheritance of the β S -mutation and is usually referred to as either ‘SCD SS’ or as ‘sickle cell anaemia’ (SCA). However, SCD can also result from the inheritance of β S in combination with a wide range of other HBB mutations, the two most common being a second structural β-globin variant β C (SCD SC) 3 and one of the many β-thalassaemia mutations that lead to the reduced production of normal β-globin (SCD S/β-thalassaemia). 4 SCD SS is the most severe form of SCD and, consequently, is the main focus of the current review.

Historical perspective

SCD was first described in the Western medical literature by the American physician James Herrick who reported the presence of ‘peculiar elongated and sickle-shaped red blood corpuscles’ in the blood film of a Grenadan student with a history of leg ulcers, shortness of breath and jaundice. 5 Pauling and Itano 6 established the fact that SCD was a molecular disease almost 50 years later while in the decades that followed, scientific advances led to descriptions of the structure of the HbS molecule, 7 molecular basis of the sickling phenomenon, 1 cloning and sequencing of the β-globin gene, development of molecular diagnostic methods 8 and establishment of prenatal diagnosis. 9

In parallel with such advances, significant progress was made towards improving clinical outcomes among those born with SCD during the 1970s and 1980s, before which very few affected subjects survived beyond 10 years. 10 In response to reports of poor funding for SCD research, a series of comprehensive SCD centres were created in the USA during the 1970s, 11 and by 1994 the median age of death had risen to 48 and 42 years in women and men, respectively. 12 , 13 Following the introduction of newborn screening programmes in cohorts in the USA, 14 Jamaica 15 and the UK, 16 and the gradual introduction of a broad range of life-saving measures (including penicillin prophylaxis, vaccination for common bacterial diseases, training of parents to detect splenic sequestration events and provision of disease-modifying treatment with hydroxycarbamide), in the US cohort overall survival to 18 years had risen to 85% by 2004 14 and to 96% by 2010, 17 while in the London cohort overall survival to 16 years was almost universal by 2007. 16 Nevertheless, despite these dramatic improvements, the outcome for adolescents and adults with SCD remains disappointing. In a recent US study, mortality among patients aged 20–25 years was twice that of patients aged 15–19 years, highlighting the importance of the transition from paediatric to adult services. 18

The burden and global distribution of SCD

The β S -mutation is the archetypal example of natural selection in humans. Heterozygotes, whose red blood cells contain both HbA and HbS, are so strongly protected from malaria 19 , 20 that the global distribution and the frequency of the β S -mutation a mutation now strongly reflects the historic incidence of death from malaria. 21 Nevertheless, despite the extraordinary protection that β S -carriers enjoy from malaria, there are few places where the carrier frequencies exceed 25% because the rise of the mutation in populations above that level has been kept in check by the profound disadvantage conferred by homozygosity. 22 Despite the fact that SCD originates in the malaria-endemic world, population migration during the last few hundreds of years, first through the slave trade and more recently for economic and work-related reasons, means that substantial numbers of children with SCD are now being born in high-income countries, particularly in the larger cities in Europe and North America. 23 No global data regarding the precise numbers of children born with SCD exist because, in contrast to Europe and North America, newborn screening for SCD is not available in most resource-poor countries with the highest predicted burdens; however, on the basis of data on carrier frequencies and global birth rates, we recently estimated that around 312 000 children are born each year with SCD SS, a figure that includes approximately 300 births in the UK and almost 3000 in the USA. 24 Given the more limited availability of detailed contemporary allele frequency data for haemoglobin C (HbC) and the β-thalassaemias, it is more difficult to estimate the numbers born with other forms of SCD, but they probably total a further 50 000–100 000 births per year. 2

Despite the numbers born with SCD in resource-poor countries, remarkably, few detailed studies have described the clinical course and complications of the disease in that context. Even today, the majority of those born with the disease in Africa, where more than 80% of affected births occur, die undiagnosed in early childhood, 22 presumably from preventable causes that include invasive bacterial diseases, 25 malaria 26 and severe acute anaemia. As a consequence, in many parts of sub-Saharan Africa, SCD is probably responsible for up to 6% of all child deaths, 2 , 27 a situation that must be addressed if recent improvements in overall child survival are to be consolidated. Because so little is known about the clinical course and natural history of SCD in resource-poor countries, the majority of this review is focused on data from Europe and North America, where most detailed studies have been conducted.

Diagnosis and pathophysiology

The diagnosis of SCD relies on the analysis of haemoglobin, most commonly using either protein electrophoresis or high-performance liquid chromatography. Subjects with the most common form of SCD, SCD SS, produce no HbA, but predominantly produce HbS along with variable amounts of haemoglobin F (HbF) and haemoglobin A 2 (HbA 2 ), while those with SCD SC produce mainly HbS and HbC. DNA-based methods are commonly used to confirm the diagnosis of SCD in more complicated cases. 28

Since SCD was first described a century ago, a great deal has been learnt about its pathophysiological consequences. Under conditions of hypoxia, acidity and cellular dehydration, the polymerisation of HbS within erythrocytes leads to their deformation into the characteristic ‘sickle’ shape. In dynamic interaction with the vascular endothelium, this sickling leads to episodic microvascular occlusion, ischaemia and reperfusion, 29 vascular and inflammatory stress, and increased expression of vascular oxidases, inflammatory cytokines and adhesion molecules. 29 In addition, chronic haemolysis results in anaemia, hypoxia, cholelithiasis, fatigue, exercise intolerability, hypercoagulability 30 and vasculopathy, 31 which lead in turn to endothelial nitric oxide depletion, development of pulmonary hypertension 32 and ischaemic strokes. 33 Recent work in transgenic sickle mice has highlighted the central role played by hypoxia in generating multi-organ damage by increased adenosine signalling via the G-protein coupled adenosine receptor ADORA2B. 34

The pathophysiology of pain in SCD remains poorly understood. 35 Nociceptive stimuli generated from cellular responses to vaso-occlusion, tissue infarction, inflammation and ischaemia-reperfusion injury activate receptors in the peripheral sensory nerves. However, neuropathic pain and increased sensitisation to mechanical touch have also been frequently noted, the latter being recently characterised as driven by increased primary afferent input to the central nervous system by the transient receptor potential vanilloid-1 channel in transgenic sickle mice. 36

Clinical features

The clinical features of SCD, described through multiple studies conducted in high-income populations in Europe and North America, are defined by chronic anaemia, sepsis, haemolysis and recurrent acute vaso-occlusive crises. The last are characterised by pain and a systemic inflammatory response that may be severe, episodic and unpredictable. Some of the more common acute clinical and laboratory features of SCD are summarised in table 1 , along with descriptions of current approaches to their management. Although this list would almost certainly look very different among children with SCD in low-income countries who are often exposed to malaria, geo-helminth infections, undernutrition and variable standards of care, this is beyond the scope of the current review.

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Common clinical presentations of SCD

Vaso-occlusive crises and bone disease

Painful vaso-occlusive crisis due to bony infarction is the commonest cause for hospital admissions. Infants may present with dactylitis or bony infarction of digits, irritability and swelling of fingers or toes. Infarction can affect any bone or joint and may mimic osteomyelitis. 37 Avascular necrosis—the result of recurrent vaso-occlusion and infarction of the articular surfaces and heads of long bones—is found in 12%–15% of children with SCA 38 , 39 and has been associated with both high haematocrit and the concomitant presence of α-thalassaemia. 40 , 41 Osteomyelitis and septic arthritis, most commonly due to Salmonella spp, Staphylococcus aureus and Gram negative enteric bacilli, 42 are also common, a cumulative incidence of 12% having been reported in one paediatric cohort in metropolitan France. 43 Osteopaenia and osteoporosis are frequent findings in SCD and patients may suffer from chronic back pain as a result of vertebral collapse. 38

Acute chest syndrome

Acute chest syndrome (ACS) is the second most common cause of hospitalisation and is characterised by intrapulmonary ischaemia and infarction, systemic hypoxia and pulmonary infiltrates on chest radiography. 44 Community-acquired pneumonias and fat embolism from bone marrow necrosis have been implicated in its pathogenesis. In a recent study, 50% of paediatric and adolescent patients with SCD reported acute pulmonary events during a median follow-up of 21 months. Children with asthma, a major cause of morbidity in SCD, suffer twice as many episodes of ACS as those without 45 while other risk factors include a high white cell count, and a high tricuspid-regurgitant jet velocity (TRV). 46 While raised TRVs have been associated with mortality in adults, 32 no such correlation has been reported in children; nevertheless, in one recent study, a gradual decline in exercise tolerance was noted in follow-up of children with elevated TRVs, suggesting that tricuspid valve disease may well progress throughout childhood. 47

Bacterial sepsis

Evidence of reduced splenic function is evident from early childhood. Functional asplenia is the norm by 6 months to 3 years of age 48 , 49 and leads to an increased susceptibility to infections, particularly those caused by encapsulated bacteria and malaria. 25 , 26 , 50 , 51 In high-income countries, mortality from sepsis was greatly reduced following the introduction of newborn screening and the early implementation of penicillin prophylaxis, while further improvements in survival and reductions in documented blood stream infections were subsequently achieved following the introduction of Haemophilus influenza e and Streptococcus pneumoniae vaccines. 17 Nevertheless, the combination of suboptimal compliance and resistance to penicillin prophylaxis, non-vaccine serotypes of S. pneumoniae , and hyposplenism means that even today children with SCD remain at increased risk of bacterial infections. 52

Sequestration crises

Splenic sequestration is defined as an acute enlargement of the spleen with a drop in haemoglobin of at least 2 g/dL from baseline and a normal or raised reticulocyte count. 53 In severe cases, it may result in hypovolemic shock and death in a matter of hours. Splenic sequestration can occur as early as 3 months of age but is rarely seen beyond the age of 6 years. Recurrence can occur in up to 50% of children. 54 Prompt transfusion can be life saving. 55 Hepatic sequestration is a rare but severe complication of SCD caused by the obstruction of hepatic sinusoidal blood flow by sickled erythrocytes and is characterised by painful hepatomegaly, anaemia and reticulocytosis. 56 Treatment is supportive, with fluids and analgesia along with early red cell exchange transfusions. 57

Ischaemic strokes and silent infarcts

SCD confers a higher risk of childhood stroke than any other paediatric disease. In all, 11% of patients with SCD develop an overt stroke by the age of 20 years, increasing to 24% by the age of 45 years. The risk of first stroke is highest in the first decade of life, being 1.02% per year between 2 and 5 years. 58 Two-thirds of children with a history of stroke will develop a second stroke within the first 2–3 years of an initial event. 59 The risk of stroke can be determined by measuring blood velocities in the middle cerebral and internal carotid arteries by transcranial Doppler (TCD) ultrasonography. In the Stroke Prevention in Sickle Cell Anaemia (STOP) trial, the risk of stroke among children with high TCD velocities was reduced by 90% by maintaining HbS concentrations at <30% through regular blood transfusions. 60 Children developed further strokes when transfusion therapy was stopped 61 or treatment was switched to hydroxycarbamide, 62 highlighting the need for life-long transfusion in this patient group. Silent cerebral infarcts (SCIs) on MRI scanning are common in asymptomatic patients with SCD and are associated with neurocognitive impairment, reduced academic achievement and stroke progression. Regular blood transfusion in children with SCI has recently been shown to reduce the incidence of SCI 63 and monitoring for worsening intellectual abilities is important. 64

Girdle syndrome and priapism

Severe abdominal pain, often unresponsive to analgesia and associated with intestinal ileus and acute ischaemic colitis, is termed ‘girdle syndrome’ owing to the circumferential distribution of pain. A high index of suspicion and early implementation of supportive therapy (including emergency red cell exchange transfusion, analgesia and fluids) may prevent irreversible ischaemic damage to the gut. 65 Priapism, defined as prolonged penile erection lasting >4 h, is a urological emergency and can result in fibrosis of the corpora cavernosa and permanent erectile dysfunction if not treated early. SCD is the commonest cause of priapism in children and is thought to be caused by chronic nitric oxide depletion within the penile vasculature due to chronic intravascular haemolysis, aberrant G-protein signalling, smooth muscle hypoxia, acidosis and impaired smooth muscle contraction. 66 Early intervention in the form of red cell exchange transfusion and surgical decompression of the corpora is essential. Recurrent, ‘stuttering’ priapism may be treated by hydroxycarbamide, chronic red cell exchange transfusions or sildenafil. 67

Standards of treatment

Universal or targeted newborn screening programmes, implementation of simple treatments such as vaccination and antibiotic prophylaxis, regular follow-up in specialist clinics and improved parental education have together led to major reductions in the early mortality from SCD in high- and middle-income countries. For example, simply teaching parents how to palpate their children's spleens led to a 90% reduction in mortality from splenic sequestration crises in Jamaica. 55 Nevertheless, despite such encouraging advances, the overall outcome of patients with SCD remains poor. The recent UK National Confidential Enquiry into Patient Outcome and Death for haemoglobinopathies 68 revealed a significant inequity of specialist care in the country and the lack of adequate knowledge of haemoglobinopathies within the medical community, and recommended the establishment of a national database to capture information regarding prevalence, therapy and adverse events of SCD.

A programme of universal screening for SCD was implemented in England in 2001 and was subsequently rolled out to Scotland and Wales 28 through which approximately 300 births and 17 000 carriers are detected each year. 69 The UK National Standards for the Treatment of SCD in Children 70 highlights the need for coordinating care between the screening service, primary care and local and specialist haemoglobinopathy teams, and mandates the prescription of penicillin to children by 6 months of age along with additional polysaccharide antigen vaccination for S. pneumoniae , and the provision of annual TCD monitoring to children over 2 years.

Adequate and prompt management of the acute complications of SCD remains the mainstay of clinical care. While the treatments of common complications are summarised in table 1 , pain relief, hydration, aggressive treatment of sepsis and blood transfusions remain central to acute management.

Specific therapies for SCD

Hydroxycarbamide.

Hydroxycarbamide (or hydroxyurea) remains the only agent that has been proven to reduce the number of episodes of painful crises, ACS and hospitalisations in randomised control trials in adults, 71 school-age children 72 and infants 73 with SCD. Despite its well known beneficial effects and excellent long-term toxicity profile, 74 utilisation remains suboptimal due to user- and prescriber-related uncertainties regarding toxicities, monitoring and efficacy. 75

Blood transfusion

A number of observational and randomised controlled trials have established the pivotal role of transfusion therapy in the management of SCD, most notably in primary stroke prevention 60 , 61 and through improved oxygenation in ACS. 76 Secondary analysis of two large paediatric randomised control trials, namely, the Stroke Prevention (STOP) and Stoke With Transfusions Changing to Hydroxyurea (SWiTCH) trials, indicated that transfusion therapy was more effective in reducing the incidence of painful crises and ACS than either standard supportive care or hydroxycarbamide. 77 , 78 Nevertheless, despite its well-recognised benefits, chronic transfusion therapy can result in iron overload (leading to organ damage and requiring additional iron chelation therapy), alloimmunsation, transfusion-acquired infections, venous access-related issues such as thrombosis and line-related sepsis and loss of work and schooling. 79 Coupled with the fact that the total economic costs of chronic transfusion therapy far exceeds those of hydroxycarbamide treatment, 80 , 81 transfusion therapy is mainly reserved for specific indications such as stroke risk reduction, renal failure or recurrent painful crises that are less responsive to treatment with hydroxycarbamide.

Allogeneic HSCT and gene therapy

Allogeneic haemopoietic stem cell transplant (HSCT) is the only curative treatment for SCD and is successful in 85%–90% of patients. 82 Transplantation offers disease-free survival and stabilisation of neurological lesions. Nevertheless, the fine balance between the benefits and risks of treatment, including long-term toxicities such as infertility and endocrinopathies, 83 the variable and unpredictable severity of SCD and the low availability of specialist services mean that HSCT is generally reserved for the most seriously affected patients. Table 2 outlines current indications for HSCT in SCD in the UK. Gene therapy has been in development for a number of years and aims to abrogate SCD-related symptoms by manipulation of haemopoietic stem cells, either by viral vector-mediated insertion of a functional β globin gene or by various gene-editing techniques that reduce intracellular sickling by enhanced production of HbF. Phase I studies of gene therapy have recently begun in several centres in the USA and Europe. 84 , 85

HSCT indications in SCD (ebmt.org/Contents/Resources/Library/EBMTESHhandbook)

Future perspectives

In the short term, refining the indications for access to known effective treatments is a major priority; for example, the accumulated data on hydroxycarbamide suggest that the benefits of the drug outweigh the risks in the vast majority of patients and that access to hydroxycarbamide therapy should be available to all who want it. At the same time, new therapies targeting specific mechanisms of HbF induction, endothelial dysfunction, pain management, organ damage and gene therapy are under intense research scrutiny. 86 Nevertheless, improving the profile of SCD as a major health problem in Africa and India, including the introduction of newborn screening programmes and the improved provision of even the most basic of medical care, will benefit the greatest number of patients with SCD worldwide. A good starting point would be the collection of more detailed and up-to-date data regarding the expected birth frequencies and outcomes of SCD in these regions at scales that will be meaningful to health planners responsible for making such decisions, while estimates of the economic costs and benefits of improved care are also needed. Such data will be most influential if the end-users are involved from the outset. At the same time, improved advocacy for SCD is needed at every level including increased education about SCD in schools and colleges in affected communities, increased involvement of patient-support groups and influential groups such as celebrities, politicians, funders and health agencies internationally. Finally, the development of cheap, reliable point of care methods for the diagnosis of SCD, akin to those developed for other diseases of poverty such as HIV and malaria, could be transformative at many different levels. Translation of research findings to clinical practice in improving patient outcomes worldwide remains the greatest challenge.

Acknowledgments

TNW is supported through a Senior Research Fellowship (091758) from the Wellcome Trust, UK

• Steinberg MH
• Serjeant GR ,
• Serjeant BE ,
• Fraser RA ,
• Pauling L ,
• Singer SJ ,
• Conner BJ ,
• Brambilla DJ ,
• Leikin SL ,
• Gallagher D ,
• Kinney TR ,
• Rogers ZR ,
• Buchanan GR
• Wierenga KJ ,
• Hambleton IR ,
• Chakravorty S ,
• McCavit TL ,
• Hamideh D ,
• Taylor SM ,
• Fairhurst RM
• Grosse SD ,
• Atrash HK ,
• Williams TN ,
• Macharia A ,
• McAuley CF ,
• Nyirongo V ,
• Worthington D ,
• Hillery CA ,
• McGowan V ,
• Machado RF ,
• Gladwin MT ,
• Sachdev V ,
• Machado R ,
• Ballas SK ,
• Adams-Graves P
• Kerstein PC ,
• Vilceanu D ,
• Saunders N ,
• Almeida A ,
• Mahadeo KM ,
• Taragin B ,
• Milner PF ,
• Adekile AD ,
• Burnett MW ,
• Neonato MG ,
• Guilloud-Bataille M ,
• Beauvais P ,
• Miller AC ,
• Macklin EA ,
• Strunk RC ,
• Minniti CP ,
• Nouraie M ,
• Gordeuk VR ,
• Pearson HA ,
• Spencer RP ,
• Cornelius EA
• William BM ,
• Thawani N ,
• Sae-Tia S ,
• Ellison AM ,
• McGowan KL ,
• Topley JM ,
• Rogers DW ,
• Stevens MC ,
• Brousse V ,
• Darvill D ,
• Gardner K ,
• Ohene-Frempong K ,
• Weiner SJ ,
• Sleeper LA ,
• Musallam KM ,
• Khoury RA ,
• Brambilla D
• Investigators SW
• DeBaun MR ,
• McKinstry RC ,
• Armstrong FD ,
• Qureshi A ,
• Donaldson JF ,
• Steinbrecher HA
• Burnett AL ,
• Trueheart IN ,
• Streetly A ,
• Latinovic R ,
• Charache S ,
• Terrin ML ,
• O'Branski EE ,
• Miller ST ,
• Steinberg MH ,
• McCarthy WF ,
• Brandow AM ,
• Jirovec DL ,
• Panepinto JA
• Vichinsky EP ,
• Neumayr LD ,
• Earles AN ,
• Alvarez O ,
• Yovetich NA ,
• Schoenike SE ,
• Locatelli F ,
• Dallas MH ,
• Triplett B ,
• Rivella S ,
• Chandrakasan S ,

Competing interests None.

Provenance and peer review Commissioned; externally peer reviewed.

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REVIEW article

Recent advances in the treatment of sickle cell disease.

• 1 Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
• 2 Division of Hematology and Oncology, Children’s National Medical Center, Washington, DC, United States

Sickle cell anemia (SCA) was first described in the Western literature more than 100 years ago. Elucidation of its molecular basis prompted numerous biochemical and genetic studies that have contributed to a better understanding of its pathophysiology. Unfortunately, the translation of such knowledge into developing treatments has been disproportionately slow and elusive. In the last 10 years, discovery of BCL11A , a major γ-globin gene repressor, has led to a better understanding of the switch from fetal to adult hemoglobin and a resurgence of efforts on exploring pharmacological and genetic/genomic approaches for reactivating fetal hemoglobin as possible therapeutic options. Alongside therapeutic reactivation of fetal hemoglobin, further understanding of stem cell transplantation and mixed chimerism as well as gene editing, and genomics have yielded very encouraging outcomes. Other advances have contributed to the FDA approval of three new medications in 2017 and 2019 for management of sickle cell disease, with several other drugs currently under development. In this review, we will focus on the most important advances in the last decade.

Introduction

Sickle cell disease (SCD) is an inherited blood disorder that first appeared in the Western literature in 1910 when Dr. James Herrick described a case of severe malaise and anemia in a 20-year-old dental student from Grenada ( Herrick, 1910 ). On examining his blood smear, he noticed many bizarrely shaped red blood cells, leading him to surmise that “…the cause of the disease may be some unrecognized change in the red corpuscle itself” ( Herrick, 2014 ). More than 100 years later we recognize that the change in the red corpuscle is caused by a single base substitution in β-globin, and that the disease is not just present in the United States (US), but prevalent in regions where malaria was historically endemic, including sub-Saharan Africa, India, the Middle East, and the Mediterranean ( Williams and Thein, 2018 ). Presence of SCD in the non-malarial regions is related to the recent migration patterns.

Currently, an estimated 300,000 affected babies are born each year, more than 80% of whom are in Africa. Due to recent population migrations, increasing numbers of individuals affected by SCD are encountered in countries that are not historically endemic for malaria, such as the US. It is estimated that 100,000 Americans are affected with SCD, the majority of whom are of African descent ( Hassell, 2010 , 2016 ). The numbers affected with SCD are predicted to increase exponentially; Piel et al. (2013) estimated that between 2010 and 2050, the overall number of births affected by SCD will be 14,242,000; human migration and further globalization will continue to expand SCD throughout the world in the coming decades. While 75% or more of newborns with SCD in sub-Saharan Africa do not make their fifth birthday ( McGann, 2014 ), in medium- to well-resourced countries almost all of affected babies can now expect to live to adulthood but overall survival still lags behind that of a non-SCD person by 20–30 years ( Telfer et al., 2007 ; Quinn et al., 2010 ; Elmariah et al., 2014 ; Gardner et al., 2016 ; Serjeant et al., 2018 ). Despite these global prevalence figures, and the fact that SCD is by far the largest public health concern among the hemoglobinopathies, it was not until 2006 when the World Health Organization (WHO) recognized SCD as a global public health problem 1 .

In 1949, Linus Pauling showed that an abnormal protein (hemoglobin S, HbS) was the cause of sickle cell anemia (SCA), making SCD the first molecular disease and motivating an enormous amount of scientific and medical research. Because of its genetic simplicity, SCA has been used to illustrate many of the advances in molecular genetics such as detection of a DNA mutation by restriction fragment enzyme analysis, and was used as proof of principle for the polymerase chain reaction (PCR) that we now take for granted ( Wilson et al., 1982 ; Saiki et al., 1985 ).

In the last 50 years, tremendous progress has been made in understanding the pathophysiology and pathobiological complexities of SCD, but developing treatments has been disproportionately slow and elusive; a history of Perils and Progress, so succinctly summarized by Wailoo (2017) . We are confident that in the next 30 years, the therapeutic landscape for SCD will change due to a combination of recent advancements in genetics and genomics, an increase in the number of competing clinical trials, and also an increased awareness from the funding bodies, in particular the NIH, USA.

Here, after a brief review of the pathophysiology, we will focus on the advances in treatment of SCD that have occurred in the last 10 years and that have reached phase 2/3 of clinical trials ( Figure 1 ).

Figure 1. Timeline review of historic events since the diagnosis of sickle cell disease with an emphasis over the last decade. SCD, sickle cell disease; HSCT, hematopoietic stem cell transplant; HU, hydroxyurea.

Pathophysiology of Sickle Cell Disease

Sickle cell disease is caused by an abnormal HbS (α 2 β S 2 ) in which glutamic acid at position 6 of the β-globin chain of hemoglobin is changed to valine. Goldstein et al. (1963) showed that this amino acid substitution arose from a single base change (A>T) at codon 6 ( rs334 ). The genetic causes of SCD include homozygosity for the rs334 mutation (HbSS, commonly referred as SCA) and compound heterozygosity between rs334 and mutations that lead to either other structural variants of β-globin (such as HbC, causing HbSC) or reduced levels of β-globin production as in β-thalassemia (causing HbS/β-thalassemia). In patients of African ancestry, HbSS is the most common cause of SCD (65–70%), followed by HbSC (about 30%), with HbS/β-thalassemia being responsible for most of the rest ( Steinberg et al., 2001 ). SCA in which the intracellular concentration of HbS is almost 100%, is by far the most severe and well described ( Brittenham et al., 1985 ). The majority of the therapeutic developments and interventions have focused on this genotype, which is also the focus of this review, although they also impact the other SCD genotypes.

The fundamental event that underlies the complex pathophysiology and multi-systemic consequences of SCD is the polymerization of HbS that occurs under low oxygen tension ( Figure 2 ). Polymerization of the de-oxygenated HbS alters the structure and function of the red blood cells (RBCs). These damaged (typically sickled shaped) RBCs are not only less flexible compared to normal RBCs, but also highly adhesive. Repeated cycles of sickling and unsickling shortens the lifespan of the damaged sickle RBCs to about 1/6th that of normal RBCs ( Bunn, 1997 ; Hebbel, 2011 ). The outcome is the occlusion of blood vessels in almost every organ of the body and chronic hemolytic anemia, the two hallmarks of the disease, that result in recurrent episodic acute clinical events, of which acute pain is the most common, and accumulative organ damage. Acute sickle pain is so severe that it is often referred to as “vaso-occlusive sickle crisis” or VOC.

Figure 2. Schematic pathophysiology review of sickle cell disease and its main different targets for intervention. Hb S, hemoglobin S.

These events trigger a cascade of pro-inflammatory activity setting off multiple pathophysiological factors that also involve neutrophils, platelets, and vascular endothelium ( Sundd et al., 2019 ). The continual release of cell-free hemoglobin from hemolysis depletes hemopexin and haptoglobin, a consequence of which is the reduced bioavailability of nitric oxide (NO), and vascular endothelial dysfunction that underlies the chronic organ damage in SCD pathology.

The sickle red blood cells do not just interact with the vascular endothelium but trigger activation of neutrophils, monocytes and platelets. During steady-state, patients with SCD have above normal values of neutrophils, monocytes and platelets which further increase during acute events ( Villagra et al., 2007 ). Neutrophilia has been consistently correlated with SCD severity ( Ohene-Frempong et al., 1998 ; Miller et al., 2000 ); neutrophils play a central role in vaso-occlusion through their interactions with both erythrocytes and endothelium upregulating expression of cytoadhesion molecules such as P- and E-selectins, current therapeutic targets ( Zhang et al., 2016 ).

Platelets, when activated, form aggregates with erythrocytes, monocytes, and neutrophils both in patients and in murine models ( Wun et al., 1997 ; Zhang et al., 2016 ). As with neutrophils, it appears that platelet aggregation is dependent on P-selectin. As part of this constant inflammatory state, the coagulation cascade is also hyperactivated in SCD. The repeated interaction between RBCs and endothelium promote expression of pro-adhesive and procoagulant proteins evidenced by increased levels of plasma coagulation factors, tissue factor (TF) and interactions between monocyte-endothelium, platelet-neutrophil and platelet-RBC. Patients with SCD have increased rates of venous and arterial thrombotic events ( Brunson et al., 2017 ).

Unraveling these pathophysiological targets has provided insights on clinical trials on anti-platelet and anti-adhesion agents, as well as anti-coagulation factors for the prevention of acute VOC pain in SCD ( Telen, 2016 ; Nasimuzzaman and Malik, 2019 ; Telen et al., 2019 ). A case in point is the development of an anti-P-selection molecule (Crizanlizumab) for treatment of sickle VOC, recently approved by the FDA in November 2019 and marketed as Adakveo ® .

New therapeutic approaches that use drugs to ameliorate the downstream sequelae of HbS polymerization have not proved to be as effective as hydroxyurea (HU) which has an “anti-sickling” effect via induction of fetal hemoglobin (HbF, α2γ2) ( Ware and Aygun, 2009 ). Other effects of HU include improvement of RBC hydration, reduction of neutrophil count, reduction of leucocyte adhesion, and reduction of pro-inflammatory markers, all of which add to the clinical efficacy of HU. In addition, HU also acts as NO donor, promoting vasodilation ( Cokic et al., 2003 ). Increasing HbF is highly effective because it dilutes the intracellular HbS concentration, thereby increasing the delay time to HbS polymerization ( Eaton and Bunn, 2017 ); in addition to which, the γ-chains also have an inhibitory effect on the polymerization process. Hydroxyurea, however, is only partially successful because the increase in fetal hemoglobin is uneven and not present in all cells. Nonetheless, the well-established clinical efficacy of HbF increase, substantiated by numerous clinical and epidemiological studies, has motivated both pharmacological and genetic approaches to induce HbF ( Nevitt et al., 2017 ).

A more detailed understanding of the switch from fetal to adult hemoglobin, and identification of transcriptional regulators such as BCL11A, aided by the developments in genetic and genomic platforms, provide hope that genomic-based approaches for therapeutic reactivation of HbF may soon be possible ( Vinjamur et al., 2018 ). In the meanwhile, a gene addition approach that infects the patient’s stem cells with a virus expressing an anti-sickling β-globin variant, T87Q, shows great promise ( Negre et al., 2016 ; Ribeil et al., 2017 ). The most successful “curative” approach so far, is transplantation with stem cells from an immunologically matched sibling but this is severely limited by the lack of availability of matched donors ( Walters et al., 1996a ; Gluckman et al., 2017 ).

Parallel to the new medications being developed blood transfusions with normal red blood cells, remain an effective and increasing therapeutic option for managing and preventing SCD complications, but this strategy has limitations (not uniformly accessible, accompanied by risks of alloimmunization, hemolytic transfusion reactions and transfusional iron overload). Blood transfusion improves the oxygen-carrying capacity and improves microvascular perfusion by decreasing the HbS percentage. A major complication of blood transfusion is hemolytic transfusion reactions that occur primarily in RBC alloimmunized patients and SCD patients, in particular, are at high risk because of the mismatch in donor pool (predominantly Northern European descent) while SCD patients are predominantly of African descent ( Vichinsky et al., 1990 ; Thein et al., 2020 ). Limiting blood from ethnic-matched donors has reduced but did not eliminate alloimmunization ( Chou et al., 2013 ), and a major cause is the mismatch between serologic Rh phenotype and RHD or RHCE genotype due to variant RH alleles in a large proportion of the individuals ( Chou et al., 2013 ). RH genotyping in addition to serologic typing may be required to identify the most compatible RBCs and recent studies have shown that a prospective rather than reactive (after appearance of allo-antibodies) genotyping approach may be feasible ( Chou et al., 2018 , 2020 ; Hendrickson and Tormey, 2018 ). Until prospective genotyping of RBC antigens become a practical feasibility, as a prevention, many blood transfusion centers have adopted extended red cell phenotyping, including ABO, Rh, Kell, Kidd, Duffy, and S and s antigens, and some centers have also adopted molecular genotyping for red blood cell phenotype prediction using microarray chips (e.g., the PreciseType HEA BeadChip assay). It should be noted that, while blood transfusion remains an important therapeutic option in SCD, evidence for its role in management of acute or chronic complications is lacking except for prevention of primary and secondary strokes ( Howard, 2016 ). Supportive evidence for the role of preoperative transfusion in patients with HbSS or HbS/β 0 -thalassemia was demonstrated in the Transfusion Alternatives Preoperatively in Sickle Cell disease (TAPS) study ( Howard et al., 2013 ).

Insight on the pathophysiology of SCD ( Figure 2 ) has allowed different targets for interventions in patients with SCD summarized under four categories of its pathobiology – (1). Modifying the genotype, (2). Targeting HbS polymerization, (3). Targeting vasocclusion, and (4). Targeting inflammation.

Understanding of the kinetics of HbS polymerization suggest that there are many ways to inhibit HbS polymerization ( Eaton and Bunn, 2017 ) other than induction of HbF ( Table 1 ). One approach is to increase oxygen affinity of the hemoglobin molecule, an example is Oxbryta TM (Voxelotor/GBT440) ( Vichinsky et al., 2019 ) that was recently approved by the FDA in November 2019, making this the second anti-sickling agent.

Table 1. Current advances on therapy for sickle cell disease.

One of the biggest challenges in managing SCD is the clinical complexity and extreme variable clinical course that cannot be explained by the specific disease genotype. Patients with identical sickle genotype still display extreme clinical course; both acquired and inherited factors contribute to this clinical complexity of SCD ( Gardner and Thein, 2016 ). Although laboratory prognostic factors (HbF, hemoglobin, reticulocyte count, leukocytosis) and clinical phenotypes (such as stroke/TIA, acute chest syndrome/pulmonary hypertension, avascular necrosis, kidney injury, or skin ulcers) have been described and analyzed, classifying disease severity remains complex and should be assessed individually. Prediction of disease severity and clinical course of SCD has been the topic of many reviews and, to date there is no clear algorithm using genetic and/or imaging, and/or laboratory markers that can reliably predict mortality risk in SCD ( Quinn, 2016 ).

Current Advances in Therapy

(1) modifying the patient’s genotype.

Modifying the patient’s genotype via hemopoietic stem cell transplantation (HSCT) was first reported to be performed over 30 years ago in an 8-year-old child who had SCD (HbSS) with frequent VOCs; she subsequently developed acute myeloid leukemia. The patient received HSCT for the acute myeloid leukemia from an HLA-matched sister who was a carrier for HbS (HbAS). She was cured of her leukemia and at the same time, her sickle cell complications also resolved ( Johnson et al., 1984 ; Johnson, 1985 ). Until then, HSCT had not been considered as a therapeutic option for SCD. This successful HSCT demonstrated that reversal of SCD could be achieved without complete reversal of the hematological phenotype to HbAA, and paved the way for bone marrow transplant (BMT) as a curative option for children with severe SCD ( Walters et al., 1996b ).

The conclusion was that, as long as stable mixed hemopoietic chimerism after BMT can be achieved, patients can be cured of their SCD without complete replacement of their bone marrow ( Walters et al., 2001 ).

Allogeneic Bone Marrow Transplant

Hematopoietic stem cell transplant (HSCT) has now become an important therapeutic option for patients with SCD. Currently there are about 35 clinical trials at ClinicalTrials.gov studying allogeneic BMT in patients with SCD. As described by Walters et al. (2010) , HSCT can establish donor-derived erythropoiesis, but even more importantly, can stabilize or even restore function in affected organs of patients with SCD when performed in time.

Between 1986 and 2013, 1,000 patients received HLA-identical matched sibling donor (MSD) HSCTs ( Gluckman et al., 2017 ). The outcomes for both children and adults were excellent, demonstrating 93% overall survival. Eighty seven percent of the patients received myeloablative chemotherapy (MAC) and the rest (13%) received reduced intensity chemotherapy (RIC). It is important to note that patients 16 years or older had worse overall survival (95% vs. 81% p = 0.001) and a higher probability of graft versus host disease (GVHD)-free survival (77% vs. 86% p = 0.001). These results should encourage physicians to provide early referrals to SCD patients for transplant evaluation so that the donor search can be started in a timely matter ( Gluckman et al., 2017 ).

Although myeloablative conditioning has achieved high rates of overall and event free survival, the conditioning is too toxic for adult patients with pre-existing organ dysfunction. Reversal of the sickle hematology without complete replacement of the patient’s bone marrow led to the development of less intense conditioning regimens expanding allogeneic transplantation in adult patients, who otherwise would not be able to tolerate the intense myeloablative conditioning. Donors could be HbAA or HbAS, and in order to reverse the sickle hematological genotype, the myeloid donor chimerism has to be >20% ( Fitzhugh et al., 2017 ).

In an international, multicenter study, 59 patients had MSD HSCT, of which 50 survived and were cured of SCD. Of the nine patients that had a negative outcome, five had graft rejection and four intracranial hemorrhage. Thirteen patients developed mixed chimerism. Of those patients that developed mixed chimerism, there was no GVHD or disease recurrence/graft rejection. Patients with stable mixed chimerism did not have worse outcomes related to complications of SCD. Hsieh et al. (2009) developed a protocol for non-myeloablative HSCT with low dose total body radiation, alemtuzumab, and sirolimus. In the initial 10 patients with SCD, nine had long-term, stable, mixed donor chimerism and reversal of their sickle cell phenotype ( Hsieh et al., 2009 ). An updated report showed that 87% of the 30 patients had long-term stable donor engraftment without acute or chronic graft-versus-host disease (Clinical trials [NCT00061568]) ( Walters et al., 2001 ; Hsieh et al., 2014 ). More recent data reported at least 95% cure rate in 234 children and young adults (<30 years) with SCA after MSD with no increased mortality compared to SCA itself and better quality of life. The data also showed that myeloablative HSCT can be a safe option for patients <15 years old if a MSD is available unless there is a clear and strong recommendation not to undergo transplant ( Bernaudin et al., 2020 ).

However, in the US, less than 15% of patients with SCD have HLA- matched siblings as donors, but a promising alternative donor source is haplo-identical family members. Studies are now underway in several centers to find a balance of conditioning regime that provides adequate immunosuppression without rejection and minimal GVHD ( Joseph et al., 2018 ). Matched unrelated donors (MUD) have shown promising results in patients with thalassemia major and are currently being evaluated in patients with SCD ( Fitzhugh et al., 2014 ). One of the main limitations, unfortunately, is the low probability of finding suitable donors for African and African American populations as per the National Marrow Donor Program and so, not sufficient MUD transplants have been completed in patients with SCD. HLA-haploidentical HSCT following RIC has been reported to show promising results with prolonged and stable engraftment, but for both unrelated umbilical cord blood (UCB) and haploidentical HSCT, rejection remains a major obstacle in the context of RIC ( Bolanos-Meade et al., 2012 ; Angelucci et al., 2014 ; Fitzhugh et al., 2014 ; Saraf et al., 2018 ; Bolanos-Meade et al., 2019 ).

Although encouraging options with promising results in clinical trials, acute and chronic GVHD remain major complications which can be life threatening and have severe effects on quality of life. Multiple factors affect the development of GVHD in patients undergoing transplant, including the source of the stem cells, the intensity of immunosuppression in the conditioning regime (dose of anti-thymoglobulin) and the mismatch status of the donor to the recipient ( Shenoy, 2013 ; Inamoto et al., 2016 ; Bernaudin et al., 2020 ).

Acute GVHD remains a concern in patients receiving mismatched donor transplants but UCB continues to show reduced rates of chronic GVHD ( Kamani et al., 2012 ). Reduced-intensity conditioning regimens have also been studied in related and unrelated HSCT, and while a suitable option for patients with a matched sibling, patients with unrelated donor should be made aware of the not-so-favorable short and long-term outcomes ( Guilcher et al., 2018 ).

As new transplant modalities emerge with less transplant related mortality, better immunomodulators to prevent GVHD are being developed and graft rejection has become less frequent and accepted indications for HSCT have become less restrictive ( Table 2 ). Nonetheless, clinicians continue to have reservation toward transplant and tend to delay the referral to a HSCT specialist because of concerns for GVHD, mortality/morbidity related to transplant itself and the risk of graft rejection, which has not been eliminated completely ( Leonard and Tisdale, 2018 ). An ongoing clinical trial will compare 2-year overall survival and outcomes related to SCD in patients that undergo transplant compared with current standard of care (ClinicalTrail.gov Identifier: NCT02766465).

Table 2. Indications for HSCT balanced with donor availability: Risk/benefit ratio considerations.

In allogeneic transplant, the source of hematopoietic stem cells (HSCs) is from a donor (matched sibling, haplo-identical family members, UCB or MUD). Allogeneic BMT using HSCs from the latter 3 donor sources are still risky; and donor availability presents a huge limitation. These limitations can be overcome by autologous transplant, in which the patient receives his own cells after being modified by gene therapy.

Autologous Hematopoietic Stem Cell Transplant Modification: Gene Editing or Gene Therapy

Genetically engineered autologous cells eliminate the need to find a HSCT donor, and thus available to all patients. Since these are the patient’s own stem cells, there is no need for immunosuppression, thus eliminating the risks of GVHD and immune-mediated graft rejection ( Esrick and Bauer, 2018 ; Orkin and Bauer, 2019 ).

Sickle cell disease patients represent a special and complicated population for this therapy for two major reasons. First, patients that undergo autologous stem cell transplant require collection of hematopoietic stem cells (CD34+) and the traditional method of collection is a bone marrow harvest done by a specialist but in patients with SCD this process yields CD34+ cells with suboptimal quantity and quality requiring multiple harvests, each harvesting procedure increasing the risk of triggering acute pain crisis. Second, the current gold standard procedure for cell mobilization is with granulocyte-colony stimulating factor (G-CSF) but this is contraindicated in patients with SCD due to risk of causing complications such as pain crisis, acute chest syndrome, and even death, from the increased white cell counts.

Recently, great advances have been made in using an alternative approach for harvesting CD34+ cells using Plerixafor. Plerixafor acts by reversibly blocking the binding between chemokine CXC-receptor 4 (CXCR4) and the stromal cell derived factor-1α triggering the mobilization of progenitor cells into the peripheral blood. It allows peripheral mobilization of stem cells by releasing CD34+ cells from the bone marrow niches, without the massive increase in white blood cells. Its development has been crucial in optimization of CD34+ collection in patients with SCD. Results have shown appropriate mobilization of CD34+ cells 6 h after a single dose of Plerixafor and are of higher quality and purity, decreasing the need for multiple bone marrow harvests and the associated stress/pain. Associated with hyper-transfusion therapy, it has become the preferred way of marrow stimulation to yield appropriate hematopoietic stem/progenitor cells in patients with SCD ( Boulad et al., 2018 ; Esrick et al., 2018 ; Hsieh and Tisdale, 2018 ; Lagresle-Peyrou et al., 2018 ).

The genetic defect in the sickle HSPCs can be corrected via several approaches.

(A) Gene addition using lentiviral vector-based strategies

(a) Anti- or non-sickling strategies: Several gene therapies based on gene addition using viral vectors to carry therapeutic genes in HSCs are being actively developed with curative purposes. Gene addition strategies that have reached clinical trials include a promising one where the patient’s stem cells are infected with a lentivirus expressing an anti-sickling β-globin variant, T87Q. The unique feature of this vector is that the amino acid substitution (β A–T 87 Q ) allows for high performance liquid chromatography (HPLC) monitoring of the transgene globin levels in the patient’s cells ( Cavazzana-Calvo et al., 2010 ). The first SCD patient who received this Bluebird vector (protocol HGB-205) was reported in 2017; engraftment was stable with no sickle cell crises reported at 15 months of follow up ( Ribeil et al., 2017 ), with further undergoing studies ( ClinicalTrials.gov Identifier: NCT02140554, NCT03282656). Other approaches to anti-sickling gene therapy in erythroid-specific lentiviral vectors include utilizing a β-globin gene with three specific point mutations that confer anti-sickling properties ( ClinicalTrials.gov Identifier: NCT02247843) or the introduction of a γ-globin coding sequence in a β-globin gene to increase HbF levels and decrease HbS ( ClinicalTrials.gov Identifier: NCT02186418) ( Cavazzana et al., 2017 ). Thus far, the most promising of these LV vectors is the one utilizing anti-sickling β-globin variant, T87Q.

(b) Hb F induction: The well-established efficacy of increasing HbF has motivated both pharmacological and genetic approaches to HbF induction.

A gene addition approach that is already in clinical trials ( ClinicalTrials.gov Identifier: NCT03282656) utilizes a lentiviral mediated erythroid specific short hairpin RNA (shRNA) for BCL11A. This shRNA is modified to target the specific gene and downregulate its expression ( Brendel et al., 2016 ). As of December 2018, three adults have been enrolled, utilizing plerixafor mobilized HSC, all three patients showed prompt neutrophil engraftment, and at 2 months follow up, the average HbF was 30% (ASH abstract #1023 – 2018 ASH conference). Other lentiviral therapies using zinc-finger nucleases (ZFN) directed against the γ-globin promoter have been proposed. This would force an interacting loop between the LCR and γ-globin which would reactivate γ-globin production, increasing HbF and decreasing HbS production at the same time. These lentiviral-based approaches still need preclinical in vivo studies to address safety and specificity before they can be considered in human patients ( Breda et al., 2016 ; Orkin and Bauer, 2019 ).

Viral vectors, such as lentivirus, are a great tool for gene therapy but these results underscore the need to develop gene transfer protocols that ensure efficient and consistent delivery of the therapeutic globin gene cargo to HSC. Their major limitations include:

(1) Their immunogenicity which can create an inflammatory response in the donor which can lead to degeneration of the transducted tissue, (2) they can produce non-specific toxins, (3) due to the semi-random integration to the genome, there is a theoretical risk of insertional mutagenesis, (4) they have limitations of transgenic capacity size. An additional challenge in SCD is the ability to maintain a persistent myeloid donor chimerism of >20% to prevent return of SCD symptoms ( Fitzhugh et al., 2017 ). Due to these limitations, long-term monitoring of patients to evaluate both safety and efficacy is necessary. Until now, over the last decade of clinical trials, no genotoxicity secondary to LV vectors has been reported but the main challenge has been to keep the myeloid donor chimerism above the 20% threshold ( Nayerossadat et al., 2012 ).

(B) Gene editing

Gene-editing corrects a specific defective DNA in its native location. SCD with its simple single base change presents a very attractive prototype. Over the last couple of decades, there has been a spectacular growth of such strategies, setting the scene for developing therapies that could precisely genetically correct a single base mutation in patient with SCD. These strategies include ZFNs, transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeat (CRISPR)-associated nuclease Cas9 approach which is the most advanced of the three. The CRISPR-Cas9 technology typically make a double-stranded break (DSB) in a particular genomic sequence directed to that site by a guide RNA. The most common method of DSB repair is non-homologous end joining, often resulting in gene disruption or knockout. This strategy is currently being tested in a clinical trial ( ClinicalTrials.gov Identifier: NCT03745287) in which the patient’s own BCL11A gene (a major inhibitor of γ-globin gene expression) is disrupted to induce HbF expression. BCL11A also has roles in lymphoid and neurological development but gene-editing for SCD exploits the erythroid-specific enhancers in intron 2 of the gene ( Bauer et al., 2013 ; Brendel et al., 2016 ). CRISPR-Cas9 technology is also being explored to mimic the rare, genetic variants that promote expression of the γ-globin genes as in hereditary persistence of fetal hemoglobin ( Traxler et al., 2016 ; Wienert et al., 2018 ). Disrupting the putative binding sites for γ-globin repressors like BCL11A to induce HbF production will be an attractive therapeutic strategy for both β-thalassemic and SCD patients ( Masuda et al., 2016 ; Liu et al., 2018 ; Martyn et al., 2018 ). The ultimate challenge, however, is to genetically correct the mutation, a single nucleotide change in the codon of the globin gene from GAG to GTG, by providing a homology template with the correct sequence at the sixth codon. Although this has been completed in preclinical studies, current techniques do not allow for specific transversion mutations like those required to cure SCD in humans ( Dever et al., 2016 ; Orkin and Bauer, 2019 ). The enormous selective advantage of red blood cells with normal hemoglobin or anti-sickling hemoglobin predicts that genetic modification of a proportion of HSCs (estimated 10–20%) may suffice as a one-off treatment ( Fitzhugh et al., 2017 ). Before gene therapy can become a reality, however, many hurdles need to be overcome; genetically manipulated HSCs need to be able to retain long-term repopulating potential; pre-transplant conditioning is toxic and needs to be modified to reduce the morbidity. A clinical trial exploring antibody-mediated non-chemotherapy conditioning is being evaluated in patients with severe combined immunodeficiency, in an attempt to reduce the exposure to chemotherapy and its toxicities is currently recruiting patients ( ClincialTrials.gov Identifier: NCT02963064). Further understanding of this technology could represent a new option for patients with SCD.

Although different gene strategies have reached clinical trials showing promising results they remain in early phases of development and allogeneic HSCT remain the only curative treatment modality for SCD. For the majority of patients without a MSD, haploidentical HSCT with recent promising data of improved overall survival presents an alternative for curative therapy. Multiple gene therapy strategies utilizing patient’s own stem cells, are also being pursued, but this has the disadvantage of myeloablative conditioning ( Leonard et al., 2020 ).

In addition to great advances in HSCT and gene therapy, new pharmacological anti-sickling approaches have developed.

(2) Targeting Hemoglobin S Polymerization

Approaches targeting HbS polymerization presents a very attractive strategy as this “puts out the fire” rather than dealing with the sequelae of the sickling event ( Eaton and Bunn, 2017 ). HbF has long been known to have a major beneficial effect in SCD – increased intracellular HbF not only dilutes the intracellular HbS concentration but inhibits sickling as the mixed hybrid tetramers do not partake in HbS polymerization. Hydroxyurea (HU) works via induction of fetal hemoglobin (HbF, α2γ2) synthesis, but hydroxyurea is only partially successful as the increase in HbF is uneven and not equally present in all the red blood cells ( Ware, 2015 ). Nonetheless, use of HU therapy in SCD has expanded substantially in recent years. Follow on studies include demontration of its efficacy and safety in the pediatric population (BABY HUG) ( Wang et al., 2011 ), the Transcranial doppler with Transfusion Changing to Hydroxyurea Study (TWiTCH) that showed HU was comparable to blood transfusions for primary stroke prevention ( Ware et al., 2016 ) although the Stroke with Transfusion Changing to Hydroxyurea study (SWiTCH) concluded that HU is not comparable to blood transfusion in secondary stroke prevention ( Ware et al., 2011 ).

More recently, two clinical studies have shown that HU is relatively safe in Sub Saharan Africa, a setting with high infectious disease and SCD burden. Hydroxyurea has been shown to not only decrease complications from SCD such as VOC, acute chest syndrome, frequency of transfusions, death and infections – including malaria but also to be a feasible approach in these under-resourced countries ( Opoka et al., 2017 ; Tshilolo et al., 2019 ).

Despite having a significant impact in patients with SCD, there are still multiple unanswered questions regarding HU. Its mechanism of action has not been fully understood and its impact on HbF will decrease over time. Older patients become more sensitive to the dosage and they require frequent blood tests and readjustment of their dose. Regardless of the advances, there is no clear evidence of the long-term effect of hydroxyurea in preventing end organ damage ( Nevitt et al., 2017 ; Luzzatto and Makani, 2019 ). There is also conflicting evidence of the effects of HU on male fertility ( DeBaun, 2014 ). Chronic complications of SCD such as recurrent episodes of priapism, asymptomatic testicular infarctions and primary hypogonadism have been described as potential etiologies of low fertility in male SCD patients. Studies in transgenic SCD mice showed that SCD itself was associated with inhibition of spermatogenesis and primary hypogonadism but when compared to HU (25 mg/kg/day), testicular volume was lower in those mice with SCD exposed to HU, inferring lower spermatogenesis. Berthaut et al. (2008) measured the semen quality of 4 patients with SCA at baseline and 4 years after starting hydroxyurea. In three of four patients the spermatozoan concentration continued to drop while patients were taking the medication and did not return to baseline after discontinuing HU ( Berthaut et al., 2008 ). Although the evidence is limited, full disclosure regarding implications on male fertility should be given to patients and families in order to make an informed decision before starting HU ( Jones et al., 2009 ).

Other than HU, other pharmacological options to increase HbF are still experimental undergoing clinical trials. Molecular studies on γ-globin identified regulatory elements in the gene expression and subsequent HbF production. Such molecules; histone deacetylase (HDAC), DNA methyltransferase 1 (DNMT1), BCL11A and SOX6 modifying HbF expression have been explored as possible therapeutic options.

One of the proposed mechanisms for HU effect on HbF is stimulation of cyclic guanosine monophosphate (cGMP). Phosphodiesterase 9 (PDE9) is a specific enzyme in charge of degrading cGMP and is highly present in neutrophils and RBCs of patients with SCD. A novel, potent and selective PDE9 inhibitor (IMR-687) has been shown to increase levels of cGMP and HbF without signs of myelosuppression in cell lines of patients with SCD. An open-label extension to a previous phase 2a study is ongoing in adults with SCD ( ClinicalTrials.gov Identifier: NCT04053803) ( McArthur et al., 2019 ).

Panobinostat is a pan HDAC inhibitor currently being studied in adult patients with SCD as a phase 1 study ( ClinicalTrials.gov Identifier: NCT01245179). In vitro analysis of human erythroid progenitor cells that underwent shRNA knockdown of HDAC1 or HDAC2 genes resulted in increased levels of γ-globin but without altering cellular proliferation of the cell cycle phase.

Associated with HU, HDAC gene inhibition produced a more pronounced increase of γ-globin and HbF ( Esrick et al., 2015 ).

DNA Methyltransferase 1 is involved in the shutting down of γ-globin gene after birth and its subsequent production. DNA methylransferase inhibitor 5-azacytidine was one of the chemotherapeutic agents used to reactivate HbF but it was quickly abandoned due to its toxicity and carcinogenicity. Decitabine, an analog of 5-azacytidine, is also a potent DNMT1 inhibitor with a more favorable safety profile but decitabine is rapidly deaminated and inactivated by cytosine deaminase, if taken orally. To overcome this limitation, a clinical study combines decitabine and tetrahydrouridine (THU), a cytosine deaminase inhibitor, as a therapeutic strategy for inducing HbF ( ClinicalTrials.gov Identifier: NCT01685515). In a phase 1 study, Molokie et al. (2017) showed that the inhibition of DNMT1 led to appropriate blood levels of decitabine that were safe and induced a large increase in fetal hemoglobin in healthy red blood cells. These agents did not induce cytoreduction, but increased platelets count that can potentially trigger vaso-occlusion in SCD patients ( Molokie et al., 2017 ).

Voxelotor (Oxbryta/GBT440) binds specifically to the N-terminus of the alpha subunit of HbS to stabilize the oxygenated hemoglobin state ( Strader et al., 2019 ), thus reducing the predisposition to sickling. Voxelotor (Oxbryta/GBT440) was approved by the FDA in November 2019 for the treatment of SCD in adults and pediatric patients 12 years of age and older. The HOPE study showed an increase in hemoglobin levels and reduced markers of hemolysis in 274 patients with HbS that were randomly assigned to receive the study drug versus placebo. These findings have not correlated with reduced episodes of pain crisis and/or end organ damage. Agents that shift Hb oxygen affinity present some concerns of potential negative effects as the bound oxygen cannot be off loaded in tissues with high oxygen requirements, particularly concerning in a disease characterized by decreased oxygen delivery ( Hebbel and Hedlund, 2018 ; Thompson, 2019 ). These concerns are being addressed in a current phase 3, double-blind, randomized, placebo-controlled, multicenter study of Voxelotor ( ClinicalTrials.gov Identifier: NCT03036813) ( Vichinsky et al., 2019 ).

Dehydration of the RBC appears to be closely controlled by the efflux of potassium through 2 specific pathways; one is the potassium chloride cotransport and the other, calcium-activated potassium efflux (Gardos channel). Senicapoc blocks the Gardos channels, thus preventing dehydration of the red cells. Preclinical and phase 1/2 showed that inhibition of potassium flow through the Gardos channel increased Hb levels and decreased hemolysis ( ClinicalTrials.gov Identifier: NCT00040677). A phase 3 study was terminated for lack of efficacy ( ClinicalTrials.gov Identifier: NCT00294541) ( Ataga et al., 2008 ; Ataga and Stocker, 2009 ).

N -Methyl D -aspartate receptors (NMDARs) are non-selective calcium channels present in erythroid precursors and circulating RBCs and have been shown to be abnormally increased in RBCs of patients with SCD ( Hanggi et al., 2014 ). These channels are closely related with RBC hydration that affects the intracellular HbS concentration and thereby HbS polymerization and sickling of RBCs. Memantine is a NMDAR inhibitor which has shown to improve hydration of RBCs of patients with SCD in vitro and to reduce sickling in the setting of deoxygenation. It is being explored in an ongoing phase 2 clinical trial ( ClinicalTrials.gov Identifier: NCT03247218).

Sanguinate which is a bovine PEGylated hemoglobin product attempts to block polymerization by targeting carbon monoxide (CO) delivery. By binding to HbS polymers, CO enhances their melting and minimize their persistence in peripheral blood. However, this equilibrium is based on high concentrations of CO. A phase 1/2 single-blind, randomized, placebo-controlled study of this agent in the management of pain crisis has been carried out but no results have yet been posted ( ClinicalTrials.gov Identifier: NCT02411708).

(3) Targeting Vasocclusion

Increased expression and activation of normally inactive erythroid adhesion molecules promote cytoadherence of sickle RBCs to the endothelium accompanied by platelets and leukocytes. Activated leukocytes and platelets further increase the risk to develop VOC ( Nasimuzzaman and Malik, 2019 ; Sundd et al., 2019 ; Telen et al., 2019 ).

Previous in vitro studies had demonstrated that glutamine depletion contributed to red blood cell membrane damage and adhesion. Uptake of L -glutamine uptake is markedly increased in patients with SCD, primarily to increase the total intracellular NAD level ( Morris et al., 2008 ). In a phase 3 study, L -glutamine demonstrated a 25% reduction in the median number of pain crisis, 30% less hospitalizations and reduced acute chest episodes in children and adults with SCD with or without HU over a 48-week period. There were 36% drop-out rate in the glutamine arm and 24% in the placebo control arm from unknown reasons. L -Glutamine appears to significantly increase NADH and NAD redox potential and decrease endothelial adhesion, but its mechanism remains still unknown and there are concerns regarding its use in patients with renal impairment, a common sickle-related complication ( Quinn, 2018 ). In July 2017, the pharmacological grade of L -glutamine (Endari) was approved by the FDA for use in patients with SCD, 5 years or older ( Niihara et al., 2018 ). Of note, L -glutamine has not been approved by the European Medicines Agency for treating SCD.

In the future it could be a useful combination therapy with HU ( Minniti, 2018 ) but uptake among patients is still low, one of the reasons is the unpleasant taste. There are potentially less expensive pharmaceutical formulations of L -glutamine available off the counter, but purity of the effective agents in these compounds have not been validated.

As the endothelium emerge as a key factor in the constant activation of adhesion molecules in sickle RBCs, these adhesion molecules present a very attractive therapeutic target. Selectins, which are present in endothelial cells and are the initial step toward a firm adhesion between RBCs and the endothelium, have been further studied and targeted as possible therapeutic approaches.

Crizanlizumab is a monoclonal antibody to P-selectin and its mechanism of action is to block the adhesion of activated erythrocytes, neutrophils and platelets. In a phase 2, multicenter, randomized, placebo controlled double blind study, crizanlizumab with or without hydroxyurea (SUSTAIN study) ( ClinicalTrails.gov Identifier: NCT01895361) showed that patients on the treatment arm had significantly lower rate of sickle-related pain crises compared to placebo with a lower incidence of adverse events - 10% of patients suffered from moderate side effects while one patient suffered from an intracranial bleed during treatment with this drug that could also interfere with platelet function via its effects on selectins ( Ataga et al., 2017 ). Post hoc analyses showed that more patients were VOC event-free in the crizanlizumab arm than in the placebo arm, and that crizanlizumab also significantly increased time-to-first VOC compared to the placebo ( Kutlar et al., 2019 ). A phase 3 interventional, multicenter, randomized, double-blind clinical trial is ongoing to assess safety and efficacy of crinalizumab with or without hydroxyurea in patients with SCD and history of VOC ( ClinicalTrials.gov Identifier: NCT03814716). In November 2019, the US Food and Drug Administration approved crizanlizumab-tmca (ADAKVEO, Novartis) to reduce the frequency of VOC in adults and pediatric patients aged 16 years and older with SCD.

Rivipansel is a pan-selectin inhibitor with its strongest activity against E-selectin. In a multicenter, randomized, double−blind, placebo−controlled phase 2 study ( ClinicalTrails.gov Identifier: NCT01119833), Rivipansel showed clinical and meaningful reductions in multiple measures of VOC compared with those receiving standard of care treatment ( Telen et al., 2015 ). A phase 3 study (Identifier: NCT02187003) to evaluate the efficacy and safety of rivipansel in the treatment of VOC in hospitalized patients with SCD was terminated (posted on ClinicalTrials.gov February 20, 2020) based on failure of the primary study (NCT02433158) to meet the study efficacy endpoints of time to readiness-for-discharge.

In a phase 1, dose-escalation study propranolol showed it significantly reduced epinephrine-stimulated sickle RBCs adhesion. A phase 2 study (NCT01077921) showed decrease in adhesion molecules such as E-selectin and P-selectin but results were not statistically significant and no clinical endpoints were discussed ( De Castro et al., 2012 ).

Due to their P-selectin mediated adhesion inhibition properties, heparinoids have been additionally investigated with interesting results. Sevuparin, a heparin derivate polysaccharide that has shown to bind to P− and L−selectins, thrombospondin, fibronectin and von Willebrand factor, all of which are thought to contribute to vasocclusion in SCD. It has been reported to inhibit sickle RBC adhesion to the endothelial cells and to reduce tumor necrosis factor-induced vasocclusion. It is currently being tested in a phase 2 clinical trial, placebo controlled, to study its efficacy and safety in patients with SCD during VOC ( ClinicalTrials.gov Identifier: NCT02515838) ( Telen et al., 2016 ). Other heparinoids such as Dalteparin showed incomplete evidence to support or refute its effectiveness in the management of patients with SCD. There are ongoing trials ( ClinicalTrials.gov Identifier: NCT02098993) to assess the feasibility of unfractionated heparin in patients with SCD admitted with pain crisis. Well-designed studies are still needed to clarify its role in the management of patients with SCD and to assess the safety of this approach ( van Zuuren and Fedorowicz, 2015 ).

Poloxamer 188 is a non-ionic block copolymer surfactant thought to seal stable defects in the microvasculature leading to an improvement in blood flow and decreasing blood viscosity. Although its mechanism is not well understood, a randomized, double-blind, placebo-controlled trial showed that it decreased the duration of sickle crisis by 8 h compared to placebo (133 h vs. 141 h, p = 0.04) and more patients receiving the medication reported crisis resolution (52% vs. 37%, p = 0.02) ( Orringer et al., 2001 ). In an early phase 2 study, one patient receiving the medication developed renal dysfunction due to presence of low molecular weight substances and a purified version was designed ( Adams-Graves et al., 1997 ). Vepoloxamer, a purified form of Poloxamer 188 with multi mechanistic properties, was believed to improve RBC adhesion, membrane fragility and organ damage. Unfortunately, a phase 3 study failed to reduce the mean duration of VOC in patients with SCD compared to placebo ( Adams-Graves et al., 1997 ).

(4) Targeting Inflammation

Continual background inflammation contributes to organ damage in patients with SCD. Persistent activation of platelets, neutrophils, monocytes, endothelium, and coagulation factors are key participants in this vicious cycle. Different therapeutic approaches have been proposed to assess the impact in patients with SCD ( Nasimuzzaman and Malik, 2019 ; Sundd et al., 2019 ; Telen et al., 2019 ).

Intravenous immunoglobulin (IVIG) and statins have been studied for their anti-inflammatory effects on neutrophils and monocyte adhesion. Patients on statin demonstrated a decrease in C-reactive protein, soluble ICAM1, soluble E-selectin and vascular endothelial growth. Simvastatin was found to reduce adhesion of white blood cells and in combination with hydroxyurea, was found to decrease the number of pain crisis and markers of inflammation ( Hoppe et al., 2017 ). Currently, there is an active clinical trial to assess the effect of simvastatin on central nervous system vasculature in patients with SCD ( ClinicalTrials.gov Identifier: NCT03599609).

N -Acetylcysteine (NAC) commonly used in respiratory conditions has also been tested for patients with SCD. In a phase 2 study, NAC proved to inhibit dense cell formation and restored glutathione levels toward normal. The decrease in irreversible sickling of RBCs was not statistically significant but a downward trend was observed ( Pace et al., 2003 ; Nur et al., 2012 ). Further studies have shown decreased red cell membrane expression of phosphatidylserine which seems to reflect overall reduced oxidative stress. To better assess its clinical effect in patients with SCD, a pilot study, currently enrolling with invitation is studying its effect in redox and RBC function during VOC ( ClinicalTrials.gov Identifier: NCT01800526).

Aberrant activation of the coagulation cascade, abnormal excess of TF on the endothelial wall and high plasma levels of different coagulation factors drive increased thrombin and fibrin production leading to further inflammation and risk of VOC ( Sundd et al., 2019 ). In a SCD mouse model, factor Xa, TF, and thrombin differentially contributed to vascular inflammation ( Sparkenbaugh and Pawlinski, 2013 ). Factor Xa inhibition demonstrated a decrease in vascular inflammation as assessed by the lower interleukin 6 levels. Although thrombin had no effect on interleukin 6, it was a significant factor for neutrophil infiltration and further inflammation ( Sparkenbaugh et al., 2014 ). A retrospective analysis of rivaroxaban, a factor Xa inhibitor, demonstrated non-inferiority with regard to thrombosis compared to warfarin with the advantage of less outpatient visits and monitoring ( Bhat and Han, 2017 ). Currently, a two-treatment phase clinical trial with rivaroxaban on the pathology of SCD has been completed but results are pending ( ClinicalTrials.gov Identifier: NCT02072668). Patients with SCD have increased platelet levels at baseline that are further increased during acute VOC. Platelet activation triggers further leukocyte activation and promote RBC adhesion to an exposed endothelium ( Conran and Belcher, 2018 ) setting off a vicious cycle of adhesion events. Antiplatelet therapy with Clopidogrel in patients with SCD, unfortunately, were disappointing. New, third generation P2Y12 inhibitors such as ticagrelor and prasugrel have also been studied in patients with SCD. Prasugrel showed appropriate levels of anti-platelet aggregation compared to healthy patients in ex vivo studies, and was well tolerated by patients, but on a 24-month follow up, patients on the treatment arm failed to show reduction in the frequency of VOC ( Heeney et al., 2016 ; Conran and Rees, 2017 ). Ticagrelor, in a phase 2b study, was well tolerated, but failed to show effect in the frequency of VOC ( Kanter et al., 2019 ) ( ClinicalTrials.gov identifier: NCT02482298). Previous studies have also showed that aspirin as an anticoagulant therapy did not provide benefit over placebo, although it is used as an analgesic in many parts of Africa ( Sins et al., 2017 ).

In patients with SCD, continual lysis of RBCs activates the inflammasome triggering the release of multiple cytokines, including IL-1β ( Awojoodu et al., 2014 ). Canakinumab is a humanized monoclonal antibody that targets interleukin 1-β (IL-1β), and thus potentially could be useful in mitigating some of the inflammation in SCD. Canakinumab was shown to be well tolerated and not associated with major side effects in pediatric and young adult patients ( Rees, 2019 ). A clinical trial to assess its efficacy, safety and tolerability is ongoing in the pediatric population ( ClinicalTrials.gov Identifier: NCT02961218).

In the last 30 years, there has been a revolution in the medical sciences, and SCD because of its genetic simplicity, has been at the forefront of the numerous scientific discoveries. Tremendous progress has been made in understanding its pathophysiology and pathobiological complexities, but developing treatments, has been disproportionately slow and elusive. However, after a century of neglect, going back to basics offers hope for translating these insights into better therapeutic options – pharmacological and genetic – and for finding curative genetic options for SCD ( Figure 3 ). Although frequent in the US, SCD is far more prevalent in Africa where patients have less access to resources, medical treatment and facilities and the consequences of the disease are devastating. As we move forward, we have to continue focus our therapeutic approaches so that they can be accessed by those that suffer the most.

Figure 3. The different therapeutic approaches for sickle cell disease and their mechanisms and current status in clinical trials. Orange: targeting hemoglobin S polymerization; gray: targeting vasocclusion; light blue: targeting inflammation and green: modification of the genotype. shRNA, short hairpin RNA; Hb S, hemoglobin S; Hb F, hemoglobin F; PDE9, phosphodiesterase 9. *FDA approved July 2017; **FDA approved November 2019; ***Terminated in February 20, 2020 due to failure to meet primary endpoints.

Author Contributions

GSC and ST wrote and revised the manuscript.

This work was supported by the Intramural Research Program of the National Heart, Lungs, and Blood Institute, NIH (ST).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

• ^ https://apps.who.int/iris/handle/10665/20890

Adams-Graves, P., Kedar, A., Koshy, M., Steinberg, M., Veith, R., Ward, D., et al. (1997). RheothRx (poloxamer 188) injection for the acute painful episode of sickle cell disease: a pilot study. Blood 90, 2041–2046.

PubMed Abstract | Google Scholar

Angelucci, E., Matthes-Martin, S., Baronciani, D., Bernaudin, F., Bonanomi, S., Cappellini, M. D., et al. (2014). Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 99, 811–820. doi: 10.3324/haematol.2013.099747

PubMed Abstract | CrossRef Full Text | Google Scholar

Ataga, K. I., Kutlar, A., Kanter, J., Liles, D., Cancado, R., Friedrisch, J., et al. (2017). Crizanlizumab for the prevention of pain crises in sickle cell disease. N. Engl. J. Med. 376, 429–439. doi: 10.1056/NEJMoa1611770

Ataga, K. I., Smith, W. R., De Castro, L. M., Swerdlow, P., Saunthararajah, Y., Castro, O., et al. (2008). Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 111, 3991–3997. doi: 10.1182/blood-2007-08-110098

Ataga, K. I., and Stocker, J. (2009). Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia. Expert Opin. Investig. Drugs 18, 231–239. doi: 10.1517/13543780802708011

Awojoodu, A. O., Keegan, P. M., Lane, A. R., Zhang, Y., Lynch, K. R., Platt, M. O., et al. (2014). Acid sphingomyelinase is activated in sickle cell erythrocytes and contributes to inflammatory microparticle generation in SCD. Blood 124, 1941–1950. doi: 10.1182/blood-2014-01-543652

Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., et al. (2013). An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342, 253–257. doi: 10.1126/science.1242088

Bernaudin, F., Dalle, J. H., Bories, D., de Latour, R. P., Robin, M., Bertrand, Y., et al. (2020). Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France. Haematologica 105, 91–101. doi: 10.3324/haematol.2018.213207

Berthaut, I., Guignedoux, G., Kirsch-Noir, F., de Larouziere, V., Ravel, C., Bachir, D., et al. (2008). Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males. Haematologica 93, 988–993. doi: 10.3324/haematol.11515

Bhat, S., and Han, J. (2017). Outcomes of rivaroxaban use in patients with sickle cell disease. Ann. Pharmacother. 51, 357–358. doi: 10.1177/1060028016681129

Bolanos-Meade, J., Cooke, K. R., Gamper, C. J., Ali, S. A., Ambinder, R. F., Borrello, I. M., et al. (2019). Lancet Haematol . 6, e183–e193.

Google Scholar

Bolanos-Meade, J., Fuchs, E. J., Luznik, L., Lanzkron, S. M., Gamper, C. J., Jones, R. J., et al. (2012). HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 120, 4285–4291. doi: 10.1182/blood-2012-07-438408

Boulad, F., Shore, T., van Besien, K., Minniti, C., Barbu-Stevanovic, M., Fedus, S. W., et al. (2018). Safety and efficacy of plerixafor dose escalation for the mobilization of CD34(+) hematopoietic progenitor cells in patients with sickle cell disease: interim results. Haematologica 103, 770–777. doi: 10.3324/haematol.2017.187047

Breda, L., Motta, I., Lourenco, S., Gemmo, C., Deng, W., Rupon, J. W., et al. (2016). Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers. Blood 128, 1139–1143. doi: 10.1182/blood-2016-01-691089

Brendel, C., Guda, S., Renella, R., Bauer, D. E., Canver, M. C., Kim, Y. J., et al. (2016). Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J. Clin. Invest. 126, 3868–3878. doi: 10.1172/JCI87885

Brittenham, G. M., Schechter, A. N., and Noguchi, C. T. (1985). Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes. Blood 65, 183–189.

Brunson, A., Lei, A., Rosenberg, A. S., White, R. H., Keegan, T., and Wun, T. (2017). Increased incidence of VTE in sickle cell disease patients: risk factors, recurrence and impact on mortality. Br. J. Haematol. 178, 319–326. doi: 10.1111/bjh.14655

Bunn, H. F. (1997). Pathogenesis and treatment of sickle cell disease. N. Engl. J. Med. 337, 762–769.

Cavazzana, M., Antoniani, C., and Miccio, A. (2017). Gene therapy for beta-hemoglobinopathies. Mol. Ther. 25, 1142–1154. doi: 10.1016/j.ymthe.2017.03.024

Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., et al. (2010). Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 467, 318–322. doi: 10.1038/nature09328

Chou, S. T., Alsawas, M., Fasano, R. M., Field, J. J., Hendrickson, J. E., Howard, J., et al. (2020). American society of hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 4, 327–355. doi: 10.1182/bloodadvances.2019001143

Chou, S. T., Evans, P., Vege, S., Coleman, S. L., Friedman, D. F., Keller, M., et al. (2018). RH genotype matching for transfusion support in sickle cell disease. Blood 132, 1198–1207. doi: 10.1182/blood-2018-05-851360

Chou, S. T., Jackson, T., Vege, S., Smith-Whitley, K., Friedman, D. F., and Westhoff, C. M. (2013). High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from RH-matched minority donors. Blood 122, 1062–1071. doi: 10.1182/blood-2013-03-490623

Cokic, V. P., Smith, R. D., Beleslin-Cokic, B. B., Njoroge, J. M., Miller, J. L., Gladwin, M. T., et al. (2003). Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J. Clin. Invest. 111, 231–239. doi: 10.1172/JCI16672

Conran, N., and Belcher, J. D. (2018). Inflammation in sickle cell disease. Clin. Hemorheol. Microcirc. 68, 263–299. doi: 10.3233/CH-189012

Conran, N., and Rees, D. C. (2017). Prasugrel hydrochloride for the treatment of sickle cell disease. Expert Opin. Investig. Drugs 26, 865–872. doi: 10.1080/13543784.2017.1335710

De Castro, L. M., Zennadi, R., Jonassaint, J. C., Batchvarova, M., and Telen, M. J. (2012). Effect of propranolol as antiadhesive therapy in sickle cell disease. Clin. Transl. Sci. 5, 437–444. doi: 10.1111/cts.12005

DeBaun, M. R. (2014). Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review. Expert Rev. Hematol. 7, 767–773. doi: 10.1586/17474086.2014.959922

Dever, D. P., Bak, R. O., Reinisch, A., Camarena, J., Washington, G., Nicolas, C. E., et al. (2016). CRISPR/Cas9 beta-globin gene targeting in human haematopoietic stem cells. Nature 539, 384–389. doi: 10.1038/nature20134

Eaton, W. A., and Bunn, H. F. (2017). Treating sickle cell disease by targeting HbS polymerization. Blood 129, 2719–2726. doi: 10.1182/blood-2017-02-765891

Elmariah, H., Garrett, M. E., De Castro, L. M., Jonassaint, J. C., Ataga, K. I., Eckman, J. R., et al. (2014). Factors associated with survival in a contemporary adult sickle cell disease cohort. Am. J. Hematol. 89, 530–535. doi: 10.1002/ajh.23683

Esrick, E. B., and Bauer, D. E. (2018). Genetic therapies for sickle cell disease. Semin. Hematol. 55, 76–86. doi: 10.1053/j.seminhematol.2018.04.014

Esrick, E. B., Manis, J. P., Daley, H., Baricordi, C., Trebeden-Negre, H., Pierciey, F. J., et al. (2018). Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients. Blood Adv. 2, 2505–2512. doi: 10.1182/bloodadvances.2018016725

Esrick, E. B., McConkey, M., Lin, K., Frisbee, A., and Ebert, B. L. (2015). Inactivation of HDAC1 or HDAC2 induces gamma globin expression without altering cell cycle or proliferation. Am. J. Hematol. 90, 624–628. doi: 10.1002/ajh.24019

Fitzhugh, C. D., Abraham, A. A., Tisdale, J. F., and Hsieh, M. M. (2014). Hematopoietic stem cell transplantation for patients with sickle cell disease: progress and future directions. Hematol. Oncol. Clin. N. Am. 28, 1171–1185. doi: 10.1016/j.hoc.2014.08.014

Fitzhugh, C. D., Cordes, S., Taylor, T., Coles, W., Roskom, K., Link, M., et al. (2017). At least 20% donor myeloid chimerism is necessary to reverse the sickle phenotype after allogeneic HSCT. Blood 130, 1946–1948. doi: 10.1182/blood-2017-03-772392

Gardner, K., Douiri, A., Drasar, E., Allman, M., Mwirigi, A., Awogbade, M., et al. (2016). Survival in adults with sickle cell disease in a high-income setting. Blood 128, 1436–1438. doi: 10.1182/blood-2016-05-716910

Gardner, K., and Thein, S. L. (2016). “Genetic factors modifying sickle cell disease severity,” in Sickle Cell Anemia - From Basic Science to Clinical Practice , eds F. F. Costa and N. Conran (Cham: Springer International), 371–397.

Gluckman, E., Cappelli, B., Bernaudin, F., Labopin, M., Volt, F., Carreras, J., et al. (2017). Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood 129, 1548–1556. doi: 10.1182/blood-2016-10-745711

Goldstein, J., Konigsberg, W., and Hill, R. J. (1963). The structure of human hemoglobin: VI. The sequence of amino acids in the tryptic peptides of the β chain. J. Biol. Chem. 238, 2016–2027.

Guilcher, G. M. T., Truong, T. H., Saraf, S. L., Joseph, J. J., Rondelli, D., and Hsieh, M. M. (2018). Curative therapies: allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease. Semin. Hematol. 55, 87–93. doi: 10.1053/j.seminhematol.2018.04.011

Hanggi, P., Makhro, A., Gassmann, M., Schmugge, M., Goede, J. S., Speer, O., et al. (2014). Red blood cells of sickle cell disease patients exhibit abnormally high abundance of N-methyl D-aspartate receptors mediating excessive calcium uptake. Br. J. Haematol. 167, 252–264. doi: 10.1111/bjh.13028

Hassell, K. L. (2010). Population estimates of sickle cell disease in the U.S. Am. J. Prev. Med. 38, S512–S521. doi: 10.1016/j.amepre.2009.12.022

Hassell, K. L. (2016). Sickle cell disease: a continued call to action. Am. J. Prev. Med. 51, S1–S2. doi: 10.1016/j.amepre.2015.11.002

Hebbel, R. P. (2011). Reconstructing sickle cell disease: a data-based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence-based medicine. Am. J. Hematol. 86, 123–154. doi: 10.1002/ajh.21952

Hebbel, R. P., and Hedlund, B. E. (2018). Sickle hemoglobin oxygen affinity-shifting strategies have unequal cerebrovascular risks. Am. J. Hematol. 93, 321–325. doi: 10.1002/ajh.24975

Heeney, M. M., Hoppe, C. C., Abboud, M. R., Inusa, B., Kanter, J., Ogutu, B., et al. (2016). A multinational trial of prasugrel for sickle cell vaso-occlusive events. N. Engl. J. Med. 374, 625–635. doi: 10.1056/NEJMoa1512021

Hendrickson, J. E., and Tormey, C. A. (2018). Rhesus pieces: genotype matching of RBCs. Blood 132, 1091–1093. doi: 10.1182/blood-2018-07-865634

Herrick, J. B. (1910). Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch. Intern. Med. 6, 517–521. doi: 10.1001/jama.2014.11011

Herrick, J. B. (2014). Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. JAMA 312:1063. doi: 10.1001/jama.2014.11011

Hoppe, C., Jacob, E., Styles, L., Kuypers, F., Larkin, S., and Vichinsky, E. (2017). Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial. Br. J. Haematol. 177, 620–629. doi: 10.1111/bjh.14580

Howard, J. (2016). Sickle cell disease: when and how to transfuse. Hematol. Am. Soc. Hematol. Educ. Program 2016, 625–631. doi: 10.1182/asheducation-2016.1.625

Howard, J., Malfroy, M., Llewelyn, C., Choo, L., Hodge, R., Johnson, T., et al. (2013). The transfusion alternatives preoperatively in sickle cell disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Lancet 381, 930–938. doi: 10.1016/S0140-6736(12)61726-7

Hsieh, M. M., Fitzhugh, C. D., Weitzel, R. P., Link, M. E., Coles, W. A., Zhao, X., et al. (2014). Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA 312, 48–56. doi: 10.1001/jama.2014.7192

Hsieh, M. M., Kang, E. M., Fitzhugh, C. D., Link, M. B., Bolan, C. D., Kurlander, R., et al. (2009). Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. N. Engl. J. Med. 361, 2309–2317. doi: 10.1056/NEJMoa0904971

Hsieh, M. M., and Tisdale, J. F. (2018). Hematopoietic stem cell mobilization with plerixafor in sickle cell disease. Haematologica 103, 749–750. doi: 10.3324/haematol.2018.190876

Inamoto, Y., Kimura, F., Kanda, J., Sugita, J., Ikegame, K., Nakasone, H., et al. (2016). Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups. Haematologica 101, 1592–1602. doi: 10.3324/haematol.2016.149427

Johnson, F. L. (1985). Bone marrow transplantation in the treatment of sickle cell anemia. Am. J. Pediatr. Hematol. Oncol. 7, 254–257.

Johnson, F. L., Look, A. T., Gockerman, J., Ruggiero, M. R., Dalla-Pozza, L., and Billings, F. T. (1984). Bone-marrow transplantation in a patient with sickle-cell anemia. N. Engl. J. Med. 311, 780–783. doi: 10.1056/NEJM198409203111207

Jones, K. M., Niaz, M. S., Brooks, C. M., Roberson, S. I., Aguinaga, M. P., Hills, E. R., et al. (2009). Adverse effects of a clinically relevant dose of hydroxyurea used for the treatment of sickle cell disease on male fertility endpoints. Int. J. Environ. Res. Public Health 6, 1124–1144. doi: 10.3390/ijerph6031124

Joseph, J. J., Abraham, A. A., and Fitzhugh, C. D. (2018). When there is no match, the game is not over: alternative donor options for hematopoietic stem cell transplantation in sickle cell disease. Semin. Hematol. 55, 94–101. doi: 10.1053/j.seminhematol.2018.04.013

Kamani, N. R., Walters, M. C., Carter, S., Aquino, V., Brochstein, J. A., Chaudhury, S., et al. (2012). Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the blood and marrow transplant clinical trials network (BMT CTN). Biol. Blood Marrow Transplant. 18, 1265–1272. doi: 10.1016/j.bbmt.2012.01.019

Kanter, J., Abboud, M. R., Kaya, B., Nduba, V., Amilon, C., Gottfridsson, C., et al. (2019). Ticagrelor does not impact patient-reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIB study. Br. J. Haematol. 184, 269–278. doi: 10.1111/bjh.15646

Kutlar, A., Kanter, J., Liles, D. K., Alvarez, O. A., Cancado, R. D., Friedrisch, J. R., et al. (2019). Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am. J. Hematol. 94, 55–61. doi: 10.1002/ajh.25308

Lagresle-Peyrou, C., Lefrere, F., Magrin, E., Ribeil, J. A., Romano, O., Weber, L., et al. (2018). Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion. Haematologica 103, 778–786. doi: 10.3324/haematol.2017.184788

Leonard, A., Tisdale, J., and Abraham, A. (2020). Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy? Br. J. Haematol. doi: 10.1111/bjh.16437 [Epub ahead of print].

CrossRef Full Text | PubMed Abstract | Google Scholar

Leonard, A., and Tisdale, J. F. (2018). Stem cell transplantation in sickle cell disease: therapeutic potential and challenges faced. Expert Rev. Hematol. 11, 547–565. doi: 10.1080/17474086.2018.1486703

Liu, N., Hargreaves, V. V., Zhu, Q., Kurland, J. V., Hong, J., Kim, W., et al. (2018). Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell 173, 430–42.e17. doi: 10.1016/j.cell.2018.03.016

Luzzatto, L., and Makani, J. (2019). Hydroxyurea - an essential medicine for sickle cell disease in Africa. N. Engl. J. Med. 380, 187–189. doi: 10.1056/NEJMe1814706

Martyn, G. E., Wienert, B., Yang, L., Shah, M., Norton, L. J., Burdach, J., et al. (2018). Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nat. Genet. 50, 498–503. doi: 10.1038/s41588-018-0085-0

Masuda, T., Wang, X., Maeda, M., Canver, M. C., Sher, F., Funnell, A. P., et al. (2016). Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 351, 285–289. doi: 10.1126/science.aad3312

McArthur, J. G., Svenstrup, N., Chen, C., Fricot, A., Carvalho, C., Nguyen, J., et al. (2019). A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease. Haematologica 105, 623–631. doi: 10.3324/haematol.2018.213462

McGann, P. T. (2014). Sickle cell anemia: an underappreciated and unaddressed contributor to global childhood mortality. J. Pediatr. 165, 18–22. doi: 10.1016/j.jpeds.2014.01.070

Miller, S. T., Sleeper, L. A., Pegelow, C. H., Enos, L. E., Wang, W. C., Weiner, S. J., et al. (2000). Prediction of adverse outcomes in children with sickle cell disease. N. Engl. J. Med. 342, 83–89. doi: 10.1056/NEJM200005253422114

Minniti, C. P. (2018). l-glutamine and the dawn of combination therapy for sickle cell disease. N. Engl. J. Med. 379, 292–294. doi: 10.1056/NEJMe1800976

Molokie, R., Lavelle, D., Gowhari, M., Pacini, M., Krauz, L., Hassan, J., et al. (2017). Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: a randomized phase 1 study. PLoS Med. 14:e1002382. doi: 10.1371/journal.pmed.1002382

Morris, C. R., Suh, J. H., Hagar, W., Larkin, S., Bland, D. A., Steinberg, M. H., et al. (2008). Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 111, 402–410. doi: 10.1182/blood-2007-04-081703

Nasimuzzaman, M., and Malik, P. (2019). Role of the coagulation system in the pathogenesis of sickle cell disease. Blood Adv. 3, 3170–3180. doi: 10.1182/bloodadvances.2019000193

Nayerossadat, N., Maedeh, T., and Ali, P. A. (2012). Viral and nonviral delivery systems for gene delivery. Adv. Biomed. Res. 1:27. doi: 10.4103/2277-9175.98152

Negre, O., Eggimann, A. V., Beuzard, Y., Ribeil, J. A., Bourget, P., Borwornpinyo, S., et al. (2016). Gene therapy of the beta-hemoglobinopathies by lentiviral transfer of the beta(A(T87Q))-globin gene. Hum. Gene Ther. 27, 148–165. doi: 10.1089/hum.2016.007

Nevitt, S. J., Jones, A. P., and Howard, J. (2017). Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database. Syst. Rev. 4:CD002202. doi: 10.1002/14651858.CD002202.pub2

Niihara, Y., Miller, S. T., Kanter, J., Lanzkron, S., Smith, W. R., Hsu, L. L., et al. (2018). A phase 3 trial of l-glutamine in sickle cell disease. N. Engl. J. Med. 379, 226–235. doi: 10.1056/NEJMoa1715971

Nur, E., Brandjes, D. P., Teerlink, T., Otten, H. M., Oude Elferink, R. P., Muskiet, F., et al. (2012). N-acetylcysteine reduces oxidative stress in sickle cell patients. Ann. Hematol. 91, 1097–1105. doi: 10.1007/s00277-011-1404-z

Ohene-Frempong, K., Weiner, S. J., Sleeper, L. A., Miller, S. T., Embury, S., Moohr, J. W., et al. (1998). Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 91, 288–294.

Opoka, R. O., Ndugwa, C. M., Latham, T. S., Lane, A., Hume, H. A., Kasirye, P., et al. (2017). Novel use of hydroxyurea in an African region with malaria (NOHARM): a trial for children with sickle cell anemia. Blood 130, 2585–2593. doi: 10.1182/blood-2017-06-788935

Orkin, S. H., and Bauer, D. E. (2019). Emerging genetic therapy for sickle cell disease. Annu. Rev. Med. 70, 257–271. doi: 10.1146/annurev-med-041817-125507

Orringer, E. P., Casella, J. F., Ataga, K., Koshy, M., Adams-Graves, P., Luchtman-Jones, L., et al. (2001). Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: a randomized controlled trial. JAMA 286, 2099–2106. doi: 10.1001/jama.286.17.2099

Pace, B. S., Shartava, A., Pack-Mabien, A., Mulekar, M., Ardia, A., and Goodman, S. R. (2003). Effects of N-acetylcysteine on dense cell formation in sickle cell disease. Am. J. Hematol. 73, 26–32. doi: 10.1002/ajh.10321

Piel, F. B., Hay, S. I., Gupta, S., Weatherall, D. J., and Williams, T. N. (2013). Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 10:e1001484. doi: 10.1371/journal.pmed.1001484

Quinn, C. T. (2016). Minireview: clinical severity in sickle cell disease: the challenges of definition and prognostication. Exp. Biol. Med. 241, 679–688. doi: 10.1177/1535370216640385

Quinn, C. T. (2018). l-Glutamine for sickle cell anemia: more questions than answers. Blood 132, 689–693. doi: 10.1182/blood-2018-03-834440

Quinn, C. T., Rogers, Z. R., McCavit, T. L., and Buchanan, G. R. (2010). Improved survival of children and adolescents with sickle cell disease. Blood 115, 3447–3452. doi: 10.1182/blood-2009-07-233700

Rees, D. C. (2019). Double-blind, randomized study of canakinumab treatment in pediatric and young adult patients with sickle cell anemia. Blood 134(Suppl._1):615.

Ribeil, J. A., Hacein-Bey-Abina, S., Payen, E., Magnani, A., Semeraro, M., Magrin, E., et al. (2017). Gene therapy in a patient with sickle cell disease. N. Engl. J. Med. 376, 848–855.

Saiki, R. K., Scharf, S., Faloona, F., Mullis, K. B., Horn, G. T., Erlich, H. A., et al. (1985). Enzymatic amplification of b-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anaemia. Science 230, 1350–1354.

Saraf, S. L., Oh, A. L., Patel, P. R., Sweiss, K., Koshy, M., Campbell-Lee, S., et al. (2018). Haploidentical peripheral blood stem cell transplantation demonstrates stable engraftment in adults with sickle cell disease. Biol. Blood Marrow Transplant. 24, 1759–1765. doi: 10.1016/j.bbmt.2018.03.031

Serjeant, G. R., Chin, N., Asnani, M. R., Serjeant, B. E., Mason, K. P., Hambleton, I. R., et al. (2018). Causes of death and early life determinants of survival in homozygous sickle cell disease: the Jamaican cohort study from birth. PLoS One 13:e0192710. doi: 10.1371/journal.pone.0192710

Shenoy, S. (2013). Hematopoietic stem-cell transplantation for sickle cell disease: current evidence and opinions. Ther. Adv. Hematol. 4, 335–344. doi: 10.1177/2040620713483063

Sins, J. W. R., Mager, D. J., Davis, S., Biemond, B. J., and Fijnvandraat, K. (2017). Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: a systematic review. Blood Adv. 1, 1598–1616. doi: 10.1182/bloodadvances.2017007211

Sparkenbaugh, E., Chantrathammachart, P., Mickelson, J., van Ryn, J., Hebbel, R. P., Monroe, D. M., et al. (2014). Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease. Blood 123, 1747–1756. doi: 10.1182/blood-2013-08-523936

Sparkenbaugh, E., and Pawlinski, R. (2013). Interplay between coagulation and vascular inflammation in sickle cell disease. Br. J. Haematol. 162, 3–14. doi: 10.1111/bjh.12336

Steinberg, M. H., Forget, B. G., Higgs, D. R., and Nagel, R. L. (2001). Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management , 1st Edn. Cambridge: Cambridge University Press.

Strader, M. B., Liang, H., Meng, F., Harper, J., Ostrowski, D. A., Henry, E. R., et al. (2019). Interactions of an anti-sickling drug with hemoglobin in red blood cells from a patient with sickle cell anemia. Bioconjug. Chem. 30, 568–571. doi: 10.1021/acs.bioconjchem.9b00130

Sundd, P., Gladwin, M. T., and Novelli, E. M. (2019). Pathophysiology of sickle cell disease. Annu. Rev. Pathol. 14, 263–292.

Telen, M. J. (2016). Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Blood 127, 810–819. doi: 10.1182/blood-2015-09-618553

Telen, M. J., Batchvarova, M., Shan, S., Bovee-Geurts, P. H., Zennadi, R., Leitgeb, A., et al. (2016). Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion. Br. J. Haematol. 175, 935–948. doi: 10.1111/bjh.14303

Telen, M. J., Malik, P., and Vercellotti, G. M. (2019). Therapeutic strategies for sickle cell disease: towards a multi-agent approach. Nat. Rev. Drug Discov. 18, 139–158. doi: 10.1038/s41573-018-0003-2

Telen, M. J., Wun, T., McCavit, T. L., De Castro, L. M., Krishnamurti, L., Lanzkron, S., et al. (2015). Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood 125, 2656–2664. doi: 10.1182/blood-2014-06-583351

Telfer, P., Coen, P., Chakravorty, S., Wilkey, O., Evans, J., Newell, H., et al. (2007). Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. Haematologica 92, 905–912. doi: 10.3324/haematol.10937

Thein, S. L., Pirenne, F., Fasano, R. M., Habibi, A., Bartolucci, P., Chonat, S., et al. (2020). Hemolytic transfusion reactions in sickle cell disease: underappreciated and potentially fatal. Haematologica 105, 539–544. doi: 10.3324/haematol.2019.224709

Thompson, A. A. (2019). Targeted agent for sickle cell disease - changing the protein but not the gene. N. Engl. J. Med. 381, 579–580. doi: 10.1056/NEJMe1906771

Traxler, E. A., Yao, Y., Wang, Y. D., Woodard, K. J., Kurita, R., Nakamura, Y., et al. (2016). A genome-editing strategy to treat beta-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat. Med. 22, 987–990. doi: 10.1038/nm.4170

Tshilolo, L., Tomlinson, G., Williams, T. N., Santos, B., Olupot-Olupot, P., Lane, A., et al. (2019). Hydroxyurea for children with sickle cell anemia in sub-saharan Africa. N. Engl. J. Med. 380, 121–131. doi: 10.1056/NEJMoa1813598

van Zuuren, E. J., and Fedorowicz, Z. (2015). Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease. Cochrane Database Syst. Rev. 6:CD010155. doi: 10.1002/14651858.CD010155.pub3

Vichinsky, E., Hoppe, C. C., Ataga, K. I., Ware, R. E., Nduba, V., El-Beshlawy, A., et al. (2019). A phase 3 randomized trial of voxelotor in sickle cell disease. N. Engl. J. Med. 381, 509–519. doi: 10.1056/NEJMoa1903212

Vichinsky, E. P., Earles, A., Johnson, R. A., Hoag, M. S., Williams, A., and Lubin, B. (1990). Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. N. Engl. J. Med. 322, 1617–1621. doi: 10.1056/NEJM199006073222301

Villagra, J., Shiva, S., Hunter, L. A., Machado, R. F., Gladwin, M. T., and Kato, G. J. (2007). Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood 110, 2166–2172. doi: 10.1182/blood-2006-12-061697

Vinjamur, D. S., Bauer, D. E., and Orkin, S. H. (2018). Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies. Br. J. Haematol. 180, 630–643. doi: 10.1111/bjh.15038

Wailoo, K. (2017). Sickle cell disease - a history of progress and peril. N. Engl. J. Med. 376, 805–807. doi: 10.1056/NEJMp1700101

Walters, M. C., Hardy, K., Edwards, S., Adamkiewicz, T., Barkovich, J., Bernaudin, F., et al. (2010). Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease. Biol. Blood Marrow Transplant. 16, 263–272. doi: 10.1016/j.bbmt.2009.10.005

Walters, M. C., Patience, M., Leisenring, W., Eckman, J. R., Buchanan, G. R., Rogers, Z. R., et al. (1996a). Barriers to bone marrow transplantation for sickle cell anemia. Biol. Blood Marrow Transplant. 2, 100–104.

Walters, M. C., Patience, M., Leisenring, W., Eckman, J. R., Scott, J. P., Mentzer, W. C., et al. (1996b). Bone marrow transplantation for sickle cell disease. N. Engl. J. Med. 335, 369–376. doi: 10.1002/ajh.24995

Walters, M. C., Patience, M., Leisenring, W., Rogers, Z. R., Aquino, V. M., Buchanan, G. R., et al. (2001). Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biol. Blood Marrow Transplant. 7, 665–673. doi: 10.1053/bbmt.2001.v7.pm11787529

Wang, W. C., Ware, R. E., Miller, S. T., Iyer, R. V., Casella, J. F., Minniti, C. P., et al. (2011). Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 377, 1663–1672. doi: 10.1016/S0140-6736(11)60355-3

Ware, R. E. (2015). Optimizing hydroxyurea therapy for sickle cell anemia. Hematol. Am. Soc. Hematol. Educ. Program 2015, 436–443. doi: 10.1182/asheducation-2015.1.436

Ware, R. E., and Aygun, B. (2009). Advances in the use of hydroxyurea. Hematol. Am. Soc. Hematol. Educ. Program 2009, 62–69.

Ware, R. E., Davis, B. R., Schultz, W. H., Brown, R. C., Aygun, B., Sarnaik, S., et al. (2016). Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD with transfusions changing to hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 387, 661–670. doi: 10.1016/S0140-6736(15)01041-7

Ware, R. E., Schultz, W. H., Yovetich, N., Mortier, N. A., Alvarez, O., Hilliard, L., et al. (2011). Stroke with transfusions changing to hydroxyurea (SWiTCH): a phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload. Pediatr. Blood Cancer 57, 1011–1017. doi: 10.1002/pbc.23145

Wienert, B., Martyn, G. E., Funnell, A. P. W., Quinlan, K. G. R., and Crossley, M. (2018). Wake-up sleepy gene: reactivating fetal globin for beta-hemoglobinopathies. Trends Genet. 34, 927–940. doi: 10.1016/j.tig.2018.09.004

Williams, T. N., and Thein, S. L. (2018). Sickle cell anemia and its phenotypes. Annu. Rev. Genomics Hum. Genet. 19, 113–147. doi: 10.1146/annurev-genom-083117-021320

Wilson, J. T., Milner, P. F., Summer, M. E., Nallaseth, F. S., Fadel, H. E., Reindollar, R. H., et al. (1982). Use of restriction endonucleases for mapping the allele for beta s-globin. Proc. Natl. Acad. Sci. U.S.A. 79, 3628–3631. doi: 10.1073/pnas.79.11.3628

Wun, T., Paglieroni, T., Tablin, F., Welborn, J., Nelson, K., and Cheung, A. (1997). Platelet activation and platelet-erythrocyte aggregates in patients with sickle cell anemia. J. Lab. Clin. Med. 129, 507–516. doi: 10.1016/s0022-2143(97)90005-6

Zhang, D., Xu, C., Manwani, D., and Frenette, P. S. (2016). Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood 127, 801–809. doi: 10.1182/blood-2015-09-618538

Keywords : sickle cell disease, anti-sickling agents, gene editing, gene therapy, hemoglobinopathies

Citation: Salinas Cisneros G and Thein SL (2020) Recent Advances in the Treatment of Sickle Cell Disease. Front. Physiol. 11:435. doi: 10.3389/fphys.2020.00435

Received: 30 December 2019; Accepted: 08 April 2020; Published: 20 May 2020.

Reviewed by:

Copyright © 2020 Salinas Cisneros and Thein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Swee L. Thein, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Background: Sickle cell disease causes significant morbidity and mortality and affects the economic and healthcare status of many countries. Yet historically, the disease has not had commensurate outlays of funds that have been aimed at research and development of drugs and treatment procedures for other diseases.

Methods: This review examines several treatment modalities and new drugs developed since the late 1990s that have been used to improve outcomes for patients with sickle cell disease.

Results: Targeted therapies based upon the pathophysiologic mechanisms of sickle cell disease that result in organ dysfunction and painful episodes include hydroxyurea, L-glutamine, crizanlizumab, and other drugs that are currently on the market or are on the verge of becoming available. These agents have the potential to improve survival and quality of life for individuals with sickle cell disease. Also discussed is stem cell transplantation that, to date, is the only curative approach for this disease, as well as the current status of gene therapy.

Conclusion: These examples demonstrate how the current knowledge of sickle cell disease pathophysiology and treatment approaches intersect. Although interest in sickle cell research has blossomed, many more clinical trials need to be initiated and subjected to more strenuous examination and analysis than have been used in the past.

• Anemia–sickle cell
• genetic therapy
• hydroxyurea
• oxidative stress
• stem cell transplantation
• INTRODUCTION

In 1910, sickle cell disease burst onto the Western medical scene as a “strange” or, as Herrick termed it, a “new, unknown disease.” 1 Physicians were intrigued by the sickled appearance of the red cells in this disorder, and case reports and analytical papers detailing the clinical features of this disorder appeared to almost always involve people of color. 2-6 The disease then became known as a “black disease.” 6-8 Not until 1949, however, was the molecular nature of sickle cell discovered. 9 In 1958, Ingram discovered the genetic basis of the disease and demonstrated that the disease originated from the substitution of a valine for glutamic acid at the sixth amino acid position of the hemoglobin beta chain. 10 This amino acid substitution, now known to be the result of a single point mutation of the hemoglobin gene, produces profound changes in the behavior and conformation of the hemoglobin molecule in individuals affected by the disease. 11

In 1927, Hahn and Gillespie had reported on the mechanism of sickle formation, observing that the sickle hemoglobin in its deoxygenated state assumed the characteristic shape, the sickle, that gives the disorder its name. 12 Cells containing deoxygenated hemoglobin not only formed this rigid shape but also were dehydrated, 13 had abnormal cell surface and distinct migratory characteristics, were sticky and prone to adhesion, and had abnormal rheologic properties. 14 , 15 Clinically, not only did patients with sickle cell disease experience repeated painful episodes (crises), but because of recurrent episodes of vaso-occlusion, they ultimately suffered chronic organ damage. Physicians noted a paucity of individuals who survived into their adult years. 6

Sickle cell disease, one of the most common inherited diseases worldwide, is now understood to be a disorder of global importance and economic as well as clinical significance. Those affected by the disease live in areas of sub-Saharan Africa, the Middle East, India, the Caribbean, South and Central America, some countries along the Mediterranean Sea, as well as in the United States and Europe. 16 The disease has, at times, through forced and unforced migration, been introduced to areas in which it was not endemic. 17 In the United States, 80,000-100,000 individuals are affected by the disorder; worldwide, more than 300,000 children are estimated to be born annually with sickle cell disease. 18-20 This number includes approximately 3,000 children born with the disease each year in the United States. 18

Since the 1980s, novel approaches for the treatment of sickle cell disease have included the introduction of penicillin prophylaxis for children with sickle cell, 21 the institution of newborn screening programs, 22 and the use of transcranial Doppler screening for detection of cerebral vasculopathy and stroke prevention. 23 Hematologists have long recognized the need for better treatments of sickle cell. Optimally, a treatment approach was needed that did not just address pain or treat and prevent sequelae of the disease (eg, susceptibility to infection from asplenia). What was needed instead was a treatment approach that worked by undercutting the pathophysiology of the disease. Research efforts previously concentrated on understanding the pathogenesis of the disease rather than on providing greater relief for the patients having the disorder. Progress in arriving at satisfactory treatment of individuals with sickle cell has often seemed to be a slow, halting process. Also, funding for research of sickle cell disease lagged behind that of other genetic diseases, fueling a suspicion that racial bias prevented significant outlays of moneys for study of the disorder. 24-27 The innovations enumerated above did result in stepwise improvements in survival, so the median life expectancy for those with homozygous disease is now into the fourth and fifth decades. 28

Beyond hydroxyurea, which was introduced into clinical practice in the 1980s for adults, 29 , 30 few new drugs have been investigated or placed on the market for the treatment of the disorder until recently. This review investigates areas of potential intervention and promise that have evolved since the late 1990s.

Notably, 2017-2018 have been heralded as the most productive years, yielding novel initiatives aimed at this disease. In 2017, the American Society of Hematology (ASH) introduced its Advocacy Efforts Related to Sickle Cell Disease and Sickle Cell Trait. 31 In February 2018, United States Senators Tim Scott and Cory Booker advanced the Sickle Cell Disease Surveillance, Prevention, and Treatment Act of 2018. 32 ASH’s efforts signaled a commitment to ensuring that individuals with sickle cell disease have access to care, as well as a concerted effort to train and educate physicians about the disease. ASH would also work with federal agencies such as the National Institutes of Health to expand, assess, and prioritize research of the disorder. The legislation introduced by the senators aims to “improve understanding of health care utilization by individuals with sickle cell disease and to establish cost-effective practices to improve and extend the lives of patients.” 32 The legislation, if passed, would award grants to enable a better understanding of the prevalence and distribution of sickle cell disease. The bill is still being considered by the Senate. Those who work in the field of sickle cell disease viewed these two initiatives as an indication of interest in the disorder by the general community and a promise of much-needed funding for the study of a hitherto neglected disease. Because many practitioners, patients, and their families have long felt that the lack of funding or interest in sickle cell disease was an indication of neglect from the general medical community, these initiatives were heartening. 25 , 33-36

• PATHOPHYSIOLOGY OF SICKLE CELL DISEASE

The Figure depicts some of the pathophysiologic components of the disorder in simplified form. New insights into the pathophysiology of the disease are summarized in several comprehensive reviews. 37-41 No longer valid is the simplistic explanation of sickle cells being solely responsible for causing vascular blockage or vaso-occlusion once red cells assume the pathognomonic sickle cell shape following exposure of the cell to deoxygenation. While vaso-occlusion is central to the understanding of the disease and can cause local hypoxemia with ensuing direct tissue injury and inflammation, the single gene mutation seen in sickle cell disease leads to complex physiologic changes. These changes result in the protean clinical manifestations of the disease. We now recognize sickle cell disease as a condition not only characterized by vaso-occlusion, anemia, and hemolysis but also one with heightened inflammation, hypercoagulability, increased oxidative stress, and defective arginine metabolism. Sickle cell disease is a vasculopathy and also features the presence of multiple nutritional and micronutrient deficiencies that adversely affect the patient. 42

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Upon deoxygenation, the sickle hemoglobin is insoluble and undergoes polymerization and aggregation of the polymers into tubulin fibers that then produce sickling. 43 , 44 Because of their rigid shape, the cells are prone to being trapped in the microcirculation, while tissues downstream of this blockage are deprived of blood flow and oxygen and suffer ischemic damage or death. This blood flow deprivation in turn leads to tissue necrosis or reperfusion injury.

These sickle cells are also prone to dehydration because of abnormalities in the Gardos channel. 13 , 45 , 46 These cells are characterized by abnormal activation of intracellular signaling pathways and have less nitric oxide 47 and adenosine triphosphate content. 48 These cells also have less antioxidant capacity. 49 , 50 As a result, many of the cellular components may have oxidative damage. 51 Oxidative damage to the cellular membrane proteins and aggregation of proteins along the inner surface of plasma membranes can lead to intracellular abnormalities at the red cell surface; such changes lead ultimately to increased phosphatidylserine exposure and the formation of microparticles that allow procoagulant activity by the red cell itself. 52

With hemolysis, free hemoglobin is released into the plasma, acting as a scavenger of nitric oxide. 53 , 54 Because arginase-1 activity, necessary for production of nitric oxide, is lower in the sickle cell than in the normal red cell, nitric oxide cannot readily be made de novo, especially in individuals who tend to hemolyze at high rates. Another result of hemolysis is the formation of reactive oxygen species by reactions involving free hemoglobin. 55

In addition, dysregulation of microRNA occurs in the sickle cell, small noncoding RNA molecules function to silence RNA, and posttranscriptional regulation of gene expression occurs. 56 Hence, gene expression is abnormal during erythropoiesis.

The abnormal adhesive properties of the sickle erythrocyte can lead to activation of adhesion receptors, such as those of the intercellular adhesion molecule-4. 57 Similarly, the glycoprotein basal cell adhesion molecule (Lutheran blood group), a transmembrane adhesion molecule found in the vascular endothelium, interacts with the unique integrin alpha 4 beta 1 expressed on sickle cells, mediating their adhesion to the endothelium. 58 , 59 The result is abnormal interactions between red cells, leukocytes, platelets, endothelium, and extracellular matrix proteins. Such abnormal cell-cell interactions lead to a steady process of adherent interactions, driving endothelial cell expression of procoagulant proteins. The mitogen-activated protein kinase ERK 1/2 and the upstream kinase responsible for its activation, MEK 1/2, are constitutively activated in sickle red cells, leading to increased adhesion. 60-62 The selectins E-selectin and P-selectin are upregulated in sickle cell disease and also mediate adhesion, with the degree of red cell adhesion correlating with greater severity of disease. 63

In addition to these changes, the cell containing sickle hemoglobin is stiffer than a normal red cell would be in circulation. 15 , 64-66 Such abnormal deformability persists even when the cell has assumed an apparently normal ovoid shape. Morphologically normal sickle hemoglobin-containing erythrocytes are just as adherent-prone as irreversibly sickled cells.

Inflammation is also key to the initiation of vaso-occlusion. 67 , 68 Even in steady state, leukocytes and platelets are activated, and markers of inflammation are elevated. Multiple inflammatory cytokines, such as interleukin (IL)-10, IL-4, macrophage-inflammatory protein (MIP-1α), and tumor necrosis factor alpha (TNF-α), are elevated even at baseline. 69 , 70 The leukotriene synthetic enzyme 5-lipoxygenase activates both monocytic and endothelial cells, leading to production of leukotrienes that are increased in steady state to the extent that elevated levels correlate with a higher painful event rate. 70

Invariant natural killer T-cells are also activated and present in increased numbers. 71 As an example of their importance, they may play a role in the pathogenesis of ischemia/reperfusion injury in sickle cell disease.

All these changes show how the disorder is a complicated patchwork of contributory pathologies that are fascinating but make it difficult to create an all-encompassing therapeutic strategy.

• TREATMENT OF SICKLE CELL DISEASE

Hemoglobin F Production

Hydroxyurea.

Patients of Arab-Indian haplotype generally manifest high hemoglobin F levels (approximately 20%) and have a mild clinical phenotype of sickle cell disease. 72 , 73 Likewise, patients who are compound heterozygotes for hereditary persistence of fetal hemoglobin (up to 30% hemoglobin F) have few if any manifestations of the disorder. 74 Therefore, the assumption seemed reasonable that inducing hemoglobin F in individuals in which it had been turned off might accrue considerable benefit to patients with sickle cell disease.

Hydroxyurea induces the production of hemoglobin F. Hemoglobin F in turn reduces hemoglobin S polymerization and subsequent sickling. For this reason, hydroxyurea has been the standard of care for patients with sickle cell disease since the late 1980s. 28 , 29 , 75-78 Until 2008-2013, no other drugs carried such promise or were on the horizon. While the efficacy of hydroxyurea is principally attributable to its ability to turn on production of hemoglobin F, other salutary effects include its reduction of the expression of adhesion molecules on red blood cells and the decrease in neutrophil, monocyte, platelet, and reticulocyte numbers that may translate into decreased blood viscosity, fewer deleterious cell-cell interactions, and a reduction in hemolysis. 76-78 The drug has been quite effective in bringing about a reduction in the number of vaso-occlusive pain or acute chest syndrome episodes, the number of hospitalizations, and the number of transfusions required by patients. 79 , 80 Most important, the demonstration of a definite survival advantage for those taking the drug would seem to be a persuasive finding for healthcare providers and patients and an inducement to take it. 80 However, as Brandow and Panepinto noted in a discussion of hydroxyurea use in sickle cell disease, “true effectiveness [of any drug] is dependent upon utilization in real clinical practice.” 81 In one study they reviewed, only 75% of providers used hydroxyurea in their patients who had 3 or more painful episodes per year, and only 30% of individuals who might be eligible for the drug were taking it. 81 Not all barriers to the use of hydroxyurea are known, but some that have been identified include fear of side effects including teratogenesis, effects on fertility, and the possibility of increased risk of malignancy. 81 , 82

Hydroxyurea is recommended for patients with sickle cell disease who meet the following criteria: 83

Patients who have ≥3 moderate to severe pain episodes in a 12-month period

Patients who have a history of stroke and a contraindication to chronic transfusions (as an alternative to receiving no transfusion)

Children who have a history of acute chest syndrome or symptomatic anemia

Infants and children 9 months of age or older who are asymptomatic or have infrequent pain episodes

Interestingly, these recommendations were made for pediatric usage even though no large, randomized trials have been conducted with children. Current usage is based on efficacy studies performed in children that include a randomized, placebo-controlled crossover trial with a small number of children and open-label single-arm studies. 84-86 Because the hydroxyurea arm showed a significant decline in pain crises, the use of hydroxyurea in children appeared to be validated and children could then be treated with this drug, despite its not having US Food and Drug Administration (FDA) approval for this patient population. Hydroxyurea has been safe with minimal side effects and has resulted in a significant decrease in mortality in both adults and children.

The primary reason for ineffectiveness with this drug seems to be noncompliance, but some individuals genuinely are nonresponders. Patient response is also variable. Reasons for the lack of consistency and for the lack of response are not known. Vascular and other changes associated with the disorder that might presage major sickle-related complications may still occur despite the use of hydroxyurea and despite any apparent beneficial effects of the drug. 87 Further, the drug can, over time, have a diminished ability to induce hemoglobin F, perhaps because of marrow exhaustion. 88 Data from 2007 suggest that polymorphisms in genes that regulate hemoglobin F expression, metabolism of the drug, and erythroid progenitor proliferation (individuals having higher degrees of reticulocytosis seem to respond better to hydroxyurea) may also be factors determining the responsiveness of an individual to hydroxyurea. 89

The fact that not everyone will be a candidate for or respond to hydroxyurea increases the exigency to explore other approaches to the treatment of sickle cell, including preventive measures. Efforts have been underway for years to take advantage of the new understanding of the pathophysiology of the disease. Therapeutic candidates ( Table ) have included drugs that are aimed at (1) finding alternative pathways for turning on hemoglobin F production; (2) preventing cellular adhesion and aggregation; (3) altering blood flow dynamics in the vasculature; (4) preventing hemoglobin S polymerization; (5) enhancing the hemoglobin’s oxygen affinity; (6) decreasing inflammation; and (7) targeting directly the genetic mutation of the sickle cell gene. As noted, complete elimination of the mutant gene is not required for clinical improvement to be seen because diminution of hemoglobin S gene expression to 50% has been demonstrated to be sufficient to allow a phenotype similar to sickle trait. 90

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Butyric Acid and Butyrate (HQK-1001)

Other drugs besides hydroxyurea have been proposed that lead to an increase in hemoglobin F. One such drug is butyric acid, a short chain fatty acid. 91-93 Its mechanism of action is not known. Although butyric acid showed early promise, formidable drawbacks to its use included the large amounts required for effect and the necessity for the drug to be given intravenously and in large volume for 4 days every 4 weeks. The inconvenience and the necessity for utilization of a central venous catheter were impediments to its use in patients.

An orally bioavailable form of butyrate, 2,2-dimethylbutyrate (HQK-1001), has been studied. In a phase 1/2 trial of HQK-1001, 21 patients having sickle cell disease completed the study. 92 Increases in hemoglobin F >1.1% above the baseline percentage were observed in 50% of subjects receiving the higher escalating doses of 20 and 30 mg/kg/day. The study period was relatively brief, so the effect on erythropoiesis was not analyzed. Also, as a phase 1/2 study, the study’s purpose was not to assess effectiveness in ameliorating sickle cell disease symptomatology. In a phase 2 trial conducted by Reid and others, the drug was given in a dose of 15 mg/kg twice daily. 93 The mean absolute increase in hemoglobin F was 0.9% with no significant difference in mean changes of hemoglobin. Of note, the mean annualized rate of pain crises for those receiving HQK-1001 was 3.5, whereas the rate for those receiving placebo was 1.7. Adverse effects included gastritis (the dose-limiting side effect), nausea, headache, and fatigue. The study terminated after a planned interim analysis, and the authors concluded that “additional studies of HQK-1001 at this dose and schedule are not recommended in [sickle cell disease].” 93

Decitabine and 5-Azacytidine

The human gamma globin gene is silenced in most individuals during early childhood and through adulthood through epigenetic gene regulation, signifying that modification of gene expression rather than alteration of the genetic code is responsible for controlling or suppressing gene expression levels. DNA methylation, carried out by the enzyme DNA methyltransferase 1 (DNMT1), then enables the developmental switch from the production of the gamma globin to the beta globin chain. 94

Researchers have proposed that interference with or depletion of DNMT1 might prevent the switchoff of hemoglobin F production. 95-100 The drug decitabine and its prodrug 5-azacytidine have been found to deplete DNMT1 levels. 101 In animals, 5-azacytidine produced increases in hemoglobin F levels up to 20 times those produced by hydroxyurea, even in animals that derived minimal benefit from hydroxyurea by being poor responders. 101 In this study with the primary endpoint of hemoglobin F production, hemoglobin F production increased in a dose-dependent fashion with the use of decitabine, and the rate of pain crisis was lower in almost all groups studied. 101 However, the drug has several shortcomings, including poor bioavailability, negligible solid tissue distribution, a very brief half-life, and formation of uridine degradation products that could potentially cause DNA damage and cytotoxicity. Teratogenesis and carcinogenesis are real concerns.

Prevention of Oxidative Stress

L-glutamine.

In 2017, considerable excitement was generated by the announcement of the commercial availability of L-glutamine (Endari), touted as the first new drug approved by the FDA for treatment of sickle cell disease in 30 years. 102 , 103 This agent’s use is based upon the fact that the sickle red cell, because of decreased redox potential, is more susceptible to oxidant stress or damage than a normal red cell. Sickle red cells absorb and utilize L-glutamine to a far greater extent than normal red cells, having rates of L-glutamine utilization that exceed de novo synthesis. Supplementation with L-glutamine therefore leads to improved transport and utilization of glutamine in the sickled erythrocyte and to a subsequent rise in the levels of the naturally occurring redox agents nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide hydrogenase. The increase in redox agents in turn improves the cellular defenses against oxidative stress.

In an open-label pilot clinical trial of the drug, all patients achieved normalization of nicotinamide adenine dinucleotide redox potential and a decrease in permanently sickled cells in peripheral blood. 104 Only 7 adult patients participated in the trial, and no clinical benefit was seen. However, Niihara and associates demonstrated in subsequent clinical trials that all patients experienced normalization of their nicotinamide adenine dinucleotide redox potential and had a decrease in clinical symptoms when given L-glutamine. 104 , 105 In a phase 3 study published in 2014 that included both adults and children, the median cumulative hospital days were lowered by 41%. 105 The frequency of vaso-occlusive episodes was decreased by 25%, and the incidence of acute chest syndrome decreased by more than 50%. 105 Side effects were negligible. However, the rate of withdrawal from the study was unexpectedly high. Patients receiving the drug were given an oral dose of 0.3 g/kg twice daily for 48 weeks, and 62% withdrew in the placebo group vs 49% in the medication arm. Such a large withdrawal of subjects affected the power of analysis for the study and possibly was responsible for the failure of the drug effect to remain statistically significant for the duration of the study. For these reasons, the data have been critically appraised by others as lacking in quality. 106 Another criticism is that the administration of the drug is “onerous”; therefore, long-term compliance might be difficult to maintain since the patient would have “to take a lot of it and mix it up and drink it down two to three times a day.” 106 Another concern is whether insurance will cover the cost of the drug because Medicaid and other insurance providers have been reluctant to cover supplements of any type. 106 , 107 The drug is expensive. A 5 g packet of L-glutamine costs $580-$620 and must be given two or three times daily. 107 While provisions are being made for patient assistance and third-party coverage, the cost is considerable. Last, efficacy is only seen after weeks or months.

Prevention of Adhesion

Crizanlizumab.

As noted previously, adhesion of platelets to red cells, monocytes, and neutrophils is an integral component of the pathogenesis of sickle cell disease. 108 , 109 The degree of red cell adhesion correlates with the severity of disease. Selectins, especially P-selectin which is upregulated in sickle cell disease, are responsible for initiation of the static adhesion of the sickle red cells to the vessel surface and the ensuing vascular obstruction that is seen in crisis or inflammation. 110

For this reason, effort has been devoted to the development of methods to block P-selectin activity. Crizanlizumab, a humanized monoclonal antibody, is one such agent. It blocks cell-cell adhesion by targeting P-selectin. 111 In a double-blind, randomized phase 2 trial, 198 patients were given either high- or low-dose crizanlizumab or placebo. 111 The annual median crisis rate decreased 45.3% in patients who received the high dose of the drug and decreased 32.6% in patients who received the low dose. Eighteen percent of the patients enrolled in the study experienced no crises at all during the treatment phase. The drug was administered by intravenous infusion and was shown to have a relatively long 30-day half-life. However, the fact that the drug is administered by intravenous infusion could possibly prove to be a drawback to its use. Also, the study’s impact and importance were diminished somewhat by not having included children.

Improvement in Flow Dynamics

Poloxamer 188.

Although most of the agents that have been discussed to this point involve a preventive approach to sickle cell disease, poloxamer 188, a nonionic block copolymer surfactant, has been shown to improve microvascular blood flow in sickle cell disease by decreasing blood viscosity. 112-115 How it does so is not well understood. However, poloxamer 188 seems to block aggregating interactions of cells to cells and cells to protein in the blood. In a randomized, double-blind, placebo-controlled trial examining the effects of poloxamer 188 on patients in active crisis, the duration of crisis was decreased in those taking the drug, with 52% reporting crisis resolution vs 37% of those on placebo. 112 Renal dysfunction, however, was reported in early trials of poloxamer 188 for treatment of patients with myocardial infarction. 113 , 114 In an early phase 2 study using poloxamer 188 in sickle cell disease, one patient (of 28) receiving the drug developed renal dysfunction (defined by a rise in serum creatinine), but he had preexistent mild renal impairment. 115 Renal involvement was subsequently presumed to be the result of the presence of low molecular weight substances in the early and less homogeneous formulations of the drug. After purification of poloxamer 188, far fewer cases of renal toxicity were reported. 116 , 117 Orringer and his coinvestigators also showed that the safety profile was acceptable. 112

Prevention of Polymerization

Voxelotor (gbt-440).

Most studies focused on preventing polymerization of the sickle erythrocyte have involved the use of drugs that could turn back the hands of the clock and switch on the production of hemoglobin F. However, a novel drug that inhibits polymerization through a groundbreaking technique has generated considerable excitement among hematologists. Voxelotor (GBT-440) is a small molecule that in binding to hemoglobin S increases the oxygen affinity of the hemoglobin S molecule. 118 , 119 Voxelotor thereby inhibits polymerization of the molecule and can prevent damage to the red cell. Clinical trials involving this drug have been quite promising. In a 90-day trial, a marked decrease in hemolysis from baseline to day 90 was observed, along with a sustained decline in the number of irreversibly sickled cells, a median decrease of about 70%. 120 Preliminary results of a phase 2a clinical trial showed that teenagers given the drug at a dose of 900 mg daily experienced improvement in the disease, while 55% had improvement of hematologic parameters such as hemoglobin and reticulocyte count. 121 In a single-center experience published in 2017, 7 patients who would not have met the strict inclusion criteria established by Global Blood Therapeutics for the company’s phase 3 trial were given the drug for periods up to 15 months. 122 One patient was noncompliant, but all patients taking the drug as instructed had increases in hemoglobin. Hospital admissions for vaso-occlusive crisis declined by 60%, chronic pain described as “background pain” decreased, all patients reported reduced fatigue, and those who required transfusion saw a decrease in transfusions by approximately 50%. For patients who required chronic supplemental oxygen, oxygen saturation increased to the extent that they were able to stop the oxygen. Of course, the experience of 7 people is not conclusive evidence of a drug’s efficacy, and a larger study is needed to prove whether the drug has true effectiveness. Such a phase 3 study is underway, and results are being accrued in an international, multicenter trial ( NCT03036813 ). 123 The FDA has designated the drug as a “breakthrough therapy.” 124

• CURES FOR SICKLE CELL DISEASE

Stem Cell Transplantation

The only cure available to patients with sickle cell disease is stem cell transplantation. However, the selection of patients who should benefit from this treatment modality is controversial. Transplant has been performed, for the most part, in patients who have suffered a stroke, have had multiple episodes of acute chest syndrome, or have had recurrent vaso-occlusive crises (≥3 episodes requiring hospitalization per year), ie, patients considered to have the worst disease severity. 125 Controversies have arisen not only about whom to transplant but also about the optimal age to transplant, source of donor cells, and type of conditioning regimen. 126-130 Most stem cell transplants thus far have relied upon myeloablative conditioning regimens and have been bone marrow–derived with human leukocyte antigen (HLA)-matched sibling donors as the source of stem cells. 131 , 132 But the probability of an individual having a matched sibling donor is only 16%-20% among minorities if an 8 of 8 allele match is sought. 126 , 133 The effort to expand the availability of transplant for most patients with sickle cell disease has led to consideration of alternative donor sources, such as cord blood, matched unrelated, and haploidentical cells.

Gluckman et al conducted a survey of 1,000 recipients of HLA-identical sibling transplants from European, American, and non-European centers. 134 Sixty percent of patients underwent myeloablative conditioning, and the unadjusted overall survival rate after 5 years and event-free survival rate were 92.9% and 91.4%, respectively. 134 Transplant led to stabilization of organ function, gradually ameliorated complications of sickle cell disease such as cardiovascular and pulmonary dysfunction, and reduced the occurrence of vaso-occlusive episodes. In another series, results from HLA-identical sibling transplants after myeloablative conditioning with antithymocyte globulin were reported. 135 The event-free survival rate for sibling transplants after myeloablative regimens was approximately 95% in this series. 135 While myeloablative conditioning has remained the standard of care for hematopoietic stem cell transplantation, it has been associated with toxicities that have included veno-occlusive disease of the liver and neurotoxicities such as seizures, stroke, and brain hemorrhage. 133 Late effects of transplant such as growth failure, hypogonadism, sterility, and secondary malignancies have also been reported. 128-133 The median age for transplantation has been 9-10 years; individuals who are older have not fared as well, with a lower probability of survival in general and of graft-vs-host-disease (GVHD)–free survival in particular. 130

Attempts at decreasing the toxicities associated with transplantation have resulted in the use of less-rigorous conditioning regimens (reduced-intensity conditioning regimens). For these transplants, the goal became producing a state of mixed chimerism in which recipient marrow is incompletely replaced by donor cells, producing in some instances a trait-like phenotype. These regimens have been better tolerated, especially in patients with preexisting comorbidities, and have resulted in an 86%-90% disease-free survival rate. 133 , 136-138 Indications of what the lower limit of red cell donor chimerism is to allow improvement of disease manifestations have varied. In 2017, Fitzhugh and colleagues published a paper in which they stated that chimerism of 20% is necessary to abrogate the sickle phenotype. 139 However, the earlier experience of Walters and coauthors cited results in which one individual with as few as 11% donor cells expressed a hemoglobin S level of 7% and ceased to have a transfusion requirement; he also did not have symptoms consistent with sickle cell disease any longer. 140 One significant problem associated with reduced-intensity transplantation remains the higher likelihood of loss of donor cells or engraftment failure.

The search for alternative sources of stem cells has also led to the use of unrelated donors. Unrelated donor marrow transplants have had less success, with 1- and 2-year event-free survival rates of 76% and 69%, respectively, and overall survival of 86% and 79%, respectively. 140 The rate of GVHD was relatively high (62%), and more GVHD-related deaths occurred than would be ordinarily seen with related donors. 140

Unrelated cord blood has also been proposed as a source of donor cells, but the graft failure rate in one study was fairly high (52%), and the overall survival was 94%. 141 In one trial utilizing a reduced-intensity conditioning regimen prior to transplantation with unrelated cord blood, a graft failure rate up to 63% was observed, leading the authors to conclude that donor engraftment needs to improve before unrelated cord blood transplants can be recommended. 142

Related cord blood transplants are characterized by a significantly longer time to engraftment for neutrophils and platelets. 143-145 In one study with a median follow-up time of 70 months, disease-free survival at 6 years was reported to be 90%. 146 No grade IV GVHD or extensive chronic GVHD was seen, and the cumulative incidence of primary graft failure was low (9%). However, a limitation of this treatment modality is the inability to transplant large individuals or adults using cord blood as a source of donor cells because of insufficient numbers of nucleated or stem cells in the aliquots to be transplanted 147 , 148 and the slower engraftment of neutrophils and delays in immune reconstitution that may place the patient at increased risk of viral illness. 144

Haploidentical transplants have been tried as well but have been reported to have a high rate of graft failure (43%). 149 To improve on this rate of engraftment failure, patients have been treated with cyclophosphamide posttransplantation. 150 , 151 Graft failure after one trial was still 43%, but no serious toxicities were seen. 150 Overall, the use of alternative donors (mismatched related or unrelated) has not resulted in the same measure of success. Graft failure rates of 38%-43% have been recorded, and long-term complications have included declines in renal, pulmonary, and cardiac function because of the transplantation procedure itself. 149 , 150

In summary, transplantation is the optimal treatment for sickle cell disease, being the only curative approach. However, clarification is needed on who is an optimal candidate, and donor sources must be expanded to balance the lesser availability of donors among minorities.

Also, a clear relationship must be established between transplantation outcomes and improved quality of life, a relationship that to date has not been seen consistently or definitively. With regard to quality of life determinations, significant improvement may occur 1 year from a successful transplant, but the data are inconclusive. 152 The reluctance of primary providers to refer individuals for transplantation is a challenge to overcome as well because, as suggested in a retrospective study of hydroxyurea, patients treated with hydroxyurea may have had better survival than those treated with allogeneic stem cell transplantation. 153

Gene Therapy

Because transplantation can be offered to relatively few individuals, hope for reaching more patients with a treatment of curative intent has focused on efforts to develop gene therapy. Recently, progress has been speeding along toward that goal. We now know that the most common single type of genetic variation in people is the single nucleotide polymorphism (SNP). Each SNP represents a nucleotide change in the DNA genome sequence and results in unique nucleotide change(s) in the genomic sequence of DNA. As a result, unique DNA patterns for each individual are produced. Capitalizing on this knowledge, investigators from several groups demonstrated that 3 SNPs are in the BCL11A and HBB gene regions that correlate with high hemoglobin F expression. 154-157 On the other hand, the gene MYB acted as a negative regulator of gamma globin expression. MYB was subsequently silenced by miR16 (microRNA R16) through binding of a 3’-untranslated region. Transfection of miR16 by Pounds and coinvestigators into human basophilic leukemia cell line KU812 cells in vitro resulted in gamma globin activation in a dose-dependent manner. 158 This work eventuated in genetic correction of the sickle cell mutation in human cells and ultimately in actual individuals. Genome editing systems, such as transcription activator–like effector nucleases (TALENs), zinc finger nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) have been developed that can target DNA sequences around sickle mutations in the beta globin gene. 158 , 159 These mutations are then cleaved in a site-specific manner, employing homologous donor templates to modify or replace altered DNA with the properly sequenced DNA. Gene modification of only 18% was sufficient to correct the sickle mutation and allow production of wild-type hemoglobin. On average, these efforts resulted in production of hemoglobin A, comprising 7.3% of total hemoglobin, with rates as high as 12.6%. 160 Effort has also been made to modify the gamma globin gene because fetal hemoglobin is a more potent antisickling hemoglobin than adult or A hemoglobin.

Gene therapy has progressed to the point of human trial and was reported in 2017 in a patient having sickle cell disease. 160 Employing a lentiviral vector encoding the human HBB variant β A-T87Q , researchers performed ex vivo gene transfer into the patient’s own hematopoietic stem cells and then performed an autologous transplant utilizing these cells. The patient had undergone myeloablation with intravenous busulfan. After transduction of CD34+ cells, a steady rise in hemoglobin A T87Q production was noted over time. The patient, previously transfusion-dependent, was able to discontinue red cell transfusions by day 88 posttransplant. The hemoglobin remained stable at levels of 10-12 grams% 6 months later. The hemoglobin percentage remained at 48% by posttransplant month 15, with a corresponding decrease in hemoglobin S levels. Despite concerns about off-target activity of CRISPR/Cas9 or similar nuclease or vector insertional error, no adverse effects were related to the lentiviral transduction of the stem cells, perhaps because lentiviruses tend to insert themselves randomly with a bias toward integration into areas of already expressed genes, thereby minimizing transactivation of nearby genes. This property acts to tamp down the potential for insertional oncogenesis. The patient had no replication-competent lentivirus extant. Most significantly, the patient had no sickle cell–related hospitalizations or other complications. Erythropoiesis progressively showed signs of normalization. No tendency towards clonal domination was detected. This case provides optimism that we are finally moving forward in the search for other curative therapies that can be offered to a wider array of patients than has ever been possible in the past.

These examples of new approaches to the treatment of patients with sickle cell disease sample some of the current attempts to moderate or cure the disorder. Interest in sickle cell research has blossomed and now can offer hope to the many individuals living with this disorder around the world. Many more clinical trials need to be initiated and subjected to more strenuous examination and analysis than have been used in the past. Efforts will have to be made to offer these therapies in less advanced countries where the majority of individuals with sickle cell disease live. These initiatives now appear more possible than ever before.

This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care, Medical Knowledge, and Practice-Based Learning and Improvement.

• ACKNOWLEDGMENTS

The author has no financial or proprietary interest in the subject matter of this article.

• © Academic Division of Ochsner Clinic Foundation
• Washburn RE
• Sickle cell anemia, a race specific disease
• Pauling L ,
• Singer SJ ,
• Conner BJ ,
• Itakura K ,
• Teplitz RL ,
• Gillespie EB
• Brugnara C ,
• de Franceschi L ,
• Mohandas N ,
• Williams TN ,
• Weatherall DJ
• Chakravorty S ,
• Williams TN
• Data & statistics on sickle cell disease. Centers for Disease Control and Prevention
• Gaston MH ,
• Verter JI ,
• Vichinsky E ,
• Bernaudin F ,
• Verlhac S ,
• Strouse JJ ,
• Lanzkron S ,
• Haywood C Jr. .
• Carroll CP ,
• Galanello R ,
• Papayannopoulou T ,
• Stamatoyannopoulos G
• Charache S ,
• American Society of Hematology
• Nelson SC ,
• Zuckerman B
• Bediako SM ,
• Odièvre MH ,
• Silva-Pinto AC ,
• Ilesanmi OO
• Gladwin MT ,
• Schechter AN ,
• Shelhamer JH ,
• Ognibene FP
• Potoka KP ,
• Hyacinth HI ,
• Brittenham GM ,
• Hofrichter J ,
• Tosteson DC ,
• Skelton TD ,
• Swofford HS ,
• Kolpin CE ,
• Reiter CD ,
• Tanus-Santos JE ,
• Lachant NA ,
• Davidson WD ,
• Adelekan DA ,
• Thurnham DI ,
• Ghebremeskel K ,
• Ibegbulam O ,
• Chirico EN ,
• McIntire LV
• El Nemer W ,
• Le Van Kim C
• Wautier MP ,
• Finnegan E ,
• Barabino GA
• Kostova EB ,
• Beuger BM ,
• Schwartz EA ,
• Palmer GM ,
• Solovey A ,
• Lamarre Y ,
• Keikhaei B ,
• Mohseni AR ,
• Norouzirad R ,
• Pathare A ,
• Knight-Perry J ,
• DeBaun MR ,
• Strunk RC ,
• Van Kaer L ,
• Parekh VV ,
• El-Hazmi MA ,
• Al-Hazmi AM ,
• Habara AH ,
• Shaikho EM ,
• Steinberg MH
• Akinsheye I ,
• Alsultan A ,
• Solovieff N ,
• Nascimento EM ,
• Cardoso GP ,
• Agrawal RK ,
• Nainiwal L ,
• Barton FB ,
• Voskaridou E ,
• Christoulas D ,
• Bilalis A ,
• Brandow AM ,
• Panepinto JA
• Jirovec DL ,
• National Heart, Lung, and Blood Institute
• Hillery CA ,
• Misiewicz V ,
• Jayabose S ,
• Sandoval C ,
• Ferster A ,
• Vermylen C ,
• Steinberg MH ,
• Terrin ML ,
• Vichinsky EP ,
• Wyszynski DF ,
• Farrell JJ ,
• Faller DV ,
• El Beshlawy A ,
• Delgrosso K ,
• Schwartz E ,
• Sankaran VG ,
• Paikari A ,
• Sankaran VG
• Lavelle D ,
• Saunthararajah Y
• Molokie R ,
• Gowhari M ,
• U.S. Food & Drug Administration
• Ortiz de Montellano PR
• Niihara Y ,
• Akiyama DS ,
• American College of Physicians
• Vercellotti ,
• Coller BS ,
• Frenette PS
• Matsui NM ,
• Yaghmai M ,
• Orringer EP ,
• Casella JF ,
• Maynard C ,
• Swenson R ,
• Collaborative Organization for RheothRx Evaluation (CORE)
• Adam-Graves P ,
• Ballas SK ,
• Luchtman-Jones L ,
• Emanuele M ,
• Balasubramaniam B
• Lehrer-Graiwer J ,
• Hemmaway CJ ,
• Metcalf B ,
• Bridges KR ,
• Gershwin B ,
• Global Blood Therapeutics Inc
• Al-Khabori M ,
• Al-Huneini M ,
• Nickel RS ,
• Hendrickson JE ,
• Arnold SD ,
• Brazauskas R ,
• Panepinto JA ,
• Walters MC ,
• Carreras J ,
• Fitzhugh CD ,
• Abraham AA ,
• Tisdale JF ,
• Gluckman E ,
• Cappelli B ,
• Eurocord, the Pediatric Working Party of the European Society for Blood and Marrow Transplantation; The Center for International Blood and Marrow Transplant Research
• Kassim AA ,
• Patience M ,
• Leisenring W ,
• Multicenter Investigation of Bone Marrow Transplantation for Sickle Cell Disease
• Ruggeri A ,
• Scaravadou A ,
• Eurocord Registry; Center for International Blood and Marrow Transplant Research; New York Blood Center
• Kamani NR ,
• Bollard CM ,
• Migliaccio AR ,
• Adamson JW ,
• Stevens CE ,
• Dobrila NL ,
• Carrier CM ,
• Rubinstein P
• Locatelli F ,
• Kabbara N ,
• Eurocord and European Blood and Marrow Transplantation (EBMT) group
• Kurtzberg J
• Gilman AL ,
• Eckrich MJ ,
• Epstein S ,
• Bolaños-Meade J ,
• Dedeken L ,
• Bezerra MA ,
• Antoniani C ,
• Meneghini V ,
• Lattanzi A ,
• Pounds CR ,
• Takezaki M ,
• Lumaquin D ,
• Ribeil JA ,
• Hacein-Bey-Abina S ,

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Last Update: September 4, 2023 .

• Continuing Education Activity

Sickle cell anemia is an inherited disorder of the globin chains that causes hemolysis and chronic organ damage. Sickle cell anemia is the most common form of sickle cell disease (SCD), with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage. Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. This activity reviews the pathophysiology, presentation, complications, diagnosis, and treatment of sickle cell anemia and also highlights the role of the interprofessional team in the management of these patients.

• Describe the pathophysiology of sickle cell anemia.
• Summarize the epidemiology of sickle-cell anemia.
• List the management options for sickle cell anemia.
• Outline the importance of cooperation among healthcare professionals to educate the patients on getting vaccinated, remaining hydrated, and timely follow-up to prevent the development of complications in those with sickle cell disease.
• Introduction

Sickle cell disease (SCD) refers to a group of hemoglobinopathies that include mutations in the gene encoding the beta subunit of hemoglobin. The first description of SCA 'like' disorder was provided by Dr. Africanus Horton in his book The Disease of Tropical Climates and their Treatment (1872). However, it was not until 1910 when Dr. James B Herrick and Dr. Ernest Irons reported noticing 'sickle-shaped' red cells in a dental student (Walter Clement Noel from Grenada). [1] In 1949, independent reports from Dr. James V Neel and Col. E. A. Beet described the patterns of inheritance in patients with SCD. In the same year, Dr. Linus Pauling described the molecular nature of sickle hemoglobin (HbS) in his paper 'Sickle Cell Anemia Hemoglobin.' Ingram Vernon, in 1956, used a fingerprinting technique to describe the replacement of negatively charged glutamine with neutral valine and validated the findings of Linus Pauling. [2]   

Within the umbrella of SCD, many subgroups exist, namely sickle cell anemia (SCA), hemoglobin SC disease (HbSC), and hemoglobin sickle-beta-thalassemia (beta-thalassemia positive or beta-thalassemia negative). Several other minor variants within the group of SCDs also, albeit not as common as the varieties mentioned above. Lastly, it is essential to mention the sickle cell trait (HbAS), which carries a heterozygous mutation and seldom presents clinical signs or symptoms. Sickle cell anemia is the most common form of SCD, with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage. [3]  

Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. In 1984, Platt et al. first reported the use of hydroxyurea in increasing the levels of HbF. [4]  Since then, the treatment of sickle cell has taken to new heights by introducing several new agents (voxelotor, crizanlizumab, L-glutamine) and, most recently, gene therapy.

Hemoglobin (Hb) is a significant protein within the red blood cell (RBC). It comprises four globin chains, two derived from alpha-globin (locus on chromosome 16) and two from beta-globin (locus on chromosome 11). There are many subtypes of Hb. The most common ones that are found in adults without hemoglobinopathies are listed here:

• HbA1- comprises two chains of the alpha-globin and two chains of the beta-globin (a2b2) - This constitutes 95% of the adult hemoglobin.
• HbA2- comprises two chains of the alpha-globin and two chains of the delta-globin (a2d2) - This constitutes less than 4% of the adult hemoglobin.
• HbF- comprises two chains of the alpha-globin and two chains of the gamma-globin (a2g2) - This Hb is more prevalent in the fetus (due to the high oxygen binding affinity that helps extract oxygen from maternal circulation).

The sickle cell mutation occurs when negatively charged glutamate is replaced by a neutral valine at the sixth position of the beta-globin chain. The mutation is transmitted via Mendelian genetics and is inherited in an autosomal codominant fashion. [5]  A homozygous mutation leads to the severest form of SCD, ie, SCA- also called HBSS disease. The coinheritance of beta-naught thalassemia and sickle cell mutation leads to HBS-Beta-0 disease, which phenotypically behaves like HBSS disease.

A heterozygous inheritance leads to HbAS. Patients with HbAS are not considered within the spectrum of SCD as most of them never present with typical symptoms of SCA. They might only be detected during childbirth, blood donation, or screening procedures. 

Several other compound heterozygotes exist where a single copy of the mutated beta-globin gene is coinherited with a single copy of another mutated gene. The second most common variant of SCD is the HbSC disease, where the sickle cell gene is coinherited with a single copy of the mutated hemoglobin C gene. HbC is formed when lysine replaces glutamine at the sixth position on the beta-globin chain. HbSC disease accounts for 30% of patients in the United States. 

• Epidemiology

The epidemiological data on SCD is scarce. It is well known that SCD and HbAS are more prevalent in sub-Saharan Africa, where the carrier of HbAS is afforded natural protection against severe Plasmodium falciparum malaria. It is estimated that ~230,000 children were born with SCA, and more than 3.5 million neonates were born with HbAS in sub-Saharan Africa in 2010. an estimated 75% of SCD-related births take place in sub-Saharan Africa. West Africa is home to the largest population of individuals with HbSC disease. [3]

The United States (US) Center for Disease Control (CDC) estimates that approximately 100,000 Americans have SCD. The CDC also estimates that 1 in 13 babies born to African-American parents have sickle cell trait, and 1 in 365 African-Americans have SCD. The estimated ratio of Hispanic Americans with SCD is 1 in 16,300. Children and adolescents make up to 40% of all SCD patients in the US. The incidence varies by state and geographical concentration of ethnicities. Besides, migration within the country and immigration from foreign countries alter the prevalence of SCD and HbAS. This is true for several countries where patients with SCD and SCA are living. Genetic studies in Brazil have also tied the origin of such patients to the slave trade originating from West Africa (Mina Coast and Angola). [6]  With the improvement in technology and ease of international migration, the incidence of SCA is predicted to rise. It is estimated that the annual number of newborns with SCA will exceed 400,000 by 2050.

There is also a stark difference in mortality and morbidity in high-income and low-income countries. Adopting vaccination guidelines for children with SCD and intensive screening procedures has sharply reduced the mortality of kids with SCD between 0 to 4 years (68% drop noted from 1999 to 2002 compared to 1983 to 1986). On the other hand, in sub-Saharan Africa, 50 to 90% of children born with SCD will die before their fifth birthday. Improving the care afforded in high-income countries and targeted training of healthcare providers have improved life expectancy. However, it still lags by decades compared to matched non-SCD cohorts (54 versus 76 years - projected life expectancy, and 33 years versus 67 years- quality-adjusted life expectancy). [7]

HbSC disease accounts for 30% of all patients with SCD in the US. As with HbAS, patients with the Hb C trait (heterozygous mutation) also remain asymptomatic for most of their lives. Although considered a milder variant of SCD, HbSC disease may present with severe morbidities. [8]

• Pathophysiology

Sickle cell anemia is characterized by two major components: Hemolysis and vaso-occlusive crises (VOC). The defect in the beta-globin gene makes the sickle hemoglobin (HbS) molecule susceptible to converting into rigid, elongated polymers in a deoxygenated state. The sickling process is cyclical initially, where sickle erythrocytes oscillate between the normal biconcave shape and the abnormal crescent shape (acquired under low oxygen pressure). However, there comes a time when the change becomes irreversible, and the sickle erythrocytes develop a permanent sickle shape, increasing the risk for hemolysis and VOC. All variants of SCD share the same pathophysiology leading to polymerization of the HbS component. [3]  

Multiple factors inherent to sickle erythrocytes, like the low affinity of HbS for oxygen, physiologically high 2,3-diphosphoglycerate, and increased sphingokinase-1 activity, lead to deoxygenation, which promotes the polymerization of HbS. In addition to this, a high concentration of HbS, abnormal activity of the Gados channel leading to dehydration, and repeated damage to the red blood cell (RBC) membrane also increase the risk of polymerization of HbS.

Oxidative stress contributes to hemolysis by auto-oxidation of HbS, leading to erythrocyte cell membrane damage. The increased expression of xanthine dehydrogenase, xanthine oxidase, and decreased expression of NADPH oxidase increase the oxidative stress within sickle RBC. A hemolyzed cell releases free hemoglobin (scavenges nitrous oxide) and arginase 1 (competes for L-arginine) that prevent the action and formation of nitrous oxide and contribute to oxidative stress and vascular remodeling (arginase-1 converts arginine to ornithine). [3]   

Besides the polymerization of the HbS and intravascular hemolysis, several other factors also contribute to vaso-occlusion. For example, the sickle RBC (expresses several adhesion molecules on the surface), free heme and Hb, reactive oxygen species, and endothelium interact with each other and with neutrophils and platelets to promote vaso-occlusion and thrombosis.  

• Histopathology

In patients with SCA, peripheral blood smear shows elongated RBC with tapering ends that look like a sickle (also called drepanocytes). Additional findings are present in a few patients. 

• Howell-Jolly bodies- Remnants of DNA are seen in the RBC and commonly seen in patients in whom the spleen has been removed. Therefore, patients with SCA have auto-splenectomy.
• Target cells (Leptocytes)- Most commonly seen in patients with Thalassemia. They are seen frequently in sickle-thalassemia syndromes and are sometimes noted in patients with SCA.
• Polychromatic cells - these are reticulocytes that signify marrow response to hemolysis. 
• Nucleated red blood cells can sometimes be visible on the peripheral smear. 

None of these findings are confirmatory. Confirmation is obtained only through hemoglobin electrophoresis, high-performance liquid chromatography, or isoelectric focusing. DNA-based techniques are not used routinely. Instead, they are used in patients with uncertain diagnoses. Pre-natal fetal testing involves using fetal DNA obtained through amniocentesis. Techniques to capture the fetal DNA in maternal blood remain investigational.

• History and Physical

Most patients with HbSS phenotype do not present with classical 'sickle cell crises' soon after birth. HbF is still present in the blood, helping maintain adequate tissue oxygenation, and it takes around 6-9 months to wean off completely. Not all SCAs have the same phenotype, and multiple phenotypes exist that can either co-exist or present as a spectrum of the disease. [3]  

• Vaso-occlusive subphenotype - Distinguished by higher hematocrit (Hct) compared to other SCA. A higher Hct leads to higher viscosity that promotes frequent vaso-occlusive crises and acute chest syndrome. 
• Higher risk of gallstones, pulmonary hypertension, ischemic stroke, priapism, and nephropathy
• Severe anemia increases cardiac workload and blood flow through organs, making them susceptible to damage.
• Higher free heme and Hb in blood vessels cause oxidative damage
• High Hb F subtype- A 10 to 15% level of HbF alleviates the symptoms of SCA. However, the distribution of HbF is not consistent throughout the body.
• Pain-sensitive subphenotype- Altered neurophysiology amongst various individuals makes them susceptible to pain. Some individuals are more susceptible to pain compared to others with SCA.

The patients with SCA present with acute or chronic complications associated with the disease. The most common acute complication of SCA is vaso-occlusive crisis (VOC). The treatment section below discusses the management of acute and chronic issues. 

Important points to be noted in the history of patients with SCA

• All patients with SCA will experience VOC during their lives. The earliest presentation is dactylitis in kids as young as six months of age.
• Any body organ can develop VOC (head, eyes, etc.), although extremities and the chest are most commonly involved. If a VOC pain sounds atypical, obtain a history to rule out other causes.
• When was the last pain crisis, and how many times in the previous year have they been admitted to the hospital with pain crises?
• If they take analgesics daily, it is prudent to know the type and quantity of the analgesic (opioid or non-opioid), the last use of analgesics, and whether they take the analgesics before coming to the ER/office.
• History of taking disease-modifying drugs (hydroxyurea, voxelotor, crizanlizumab, etc.) 
• A history of substance abuse, psychiatric disorders, and use of psychotropic medications must be obtained. 
• History of receiving blood transfusions and exchange transfusions- helps assess the risk of iron overload, presence of alloantibodies (multiple transfusions in the past can lead to the development of alloantibodies, which will help assess the risk of transfusion reactions), and previous transfusion reactions. 
• History of any other diseases that may or may not be associated with SCA - previous history of stroke, thrombosis, priapism, etc.
• It is also advised to get in touch with the primary hematologist taking care of the patient- it is valuable to have their input in understanding the patient's normal physiology. 
• History of previous surgeries.
• History of life-threatening crises in the past- if present, should alert the clinician to ensure that a similar event is not occurring again. For example, fat embolism may occur more frequently in patients with SCA. 

The physical exam should focus on the general system exam to determine the need for oxygen requirements, pain management, and blood/exchange transfusion. However, a focused exam is necessary to rule out any organ-specific problem. For example, a rapidly enlarging liver or spleen should alert the physician about sequestration crises. 

Patients with SCA are usually diagnosed in childhood. Intensive newborn screening programs in developed countries can identify patients in the neonatal stage. In the US, universal screening for SCA was implemented in all states by 2007. High-performance liquid chromatography and isoelectric focusing are the methods used in the US. In Europe, most countries deploy targeted screening in high-risk areas (where SCA is more common) and not a universal screen. In sub-Saharan Africa, no country has adopted a screening program. In India, the solubility test is used as the first step- if positive, then high-performance liquid chromatography is used to confirm at the reference center. [3]

Acute Complications in Patients with SCA

Acute Chest Syndrome (ACS):  ACS is the most common complication of SCA. It is also the most common cause of death and the second most common cause of hospital admission. A patient can either present with ACS or may develop it during hospitalization for any other reason. Hence, it is prudent to monitor all patients with SCA admitted to the hospital for ACS. It is important to recognize ACS early and act upon it to prevent respiratory failure.

• The risk factors for ACS include a previous history of ACS, asthma, or recent events like recent surgical procedures, pulmonary embolism, fluid overload, infection, etc.
• The clinical features include sudden onset of cough and shortness of breath. Fever may or may not be a part of the spectrum of presentation. If present, then it usually points towards infection.
• Laboratory evaluation includes a complete blood count with differential chemistries, including liver and kidney evaluation, blood cultures, and sputum cultures.
• Chest X-ray shows a new pulmonary infiltrate- this is a quintessential feature of defining ACS. CT and perfusion mismatch scans are only used if there is a strong clinical suspicion of pulmonary or fat embolism. Therefore, they are not usually helpful in acute settings.

Sequestration Crises: This can either be hepatic or splenic sequestration.

• Patients experience rapid spleen enlargement associated with pain in the left upper quadrant. In children with SCA, it is common in children between 1 to 4 years of age, as the spleen is still intact.
• Patients with non-SCA variants (HbSC, HbS-beta+ thalassemia) are not prone to 'auto-splenectomy' commonly seen in patients with SCA. Hence, they can develop splenic sequestration later in life. Such patients may have baseline splenomegaly, causing hypersplenism. Parents and patients must receive counseling regarding the signs and symptoms of an enlarging spleen.
• Younger patients present with acute anemia and hypovolemic shock due to smaller circulating volumes, whereas adults may present with a more insidious onset.
• Pain occurs due to stretching of the splenic capsule and new infarcts.
• Blood count shows a drop in Hb by more than 2gm/dL, increased reticulocyte count, and nucleated red blood cells. 
• Hepatic sequestration: Hepatic sequestration can occur across all phenotypes of SCA. Like the spleen, patients may have a baseline enlargement of the liver. Hepatic sequestration is also defined as rapid enlargement of the liver with stretching of the capsule. The hemoglobin shows a drop of more than 2gm/dL. Liver enzymes may not get elevated.

Acute Stroke:  Stroke is the most devastating complication of SCA. Since the advent of transcranial Doppler (TCD) and the institution of primary prevention programs, the incidence of stroke has gone down in patients with SCA. In the absence of primary prevention, ~10% of children suffer from overt stroke, and approximately 20 to 35% have silent cerebral infarcts. TCD is not useful for adults. 

• Severe headache, altered mental status, slurred speech, seizures, and paralysis- are signs of stroke. 
• Urgent neurological consultation and CT scan followed by MRI/MRA must be done. 

Aplastic crises:  It is usually precipitated by parvovirus B-19 and is defined as a rapid drop in Hb at least 3 to 6 gm/dL below the baseline. Patients present with severe fatigue, anemia, shortness of breath, and even syncope. Blood counts show severely low hemoglobin with near-absent reticulocytes. Bone marrow biopsy shows arrest in the pro-normoblast stage in patients with acute parvovirus infections. [9]

Acute intrahepatic cholestasis (AIC):  Presents with sudden onset right upper quadrant pain. Physical exam shows worsening jaundice, enlarging and tender liver, and clay-colored stools. Labs show very high bilirubin levels, elevated alkaline phosphatase, and coagulopathy. The hemolysis parameters may be normal. AIC is a medical emergency.

Infections in patients with SCA can be a harbinger of infection with Streptococcus pneumoniae infection or osteomyelitis.

• The use of prophylactic antibiotics and pneumococcal vaccinations has reduced their incidence. However, loss of splenic function in SCA patients puts them at risk of invasive bacterial species.
• Osteomyelitis can be unifocal or multifocal- Staphylococcus aureus , Salmonella , and other enteric organisms can cause osteomyelitis in SCA patients. 

Priapism  is defined as a sustained, unwanted, painful erection lasting more than 4 hours. It is a common condition among patients with SCA, affecting 35% of all men/boys. 

Acute Ocular Complications

• The complication presents similarly in patients with SCA and sickle cell trait.
• The low oxygen pressure and acidotic nature of the aqueous humor promote sickling of the RBC, which leads to blockage of the trabecular network and an acute rise in intraocular pressure (IOP). 
• High IOP is poorly handled in patients with SCA - which can lead to CRAO and secondary hemorrhages. 
• Central retinal artery occlusion (CRAO)- Results from thrombus formation in the retinal artery leading to infarction of the retina, macular ischemia, or macular infarction. CRAO can occur spontaneously or secondary to increased IOP (from hyphema), Moyamoya syndrome, or ACS in patients with SCA. 
• Patients present with proptosis, local pain, and edema of the lid or orbit.
• The exam shows reduced extraocular motility and decreased visual acuity.
• CT scan helps in distinguishing this from orbital cellulitis/ infection. 
• Orbital Compression Syndrome (OCS) - also called orbital apex syndrome, is characterized by ophthalmoplegia and vision loss secondary to events occurring at the orbital apex. Cranial nerves II, III, IV, VI, and the first division of CN V can be involved. MRI of the orbits is the best modality for diagnosis. 

Chronic Complications in Patients with SCA

Iron Overload:  Iron (Fe) overload is a common problem in SCA patients due to repeated transfusions and chronic hemolysis. Each unit of packed RBC contains 200 to 250 mg of iron. Excessive iron mainly affects the heart, lungs, and endocrine glands. [10]  Hepatic cirrhosis from excessive iron is a major cause of death in patients with SCA. Clinical trials in patients with thalassemia have shown that systemic iron load correlates directly with survival and cardiac incidents. [11]

Avascular Necrosis (AVN) of Joints:  AVN of the femoral head is a common cause of chronic pain and disability in SCA patients. Although the hip joint is the most common joint to be involved, other joints can also be affected. AVN occurs at the distal portion of the bone, where collateral circulation is poor. The capillaries get occluded by sickle RBCs, leading to hypoxia and bone death. Risk factors for AVN of the femoral head include age, frequency of painful episodes, hemoglobin level, and alpha-gene deletion. In patients with HbSS, the overall prevalence is 50 percent by age 33. HbSS-alpha thalassemia and HbSS-Beta-0 thalassemia are at higher risk of developing AVN early in life. 

Leg Ulcers : More common in SCA compared to other SCD genotypes. Approximately 2.5% of patients with SCA above ten years of age have leg ulcers. Leg ulcers are more common in men and older people and less common in people with high total hemoglobin, alpha-gene deletion, and high levels of HbF. Trauma, infections, and severe anemia also increase the risk of leg ulcers. The ulcers occur more commonly on the medial and lateral surfaces of the ankles. They vary in size and depth, and chronic ulcers may lead to osteomyelitis, especially if they are deep enough to expose the bone.

Pulmonary Artery Hypertension (PAH) : Affects 6 to 11% of patients with SCA. PAH in SCA is classified under World Health Organization (WHO) group V. However, chronic hemolysis leads to pulmonary vascular changes classified under WHO group 1 in up to 10% of all SCA patients. PAH in SCA can also occur due to left heart dysfunction (Group II), chronic lung disease from SCA (Group III), chronic thromboembolism (Group IV), or extrathoracic causes (Group V). 

The patient may complain of dyspnea on exertion, swelling in the legs, or present with symptoms of underlying disease (like a history of thrombosis, heart failure, etc.). An echocardiogram helps in estimating the tricuspid regurgitant jet velocity (TRV). Elevated TRV is associated with increased mortality in adults. However, TRV can be transiently elevated during acute chest syndrome. Serum NT-pro-BNP is directly correlated with mortality as well. The final diagnosis is made with a right heart catheterization.  

Renal complications: Chronic kidney disease (CKD) occurs in approximately 30% of adult patients with SCA. The acidotic, osmotic, and hypoxic environment of the kidney increases the risk of polymerization of HbS, leading to the sickling of RBC. SCA patients secrete excessive creatinine in their proximal tubules. Hence, it becomes challenging to identify early signs of kidney disease, as creatinine takes a longer time to rise. Microalbuminuria (30-300mg albumin in 24-hour urine collection) is often the first manifestation of CKD. Spot urine-creatinine ratio is not validated in SCA patients due to hypersecretion of creatinine.

• Hypoesthenuria- Inability to concentrate urine due to loss of deep juxtamedullary nephrons. It is the most common complication in SCA patients. It leads to frequent urination and increases the risk of dehydration. It also increases the risk of enuresis in children.
• Renal papillary necrosis occurs due to obstruction of the vessels supplying the vasa recta, resulting in medullary infarction. It presents with hematuria. It is more common in patients with HbSC disease.
• Asymptomatic Proteinuria: It is present in 15 to 50% of patients. It develops early in life due to hyperfiltration and loss of selectivity for albumin.

Ophthalmologic Complications: Chronic eye complications are more common in patients with HbSC and HbSS disease. They are found in up to 50% of patients.

• Proliferative Sickle Retinopathy occurs due to vaso-occlusion of vitreal arterioles, leading to ischemia which leads to neovascularization. Neovascular tissue is predisposed to hemorrhage and vitreal traction forces, resulting in vitreal hemorrhage (the most severe complication of proliferative sickle retinopathy). 
• Treatment / Management

Patients with SCA present with acute and chronic complications. 

Management of Acute Complications

Pain management is a critical part of SCA. It is challenging for clinicians to accurately assess patients' needs, especially if they meet them for the first time. Patients with SCA often suffer from the stigma of requiring high doses of opioids for pain control, which leads to them being labeled as 'opioid abusers,' 'manipulators,' or even' drug seekers.'  [12]

• Analgesic administration starts simultaneously with evaluating the cause, ideally within 30 minutes of triage and 60 minutes of registration.
• Develop individualized pain management plans - this should be made available to the emergency room and should be implemented each time the patient presents with VOC and pain.
• NSAIDs are used in patients with mild to moderate pain who report prior episodes of relief with NSAIDs
• Any patient presenting with severe pain- preferably used parenteral opioids. An intravenous route is preferred; however, if access is difficult, use the subcutaneous route.
• The dose of parenteral opioids is calculated based on the total dose of short-acting oral opioids taken at home.
• Pain should be reassessed every 15 to 30 minutes, and readminister opioids if needed. The escalation of opioids is done in 25% increments.
• Patient-controlled analgesia (PCA) is preferred. If an "on-demand" setting is used in PCA, then continue long-acting analgesia.
• When pain control is achieved, "wean off" parenteral opioids before converting to oral medications.
• Calculate the inpatient analgesic requirement at discharge and adjust home doses of short and long-acting opioids accordingly.
• Meperidine is not used in managing VOC-related pain unless this is the only medication that controls the pain.
• Antihistamines only help in controlling opioid-related itching. When required, use oral formulations only—readminister every 4 to 6 hours as needed.
• Incentive spirometry
• Intravenous hydration
• Supplemental oxygen is needed only if saturation drops below 95% on the room air.

Management of Chronic Pain

Chronic pain management in SCA patients focuses on the safe and adequate use of pain medications, particularly opioids. A comprehensive assessment of the patient's ailment, the kind and doses of pain medicine required to control pain, and the functional outcomes of using these medications are made at each encounter. The process involves collaboration with multiple specialties, like psychiatry, social work, etc., to administer the right pain medicine in the proper doses. 

The strategy adopted in the clinic to prescribe pain medicine involves:

• One person must be assigned to prescribe long-term opioids. They should document all encounters extensively involving the physical exam, lab work, etc. 
• Assess each patient for non-SCA-related pain and treat/refer to the appropriate specialty for managing this pain.
• Limit prescribing pain medicines without meeting the patient- every patient must be physically assessed every 2 to 3 months or sooner.
• Develop an individualized pain management plan for each patient, reassess this plan annually, and modify it accordingly.
• Encourage patients to explore alternative methods of controlling pain, like direct massage, self-hypnosis, and music therapy.

Acute Chest Syndrome (ACS):  It is an emergency regardless of the sickle cell disease phenotype. It can lead to respiratory failure and death if not managed as an emergency.

• All patients must be hospitalized-
• Upon admission, start treatment with antibiotics, including coverage for atypical bacteria.
• Supplemental oxygen is provided to those with oxygen saturation of less than 95% at room air.
• "Early" administration of simple blood transfusion is recommended for hypoxic patients. However, exchange transfusion is recommended at the earliest opportunity.
• Close monitoring for worsening respiratory status, increasing oxygen requirement, worsening anemia, and bronchospasm (use of beta-adrenergic dilators is encouraged in asthmatics) must be done. Intensive care units must be on standby to receive such patients who experience worsening respiratory status.
• Closely monitor predictors of severity- increasing respiratory rate, worsening hypoxia, decreasing hemoglobin or platelet count, multilobar involvement on chest X-ray, and developing neurological complications.
• Incentive spirometry and hydration (intravenous or oral) must always be encouraged. 
• ACS is a strong indicator for initiating disease-modifying therapy (hydroxyurea, etc.) or starting the patient on a chronic blood transfusion program.

Sequestration Crises

• Intravenous fluids for hydration, pain control, and simple/exchange blood transfusion are central to managing sequestration crises.
• Never correct anemia completely- when the crises resolve, and the organs shrink, the sequestered blood re-enters the circulation, leading to increased hematocrit and viscosity, increasing the risk of thrombotic and ischemic events.
• Splenectomy is recommended for patients with life-threatening episode splenic sequestration crises or with recurrent splenic sequestration. It is also offered to those who have baseline hypersplenism.
• Instruct patients and parents in monitoring the size of the liver and spleen regularly.

Acute Stroke:  Urgent neurology and transfusion medicine consultation are needed to provide optimal care and prevent long-term damage.

• Simple or exchange blood transfusion emergently.
• Start a program of chronic exchanges or blood transfusion. 
• Where blood transfusion cannot be used (iron overload, excessive alloantibodies) or is unavailable, start on long-term disease-modifying therapy. SWiTCH trial demonstrated that chronic transfusions are a better way to manage patients with stroke.

Aplastic Crises:  Parvovirus infections cause a transient drop in hemoglobin. Humoral immunity develops within 7 to 10 days that stays for life. The patient is extremely susceptible to developing ACS or stroke during the acute period. Initiate exchange/simple transfusion to bring Hb to a safe level, not necessarily to normal/baseline level.

Infections presenting with fever:  Oral empiric antibiotics are given promptly while evaluating the reason for the fever. For ill-appearing patients, admit them and administer intravenous antibiotics.

Priapism: Early recognition is the key to management. Delayed management can lead to impotence. Urologists need to be involved early on in the care of such patients. 

• Conservative measures include using analgesics, hydration, and sedation - which usually leads to detumescence and retains potency. Most experts would call for upfront urologic management rather than losing time trying conservative measures. [13]
• Urologists can perform penile aspiration or irrigation of corpora cavernosa with alpha-adrenergic drugs.
• Blood transfusion/ exchange transfusion is not useful - few authors have reported neurological complications with the use of blood transfusion (ASPEN syndrome). Hence it is best to avoid blood transfusion.

Acute ocular Complications:  All ocular complications must be managed in consultation with ophthalmologists and hematologists to prevent vision loss. 

• Hyphema- Anterior chamber paracentesis or surgical intervention to manage the thrombus must be done promptly.
• Reducing intraocular pressure helps prevent CRAO and other compression issues. 
• Infections are managed with prompt administration of antibiotics. 
• Corticosteroids are used to relieve excessive pressure in patients with OCS.

Chronic Complications

Avascular Necrosis:  About 40 to 80% of cases of hip joint AVN are bilateral; therefore, both joints should be investigated simultaneously. Pain management and physical therapy are to be initiated as early as possible. Advanced cases may require hip arthroplasty.

Leg Ulcer: Conservative measures involve wound care, wet-to-dry dressings, and pain control. Hydroxyurea is avoided in patients with open leg ulcers, as it may prevent healing. Frequent evaluation for the stage of healing or lack of infection, osteomyelitis must be done. Local and systemic antibiotics are used for infected ulcers.

Pulmonary Hypertension:  Patients with higher TRV are referred to pulmonologists for management. Small studies have shown increased mortality with sildenafil.

Renal Complications: Refer SCA patients with micro- or microalbuminuria to nephrologists for detailed workup and consideration of angiotensin-converting enzyme inhibitor (ACE-inhibitor). Follow patients closely who have modest elevation in creatinine (>0.7 mg/dL in children, >1.0 mg/dL in adults), and refer to a nephrologist at the earliest sign of worsening creatinine.

Ophthalmologic Complications: Refer SCA patients regularly for ophthalmologic evaluation, especially if they complain of slow vision changes. Direct and indirect ophthalmoscopy, slit-lamp biomicroscopy, and fluorescein angiography are used to evaluate SCA patients. Laser photocoagulation therapy is used to manage proliferative sickle retinopathy. A vitrectomy or retinal repair may be needed in the rare event of vitreal hemorrhage or retinal detachment. 

Iron Overload

Unlike hemochromatosis, phlebotomy is not an option in patients with SCA. Preventing iron overload with good transfusion practices is the best way to deal with iron overload. Patients with SCA need not follow the rule of having hemoglobin close to 7gm/dL. Packed RBC transfusion should be restricted to the management of symptoms. Choosing exchange transfusion over simple transfusion also helps to reduce/prevent iron overload.

Indications to start iron chelation therapy

• A liver iron concentration (LIC) greater than 3 mg iron (Fe)/gm dry weight
• Cardiac T2* < 20 milliseconds
• Serum ferritin greater than 1000 on two different occasions 15 days apart
• Age greater than two years
• Expected survival beyond one year
• Number of transfusions of packed RBC in 1 year- > 10 in pediatric patients OR > 20 in adults. 

Goals of therapy

• Serum ferritin < 1000 mcg/L,
• LIC <7mg Fe/gm dry weight
• Cardiac T2* > 20 milliseconds

When do patients need modification of treatment?

• Treatment needs to be intensified if LIC > 15 mg Fe/gm dry weight and deescalated when LIC < 3 mg Fe/gm dry weight.
• Treatment needs to be intensified if serum ferritin > 2500 IU/L and deescalated when serum ferritin < 300 IU/L
• Treatment needs to be intensified when cardiac MRI shows T2* < 15 milliseconds or when cardiac symptoms occur (like heart failure, arrhythmias)

Iron Chelators

• Disperse tab formulation: Initial dose: 10mg/kg/day. Maximum dose: 20mg/kg/day
• Tablet or granule formulation: Initial dose: 7mg/kg/day. Maximum dose: 14mg/kg/day
• It does not interfere with the pharmacodynamics of hydroxyurea; hence it can be used simultaneously.
• Adverse effects- gastrointestinal intolerance, dose-dependent rise in serum creatinine, liver dysfunction.
• Daily subcutaneous infusions via portable infusion pump given over 8 to 24 hours; 1 to 2 gm/day 
• It can be given as a daily IV infusion also. 40 to 50 mg/kg/day (max dose 60 mg/kg/day) over 8 to 12 hours (max rate 15 mg/kg/hour) 
• IM route is acceptable for children but not preferred for adults. 0.5 to 1mg/day
• Adverse effects- Injection site reactions, cardiovascular shock (if administered too fast), blood dyscrasias, growth retardation.  
• Adverse effects - agranulocytosis, hepatotoxicity, gastrointestinal symptoms, and arthralgia.

Blood transfusion:  Blood transfusions form an integral part of the management of SCA. The goal of transfusion is to increase the oxygen-carrying capacity of blood and reduce the HbS component. A blood transfusion (simple or exchange) is given to keep the HbS level below 30% (STOP 1 and 2 trials). [14]  In patients receiving regular exchange transfusions (history of stroke, intolerance, or contraindication to hydroxyurea), a more practical target for HbS is 25% to prevent a rise of HbS beyond 30%.

What types of blood transfusion are used in SCA?

• Simple transfusion: Transfusion of matched packed red blood cells (PRBC)
• Exchange transfusion: Transfusion of PRBC while removing blood from the patient at the same time.

Who should receive blood transfusions?

• Hb < 7gm/dL or drop of >2 gm/dL from baseline- consider simple or exchange transfusion. 
• Twin pregnancy- consider prophylactic exchange transfusion
• Hb less than 9 gm/dL- Simple transfusion
• Hb more than 9gm/dL- Partial exchange transfusion

What kind of transfusion practice should be followed?

• Severe ACS - oxygen saturation less than 90% even when started on supplemental oxygen. 
• Multiorgan Failure
• Acute ischemic stroke
• Splenic sequestration - never corrects the anemia completely.
• Acute anemia

Complications from Chronic Transfusions

• Alloimmunization- increases the risk of transfusion reactions, especially delayed hemolytic transfusion reactions. 
• Iron overload
• Transmission of blood-borne diseases like hepatitis B, C, and HIV; extremely low risk due to intensive screening of donors and blood products.
• Differential Diagnosis

In general, globin gene mutations affecting hemoglobin are common and affect 7% of the entire world population. [15]  Over 1000 variations of hemoglobin exist. However, only a handful of variations are significant clinically. 

Common Variants of SCA or HbSS Disease

• Hemoglobin S-beta-0 thalassemia (Clinically behaves exactly like HbSS disease)
• Hemoglobin SC (a milder variant of SCD) - can have a phenotypic presentation of sickle cell anemia.
• Hemoglobin S-beta+ thalassemia (a milder variant of SCD)

Several other hemoglobin variants are present that can mimic SCA if they are inherited along with HbS.

• Hemoglobin Jamaica-Plain (beta-68 [E12] Leu -> Phe)
• Hemoglobin Quebec-Chori (beta-87 [F3] Thr > Ile)
• Hemoglobin D-Punjab (beta-globin, codon 121, glutamine to glutamic acid)
• Hemoglobin O-Arab
• Hemoglobin E

Other conditions that can present with hemolysis, where SCA can be ruled out with history, examination, hemoglobin electrophoresis, and study of the peripheral smear

• Antibody-mediated autoimmune hemolytic anemia (both warm and cold antibodies)
• Other hemoglobinopathies- alpha or beta-thalassemia
• Paroxysmal nocturnal hemoglobinuria
• RBC-membrane defects (hereditary spherocytosis, hereditary elliptocytosis)
• Enzyme defects (pyruvate kinase deficiency, glucose-6-phosphate deficiency)
• Drug-induced hemolysis
• Transfusion-related hemolysis (acute or delayed hemolytic reaction)
• Microangiopathic hemolytic anemia (atypical or typical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura)
• Infectious causes (malaria, babesiosis, Rickettsia , Clostridia , Bartonella )
• Vasculitis-induced hemolysis
• Medical Oncology

The goal of disease-modifying therapy in sickle cell anemia is to reduce the frequency of vaso-occlusive crises (VOC) and pain crises and prevent organ damage. These medications usually do not have a role "during" acute crises. Hydroxycarbamide, or hydroxyurea, was the first drug approved by the FDA for use in patients with SCA. However, the USFDA approved hydroxyurea for pediatric patients two years and above only in 2017 (based on the ESCORT HU trial).   

Disease-Modifying Drugs/Therapy

The goal of disease-modifying therapy in patients with SCA is to alter the kinetics of sickle erythrocytes. Hydroxyurea does this by increasing the concentration of fetal hemoglobin (HbF).

Hydroxyurea:  This is a ribonucleotide reductase inhibitor that increases the concentration of HbF in patients with SCD. It not only increases the intracellular concentration of HbF but also increases the number of erythrocytes containing HbF. In addition to this, hydroxyurea also reduces the number of circulating reticulocytes and leukocytes, raises the volume of an RBC (high MCV is noted in patients receiving hydroxyurea), reduces the deformability of RBC, improves the flow of blood through capillaries, and alters the expression of adhesion molecules hence preventing vaso-occlusive crises. The initial trials with hydroxyurea (Phase-III Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH)) demonstrated a clear benefit over placebo in reducing the incidence of pain crises and the cost of care. Long term, the MSH study also showed a mortality benefit. In the pediatric age group, two seminal trials (HUG-KIDS-Phase I/II and BABY HUG-phase III) demonstrated good tolerability and led to the drug's approval. [16] [17]  

• Having three or more sickle cell-associated moderate to severe pain crises within a 12-month period; treat with hydroxyurea.
• Those with sickle cell-associated pain that interferes with daily activities of living and quality of life
• History of severe and/or recurrent ACS
• Severe symptomatic chronic anemia that interferes with daily activities or quality of life
• Infants 9 months of age and older, children, and adolescents with SCA offer hydroxyurea regardless of clinical severity to reduce SCA-related complications (e.g., pain, dactylitis, ACS, anemia)
• For those with chronic kidney disease, taking erythropoietin and hydroxyurea can be added to improve anemia.
• DO NOT give hydroxyurea to pregnant women and lactating mothers who choose to breastfeed their babies.
• Dosing for adults: Start with 15 mg/kg/day. Round up to the closest 500 mg. For patients with CKD- start at 5 to 10 mg/kg/day. 
• Dosing for infants and children: start at 20 mg/kg/day
• Target absolute neutrophil count (ANC) above 2000/microL and platelet count above 80,000/microL. In younger patients, an ANC of 1250/microL is allowed if baseline counts are low.
• Monitor blood counts every four weeks when increasing the dose of hydroxyurea.
• Clinical response takes 3 to 6 months to develop. Hence, a minimal trial of 6 months of daily continued use of hydroxyurea is conducted before considering alternative therapies. 
• Daily adherence is a must. It must be emphasized to the patient.
• If a positive response is seen, then hydroxyurea must be continued indefinitely. 
• Myelotoxicity is the most common and most substantiated adverse effect of hydroxyurea. The rest of the adverse effects reported in the literature, especially carcinogenesis and leukemia, have never been demonstrated in large studies. 
• Avoid the use of hydroxyurea in patients with leg ulcers.

Voxelotor:  Voxelotor acts by inhibiting the polymerization of HbS and increasing the affinity for oxygen. It is dosed at 1500 mg by mouth daily and is approved for SCA treatment in patients 12 years of age and older. Voxelotor can be given with or without hydroxyurea. USFDA approved it in 2019 based on the results of the phase 3 HOPE trial (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) evaluating voxelotor (1500 mg versus 900 mg versus placebo in 1:1:1 design). [18] [19]  

The most common adverse reactions are headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia. Voxelotor interferes with high-performance liquid chromatography (HPLC). Hence, the hemoglobin quantification is not accurate when the patient is on voxelotor. HPLC should be done when the patient is off therapy. Also, the use of voxelotor may increase the Hb, but there is no evidence to suggest discontinuation of exchange transfusion in patients receiving this for stroke prophylaxis.

Crizanlizumab:  A humanized immunoglobulin G2-Kappa monoclonal antibody inhibits P-selectin, thereby blocking its interaction with P-selecting glycoprotein-1. This leads to reduced interaction between activated endothelium, platelets, leukocytes, and sickled RBCs, leading to reduced VOC. [20]  The phase II SUSTAIN trial demonstrated a clinical benefit of Crizanlizumab by demonstrating a reduction in pain crises, VOC, emergency room visits, and increased median time to first crises. Although the hospitalization rate was numerically lower in the intervention group, the difference was not statistically significant compared to the placebo group. [21]

It is approved for the treatment of SCA in patients 16 years of age and older. It is dosed as a 5 mg/kg intravenous infusion administered over 30 minutes at weeks 0 and 2 and then every four weeks. The most common adverse reactions are nausea, arthralgia, back pain, and pyrexia. Infusion-related reactions can occur. Crizanlizumab can interfere with platelet counts; send the blood immediately before administration or in citrated tubes. 

L-Glutamine:  Glutamine is the most abundant amino acid in the body. It is not an essential amino acid under normal circumstances, but in patients with SCA, a high hemolysis rate increases the demand for glutamine. L-glutamine is available in a medical formulation. The exact mechanism of action of L-glutamine remains anecdotal. It is believed to work by scavenging for reactive oxygen species and acting as a substrate for the regeneration of nitrous oxide, NAD, and NADH. [22]  The USFDA approved L-glutamine in 2017 after positive results from the phase III trial. The authors demonstrated a statistically lower number of pain crises, fewer hospitalizations, fewer cumulative days in the hospital, prolonged time to first and second pain crises, and a reduced number of ACS. [23]  Adverse events include constipation, nausea, headache, abdominal pain, cough, extremity pain, back pain, and chest pain. There is an additional concern that L-glutamine may increase mortality and the rate of multiorgan failure. However, these are yet exploratory. 

Hematopoietic Stem Cell Transplant

Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative option in SCA patients where cure rates approach approximately 90%. Improving the quality of life and reducing the cost of managing long-term complications trumps the cost of performing allogeneic HSC. Pre-school age is considered the best time to perform HSCT, with increased mortality recorded in older patients. A myeloablative or a non-myeloablative regimen can be used; however, myeloablative regimens are not recommended for adults. A matched sibling donor is preferred for performing allogeneic HSCT. Due to the lack of matched sibling donors, other approaches like a matched unrelated donor, umbilical cord blood transplant, and haploidentical transplant are also being explored. [24] [25]

Potential barriers to performing allogeneic HSCT

• Alloimmunization due to repetitive transfusions (exchange of blood)
• Organ dysfunction due to SCA (possibly a reason why younger patients do better)
• Lack of matched sibling donors/ insurance.

Indications for performing allogeneic HSCT

• Stroke (most common and strongest indication to perform allogeneic HSCT.
• Abnormal transcranial doppler
• Acute chest syndrome
• Recurrent VOC not controlled with medical therapy or chronic transfusions

The complications with allogeneic HSCT:

• Transplant-related mortality approaches 7 to 10%, comparable with SCD-related mortality
• Graft rejection OR graft failure - less with myeloablative regimens (7 to 11%) compared to non-myeloablative regimens (11 to 50%)
• Graft-versus-host disease and related morbidity
• Transplant-related complications like lung injury, endocrine, and metabolic adverse events

The recent approvals of newer agents and the emergence of gene-editing techniques have expanded the options for SCA patients. Also, extending the benefit of HSCT to low-income countries remains a significant challenge. 

Future Perspectives

Gene editing is a new therapy focus whereby researchers attempt to increase the HbF level in patients with SCA. This technique is being developed alongside HSCT. Many approaches to gene editing are in clinical trials right now. [26] [27]

• Viral gene addition using lentivirus: The technique aims to add a modified beta or gamma-globin gene to reduce the HbS component and increase the HbA (beta-globin gene) or the HbF (gamma-globin gene).
• CRISPR (Clustered regularly interspaced short palindromic repeats): Targets the expression of BCL11A, which normally downregulates gamma-globin expression. By introducing insertions and deletions in the BCL11A erythroid lineage-specific enhancer on chromosome 2, BCL11A is downregulated, resulting in increased expression of the gamma-globin gene, which subsequently increases HbF.

Cost Factor

The annual cost of the voxelotor is approximately $125,000. Each vial of crizanlizumab costs approximately $2400, with a yearly cost of $84,852 and $113,136 per year for most patients. The monthly cost of the L-glutamine formulation is $3000 for adults and up to $1000 for the pediatric age group. A myeloablative regimen for HSCT can lead to a cost of approximately $280,000 at 100 days of care/admission. [28]  In addition, the advanced level of expertise and dedicated infrastructure required to deliver such care also comes at a considerably high cost. Considering such high costs for the newer therapies, bringing them to lower-income regions like sub-Saharan Africa is a challenge, where approximately 6 million suffer from sickle cell anemia. 

Most of the survival data in patients with SCA does not factor in the advent of new medications. The Cooperative Study of Sickle Cell Disease (CSSCD) (between 1978-88) reported the median age of death for women and men as 42 and 48 years, respectively. This study also showed that acute chest syndrome, renal failure, seizures, high leukocyte count, and low levels of HbF were associated with an increased risk of early death in patients with SCA. [29]  More recent studies have shown that elevated tricuspid regurgitant jet velocity on echocardiography, prolonged QTc interval, pulmonary hypertension, high N-terminal pro-brain natriuretic peptide, history of asthma and/or wheezing, history of end-stage renal disease requiring dialysis, and the severity of hemolysis are independent risk factors towards early death in patients with SCA. [30]

More recent data combining nine studies from Europe and North America (evaluating 3257 patients) listed the following as predictors of mortality:

• Age (per 10-year increase in age)
• Tricuspid regurgitant jet velocity 2.5 m/s or more
• Reticulocyte count
• Log(N-terminal-pro-brain natriuretic peptide)
• Fetal hemoglobin [30]

With the approval of newer drugs (voxelotor and crizanlizumab) in 2019, increased use of hematopoietic stem cell transplant, and exploration of newer techniques like gene therapy, survival is bound to increase along with the quality of life. 

• Complications

SCA can lead to acute complications and chronic complications

Acute complications: Most acute complications are associated with occlusion of the small to medium-sized vessels (sometimes large-sized vessels) due to polymerization of HbS and hemolysis. 

• Sequestration crises: splenic or hepatic sequestration
• Fat embolism
• Bone infarction/necrosis
• Coagulopathy: increases the risk of both arterial and venous clots- stroke, myocardial infarction, venous thrombosis
• Ophthalmic: vitreous hemorrhage, retinal detachment, retinal artery/vein occlusion
• Aplastic crises: in association with parvovirus infection
• Papillary necrosis
• Delayed growth and development and growth retardation
• Cardiac: cardiomegaly, cardiomyopathy, left ventricular hypertrophy, arrhythmia, congestive heart failure
• Pulmonary: pulmonary edema, sickle cell lung disease, pulmonary hypertension
• Hepatobiliary: hepatomegaly, intrahepatic cholestasis, cholelithiasis, viral hepatitis
• Splenic complications: splenomegaly, hyposplenia, asplenia
• Renal: acute and chronic renal failure, pyelonephritis, renal medullary carcinoma
• Musculoskeletal: degenerative changes, osteomyelitis, septic arthritis, osteonecrosis, osteopenia/osteoporosis
• Neurologic: aneurysm, mental retardation
• Ophthalmic: proliferative sickle retinopathy, vitreous hemorrhage, retinal detachment, nonproliferative retinal changes
• Endocrine: primary hypogonadism, hypopituitarism, hypothalamic insufficiency
• Iron overload due to repeated transfusions and chronic hemolysis
• Deterrence and Patient Education

SCA is a debilitating disease that affects a patient physically and has significant emotional and psychiatric consequences. The stigma of being diagnosed with SCA has been well documented. Many SCA patients are inaccurately labeled as drug seekers and opioid abusers due to the need for an inordinately high amount of opioids for pain control. In addition, frequent interactions with different providers (in the emergency rooms, hospital admissions, etc.) can lead to inconsistent care. In such a scenario, the patients need to be an advocate for themselves. The following points can act as a guide for patient education.

• Show consistency in outpatient clinics and show up for your appointments. Regularity in visits to your providers helps to build trust within the system.
• Discuss pain requirements for pain medications with your provider with an open mindset- They may appear restrictive in prescribing pain medications, especially opioids. Still, they are trying to help you by protecting you against overdosing. 
• Use the same emergency room, or at least the ER within the same hospital system. It is useful and helps in developing familiarity with the people who work in that ER. It also allows easy access to your individualized plan of care, which your provider develops for such situations. 
• Adherence to disease-modifying therapy will help reduce the events of pain crises and prevent long-term organ damage. 
• Always be receptive to alternative ways of getting control over pain - including music therapy, self-hypnosis, and deep muscle relaxation. 
• Patients can adopt protective measures- stay warm and avoid exposure to extreme temperatures, adequate hydration, and breathing exercises at home. 
• Enhancing Healthcare Team Outcomes

SCA is a systemic disorder that affects the entire body. The disease not only manifests with physical symptoms (pain crises, organ damage, etc.) but also has numerous psycho-social implications. Most patients with SCA belong to the African-American community and a minority to Hispanic and other communities, which makes them prone to certain prejudices. Besides, the high demand for opioids to manage chronic pain makes the situation even more challenging. [31]  All providers must keep aside their inherent prejudice when caring for a patient with SCA, working collaboratively as an interprofessional team. Almost all specialties need to be involved in managing patients with SCA. However, the hematology team dedicated to taking care of SCA patients must be the primary physicians for these patients.

Specialties like ophthalmology, orthopedics, psychiatry, gastroenterology, and cardiovascular medicine interact closely with SCA patients. However, this does not diminish the importance of other specialties. Pharmacy and nursing also play a vital role. With the advent of newer drugs and infusions and SCA affecting liver and kidney function, pharmacists and nursing experts are required to ensure safe dosage and medication delivery to the patient. 

The data presented here is derived mostly from large and small randomized clinical trials. [Level 1 and 2] Few aspects of care presented here are from cohort and case-control studies. [Level 3]

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Sickle Cell Anemia, Hemoglobin C Contributed by Ed Uthman (CC BY 2.0 https://creativecommons.org/licenses/by/2.0)

Disclosure: Ankit Mangla declares no relevant financial relationships with ineligible companies.

Disclosure: Moavia Ehsan declares no relevant financial relationships with ineligible companies.

Disclosure: Nikki Agarwal declares no relevant financial relationships with ineligible companies.

Disclosure: Smita Maruvada declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Mangla A, Ehsan M, Agarwal N, et al. Sickle Cell Anemia. [Updated 2023 Sep 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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