research paper on sickle cell disease

• 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

32k Accesses

48 Citations

2 Altmetric

Metrics details

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.

Download references

Acknowledgements

We would like to acknowledge Lana Mucalo, MD, for supporting data collection for this manuscript.

Author information

Authors and affiliations.

Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, USA

A. M. Brandow

Division of Hematology, Oncology and Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

You can also search for this author in PubMed   Google Scholar

Contributions

AB and RL contributed equally to the writing and editing of this manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to R. I. Liem .

Ethics declarations

Ethics approval and consent to participate, consent for publication, competing interests.

The authors have no competing interests to declare.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Brandow, A.M., Liem, R.I. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol 15 , 20 (2022). https://doi.org/10.1186/s13045-022-01237-z

Download citation

Received : 30 September 2021

Accepted : 15 February 2022

Published : 03 March 2022

DOI : https://doi.org/10.1186/s13045-022-01237-z

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Sickle cell anemia

Journal of Hematology & Oncology

ISSN: 1756-8722

• General enquiries: [email protected]

Featured Clinical Reviews

• Screening for Atrial Fibrillation: US Preventive Services Task Force Recommendation Statement JAMA Recommendation Statement January 25, 2022
• Evaluating the Patient With a Pulmonary Nodule: A Review JAMA Review January 18, 2022
• Download PDF
• CME & MOC
• Share X Facebook Email LinkedIn
• Permissions

Sickle Cell Disease : A Review

• 1 Division of General Pediatrics, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts
• 2 Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston
• 3 School of Medicine, Division of Hematology and Oncology, University of California Davis, Sacramento
• Comment & Response A Review of Sickle Cell Disease—Reply Patricia L. Kavanagh, MD; Titilope Fasipe, MD, PhD; Ted Wun, MD JAMA
• Comment & Response A Review of Sickle Cell Disease Nikolaos Vlachadis, MD, DMD, MPH, MSc, DSc; Nikolaos Vrachnis, MD, PhD JAMA
• JAMA Clinical Guidelines Synopsis Diagnosis and Management of Priapism Richard J. Fantus, MD; Robert E. Brannigan, MD; Andrew M. Davis, MD, MPH JAMA

Importance   Sickle cell disease (SCD) is an inherited disorder of hemoglobin, characterized by formation of long chains of hemoglobin when deoxygenated within capillary beds, resulting in sickle-shaped red blood cells, progressive multiorgan damage, and increased mortality. An estimated 300 000 infants are born annually worldwide with SCD. Most individuals with SCD live in sub-Saharan Africa, India, the Mediterranean, and Middle East; approximately 100 000 individuals with SCD live in the US.

Observations   SCD is diagnosed through newborn screening programs, where available, or when patients present with unexplained severe atraumatic pain or normocytic anemia. In SCD, sickling and hemolysis of red blood cells result in vaso-occlusion with associated ischemia. SCD is characterized by repeated episodes of severe acute pain and acute chest syndrome, and by other complications including stroke, chronic pain, nephropathy, retinopathy, avascular necrosis, priapism, and leg ulcers. In the US, nearly all children with SCD survive to adulthood, but average life expectancy remains 20 years less than the general population, with higher mortality as individuals transition from pediatric to adult-focused health care systems. Until 2017, hydroxyurea, which increases fetal hemoglobin and reduces red blood cell sickling, was the only disease-modifying therapy available for SCD and remains first-line therapy for most individuals with SCD. Three additional therapies, L-glutamine, crizanlizumab, and voxelotor, have been approved as adjunctive or second-line agents. In clinical trials, L-glutamine reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo. Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo. Voxelotor increased hemoglobin by at least 1 g/dL, significantly more than placebo (51% vs 7%). Hematopoietic stem cell transplant is the only curative therapy, but it is limited by donor availability, with best results seen in children with a matched sibling donor. While SCD is characterized by acute and chronic pain, patients are not more likely to develop addiction to pain medications than the general population.

Conclusions and Relevance   In the US, approximately 100 000 people have SCD, which is characterized by hemolytic anemia, acute and chronic pain, acute chest syndrome; increased incidence of stroke, nephropathy, and retinopathy; and a life span that is 20 years shorter than the general population. While hydroxyurea is first-line therapy for SCD, L-glutamine, crizanlizumab, and voxelotor have been approved in the US since 2017 as adjunctive or second-line treatments, and hematopoietic stem cell transplant with a matched sibling donor is now standard care for severe disease.

Read More About

Kavanagh PL , Fasipe TA , Wun T. Sickle Cell Disease : A Review . JAMA. 2022;328(1):57–68. doi:10.1001/jama.2022.10233

Manage citations:

© 2024

Artificial Intelligence Resource Center

Cardiology in JAMA : Read the Latest

Browse and subscribe to JAMA Network podcasts!

Others Also Liked

Select your interests.

Customize your JAMA Network experience by selecting one or more topics from the list below.

• Academic Medicine
• Acid Base, Electrolytes, Fluids
• Allergy and Clinical Immunology
• American Indian or Alaska Natives
• Anesthesiology
• Anticoagulation
• Art and Images in Psychiatry
• Artificial Intelligence
• Assisted Reproduction
• Bleeding and Transfusion
• Caring for the Critically Ill Patient
• Challenges in Clinical Electrocardiography
• Climate and Health
• Climate Change
• Clinical Challenge
• Clinical Decision Support
• Clinical Implications of Basic Neuroscience
• Clinical Pharmacy and Pharmacology
• Complementary and Alternative Medicine
• Consensus Statements
• Coronavirus (COVID-19)
• Critical Care Medicine
• Cultural Competency
• Dental Medicine
• Dermatology
• Diabetes and Endocrinology
• Diagnostic Test Interpretation
• Drug Development
• Electronic Health Records
• Emergency Medicine
• End of Life, Hospice, Palliative Care
• Environmental Health
• Equity, Diversity, and Inclusion
• Facial Plastic Surgery
• Gastroenterology and Hepatology
• Genetics and Genomics
• Genomics and Precision Health
• Global Health
• Guide to Statistics and Methods
• Hair Disorders
• Health Care Delivery Models
• Health Care Economics, Insurance, Payment
• Health Care Quality
• Health Care Reform
• Health Care Safety
• Health Care Workforce
• Health Disparities
• Health Inequities
• Health Policy
• Health Systems Science
• History of Medicine
• Hypertension
• Images in Neurology
• Implementation Science
• Infectious Diseases
• Innovations in Health Care Delivery
• JAMA Infographic
• Law and Medicine
• Leading Change
• Less is More
• LGBTQIA Medicine
• Lifestyle Behaviors
• Medical Coding
• Medical Devices and Equipment
• Medical Education
• Medical Education and Training
• Medical Journals and Publishing
• Mobile Health and Telemedicine
• Narrative Medicine
• Neuroscience and Psychiatry
• Notable Notes
• Nutrition, Obesity, Exercise
• Obstetrics and Gynecology
• Occupational Health
• Ophthalmology
• Orthopedics
• Otolaryngology
• Pain Medicine
• Palliative Care
• Pathology and Laboratory Medicine
• Patient Care
• Patient Information
• Performance Improvement
• Performance Measures
• Perioperative Care and Consultation
• Pharmacoeconomics
• Pharmacoepidemiology
• Pharmacogenetics
• Pharmacy and Clinical Pharmacology
• Physical Medicine and Rehabilitation
• Physical Therapy
• Physician Leadership
• Population Health
• Primary Care
• Professional Well-being
• Professionalism
• Psychiatry and Behavioral Health
• Public Health
• Pulmonary Medicine
• Regulatory Agencies
• Reproductive Health
• Research, Methods, Statistics
• Resuscitation
• Rheumatology
• Risk Management
• Scientific Discovery and the Future of Medicine
• Shared Decision Making and Communication
• Sleep Medicine
• Sports Medicine
• Stem Cell Transplantation
• Substance Use and Addiction Medicine
• Surgical Innovation
• Surgical Pearls
• Teachable Moment
• Technology and Finance
• The Art of JAMA
• The Arts and Medicine
• The Rational Clinical Examination
• Tobacco and e-Cigarettes
• Translational Medicine
• Trauma and Injury
• Treatment Adherence
• Ultrasonography
• Users' Guide to the Medical Literature
• Vaccination
• Venous Thromboembolism
• Veterans Health
• Women's Health
• Workflow and Process
• Wound Care, Infection, Healing
• Register for email alerts with links to free full-text articles
• Access PDFs of free articles
• Manage your interests
• Save searches and receive search alerts

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 15 March 2024

Innovators want pills to treat sickle cell disease. Can they match gene therapy?

• Cormac Sheridan 1  

Nature Biotechnology volume  42 ,  pages 347–350 ( 2024 ) Cite this article

1615 Accesses

11 Altmetric

Metrics details

Although CRISPR-based gene therapy for sickle cell disease offers transformative outcomes, drugmakers are striving to develop treatments that are easy to manufacture and can reach much larger numbers of patients.

You have full access to this article via your institution.

Just as the world’s first CRISPR-based gene editing therapy gained approval for treating sickle cell disease late last year, Pfizer was unveiling its progress with an investigational oral drug for the same condition. Regulatory backing for Casgevy (exagamglogene autotemcel) received far more attention, given its historic significance and dramatic effects on relieving acute symptoms of the condition. But for many people living with sickle cell disease an oral drug such as GBT021601 might be more important. GBT021601 (also called osivelotor ) is a small-molecule drug and is not hard to manufacture in large quantities. In contrast, both Casgevy, which Vertex and CRISPR Therapeutics co-developed, and Lyfgenia (lovotibeglogene autotemcel), the ex vivo-engineered cell therapy from Bluebird Bio that gained approval at the same time, are difficult to scale and will only have a limited reach. Oral and injected drugs (Table 1 ) may not offer the profound effects on acute sickle cell symptoms observed with Casgevy and Lyfgenia, but their greater accessibility means they will have a bigger impact on the global disease burden.

The drug GBT021601 came into Pfizer’s hands through its $5.4-billion acquisition of Global Blood Therapeutics in 2022. It is a more potent successor to another drug from Global Blood Therapeutics, Oxbryta (voxelotor), which gained approval in 2019. Both act by preventing the mutant, sickling form of hemoglobin, known as HbS, from polymerizing, which gives rise to rigid, sickle-shaped red blood cells. These misshapen erythrocytes, which are the hallmark of the condition, are unable to move through blood vessels as readily as their healthy counterparts, resulting in blockages in blood vessels, impaired blood flow to tissues, red blood cell destruction by hemolysis and, in the long-term, organ damage, stroke and other problems.

In people with sickle cell disease, hemoglobin adopts the ‘sickling’ conformation only in hypoxic conditions, when the molecule is deoxygenated. Oxbryta and GBT021601 counter these processes by increasing the affinity of HbS for oxygen and lengthening the time patients’ hemoglobin remains functional.

Oxbryta gained approval based on its ability to boost functioning hemoglobin by at least 1 gram per deciliter of blood — known as a ‘hemoglobin response’ — after 24 weeks of daily dosing. In a pivotal trial, Oxbryta enabled a hemoglobin response in just over 51% of patients, compared with 6.5% of patients on placebo. “We know that every gram increase in hemoglobin is associated in retrospective studies with improvements in long-term outcomes,” says Kim Smith-Whitley, a pediatric hematologist, site head and advisor of scientific & clinical affairs at Pfizer. The drug’s ability to reduce vaso-occlusive crises (VOCs) — a key efficacy measure — was variable, however. These severe acute episodes of inflammatory pain arise from blockages in blood vessels and often require hospitalization. In a real-world study of Oxbryta, the number of VOCs patients experienced in a year dropped 23% from baseline. In contrast, in the phase 3 trial that secured its approval, the drug had only a limited impact on this parameter. That may reflect the variability of the condition, between different patients and across the lifetime of individual patients.

Pfizer hopes that GBT021601’s higher affinity for oxygen will translate into a superior safety and efficacy profile over that of Oxbryta. “I do think ’601 has the potential to be more efficacious at a lower dose,” says Smith-Whitley.

Jefferies, an investment bank, has set out a bullish investment case for GBT021601, based on interim data Pfizer unveiled at the American Society of Hematology’s 2023 annual meeting. After 12 weeks’ therapy, patients in the high-dose and low-dose arms of an ongoing phase 2/3 study achieved mean increases in hemoglobin of 3.17 g/dL and 2.67 g/dL, respectively. (Their baseline levels ranged from 5.5 to 10.5 g/dL). That boost is “comparable” to that of gene therapy, according to an investor note from Jefferies analysts, who have forecast peak sales of $2.2 billion for the product. That improved efficacy is also reflected in an effect on VOCs: the annualized rate of such events dropped from the baseline level of 2.3 episodes per year to 1.2. (The two approved genetic therapies eliminated VOCs in the vast majority of patients.) GBT021601 also appears to be more tolerable than Oxbryta, which is administered at a high dose. During the trial, proportionally fewer patients stopped taking the drug because of gastrointestinal side effects than is historically the case with Oxbryta.

Several other drug developers, including Fulcrum Therapeutics, are attempting to induce fetal hemoglobin (HbF) expression, a strategy similar to that pursued by gene therapy and gene editing firms. HbF, the main oxygen transport protein during pregnancy and early infancy, comprises two α-globin and two γ-globin chains and is therefore unaffected by sickle cell disease, which arises from a single amino acid substitution in the β-globin chain of adult hemoglobin. Hereditary persistence of HbF, which can arise through mutations in a number of genes, has long been recognized to protect against severe symptoms of sickle cell disease.

Approved gene therapy Casgevy — as well as a number of other gene editing therapies in development, including Beam Therapeutics’ ex vivo base editing therapy BEAM-101 and Editas Medicine’s renizgamglogene autogedtemcel (formerly EDIT-301) — induces HbF production. They do so by disrupting an enhancer bound by the BCL11A erythroid-specific zinc-finger transcription factor, which suppresses γ-globin expression. Fulcrum set out to identify small-molecule targets that could also modulate HbF gene expression. Using a CRISPR-based screening system, it identified EED (embryonic ectoderm development), a component of the Polycomb repressive complex 2 (PRC2), as an epigenetic regulator of HbF expression. From this effort emerged pociredir, a small molecule that binds EED, resulting in PRC2 inhibition and increased HbF production. “After only six weeks of dosing, we were able to get patients to around 25%,” says CEO Alex Sapir. “We could potentially get up to fetal hemoglobin levels that are comparable with what is being seen with cell and gene therapy.”

Progress with pociredir was temporarily halted, however, when the US Food and Drug Administration placed a clinical hold on the program in February 2023, following the emergence of secondary malignancies associated with a third-party cancer drug that also targets PRC2. “We believe it’s tazemetostat,” says Paul Bruno, executive vice president, corporate and business development at Fulcrum, referencing a drug for lymphoma and sarcoma that Paris-based Ipsen markets as Tazverik. Although the agency lifted the hold after six months, it has imposed restrictive inclusion criteria, which limits the resumed study to patients with severe sickle cell disease.

Several other targets linked to HbF expression have recently emerged. A team of scientists at Basel, Switzerland-based Novartis has used phenotypic screening to identify compounds that degrade a transcription factor, Wiz, thereby de-repressing γ-globin expression and boosting HbF production in patient-derived cells. Others are attempting to drug BCL11A directly. Scientists at the lab of Stuart Orkin, of the Dana-Farber Cancer Institute in Boston, reported at the American Society of Hematology annual meeting last year that BCL11A functions as a tetramer and that its stability depends on a particular zinc finger domain, an unexpected finding that means it has a stable structure that can be targeted with small molecules.

At the other end of the development cycle, Agios Pharmaceuticals is seeking to extend the use to sickle cell disease of Pyrukynd (mitapivat), a small molecule already approved for patients with hemolytic anemia due to pyruvate kinase deficiency. In either indication the goal is to reduce hemolysis and extend the lifespan of patients’ red blood cells. “The hemolytic anemias create profound metabolic oxidative stress in the cell,” says CEO Brian Goff. Moreover, the large-scale release of the contents of lysed red blood cells into the circulation is toxic . The enzyme pyruvate kinase catalyzes the conversion of phosphoenol pyruvate to pyruvate while generating adenosine triphosphate. Increasing the enzyme’s activity improves the cells’ energy status, but it also depletes levels of the glycolysis pathway intermediate 2,3-diphosphoglycerate, which is a negative allosteric regulator of hemoglobin’s oxygen affinity. In sickle cell disease, this additional effect could lower hemoglobin polymerization. Agios has a second pyruvate kinase activator in the clinic, which has enhanced efficacy and may allow a once-daily dose regimen. Also pursuing a pyruvate kinase activator is Novo Nordisk, of Bagsværd, Denmark. The pharma paid $1.1 billion to move into this space in 2022, when it acquired Forma Therapeutics, the biotech developing etavopivat.

At present, neither drug therapies nor gene or gene editing therapies are a panacea. Casgevy and Lyfgenia appear to be remarkably effective, but only a small number of patients will benefit from these therapies. Small molecules are inherently scalable, but they do not offer the transformative outcomes available with ex vivo gene or gene editing therapies.

In vivo gene or gene editing therapy would bypass these problems. That may seem a remote prospect at this point, but it is the long-term ambition of a partnership between the Innovative Genomics Institute (IGI) at the University of California, Berkeley, led by Jennifer Doudna, and Pioneer Science, a Brazilian philanthropic organization based in Rio de Janeiro.

The initial plan is to develop an ex vivo CRISPR-based therapy, which will be available in Brazil on a not-for-profit basis. “The special thing about the way that we’re delivering the CRISPR enzyme is that it can be modified for in vivo use,” says Ross Wilson, of UC Berkeley and the IGI, who is principal investigator on the US side of the alliance.

A new delivery technology could make this possible. Wilson’s group has previously reported on an amphiphilic peptide they identified by screening. The team succeeded in editing T cells, B cells and natural killer cells simply by simply mixing the peptide with a CRISPR ribonucleoprotein. It does not require any dedicated hardware and, because the approach avoids electroporation, which is damaging to cells, it may lead to an improved product profile. “Our current data suggest that the cells are doing just fine. That’s one of the goals, to put the cells in a healthier state, that is less impacted by electroporation, to improve engraftment and minimize risks of adverse events,” he says.

The team is now refining a protocol for editing hematopoietic stem and precursor cells of patients with sickle cell disease before transferring the technology and know-how to Brazil. Bruno Solano, a physician-scientist who has posts at the Instituto D’Or de Pesquisa e Ensino and Hospital São Rafael in Salvador, will lead the clinical development and rollout of the therapy in the country. A cell therapy specialist, he already has experience in administering chimeric antigen receptor T cell therapy to patients with cancer. Brazil has close to 100,000 people with sickle cell disease, which is similar in scale to the US patient population, but, says Solano, the prevalence is particularly concentrated in the Bahia region in the northeast, where about one in every 650 people has the condition. “It’s the highest incidence in the country.”

Successfully delivering a CRISPR-based therapy to Brazilian patients would represent an important step in globalizing this transformative approach. There is a still a long way to go before all patients can receive effective therapies. Sub-Saharan Africa is where the need is greatest and is growing most rapidly: according to a study published last year, the region accounted for 79% of all new cases in 2021. Tackling this huge burden of disease remains a critically important task.

Author information

Authors and affiliations.

Dublin, Ireland

Cormac Sheridan

You can also search for this author in PubMed   Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Sheridan, C. Innovators want pills to treat sickle cell disease. Can they match gene therapy?. Nat Biotechnol 42 , 347–350 (2024). https://doi.org/10.1038/s41587-024-02179-2

Download citation

Published : 15 March 2024

Issue Date : March 2024

DOI : https://doi.org/10.1038/s41587-024-02179-2

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Effect of allogeneic hematopoietic stem cell transplantation on sickle cell disease-related organ complications: A systematic review and meta-analysis

Affiliations.

• 1 Department of Hematology, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, The Netherlands.
• 2 Department of Pediatrics, Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, USA.
• 3 Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands.
• PMID: 38517255
• DOI: 10.1002/ajh.27297

Sickle cell disease (SCD)-related organ complications are a major cause of morbidity and mortality in patients with SCD. We sought to assess whether hematopoietic stem cell transplantation (HSCT) stabilizes, attenuates, or exacerbates organ decline. We performed a systematic review and meta-analysis of trials investigating organ function before and after HSCT in patients with SCD. We searched MEDLINE/PubMed and EMBASE up to September 21, 2023. Continuous data were expressed as standardized mean difference (SMD) and pooled in a weighted inverse-variance random-effects model; binomial data were expressed as risk ratio (RR) using the Mantel-Haenszel random-effects meta-analyses. Of 823 screened studies, 34 were included in this review. Of these, 17 (774 patients, 23.6% adults, 86.3% HLA-identical sibling donor, 56.7% myeloablative conditioning regimen) were included in the meta-analyses. Pulmonary function remained stable. Mean tricuspid regurgitant jet velocity decreased but did not reach statistical significance. In children, estimated glomerular filtration rate decreased (SMD -0.80, p = .01), and the presence of proteinuria increased (RR 2.00, p = <.01), while splenic uptake and phagocytic function improved (RR 0.31, p = <.01; RR 0.23, p = <.01). Cerebral blood flow improved (SMD -1.39, p = <.01), and a low incidence of stroke after transplantation in high-risk patients was found. Retinopathy and avascular osteonecrosis were investigated in only one study, showing no significant changes. While HSCT can improve some SCD-related organ dysfunctions, transplantation-related toxicity may have an adverse effect on others. Future research should focus on identifying individuals with SCD who might benefit most from HSCT and which forms of organ damage are more likely to exacerbate post-transplantation.

© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.

Publication types

Advertisement

SUCCESSES AND PITFALLS IN ORPHAN DRUG DEVELOPMENT FOR SICKLE CELL DISEASE

• Split-Screen
• Request Permissions
• Cite Icon Cite
• Search Site
• Open the PDF for in another window

Enrico Costa , Antonella Isgrò , Mariane de Montalembert , Hubert G.M. Leufkens , Russell E. Ware , Lucia De Franceschi; SUCCESSES AND PITFALLS IN ORPHAN DRUG DEVELOPMENT FOR SICKLE CELL DISEASE. Blood Adv 2024; bloodadvances.2023011730. doi: https://doi.org/10.1182/bloodadvances.2023011730

Download citation file:

• Ris (Zotero)
• Reference Manager

20 years of sickle cell orphan drug development has ~12% success rate, with highest rates when targeting early pathophysiological steps.

Failure rates for lack of efficacy were highest in late stages of drug development when vaso-occlusive crisis was the key clinical endpoint.

Sickle cell disease (SCD) is a hereditary red cell disorder with large global burden problem. In the United States (US) and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the US and Europe over the last two decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 OD for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021) development of 34/57 ODs was completed. Four OD were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared to products targeting disease consequences. Large companies showed a fourfold higher success rate compared to small-medium enterprises. Failures in clinical development were mainly seen in Phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study endpoint, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical endpoints. -

Article PDF first page preview

Supplemental data, email alerts, affiliations.

• Current Issue
• Latest Articles
• Collections
• Community Conversations
• Blood Advance Talks
• Permissions
• Submit to Blood Advances
• Order Reprints
• Advertising in Blood Advances

American Society of Hematology

• 2021 L Street NW, Suite 900
• Washington, DC 20036
• TEL +1 202-776-0544
• FAX +1 202-776-0545

ASH Publications

• Blood Advances
• Hematology, ASH Education Program
• ASH Clinical News
• The Hematologist
• Publications
• Privacy Policy
• Cookie Policy
• Terms of Use

This Feature Is Available To Subscribers Only

Sign In or Create an Account

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.

Articles about Sickle Cell Disease

• Featured Topics

Recent Scientific Articles

Additional selected articles.

Featured Topics on Sickle Cell Disease

Sickle Cell Data Collection Program This World Sickle Cell Day 2023, learn about CDC’s SCDC program, and find a suite of online resources that can help you or someone you know live healthy with SCD.

Stories of Sickle Cell Learn about sickle cell disease and the Stories of Sickle Cell project.

CDC Study Highlights Importance of Increasing Flu Vaccine for People with Sickle Cell Disease Flu vaccination is particularly important for people who are at higher risk of serious complications from influenza. This includes people with SCD.

What is Sickle Cell Disease? Learn about sickle cell disease and find resources for patients and caregivers.

Sickle Cell Summer Camp Learn about Sickle Cell Camp and find one near you.

Did You Know Sickle Cell Has Many Faces? Learn about the many faces of sickle cell disease and read Mimi’s story.

Sickle Cell Disease Monitoring CDC is working to raise awareness about sickle cell disease. You can help by reading and sharing our resources with friends and family.

Taking Charge of Your Health and Health Care Learn how young people with sickle cell disease can take a more active role in their health care.

Caregivers and Sickle Cell Disease Learn the effect sickle cell disease has on family members & caregivers.

* These CDC scientific articles are listed in order of date published from 2014 to present.

Use of Recommended Health Care Measures to Prevent Selected Complications of Sickle Cell Anemia in Children and Adolescents — Selected U.S. States, 2019 Schieve LA, Simmons GM, Payne AB, et al. MMWR Morb Mortal Wkly Rep 2022;71:1241–1246. DOI:  http://dx.doi.org/10.15585/mmwr.mm7139e1 .

• Vital Signs : Preventing Sickle Cell Anemia Complications in Children

Surveillance for Sickle Cell Disease — Sickle Cell Data Collection Program, Two States, 2004–2018. Snyder AB, Lakshmanan S, Hulihan MM, et al. MMWR Surveill Summ 2022;71(No. SS-9):1–18. DOI: http://dx.doi.org/10.15585/mmwr.ss7109a1 .

Prioritizing Sickle Cell Disease. Lewis L. Hsu, W. Craig Hooper, Laura A. Schieve. Pediatrics December 2022; 150 (6): e2022059491. 10.1542/peds.2022-059491

Sickle Cell Disease: A Review Kavanagh PL, Fasipe TA, Wun T. JAMA. 2022;328(1):57–68. doi:10.1001/jama.2022.10233

COVID-19 and Sickle Cell Disease-Related Deaths Reported in the United States. Payne AB, Schieve LA, Abe K, Hulihan M, Hooper WC, Hsu LL. [published online ahead of print, 2022 Jan 21]. Public Health Rep. 2022;333549211063518. doi:10.1177/00333549211063518.

• Key findings from this article

Influenza vaccination rates and hospitalizations among Medicaid enrollees with and without sickle cell disease, 2009-2015. Payne AB, Adamkiewicz TV, Grosse SD, Steffens A, Shay DK, Reed C, Schieve LA. Pediatr Blood Cancer. 2021 Sep 20:e29351. doi: 10.1002/pbc.29351. Epub ahead of print. PMID: 34542932.

Coronavirus Disease Among Persons with Sickle Cell Disease, United States, March 20–May 21, 2020 Panepinto JA, Brandow A, Mucalo L, Yusuf F, Singh A, Taylor B, Payne AB, Peacock G, Schieve LA. Emerging Infectious Diseases. 2020 Oct. doi: 10.3201/eid2610.202792.

Trends in sickle cell disease-related mortality in the United States, 1979-2017 Payne AB, Mehal JM, Chapman C, Haberling DL, Richardson LC, Bean CJ, Hooper WC. Annals of Emergency Medicine. 2020; 76 (3S):S28-S36

Using surveillance to determine the number of individuals with sickle cell disease in California and Georgia, 2005-2016 Aluc A, Zhou M, Paulukonis ST, Snyder AB, Wong D, Hulihan MM. [published online ahead of print, 2020 Aug 12]. Pediatr Hematol Oncol. 2020;1-5. doi:10.1080/08880018.2020.1779886

Impact of Medicaid expansion on access and healthcare among individuals with sickle cell disease Kayle M, Valle J, Paulukonis S, Holl JL, Tanabe P, French DD, Garg R, Liem RI, Badawy SM, Treadwell MJ. Pediatr Blood Cancer. 2020 May;67(5):e28152.

Acute Care Utilization at End of Life in Sickle Cell Disease: Highlighting the Need for a Palliative Approach Johnston EE, Adesina OO, Alvarez E, Amato H, Paulukonis S, Nichols A, Chamberlain LJ, Bhatia S. J Palliat Med. 2020 Jan;23(1):24-32.

Characterizing complication risk from multisite, intermittent transfusions for the treatment of sickle cell disease Tang A, Branscomb J, Zhou M, Snyder A, Eckman J. Pediatr Blood Cancer. 2019 Oct;66(10):e27921.

Health literacy and knowledge of chronic transfusion therapy in adolescents with sickle cell disease and caregivers Yee MEM, Meyer EK, Fasano, RM, Lane PA, Josephson CD, Brega AG. Pediatr Blood Cancer . 2019 Jul;66(7):e27733.

Understanding the Complications of Sickle Cell Disease Tanabe P, Spratling R, Smith D, Grissom P, Hulihan M.  American Journal of Nursing 2019 June; 119 (6) 26-35. doi: 10.1097/01.NAJ.0000559779.40570.2c

Improving an Administrative Case Definition for Longitudinal Surveillance of Sickle Cell Disease Snyder AB, Zhou M, Theodore R, Quarmyne MO, Eckman J, Lane PA. Public Health Rep. 2019 May/Jun;134(3):274-281. doi: 10.1177/0033354919839072.

Transfusion service knowledge and immunohaematological practices related to sickle cell disease and thalassemia Fasano RM, Branscomb J, Lane PA, Josephson CD, Snyder AB, Eckman JR. Transfus Med. 2019 Feb 10.

Facilitators and Barriers to Minority Blood Donations: A Systematic Review Spratling R, Lawrence RH. Nurs Res. 2019 Mar 1. [Epub ahead of print].

A Strategic Planning Tool for Increasing African American Blood Donation Singleton A, Spratling R. Health Promot Pract. 2018 May 1:1524839918775733. doi: 10.1177/1524839918775733.

Hemoglobin A clearance in children with sickle cell anemia on chronic transfusion therapy Yee MEM, Josephson CD, Winkler AM, Webb J, Luban NLC, Leong T, Stowell SR, Roback JD, Fasano RM. Transfusion. 2018 Apr 17. doi: 10.1111/trf.14610.

CDC Grand Rounds: Improving the Lives of Persons with Sickle Cell Disease Hulihan M, Hassell KL, Raphael JL, Smith-Whitley K, Thorpe P. MMWR Morb Mortal Wkly Rep. 2017 Nov 24;66(46):1269-1271. doi: 10.15585/mmwr.mm6646a2.

Red blood cell minor antigen mismatches during chronic transfusion therapy for sickle cell anemia Yee MEM, Josephson CD, Winkler AM, Webb J, Luban NLC, Leong T, Stowell SR, Fasano RM. Transfusion. 2017 Nov;57(11):2738-2746. doi: 10.1111/trf.14282.

The accuracy of hospital ICD-9-CM codes for determining Sickle Cell Disease genotype Snyder AB, Lane PA, Zhou M, Paulukonis ST, Hulihan MM. J Rare Dis Res Treat. 2017;2(4):39-45.

Emergency Department Utilization by Californians with Sickle Cell Disease, 2005-2014 Paulukonis ST, Feuchtbaum L, Coates TD, Neumayr LD, Treadwell MJ, Vichinsky EP, Hulihan MM. Pediatric Blood & Cancer. 2016 Dec 21. Published online ahead of print.

• Key findings from this article.

Community engagement to inform the development of a sickle cell counselor training and certification program in Ghana Anie KA, Treadwell MJ, Grant AM, Dennis-Antwi JA, Asafo MK, Lamptey ME, Ojodu J, Yusuf C, Otaigbe A, Ohene-Frempong K. J Community Genet. 2016 Jul;7(3):195-202. doi: 10.1007/s12687-016-0267-3.

Emergency Department Visits and Inpatient Admissions Associated with Priapism among Males with Sickle Cell Disease in the United States, 2006-2010 Dupervil B, Grosse S, Burnett A, Parker C. PLoS One. 2016 Apr 14;11(4):e0153257. doi: 10.1371/journal.pone.0153257.

Defining Sickle Cell Disease Mortality Using a Population-Based Surveillance System, 2004 through 2008 Paulukonis ST, Eckman JR, Snyder AB, Hagar W, Feuchtbaum LB, Zhou M, Grant AM, Hulihan MM. Public Health Rep. 2016 Mar-Apr;131(2):367-75.

Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: deviations from Hardy-Weinberg equilibrium Piel FB, Adamkiewicz TV, Amendah D, Williams TN, Gupta S, Grosse SD. Genet Med. 2016 Mar;18(3):265-74. doi: 10.1038/gim.2015.143.

Contribution of Sickle Cell Disease to the Pediatric Stroke Burden Among Hospital Discharges of African-Americans-United States, 1997-2012 Baker C, Grant AM, George MG, Grosse SD, Adamkiewicz TV. Pediatr Blood Cancer. 2015 Dec;62(12):2076-81. doi: 10.1002/pbc.25655.

Mortality of New York children with sickle cell disease identified through newborn screening Wang Y, Liu G, Caggana M, Kennedy J, Zimmerman R, Oyeku SO, Werner EM, Grant AM, Green NS, Grosse SD. Genet Med. 2015 Jun;17(6):452-9. doi: 10.1038/gim.2014.123.

Health policy for sickle cell disease in Africa: experience from Tanzania on interventions to reduce under-five mortality Makani J, Soka D, Rwezaula S, Krag M, Mghamba J, Ramaiya K, Cox SE, Grosse SD. Trop Med Int Health. 2015 Feb;20(2):184-7. doi: 10.1111/tmi.12428.

State-based surveillance for selected hemoglobinopathies Hulihan MM, Feuchtbaum L, Jordan L, Kirby RS, Snyder A, Young W, Greene Y, Telfair J, Wang Y, Cramer W, Werner EM, Kenney K, Creary M, Grant AM. Genet Med. 2015 Feb;17(2):125-30. doi: 10.1038/gim.2014.81.

Attitudes toward Management of Sickle Cell Disease and Its Complications: A National Survey of Academic Family Physicians Mainous AG 3rd, Tanner RJ, Harle CA, Baker R, Shokar NK, Hulihan MM. Anemia. 2015;2015:853835. doi: 10.1155/2015/853835.

Population based surveillance in sickle cell disease: methods, findings and implications from the California registry and surveillance system in hemoglobinopathies project (RuSH). Pediatr Blood Cancer Paulukonis ST, Harris WT, Coates TD, Neumayr L, Treadwell M, Vichinsky E, Feuchtbaum LB. 2014 Dec;61(12):2271-6. doi: 10.1002/pbc.25208.

Incidence of sickle cell trait–United States, 2010 Ojodu J, Hulihan MM, Pope SN, Grant AM; Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2014 Dec 12;63(49):1155-8.

Obstetrician-gynecologists’ knowledge of sickle cell disease screening and management Azonobi IC, Anderson BL, Byams VR, Grant AM, Schulkin J. BMC Pregnancy Childbirth. 2014 Oct 14;14:356. doi: 10.1186/1471-2393-14-356.

Discordance between self-report and genetic confirmation of sickle cell disease status in African-American adults Bean CJ, Hooper WC, Ellingsen D, DeBaun MR, Sonderman J, Blot WJ. Public Health Genomics. 2014;17(3):169-72. doi: 10.1159/000360260.

Invasive pneumococcal disease among children with and without sickle cell disease in the United States, 1998 to 2009 Payne AB, Link-Gelles R, Azonobi I, Hooper WC, Beall BW, Jorgensen JH, Juni B, Moore M; Active Bacterial Core Surveillance Team. Pediatr Infect Dis J. 2013 Dec;32(12):1308-12. doi: 10.1097/INF.0b013e3182a11808.

Acute chest syndrome is associated with single nucleotide polymorphism-defined beta globin cluster haplotype in children with sickle cell anaemia Bean CJ, Boulet SL, Yang G, Payne AB, Ghaji N, Pyle ME, Hooper WC, Bhatnagar P, Keefer J, Barron-Casella EA, Casella JF, Debaun MR. Br J Haematol. 2013 Oct;163(2):268-76. doi: 10.1111/bjh.12507.

Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia Wang WC, Oyeku SO, Luo Z, Boulet SL, Miller ST, Casella JF, Fish B, Thompson BW, Grosse SD; BABY HUG Investigators. Pediatrics. 2013 Oct;132(4):677-83. doi: 10.1542/peds.2013-0333.

Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity Wang Y, Kennedy J, Caggana M, Zimmerman R, Thomas S, Berninger J, Harris K, Green NS, Oyeku S, Hulihan M, Grant AM, Grosse SD. Genet Med. 2013 Mar;15(3):222-8. doi: 10.1038/gim.2012.128.

Sickle cell disease in pregnancy: maternal complications in a Medicaid-enrolled population Boulet SL, Okoroh EM, Azonobi I, Grant A, Craig Hooper W. Matern Child Health J. 2013 Feb;17(2):200-7. doi: 10.1007/s10995-012-1216-3.

Join the Public Health Webinar Series on Blood Disorders

• Upcoming webinar
• View past webinars

Exit Notification / Disclaimer Policy

• The Centers for Disease Control and Prevention (CDC) cannot attest to the accuracy of a non-federal website.
• Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.
• You will be subject to the destination website's privacy policy when you follow the link.
• CDC is not responsible for Section 508 compliance (accessibility) on other federal or private website.

Advertisement

Abstract 3853: T cell ferroptosis attenuates antitumor immune responses in sickle cell disease

• Split-Screen
• Article contents
• Figures & tables
• Supplementary Data
• Peer Review
• Get Permissions
• Cite Icon Cite
• Search Site
• Version of Record March 22 2024

Zilong Zhao , Benxia Hu , Yalan Deng , Melinda Soeung , Giannicola Genovese , Wenbo Li , Pavlos Msaouel , Liuqing Yang , Chunru Lin; Abstract 3853: T cell ferroptosis attenuates antitumor immune responses in sickle cell disease. Cancer Res 15 March 2024; 84 (6_Supplement): 3853. https://doi.org/10.1158/1538-7445.AM2024-3853

Download citation file:

• Ris (Zotero)
• Reference Manager

Background: Sickle cell disease (SCD) is the most common inherited blood disorder and arises from homozygosity for the HbS mutation (GAG>GTG: βGlu6Val) leading to the production of abnormal hemoglobin that cause sickle shaped red blood cells (RBCs). Individuals with SCD are at higher risk than the general population for developing hematologic malignancies or solid tumors such as renal medullary carcinoma (RMC). Although relatively rare, RMC is one of the most aggressive kidney cancers and is the third most common kidney cancer among children and young adults who harbor sickle hemoglobinopathies such as SCD or sickle cell trait (SCT) which occurs due to heterozygosity for the HbS mutation. Molecular profiling studies have shown that most cases involve biallelic inactivation of the SMARCB1 gene, either through simultaneous hemizygous loss and translocation or by homozygous loss. The loss of SMARCB1 and subsequent dysregulation of chromatin remodeling are key factors contributing to the development and progression of renal medullary carcinoma. Despite manifesting an inflamed tumor immune microenvironment, RMC consistently demonstrates resistance to conventional immune checkpoint inhibitors (ICI). Ameliorating the efficacy of immunotherapy of RMC is vital for research and potential therapeutic interventions by targeting CD8 + T cells.

Methods: CyTOF was performed by using the spleen of WT mice and SCD mouse model. mRNA was isolated from CD8 + T cells of Peripheral Blood Mononuclear Cell (PBMC) collected from healthy donors and SCD patients followed by bulk RNA sequencing. Hi-C was conducted using CD8 + T cells isolated from PBMC of healthy donors and SCD patients. We employed DNA FISH (Fluorescence in Situ Hybridization) to examine alterations in gene architecture within CD8 + T cells under varying conditions.

Results: RMC tumors exhibit accelerated tumor growth and reduced numbers of tumor resident CD8 + T cells in SCD mice model compared with WT control. CD8 + T cells in the SCD associated tumor microenvironment (TME) are subjected to ferroptosis by downregulation of SLC7A11; however, SMARCB1 loss promotes the resistance of RMC tumor cells to ferroptosis. Genomic architecture of CD8 + T cells is altered under SCD conditions, potentially contributing to immune dysfunction.

Conclusions: Our research has identified significant alterations in the 3D genome architecture of CD8 + T cells in individuals with SCD. These alterations lead to transcriptional inhibition of SLC7A11, resulting in CD8 + T cell ferroptosis and a hindered anti-tumor immune response in RMC. These findings elucidate the mechanistic relationship of SCD with ICI resistance in cancers such as RMC and provide novel avenues for therapeutically sensitizing tumors to immunotherapies in individuals with SCD.

Keywords: Sickle Cell Disease, Renal Medullary Carcinoma, SMARCB1, Ferroptosis, Genomic Architecture Alteration, Hi-C, SLC7A11

Citation Format: Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Giannicola Genovese, Wenbo Li, Pavlos Msaouel, Liuqing Yang, Chunru Lin. T cell ferroptosis attenuates antitumor immune responses in sickle cell disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3853.

Citing articles via

Email alerts.

• Online First
• Collections
• Online ISSN 1538-7445
• Print ISSN 0008-5472

AACR Journals

• Blood Cancer Discovery
• Cancer Discovery
• Cancer Epidemiology, Biomarkers & Prevention
• Cancer Immunology Research
• Cancer Prevention Research
• Cancer Research
• Cancer Research Communications
• Clinical Cancer Research
• Molecular Cancer Research
• Molecular Cancer Therapeutics
• Info for Advertisers
• Information for Institutions/Librarians

• Privacy Policy
• Copyright © 2023 by the American Association for Cancer Research.

This Feature Is Available To Subscribers Only

Sign In or Create an Account

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• HHS Author Manuscripts

Stigma of Sickle Cell Disease: A Systematic Review

Dominique bulgin.

a Duke University School of Nursing, Durham, North Carolina, USA

Paula Tanabe

b Full Professor, Duke University School of Nursing, Durham, North Carolina, USA

Coretta Jenerette

c University of North Carolina at Chapel Hill, School of Nursing, Chapel Hill, North Carolina, USA

The aim of this systematic review was to synthesize the literature regarding health-related stigma in adolescents and adults living with sickle cell disease (SCD). Four domains were identified from 27 studies: 1) social consequences of stigma, 2) the effect of stigma on psychologicalwell-being, 3) the effect of stigma on physiological well-being, and 4) the impact of stigma on patient-provider relationships and care-seeking behaviors. Current literature revealed that SCD stigma has detrimental consequences. Methodological issues as well as research and practice implications were identified. Future research should further examine the impact of health-related stigma on self-management of SCD.

Introduction

Sickle cell disease (SCD) is a genetically inherited disorder of the hemoglobin that can lead to serious health complications including infection, stroke, and acute and chronic pain. SCD affects 7 million people worldwide ( Yawn et al., 2014 ). According to the Center for Disease Control (CDC), in the United States (US), between 90,000 to 100,000 Americans are diagnosed with SCD and approximately 1 out of every 500 newborn Black infants is at risk for inheriting SCD ( CDC, 2015 ). SCD is a major public health concern, with estimated healthcare costs for individuals amounting to millions of dollars annually and around 80.5% of cost being associated with hospital care ( Kauf, Coates, Huazhi, Mody-Patel, & Hartzema, 2009 ). Comprehensive care is essential for avoiding hospitalizations and increasing quality of life in individuals with SCD, but unfortunately there is less access to comprehensive care for SCD than for other genetic disorders like cystic fibrosis and hemophilia ( Grosse et al., 2009 ). The disparities in comprehensive care stemfrom fewer SCDdisease centers being available, SCD centers being utilized less, and gaps in both funding support for SCD and implementation of clinical advances ( Grosse et al., 2009 ; Smith, Oyeku, Homer, & Zuckerman, 2006 ). The cause and perpetuation of these disparities are linked to the stigma that this population faces.

Stigma involves some type of labeling that leads to negative consequences for the stigmatized individuals ( Link & Phelan, 2013 ). Goffman (1986) social theory of stigma defined it as “an attribute that is deeply discrediting” (p. 4). Stigmatization due to health status is referred to as health-related stigma and involves devaluation, judgment, or social disqualification of individuals based on a health condition ( Weiss, Ramakrishna, & Somma, 2006 ). According to Scambler (2009) sources of health-related stigma frequently include family members, the general public, and health care providers. Any of the stigma and stigma-related concepts defined in Table 1 could be a consequence of, or related to health-related stigma. Individuals with SCD face many obstacles to receiving care; but stigma is one of the most influential and ominous. People who have SCD may experience health-related stigma for a variety of reasons including race, disease status, socioeconomic status, delayed growth and puberty, and/or having chronic and acute pain that needs to be managed with opioids ( Bediako & Moffitt, 2011 ; Bhatt-Poulose, James, Reid, Harrison, & Asnani, 2016 ; Haywood, Tanabe, Naik, Beach, & Lanzkron, 2013 ; Lazio et al., 2010 ; Penner et al., 2010 ).

Types of stigma and stigma-related concepts

While there are many sources of stigma experienced by persons with SCD, racism is an important source as most affected individuals in the US are Black. Despite SCD being a genetic disease, it is impacted by racism and health care equity issues, including hindered access to care and less funding support. Cystic fibrosis, a genetic disease that primarily affects individuals that are White and occurs in approximately 30,000 individuals in the US, is more than eight times more likely to receive funding than SCD despite there being far more people affected by SCD ( Strouse, Lobner, Lanzkron, MHS, & Haywood, 2013 ). Racism frequently interacts and exacerbates other sources of health-related stigma in SCD, including disease and opioid based stigmas. Due to the complex juxtaposition of these concepts, racism is not only recognized as a source of stigma, but is also seen as akin to stigma.

Although health-related stigma plays a significant role in the lives of individuals living with SCD, there is currently no published synthesis in the literature. A systematic review can provide information on the current body of health-related SCD stigma literature, including gaps in the literature, that will lead to a more methodical approach as this area is studied further. This systematic reviewsynthesizes the primary empirical literature to address the question: What is the state of the knowledge regarding health-related stigma in adolescents and adults living with SCD? This paper 1) describes the methods of the review, 2) synthesizes and discusses the findings, and 3) identifies implications for research and clinical practice.

This review synthesizes the research literature on stigma of SCD in adolescents and adults with SCD identified from electronic searches of PubMed, CINAHL, PsycINFO, Medline, and SocINDEX. Peer-reviewed research studies were included if they were: (a) written in English and (b) provided adolescent (ages 10–19) and/or adult specific findings. Studies conducted in adolescents were included as previous studies suggest that individuals with SCD in adolescence have similar experiences and consequences of stigma as adults (i.e. greater disease burden and lower quality of life) ( Adeyemo, Ojewunmi, Diaku-Akinwumi, Ayinde, & Akanmu, 2015 ; Wakefield et al., 2017 ). Adolescent populations are those that are within age limits of 10 to 19, the range that is consistent with the World Health Organization’s (WHO) definition of adolescence ( WHO, 2015 ). All genotypes of SCD were included. Exclusion criteria included editorials; case studies; and studies focusing on caregiver, parent, or healthcare provider perspectives. The key word “sickle cell” was searched in combination with “stigma”, “health-related stigma”, and previously identified surrogate terms for stigma including “discrimination”, “prejudice”, “injustice”, “devalued”, and “dehumanized”( Corrigan, 2004 ; Jacob, 2001 ; Maxwell, Streetly, & Bevan, 1999 ). The search also included hand searches of tables of reference lists of selected studies. The PRISMA flow diagram ( Figure 1 ) depicts the results of the literature search including the number of studies reviewed at each stage and the reasons for exclusion of full text studies ( Liberati et al., 2009 ).

Literature Search Flow Chart. Source: Adapted from PRISMA 2009 Flow Diagram (Moher et al., 2009).

Twenty-seven peer-reviewed studies, published between 2004 and 2017 met the inclusion criteria for analysis. Most studies used descriptive designs (one was a randomized control trial); and authors were nurses, psychologists, hematologists, social workers, sociologists, geneticists, and bioethicists. Data were abstracted using Garrard (2013) matrix method and organized by main concepts, measures, samples, methods, main findings, and limitations. The matrix method uses a structured abstraction strategy to accomplish four fundamental tasks when reviewing literature: 1) deciding what documents to review, 2) comprehending the documents, 3) evaluating the documents, and 4) synthesizing the literature ( Garrard, 2013 , p. 6, 17–18). Table 2 summarizes the studies synthesized.

Synthesis of Articles

Four domains were identified from 27 studies: 1) the social consequences of stigma, 2) the effect of stigma on psychological well-being, 3) the effect of stigma on physiological well-being, and 4) the impact of stigma on patient-provider relationships and care-seeking behaviors. The four domains provided insight into the state of the literature regarding stigma of SCD and the impact that it has on the lives of individuals with SCD. However, due to the complexity of human experiences and disease processes, the consequences of stigma of SCD often simultaneously affect multiple domains. Additionally, the studies included conceptualized the consequences of stigma differently and a single study can have information applicable tomore than one domain.

Measures of stigma in SCD

Of the 27 studies reviewed, five used scales adapted for stigma of SCD ( Bediako et al., 2014 ; Blake et al., 2017 ; Holloway, McGill, & Bediako, 2016 ; Jenerette, Brewer, Crandell, & I. Ataga, 2012 ; Jenerette, Brewer, Edwards, Mishel, & Gil, 2014 ). The remainder did not include a scale, adapted a scale about stigma or a stigma-related concept fromanother population, or interviewed participants about stigma and stigma-related concepts. Blake et al. (2017) utilized a SCD stigma scale that has not yet been published and the other 4 studies utilized either the Measure of Sickle Cell Stigma or the SCD Health-Related Stigma Scale.

Stigma of SCD is a multidimensional construct and the two tools developed to measure it reflect the multiple dimensions that comprise stigma ( Bresnahan & Zhuang, 2011 ). Jenerette et al. (2012) developed the Sickle Cell Disease Health-Related Stigma Scale (SCD-HRSS) by modifying the Chronic Pain Stigma Scale ( Reed, 2005 ). The SCD-HRSS has 40 items and 4 subscalesmeasuring health-related stigma fromdoctors, nurses, family, and the general public. The total SCD-HRSS has a Cronbach’s alpha reliability score of 0.84 and scores range 0.68–0.82 for subscales. Bediako et al. (2014) critiqued the SCD-HRSS and asserted that while the SCD-HRSS addresses public and external stigma perceived by individuals with SCD, there is no scale to address the interpersonal components of stigma, including internalized, anticipated, and self-stigmas. They developed the Measure of Sickle Cell Stigma (MoSCS), to address this gap in the measurement of SCD stigma. The MoSCS was developed using a scale developed to address HIV stigma ( Berger, Ferrans, & Lashley, 2001 ). TheMoSCS has 11 items and 4 subscales assessing internalized stigma, social exclusion, disclosure concerns, and expected discrimination. The total MoSCS scale has a Cronbach’s alpha reliability of 0.87 and scores range 0.74–0.89 for subscales.

The review of literature revealed four domains. Thedomains are defined in Table 3 and each are described below. In some cases a study’s findings supported more than one domain as the impact of stigma in one area does not preclude its impact in another.

Domain 1: Social consequences of stigma

Eight studies contained findings regarding social stigma enacted from the general public and family/friends as well as disadvantageous social consequences of stigma. Individuals with SCD reported experiencing negative reactions from family/friends, co-workers, peers, and community members regarding their SCD status ( Ola, Yates, & Dyson, 2016 ). The general public is often not educated about SCD and form their own, typically negative, opinions about people with SCD as a result ( Royal, Jonassaint, Jonassaint, & De Castro, 2011 ; Sankar, Cho, Wolpe, & Schairer, 2006 ). This results in people with SCD being devalued and experiencing status loss. They also have their pain experiences discredited by others and are accused of being weak, lazy, or pretending to be ill ( Ola et al., 2016 ; Royal et al., 2011 ). People with SCD reported being treated as if they have a physical or cognitive impairment that will make them incapable of achieving goals and life milestones ( Royal et al., 2011 ). They also reported stigmatizing experiences in intimate relationships, due to SCD complications, such as pain, priapism, and delayed puberty, impairing their sexuality ( Cobo Vde, Chapadeiro, Ribeiro, Moraes-Souza, & Martins, 2013 ; Cole, 2007 ).

A variety of disclosure concerns associated with revealing SCD status to others emanate from the social stigma felt by individuals with SCD; and thus they are often private about their disease status and regret telling others when they do reveal their status. Reported reasons for disclosure concerns include fear of being treated differently, either pitied or discriminated against. People with SCD also reported discrimination experiences with employment and receiving healthcare as a result of revealing their disease status ( Cole, 2007 ; Dyson et al., 2010 ; Kass et al., 2004 ). They may choose not to disclose their disease status to avoid the anxiety of anticipated stigma and the attributional ambiguity associated with not knowing whether the treatment they are receiving is the result of stigma. Social stigma can severely impact ability to obtain resources and lead to racial, socioeconomic, and medical unfairness ( Cole, 2007 ; Labrousse, 2007 ; Ola et al., 2016 ).

Domain 2: Effects of stigma on psychological well-being

Stigmatizing social experiences can lead to harmful effects on psychological well-being including internalized stigma, social isolation, anxiety, depression, and suicidal ideation and suicide attempts ( Labrousse, 2007 ; Ola et al., 2016 ). Nine studies described findings related to the negative effects stigma has on the quality of life, mental health, and psychological wellbeing of individuals with SCD. Adolescents with SCD (>13 years old) reporting high levels of perceived racial bias and stigma in both health-related and community contexts also hadworsened quality of life ( Adeyemo et al., 2015 ; Wakefield et al., 2017 ). Stigma can impact physical functioning, daily roles, general health perception, and social function ( Adeyemo et al., 2015 ).

Stigma also influences stress levels among individuals with SCD who reported stressful experiences during hospital care, including being stigmatized as drug seeking, delayed care in the emergency department, and healthcare providers doubting their reports of pain ( Cole, 2007 ). Although stress can have physiological and psychological effects, stress is included in domain 2 because the studies summarized primarily focused on the psychological nature of stress. Perceived injustice from healthcare providers was a significant predictor of stress in individuals with SCD ( Ezenwa, Molokie, Wilkie, Suarez, & Yao, 2015 ). Stress can also occur during their daily lives due to stigmatizing experiences, including underestimation by teachers or losing their jobs due to their SCD status ( Cole, 2007 ). An additional daily stressor for individuals with SCD is the illness uncertainty experienced regarding pain crises and unforeseen complications. A study conducted by Blake et al. (2017) revealed that illness uncertainty and stigma share a small but significant correlation.

Due to the stress associated with revealing disease and health status, individuals tended to be selective when disclosing; in some situations this can be disadvantageous. Derlega et al. found that individuals that talk to God or family/friends about their SCD pain had positive psychological adjustment and were more likely to seek care and also had lower awareness of disease stigma or being stereotyped ( Derlega et al., 2014 ). These findings underscore the importance of strong support in improving both psychological and physical wellbeing in individuals with SCD. The stress associated with stigmatization negatively impacts the mental health of individuals with SCD ( Cole, 2007 ; Derlega et al., 2014 ). They are at risk for internalized stigma. Depressive symptoms, including feeling hopeless and loss of interest in daily activities, have been positively associated with internalized stigma in people with SCD ( Holloway et al., 2016 ). Additionally, individuals who experience high rates of stigma are more likely to report anxiety, depressive symptomatology, stress, and anger in comparison to those reporting low rates of stigma ( M. Ezenwa et al., 2016 ; Mathur et al., 2016 ).

Domain 3: Effects of stigma on physiologicalwell-being

Ten studies described the impact of stigma on physiological well-being. Individuals with SCD reported being stigmatized as drug seeking or drug addicts and having their experiences of pain discredited by healthcare providers ( Labrousse, 2007 ; Mathur et al., 2016 ; Mulchan, Valenzuela, Crosby, & Sang, 2016 ). They experienced inadequate pain management and long wait times in the emergency department that correlated with their disease status and race ( Haywood et al., 2013 ; Labore, Mawn, Dixon, & Andemariam, 2017 ). Haywood et al. (2013) illuminated the systematic nature of long wait emergency department wait times for SCD, despite the high triage priority rating of vaso-occlusive crises. Individuals with SCD waited 25% longer than the general population and 50%longer than thosewith long bone fractures after considering race and triage priority. Individuals with SCD adapted their behaviors to cope with anticipated stigma. Delayed care seeking and maladaptive pain coping strategies are related to experiences of stigma ( Jenerette, Brewer, & Ataga, 2014 ; Labore et al., 2017 ). Ezenwa et al. found that individuals perceiving healthcare injustice from physicians and nurses were more likely to cope with their pain using maladaptive mechanisms, such as pain catastrophizing and isolation; while those who experienced healthcare justice coped with their pain using prayer, calming, attention diversion, and increased behavioral activity ( Ezenwa et al., 2015 ). The maladaptive behaviors that form as a result of stigma can severely impact both physiological and psychological health status in SCD.

Stigmahas been found to exacerbate the pain that people with SCD experience as a result of their disease pathology. People with SCD that reported experiencing higher rates of disease and race-based discrimination in healthcare settings also reported greater pain, pain severity, pain burden, and pain interference with functionality, sleep, and daily activities ( Haywood et al., 2014 ; Mathur et al., 2016 ; Wakefield et al., 2017 ). Finally, the effects of stigma on mental health can also impact physiological wellbeing in the form of self-harming behaviors and suicide ( Ola et al., 2016 ). This underscores the simultaneous effect that stigma has on physiological and psychological wellbeing.

Domain 4: Impacts of stigma on patient-provider relationships and care-seeking behaviors

Eleven studies contained results pertaining to how stigma stemming from healthcare settings and providers influenced care-seeking behaviors and patient-provider relationships. Individuals with SCD reported that race and disease based discrimination impacts the healthcare they receive ( Mulchan et al., 2016 ; Nelson & Hackman, 2013 ; Royal et al., 2011 ). Those that have experiences with discrimination were more likely to be non-adherent to medical recommendations and reported low levels of trust in healthcare providers ( Haywood et al., 2014 ). Additionally, people with SCD often identified a lack of awareness and education surrounding SCD in the healthcare provider community as a contributor to the stigma they experience ( Cole, 2007 ).

Stanton et al. (2010) illuminated how the presence of stigma makes it difficult to improve patient-provider relationships by assessing the relationships between perceived discrimination and optimism (the expectation that good things will happen). They found that individuals that had high discrimination experiences and optimism, had an increase in hospitalizations in comparison to those with high discrimination experiences and low optimism ( Stanton et al., 2010 ). Having a pessimistic outlook towards healthcare systems and providers may be more protective in terms of health outcomes; however pessimistic outlooks toward healthcare systems can further hinder patient-provider relationships. Furthermore, strained patient-provider relationships can result in hindered care-seeking behaviors.

Individuals with SCD also alter their care-seeking behaviors based on their experiences with stigma. Young adults with SCD (ages 21–25) reported experiencing lack of empathy from healthcare providers regarding their pain, long wait times in the emergency department, inadequate pain management in the emergency department, and anticipated stigma when seeking care for pain. One qualitative study illustrated this stigma in an example: if an asthmatic patient knows the specific amount of prednisone they need for treatment they will be commended by the healthcare community, while a SCD patient in a pain crisis will be labeled as drug seeking if they are able to vocalize the type and dosage of opioids they need ( Mulchan et al., 2016 ). Individuals with SCD reported adjusting their care seeking behaviors by treating their pain at home and/or waiting until pain becomes unbearable before seeking care for their pain, as a result of stigmatizing experiences ( Labore et al., 2017 ). Jenerette et al. (2014) found that 88% of young adults with SCD wait until their pain is an average of 8.7 on a scale of 1–10 before seeking care and factors that influence this decision included anticipated stigma.

The impact of stigma on patient-provider relationships creates challenges when developing interventions to decrease stigma and improve health outcomes in SCD. Jenerette et al. (2014) conducted a pilot study to test an intervention to decrease stigma in young adults with SCD based on the Theory of Self-Care Management of SCD ( Jenerette & Murdaugh, 2008 ). The intervention focused on prompt cue recognition and early care seeking. The study used a randomized control trial method with an intervention group and attention control group (participants in this group participated in activities that imitated the time and attention provided by the intervention) in a population of 90 young adults with SCD ages 18–35. The treatment group was found to increase awareness of stigma, rather than decrease perceptions of stigma ( Jenerette et al., 2014 ). This is the only intervention study that has attempted to decrease stigma and improve care-seeking behaviors amongst individuals with SCD. This pilot study had a high attrition rate which could have influenced results. Although important lessons were learned in this pilot, results support the insidious and complex nature of health-related stigma in SCD.

This systematic review examined the empirical literature on SCD-related stigma in adults and adolescents with SCD. Twenty-seven descriptive studies and one intervention study were reviewed. Overall the review demonstrates the impact that stigma has on the lives and health of individuals with SCD, including hindering physiological and psychological wellbeing, having harmful social consequences, and impairing healthcare interactions. Methodological issues amongst the studies and gaps in the literature were identified. Additionally, practice implications for nurses and limitations of the study itself were noted.

Methodological issues

There are several methodological issues that create gaps in the current understanding of SCD stigma. Firstly, all studies assessing perceived stigma in SCD were descriptive and cross-sectional, except one longitudinal, randomized control trial ( Jenerette et al., 2014 ). There is limited knowledge about the causal relationships stigma has and how to decrease stigma. Additionally, studies describing perceived stigma were mainly quantitative with few mixed methods and qualitative explorations the meaning of the stigmatizing experiences. More qualitative explorative studies that describe the experiences of individuals with SCD are needed to fully understand the nuanced and layered stigma that individuals with SCD experience. Additionally, grounded theory designs may be useful to further the conceptual understanding of the components of stigma and their relationship, and thus contribute to theory development. An improved theorized concept of SCD stigma may lead to the development of useful interventions in this population. The literature of stigma in SCD could benefit from longitudinal studies tracking stigma across time and in depth qualitative and mixed methods explorations of stigma and related concepts. Finally, exploring SCD stigma using structural equation modeling could potentially identify latent variables and reveal not yet explored variable relationships effecting intra- and interpersonal aspects of SCD stigma. Longitudinal, mixed-method, qualitative studies, and structural equation modeling could illuminate the mechanisms through which stigma operates and impacts the wellbeing of individuals with SCD; thus, leading to the development of successful interventions to decrease stigma.

Another methodological issue that limits the current understanding of stigma of SCD is the systematic exclusion of individuals who do not have access to comprehensive SCD care. Studies assessing perceived stigma primarily recruited participants from academic SCD centers. This creates a significant gap in understanding and limits the generalizability of the studies, as individuals who do not have access to comprehensive care centers may be more vulnerable to stigma. For instance, these individuals may have fewer options for healthcare due to socioeconomic status or have more encounters with healthcare providers that are not educated about SCD. In order to develop a complete understanding of SCD stigma individuals outside of comprehensive care settings need to be studied.

The literature of stigma and SCD could also benefit from the use of conceptual frameworks that assist in understanding the interaction between the social determinants of health. Intersectionality theory asserts that experiences with discrimination and injustice are distinct depending characteristics including race, class, age, and gender ( Winker & Degele, 2011 ). Understanding how different aspects of individuals’ identities intersect has the potential to reveal the intricacies of the processes that cause health inequities ( Bauer, 2014 ). While Cobo et al. describes how stigma in intimate partner relationships differs depending on gender, there are amultitude of other ways experiences of stigma can vary depending on clinical and demographic characteristics. Studying these intersections will provide a more complete understanding of stigma of SCD; and advance knowledge of how different individuals experience and cope with stigma. Coping with the stigma of SCD can lead to both positive and negative adaptive efforts. Identifying these efforts were not a part of the search strategy; however, this review supports the importance of coping while living with a life-long chronic condition, and its relevance to both researchers and clinicians. In summary, severalmethodological gaps in the literature were identified: (1) mixed-method and qualitative studies that describe the stigma experiences of individuals with SCD, (2) longitudinal studies that describe the effect stigma has on the trajectory of SCD, (3) structural equation modeling designed to uncover latent variables and unexplored relationships affecting SCD stigma, (4) interventions aimed to decrease stigma, (5) sampling methods that include individuals who do not have access to comprehensive SCD care, and (6) studies exploring intersectional identities in SCD. Addressing methodological gaps in the literature can lead to a more complete understanding of stigma of SCD.

Research implications

Several gaps have been identified that require further research to improve the understanding of stigma of SCD. First, the compounded or layered nature of stigma makes it difficult to precisely pinpoint the influence of stigma on the lives of individuals with SCD. Many of the studies conflated racism and stigma. Royal et al. (2011) attempted to uncover the role that race plays in SCD stigma; one participant in this study noted, “My race does influence my experience with SCD because blacks are viewed in a negative light. Racism is an added burden to my experience as a person with SCD” (p. 397). Additionally, Haywood et al. (2013) were able to unearth data confirming that both race and disease status contribute to longer wait times for individuals with SCD. However, this is the extent of the literature of layered stigma in SCD; studying layered stigma using intersectionality theory could address this gap in the literature.

Studying layered stigma from a global perspective can also contribute to our understanding of stigma of SCD. Layered stigma in SCD is a significant barrier in the health and overall wellbeing of individuals with SCD. Studies designed to improve our understanding of stigma’s impact on intersectional identities can improve our understanding how racism and health-related and disease stigma function together. For instance, while racial stigma might not manifest as abundantly as it does in theUnited States and United Kingdom, colorism is a global phenomenon. There are currently no publications addressing how colorism influences SCD stigma and health outcomes. Publications in Nigeria, Brazil, England, and the United States have revealed that disease stigma manifests and operates similarly regardless of country ( Adeyemo et al., 2015 ; Cobo Vde et al., 2013 ; Dyson et al., 2010 ; Ola et al., 2016 ), however racial stigma may manifest differently in countries where Black people are the majority. Studying SCD stigma globally would increase our understanding of how layered stigma operates and also provide opportunities to address reducing SCD stigma and improving health outcomes worldwide.

The study of how institutionalized stigma contributes to health inequities in SCD is also relatively unaddressed in SCD stigma literature. While there are publications acknowledging health inequity and disparity in SCD ( Grosse et al., 2009 ; Smith et al., 2006 ), more exploration of how structural discrimination can contribute to poor wellbeing and health outcomes in individuals with SCD is needed. Understanding how stigma functions outside of personal and interpersonal domains is important, as institutionalized or structural stigma can impact the daily lives, coping behaviors, self-management strategies, and overall wellbeing of individuals with SCD as well.

There is also a limited understanding of internalized stigma. The majority of SCD literature focuses on perceived stigma in SCD and its effects on patient-provider relationships, care-seeking behaviors, and the mental and physical wellbeing of individuals with SCD. However, the impact of internalized stigma also needs to be assessed, as Holloway et al. (2016) found a positive relationship between internalized stigma and depressive symptoms. Additionally, SCD stigma often goes unrecognized, unaddressed, and is not measured in studies assessing psychological wellbeing in SCD, despite all of the literature confirming that stigma is associated with poor psychological outcomes. Learning more about internalized stigma and its influence on mental health, coping with pain, and disease management is necessary to develop a more complete understanding of SCD.

Although there are several sources of SCD stigma, current literature tends to focus primarily on stigma from healthcare providers. Encounters with healthcare providers and systems is only one aspect of individuals with SCD lives. More studies are needed that assess the stigma that individuals with SCD experience fromtheir family and friends. In diabetes literature, stigma from the general public can cause individuals not to perform self-management behaviors and this can lead to worsened health outcomes ( Tak-Ying Shiu, Kwan, & Wong, 2003 ). A more comprehensive view of how sources of stigma impact the lives of individuals with SCD is needed to strengthen understandings of SCD stigma.

The literature addresses how SCD stigma impacts care-seeking behavior, while other self-management behaviors such as stress management and medication adherence are less frequently addressed. Grasping the link between stigma and self-management in SCD is crucial as this knowledge can be used to develop interventions to improve quality of life and health outcomes in SCD ( Matthie, Hamilton, Wells, & Jenerette, 2015 ; Matthie, Jenerette, & McMillan, 2015 ). The Theory of Self-Care Management of Sickle Cell Disease can be used to inform future interventions focusing on health-related stigma as an outcome and studies seeking to explore the relationship between stigma and SCD ( Jenerette & Murdaugh, 2008 ).

Finally, exploring the link between chronic stress and stigma could reveal key information about the impact that stigma has on physiological and psychological wellbeing. Both self-reported measures and physiological markers of stress should be studied. In obesity and stigma literature, exposure to stigma was found to increase cortisol levels, thus increasing potentially harmful physiological consequences of stigma on wellbeing ( Schvey, Puhl, & Brownell, 2014 ). Other factors that may mediate the relationship between stigma and wellbeing that are inadequately explored in SCD literature include coping mechanisms, disease self-management, and social support. Having social support influences response to stigma, coping mechanisms, and disease self-management strategies ( Scambler, 2009 ). Understanding these mediating factors could contribute to a better understanding of stigma of SCD and ways to reduce it.

Practice implications

Nurses can decrease stigma bymaking themselves aware of their own biases and educating themselves as well as other healthcare professionals about appropriate ways to interact with and care for individuals with SCD. Despite, its potential to affect social functioning, physiological and psychological wellbeing, and health outcomes in SCD, stigma often goes unrecognized and its affects are unassessed. Nurses can also decrease the effects of stigma by recognizing stigma and employing interventions to decrease or treat the effects of stigma, such as assessing for mental healthcare needs and addressing challenges related to support.

Limitations

This review has limitations. Studies written in other languages were excluded, which limits the generalizability of the findings to non-English speaking populations of individuals with SCD. Additionally, there is the potential for error because a single reviewer performed the search and developed the matrices.

Stigma of SCD is a pressing health concern. Factors that contribute to stigma in SCD include disease status, pain and opioid use, racism, disease severity, and sociodemographic characteristics. Stigma can stem from sources including institutions, healthcare providers, general public, and family and friends. Current literature surrounding stigma in SCD reveals that stigma has detrimental consequences for individuals with SCD, including having negative social consequences, impairing healthcare interactions, and hindering physiological and psychosocial wellbeing.

Acknowledgments

I am in gratitude to Drs. Coretta Jenerette and Paula Tanabe for their guidance, support, and attentiveness throughout the development of this manuscript.

The first author received by grants from the National Institutes of Health, National Research Service Award, 1F31NR017344-01 and the Jonas Nurse Leaders Scholar Program.

Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/imhn .

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

We certify that there is no conflict of interest with any organizations regarding the material discussed in this manuscript.

• Adeyemo TA, Ojewunmi OO, Diaku-Akinwumi IN, Ayinde OC, Akanmu AS. Health related quality of life and perception of stigmatisation in adolescents living with sickle cell disease in Nigeria: A cross sectional study. Pediatric Blood & Cancer. 2015; 62 (7):1245–1251. doi: 10.1002/pbc.25503. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Bauer GR. Incorporating intersectionality theory into population health research methodology: Challenges and the potential to advance health equity. Social Science & Medicine. 2014; 110 :10–17. doi: 10.1016/j.socscimed.2014.03.022. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Bediako SM, Lanzkron S, Diener-West M, Onojobi G, Beach MC, Haywood C., Jr The Measure of Sickle Cell Stigma: Initial findings fromthe Improving Patient Outcomes through Respect and Trust study. Journal of Health Psychology. 2014; 21 (2):808–820. doi: 10.1177/1359105314539530. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Bediako SM, Moffitt KR. Race and social attitudes about sickle cell disease. Ethnicity & Health. 2011; 16 (4–5):423–429. doi: 10.1080/13557858.2011.552712. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Berger BE, Ferrans CE, Lashley FR. Measuring stigma in people with HIV: Psychometric assessment of the HIV stigma scale. Research in Nursing & Health. 2001; 24 (6):518–529. doi: 10.1002/nur.10011. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Bhatt-Poulose K, James K, Reid M, Harrison A, Asnani M. Increased rates of body dissatisfaction, depressive symptoms, and suicide attempts in Jamaican teens with sickle cell disease. Pediatr Blood Cancer. 2016; 63 (12):2159–2166. doi: 10.1002/pbc.26091. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Blake A, Asnani V, Leger RR, Harris J, Odesina V, Knight-Madden J, … Asnani MR. Stigma and illness uncertainty: Adding to the burden of sickle cell disease. Hematology. 2017; 23 (2):122–130. doi: 10.1080/10245332.2017.1359898. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Bresnahan M, Zhuang J. Exploration and validation of the dimensions of stigma. Journal of Health Psychology. 2011; 16 (3):421–429. doi: 10.1177/1359105310382583. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• CDC. Sickle Cell Disease: Data and Statistics. 2015 Retrieved from http://www.cdc.gov/ncbddd/sicklecell/data.html .
• de Cobo VA, Chapadeiro CA, Ribeiro JB, Moraes-Souza H, Martins PR. Sexuality and sickle cell anemia. Revista Brasileira de Hematologia e Hemoterapia. 2013; 35 (2):89–93. doi: 10.5581/1516-8484.20130027. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Cole PL. Black women and sickle cell disease: Implications for mental health disparities research. Californian Journal of Health Promotion. 2007; 5 (4):24–39. Retrieved from http://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=105172329&site=ehost-live . [ Google Scholar ]
• Corrigan P. How stigma interferes with mental health care. American Psychologist. 2004; 59 (7):614. doi: 10.1037/0003-066X.59.7.614. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Derlega VJ, Janda LH, Miranda J, Chen IA, Goodman BM, III, Smith W. How patients’ self-disclosure about sickle cell pain episodes to significant others relates to living with sickle cell disease. Pain Medicine. 2014; 15 (9):1496–1507. doi: 10.1111/pme.12535. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Dyson SM, Atkin K, Culley LA, Dyson SE, Evans H, Rowley DT. Disclosure and sickle cell disorder: A mixed methods study of the young person with sickle cell at school. Social Science & Medicine. 2010; 70 (12):2036–2044. doi: 10.1016/j.socscimed.2010.03.010. Retrieved from http://www.sciencedirect.com/science/article/pii/S0277953610002376 . [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Ezenwa M, Yao Y, Molokie R, Wang Z, Suarez M, Zhao Z, … Wilkie D. The association of sickle cell-related stigma with physical and emotional symptoms in patients with sickle cell pain. J Pain. 2016; 17 (4s):S15. doi: 10.1016/j.jpain.2016.01.060. [ CrossRef ] [ Google Scholar ]
• Ezenwa MO, Molokie RE, Wilkie DJ, Suarez ML, Yao Y. Perceived injustice predicts stress and pain in adults with sickle cell disease. Pain Management Nursing. 2015; 16 (3):294–306. doi: 10.1016/j.pmn.2014.08.004. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Garrard J. Health sciences literature review made easy. Burlington, MA: Jones & Bartlett Publishers; 2013. [ Google Scholar ]
• Goffman E. Stigma: Notes on the management of spoiled identity. New York: Simon & Schuster Inc, New York; 1986. (Reissue Edition) [ Google Scholar ]
• Grosse SD, Schechter MS, Kulkarni R, Lloyd-Puryear MA, Strickland B, Trevathan E. Models of comprehensive multidisciplinary care for individuals in the United States with genetic disorders. Pediatrics. 2009; 123 (1):407–412. doi: 10.1542/peds.2007-2875. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Haywood C, Jr, Lanzkron S, Bediako S, Strouse JJ, Haythornthwaite J, Carroll CP, … Beach MC. Perceived discrimination, patient trust, and adherence to medical recommendations among persons with sickle cell disease. Journal of General Internal Medicine. 2014; 29 (12):1657–1662. doi: 10.1007/s11606-014-2986-7. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Haywood C, Jr, Tanabe P, Naik R, Beach MC, Lanzkron S. The impact of race and disease on sickle cell patient wait times in the emergency department. American Journal of Emergency Medicine. 2013; 31 (4):651–656. doi: 10.1016/j.ajem.2012.11.005. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Haywood C, Diener-West M, Strouse J, Carroll CP, Bediako S, Lanzkron S, … Haywood C., Jr Perceived discrimination in health care is associated with a greater burden of pain in sickle cell disease. Journal of Pain & Symptom Management. 2014; 48 (5):934–943. doi: 10.1016/j.jpainsymman.2014.02.002. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Holloway BM, McGill LS, Bediako SM. Depressive Symptoms and Sickle Cell Pain: TheModerating Role of Internalized Stigma. Stigma Health. 2016; 2 (4):271–280. doi: 10.1037/sah0000060. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Jacob E. The pain experience of patients with sickle cell anemia. PainManagement Nursing. 2001; 2 (3):74–83. doi: 10.1053/jpmn.2001.26119. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Jenerette C, Brewer CA, Crandell J, Ataga IKI. Preliminary validity and reliability of the Sickle Cell Disease Health-Related Stigma Scale. Issues In Mental Health Nursing. 2012; 33 (6):363–369. doi: 10.3109/01612840.2012.656823. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Jenerette CM, Brewer CA, Ataga KI. Care seeking for pain in young adults with sickle cell disease. Pain Management Nursing. 2014; 15 (1):324–330. doi: 10.1016/j.pmn.2012.10.007. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Jenerette CM, Brewer CA, Edwards LJ, Mishel MH, Gil KM. An intervention to decrease stigma in young adults with sickle cell disease. Western Journal of Nursing Research. 2014; 36 (5):599–619. doi: 10.1177/0193945913512724. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Jenerette CM, Murdaugh C. Testing the Theory of Self-care Management for sickle cell disease. Research in Nursing Health. 2008; 31 (4):355–369. doi: 10.1002/nur.20261. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Kass NE, Hull SC, Natowicz MR, Faden RR, Plantinga L, Gostin LO, Slutsman J. Medical privacy and the disclosure of personal medical information: The beliefs and experiences of those with genetic and other clinical conditions. American Journal of Medical Genetics A. 2004; 128a (3):261–270. doi: 10.1002/ajmg.a.30057. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Kauf TL, Coates TD, Huazhi L, Mody-Patel N, Hartzema AG. The cost of health care for children and adults with sickle cell disease. American Journal of Hematology. 2009; 84 (6):323–327. doi: 10.1002/ajh.21408. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Labore N, Mawn B, Dixon J, Andemariam B. Exploring Transition to Self-Management Within the Culture of Sickle Cell Disease. Journal of Transcultural Nursing. 2017; 28 (1):70–78. doi: 10.1177/1043659615609404. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Labrousse W. Lived experience of young Haitian-American women with sickle cell disease. 68. ProQuest Information & Learning; US: 2007. Retrieved from http://search.ebscohost.com/login.aspx?direct=true&db=psyh&AN=2007-99220-004&site=ehost-live&scope=siteAvailablefromEBSCOhostpsyhdatabase . [ Google Scholar ]
• Lazio MP, Costello HH, Courtney DM, Martinovich Z, Myers R, Zosel A, Tanabe P. A comparison of analgesic management for emergency department patients with sickle cell disease and renal colic. Clinical Journal of Pain. 2010; 26 (3):199–205. doi: 10.1097/AJP.0b013e3181bed10c. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, … Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. British Medical Journal. 2009; 339 :b2700. doi: 10.1136/bmj.b2700. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Link BG, Phelan JC. Handbook of the sociology of mental health. Springer; 2013. Labeling and stigma; pp. 525–541. [ Google Scholar ]
• Mathur VA, Kiley KB, Haywood C, Jr, Bediako SM, Lanzkron S, Carroll CP, … Campbell CM. Multiple Levels of Suffering: Discrimination in Health-Care Settings is Associated With Enhanced Laboratory Pain Sensitivity in Sickle Cell Disease. Clinical Journal of Pain. 2016; 32 (12):1076–1085. doi: 10.1097/ajp.0000000000000361. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Matthie N, Hamilton J, Wells D, Jenerette C. Perceptions of young adults with sickle cell disease concerning their disease experience. Journal of Advanced Nursing. 2015; 72 (6):1441–1451. doi: 10.1111/jan.12760. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Matthie N, Jenerette C, McMillan S. Role of self-care in sickle cell disease. Pain Management Nursing. 2015; 16 (3):257–266. doi: 10.1016/j.pmn.2014.07.003. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Maxwell K, Streetly A, Bevan D. Experiences of hospital care and treatment-seeking behavior for pain from sickle cell disease: Qualitative study. Western Journal of Medicine. 1999; 171 (5–6):306–313. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1308742/pdf/westjmed00315-0020.pdf . [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Mulchan SS, Valenzuela JM, Crosby LE, Sang CDP. Applicability of the SMART model of transition readiness for sickle-cell disease. Journal of Pediatric Psychology. 2016; 41 (5):543–554. doi: 10.1093/jpepsy/jsv120. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Nelson SC, Hackman HW. Race matters: Perceptions of race and racism in a sickle cell center. Pediatric Blood & Cancer. 2013; 60 (3):451–454. doi: 10.1002/pbc.24361. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Ola BA, Yates SJ, Dyson SM. Living with sickle cell disease and depression in Lagos, Nigeria: A mixed methods study. Social Science & Medicine. 2016; 161 :27–36. doi: 10.1016/j.socscimed.2016.05.029. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Penner LA, Dovidio JF, West TV, Gaertner SL, Albrecht TL, Dailey RK, Markova T. Aversive Racism andMedical Interactions with Black Patients: A Field Study. Journal of Experimental Social Psychology. 2010; 46 (2):436–440. doi: 10.1016/j.jesp.2009.11.004. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Reed P. Chronic pain stigma: Development of the Chronic Pain Stigma Scale. 2005 Available from http://worldcat.org/z-wcorg/database .
• Royal CD, Jonassaint CR, Jonassaint JC, De Castro LM. Living with sickle cell disease: Traversing ‘race’ and identity. Ethnicity & Health. 2011; 16 (4–5):389–404. doi: 10.1080/13557858.2011.563283. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Sankar P, Cho MK, Wolpe PR, Schairer C. What is in a cause? Exploring the relationship between genetic cause and felt stigma. Genet Med. 2006; 8 (1):33–42. doi: 10.1097/01.gim.0000195894.67756.8b. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Scambler G. Health-related stigma. SociolHealth Illness. 2009; 31 (3):441–455. doi: 10.1111/j.1467-9566.2009.01161.x. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Schvey NA, Puhl RM, Brownell KD. The stress of stigma: Exploring the effect of weight stigma on cortisol reactivity. Psychosomatic Medicine. 2014; 76 (2):156–162. doi: 10.1097/PSY.0000000000000031. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Smith LA, Oyeku SO, Homer C, Zuckerman B. Sickle cell disease:Aquestion of equity and quality. Pediatrics. 2006; 117 (5):1763–1770. doi: 10.1542/peds.2005-1611. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Stanton MV, Jonassaint CR, Bartholomew FB, Edwards C, Richman L, DeCastro L, Williams R. The association of optimism and perceived discrimination with health care utilization in adults with sickle cell disease. Journal of National Medical Association. 2010; 102 (11):1056–1063. doi: 10.1016/S0027-9684(15)30733-1. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Strouse J, Lobner K, Lanzkron SMHS, Haywood C. NIH and National Foundation Expenditures For Sickle Cell Disease and Cystic Fibrosis Are Associated With Pubmed Publications and FDA Approvals. Blood. 2013; 122 (21):1739–1739. [ Google Scholar ]
• Tak-Ying Shiu A, Kwan JJYM, Wong RYM. Social stigma as a barrier to diabetes self-management: Implications for multi-level interventions. Journal of Clinical Nursing. 2003; 12 (1):149–150. doi: 10.1046/j.1365-2702.2003.00735.x. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Wakefield EO, Popp JM, Dale LP, Santanelli JP, Pantaleao A, Zempsky WT. Perceived Racial Bias and Health-Related Stigma Among Youth with Sickle Cell Disease. Journal of Developmental and Behavioral Pediatrics. 2017; 38 (2):129–134. doi: 10.1097/dbp.0000000000000381. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Weiss MG, Ramakrishna J, Somma D. Health-related stigma: Rethinking concepts and interventions 1. Psychology Health & Medicine. 2006; 11 (3):277–287. doi: 10.1080/13548500600595053. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• WHO. Maternal, newborn, child and adolescent health. 2015. [ Google Scholar ]
• Winker G, Degele N. Intersectionality as multi-level analysis: Dealing with social inequality. European Journal of Women’s Studies. 2011; 18 (1):51–66. doi: 10.1177/1350506810386084. [ CrossRef ] [ Google Scholar ]
• Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, … John-Sowah J. Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members. JAMA. 2014; 312 (10):1033–1048. doi: 10.1001/jama.2014.10517. [ PubMed ] [ CrossRef ] [ Google Scholar ]

StarsInsider

Everything you need to know about sickle cells and sickle cell disease

Posted: February 13, 2024 | Last updated: February 13, 2024

Sickle cell disease is a condition little understood by most people around the world, despite it being the number one most common inherited disease in the world. Sickle cell disease is a blood disease, and can affect the most fundamental functions of an individual's body. Thankfully, medical scientists have gained massive amounts of new understanding surrounding this mysterious genetic disorder, and with their understanding has come more public attention, more research funding, and more empathy on a societal level.

Let's look at the basics of sickle cell disease: what it is, what there is to do about it, and why it's important that we support those afflicted. Read on to learn more.

You may also like: Who are the world's most generous celebrities?

What are sickle cells?

Sickle cells are mutated red blood cells that are shaped and act differently from normal red blood cells. They have a far shorter lifespan than normal red blood cells, and inhibit hemoglobin's ability to carry oxygen throughout the body.

Follow us and access great exclusive content every day

What is hemoglobin?

Hemoglobin is an iron-rich protein that carries oxygen throughout the body via red blood cells. The shape and nature of sickle cells makes the job of the body's hemoglobin protein much more difficult.

You may also like: Scary abandoned amusement parks

Why are they called sickle cells?

Sickle cells simply gain their name from their shape. As opposed to the round, globulous figure of healthy red blood cells, sickle cells take on a crescent shape, like that of a, you guessed it, sickle.

How do sickle cells work?

Because of their weakened figure, sickle cells have a lifespan of only around 20 days. In comparison, healthy blood cells live for around 120 days on average, giving them much more time to do their job. Additionally, the irregular shape of sickle cells causes them to group in clusters within the veins, causing painful and life-threatening disturbances in the body's blood circulation .

You may also like: The coldest places in America

What is the origin of sickle cells?

Sickle cells are simply mutated blood cells, and have no exact cause or reason for existing. Genetics tells us the culprit of sickle cells is nothing more than a defective gene, a luck of the draw.

What is sickle cell disease?

Sickle cell disease, or SCD, is a broad term for the many ailments that can be caused by the presence of sickle cells in an individual's body.

You may also like: Daniel Radcliffe and his more than two decades in the spotlight

The presence of sickle cells isn't something that can be controlled, and sickle cell disease isn't contagious. It is at its core a genetic condition, passed down hereditarily.

How does one get SCD?

A person can only contract SCD if they inherit a sickle cell gene from each parent. If both parents of a child have a sickle cell trait gene, genetics tells us that there is a 25% chance that their child will be born with SCD.

You may also like: The most iconic stars of the silent film era

What's the difference between a sickle cell trait and SCD?

People with a sickle cell "trait" gene have just that: one single gene copy of a sickle cell mutation. The vast majority of people with sickle cell traits feel no symptoms and face no danger, but it is still important for you and your partner to get tested if you are planning on having children. If both you and your partner have sickle cell traits, there is a chance your child will inherit both and be born with sickle cell disease.

The many faces of SCD

Sickle cell disease manifests itself in many ways and can vary in severity. There are five main types of SCD, and they're distinguished from one another based on the exact nature of the sickle cell genes, the number of sickle cells produced, and the way hemoglobins act within the blood cells. The most common and most dangerous strain of SCD is known as sickle cell anemia.

You may also like: The most beautiful sunsets in the UK

What is sickle cell anemia?

Sickle cell anemia occurs when sickle cells are misshapen, fragile, and large in numbers. All three of these factors inhibit the flow of oxygen throughout the body, causing pain, fatigue, and numerous other symptoms.

How many people in the world have SCD?

Annually, around 300,000 children worldwide are born with some form of sickle cell disease. A third of the worldwide cases are born within the United States.

You may also like: Never offer yellow roses to the love of your life

How can SCD affect your life?

The flow of oxygen through one's body, the very thing that SCD inhibits, is such a fundamental function of the body that its effects on one's livelihood are wide-reaching and impossible to overstate.

Common symptoms

Vision problems are common in individuals with SCD, as the visual organs are deprived of oxygen and are unable to develop properly. Other growth issues can occur for the same reason, including a delay in puberty in children. Chronic pain and swelling of the hands and feet are other common symptoms.

You may also like: Understanding the "Kate Middleton effect"

Higher risk of stroke

The constant lack of oxygen flowing to the brain also makes sufferers of SCD much more likely to suffer strokes. By the age of 45, nearly a quarter of all individuals with SCD will have a stroke.

Sickle cell crises

Common and lengthy bursts of intense, localized pain known as "crises" are also common in those with SCD. Crises occur when a certain part of the body becomes severely deprived of oxygen for a time. The pain can be excruciating, and last for up to a full week with no letting up.

You may also like: Stars who suffer from rare diseases

Children are at the highest risk

Children are at the highest risk when it comes to SCD. Babies born with any type of sickle cell condition must be closely monitored for most of their childhood, as life-threatening conditions can pop up frighteningly quickly.

Serious complications of SCD in children

In short, all of the symptoms of SCD are more severe and more dangerous in children. Their smaller blood vessels leave even less room for blood cells to move throughout the body, and crises, which can start at as young as five months old, can be too severe for their little bodies to handle.

You may also like: Avoid these "healthy" foods and live longer

Can SCD be cured?

So far, there is no completely safe cure for SCD. Stem cell research has proven to be promising, but stem cell transplants for blood cells are still too risky to be considered a viable cure. However, as science progresses, there is hope for the future.

Can SCD be treated?

Thankfully, there are many treatments available for sickle cell disease that can provide immense amounts of relief, and allow those afflicted to leave relatively normal, happy lives.

You may also like: Films, apps, and fatherhood: What's next for the 'GoT' cast?

Treatments for SCD

Numerous non-habit-forming pain medications have been developed specifically to lessen the frequency and severity of pain crises, and cardiovascular exercise is recommended to help promote the flow of blood and oxygen throughout the body.

Treatment for children is trickier, as many of the medications prescribed to adults are too intense for children and can cause more harm than good. Some medications, however, like hydroxyurea, have been approved for pediatric use.

You may also like: Angry stars who have walked off set

Making great strides

For centuries, sickle cell disease had no name and confounded medical professionals around the world. Thankfully, medical science in recent decades has made leaps and bounds when it comes to understanding this genetic disease, and how to treat it.

Bone marrow transplants

Bone marrow and stem cell transplants are the only procedures proven to cure SCD. Both procedures introduce new, healthy blood cells into your system that begin to multiply and outlive the body's sickle cells until there are no sickle cells left to reproduce. However, grave complications can arise through these types of transplants, no matter how good the doctor is. A common adverse reaction of such procedures is known as graft-versus-host disease, in which the new cells attack their new environment and destroy it from the inside.

Pediatric penicillin

The advent of pediatric antibiotics like penicillin has also been a great help in the fight against SCD. Penicillin has been proven to protect children against numerous infections that are immensely common in kids with SCD.

Blood transfusions

Regular blood transfusions, while a hassle and can be considered invasive by some, are an indispensable aspect of treatment for those trying to live a normal life with SCD. The introduction of healthy blood into one's bloodstream lowers the percentage of sickle cells, thus minimizing the rick of clotting and pain crises, as well as promoting the flow of oxygen throughout the body.

You may also like:

Newborn screenings in the United States

It is also essential to catch SCD as soon as possible, in order to minimize the rate of infantry mortality due to sickle cells. Since doctors know that people with SCD are born with it, one of the first exams done to a newborn baby is a heel-stick test where their blood is tested for sickle cells so that treatment can begin immediately, if need be.

The average lifespan of someone with SCD

Despite the great advancements in the understanding and treatment of sickle cell disease, it is an affliction that is devastatingly hard on the body. The average lifespan for individuals afflicted by SCD is only around the mid-forties. That being said, the oldest known person to ever live with SCD, Ernestine Diamond, lived until she was 94.

You may also like: Otherworldly encounters: Celebrities who believe in aliens

Living with SCD

Although one must come to terms with a dishearteningly short lease on life, the treatments and therapies available today all but guarantee that anyone living with sickle cell disease is given the opportunity to live a happy and fulfilling life.

Sources: (Nationwide Children's Hospital) (Mayo Clinic)

See also: Signs you have iron deficiency

More for You

Matt Gaetz Ethics Complaint Allegations—What We Know

16 Compliments You Didn’t Realize Are Actually Pretty Insulting

17 McDonald's Menu Items From The 1980s You Probably Forgot About

Lando Norris responds as fan heckles him in paddock over unwanted F1 record

Ron Harper, ‘Land of the Lost' and ‘Planet of the Apes' Actor, Dies at 91

Indiana State’s ridiculously fun NIT run is a reminder of how dumb the selection committee was

US embassy in Paris issues security alert for Americans in France after Moscow terrorist attack

34-year-old making $49,000 a month in passive income: What I always tell people who want to build successful side hustles

3 things to never do at work, according to an HR professional with 10 years' worth of experience

Ukraine destroying Musk’s Starlink systems being used by Russia

'Beetlejuice Beetlejuice' Trailer: Michael Keaton & Winona Ryder Meet Again, Jenna Ortega Joins Ghastly Family | THR News Video

Stop Soaking Your Dry Beans—Camellia Beans Says You're Wasting Your Time

Congressional diversity and inclusion office shut down by $1.2T government funding deal

Maxwell Announces the Serenade Tour with Special Guest Jazmine Sullivan — See the Full List of Dates!

What to do when your CD matures, according to experts

Changes to NFL kickoff rules unanimously approved by committee, per source

Red Bull identify the culprit behind Sergio Perez’s dramatic pace drop in Australia

What Does a Red or Yellow Dot on Your Tires Mean?

Manufacturing firm ordered to turn over $1.5M in profits for child labor violations

Rapper Sean 'Diddy' Combs' homes raided by Homeland Security

An official website of the United States government

Here’s how you know

Official websites use .gov A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS A lock ( A locked padlock ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.

• Heart-Healthy Living
• High Blood Pressure
• Sickle Cell Disease
• Sleep Apnea
• Information & Resources on COVID-19
• The Heart Truth®
• Learn More Breathe Better®
• Blood Diseases and Disorders Education Program
• Publications and Resources
• Blood Disorders and Blood Safety
• Sleep Science and Sleep Disorders
• Lung Diseases
• Health Disparities and Inequities
• Heart and Vascular Diseases
• Precision Medicine Activities
• Obesity, Nutrition, and Physical Activity
• Population and Epidemiology Studies
• Women’s Health
• Research Topics
• Clinical Trials
• All Science A-Z
• Grants and Training Home
• Policies and Guidelines
• Funding Opportunities and Contacts
• Training and Career Development
• Email Alerts
• NHLBI in the Press
• Research Features
• Past Events
• Upcoming Events
• Mission and Strategic Vision
• Divisions, Offices and Centers
• Advisory Committees
• Budget and Legislative Information
• Jobs and Working at the NHLBI
• Contact and FAQs
• NIH Sleep Research Plan
• News and Events
• < Back To All News

Researchers study a new way to treat sickle cell disease

Activating a protein in red blood cells may improve anemia and alleviate acute episodes of severe pain for people living with sickle cell disease   

Swee Lay Thein, M.B., D.Sc. , a senior investigator and chief of NHLBI’s Sickle Cell Branch , shares insight into a decade-long research journey that may lead to new ways to help people living with sickle cell disease.    

Q: What is sickle cell disease?    

Sickle cell disease (SCD) is an inherited blood condition that occurs when the body produces an abnormal hemoglobin. Hemoglobin is a protein in red blood cells that helps deliver oxygen to different tissues in organs throughout the body. However, in SCD, the abnormal hemoglobin (HbS) forms fibers under low oxygen conditions, changing red blood cells from normal donut-shaped discs to abnormal shapes, including crescent-shaped moons. These changes are referred to as “sickling.” When red blood cells sickle, they can clump together with other cells in the blood and block blood flow, which can lead to complications – especially severe pain.   

Q: Why is it important to study new ways to treat pain in SCD?   

A: For people living with SCD, acute pain is so severe that it is called a “crisis.” Sickled red blood cells are also highly fragile and have a short life span. Therefore, people living with SCD experience anemia throughout their life. To prevent pain crises and alleviate anemia in people living with SCD, researchers, including those in our group, have been studying new ways to prevent blood cells from sickling. We believe that reducing sickling should also improve anemia as red blood cells will be less likely to breakdown.

Q: What are you and researchers studying as a new treatment option for SCD pain?  

A: When we looked at genes involved with SCD, we found that children and adults hospitalized for sickle pain were more likely to have variations of the gene PKLR . This gene expresses production of the enzyme pyruvate kinase (PKR) in red blood cells, which is a kind of protein that supports cellular health and metabolism. This discovery led to us study how treatments that stimulate PKR activity may prevent or alleviate severe pain crises. This is important, because generally when people have a PKR deficiency, as caused by inherited mutations in the PKLR gene, referred to as pyruvate kinase deficiency , their red blood cells are very fragile and they have severe anemia. This drug was originally developed for treating patients with inherited pyruvate kinase deficiency and recently approved by the Food and Drug Administration in February 2022. If activating PKR can improve red blood cell health, it will make sickle cell disease milder and provide a new treatment strategy for patients.

Interestingly, this research started after it was reported that sickle cell carriers who have no clinical symptoms can still have SCD (like those with two copies of the sickle gene). The reason, we’re finding, is due to adaptive PKLR mutations.  

Q: What are the next steps for clinical research?    

When we conducted an early phase 1 clinical research trial , we found that activating PKR in patients with SCD through an oral therapy was safe and well tolerated. We’ll continue to assess the long-term safety and efficacy of this approach with more research. We’ll specifically look at how this oral therapy may reduce the number of sickling events people experience and also see if it can improve anemia.    

Q: What is unique about this treatment approach?    

This treatment approach is still in the early research phases, but it has the potential to break new ground. Other anti-sickling therapies have targeted the problem in conventional ways by looking at how to increase the size of red blood cells, how to improve cell hydration, how to improve hemoglobin binding of oxygen, and how to increase fetal hemoglobin. The goal of these therapies has been to help cells deliver oxygen to tissues throughout the body. But we started our research by studying characteristics of the patients themselves. Then, we assessed how repurposing a drug developed for treating PKR deficiency may help people with SCD.  

Researchers also saw that the initial promising outcome had similar effects in healthy volunteers – people without mutated PKLR genes. They found that activating PKR increases ATP, an energy molecule, which is useful for other conditions. This is a good example of “bed-to-bench-to-bed” research.    

Q: How may these insights into PKLR’s anti-sickling properties inform other areas of research?    

A: There could be multiple ways to mitigate sickling. For example, other molecules involved in cellular health and energy production could activate PKR and produce similar anti-sickling properties.    

We also envision that people could take PKR activators with other SCD pain therapies, such as hydroxyurea. These therapies may also provide options for people with SCD who cannot tolerate hydroxyurea, a standard therapy for SCD that has been used for more than 30 years.     

Q: What treatment options are currently available for people with SCD who experience a pain crisis?    

Current treatment options - hydroxyurea, crizanlizumab, and voxelotor – aim to reduce the frequency of painful crises but they do not alleviate the pain, which requires strong painkillers. For example, hydroxyurea supports hemoglobin production and has been shown to reduce about half of the number of painful events a person with SCD may experience.

Voxelotor also supports hemoglobin production, and some studies have shown it can boost hemoglobin levels by 40%.  

Crizanlizumab takes a different approach in supporting circulation. Instead of focusing on improving hemoglobin in red blood cells, this therapy aims to make blood vessel walls less sticky, which helps prevent sickled cells from clotting together and altering blood flow.    

Since these therapies have different side effects, it’s important for people living with SCD to work with their healthcare provider to identify a treatment approach that works best for them.    

Q: What other SCD topics are you and researchers at NHLBI studying?    

A: We continue to work with William A. Eaton, M.D., Ph.D. , an investigator at the National Institute of Diabetes and Digestive and Kidney Diseases, to study “anti-sickling” properties of cells. We are assessing how this information may help create new therapies and drugs to help people living with SCD and other types of inherited blood conditions. We are also working with Bruce J. Tromberg, Ph.D ., and his team at the National Institute of Biomedical Imaging and Bioengineering to explore optical techniques of monitoring effects of new SCD treatments on  vascular health, which will help us assess the effectiveness of these treatments for patients with SCD.

Additionally, we’re conducting preclinical research to better understand what can go wrong in people with SCD. As researchers, we’re objective throughout the scientific process. However, we’re always looking for new and improved ways to help people living with this disease.    

Q: Where can people go to learn more?   

We recently published research about PKR expression and SCD in Blood , Blood Advances , and Blood, Cells, Molecules, and Diseases .    

To learn more about sickle cell disease, visit https://www.nhlbi.nih.gov/health-topics/education-and-awareness/sickle-cell .    

To learn more about the Laboratory of Sickle Cell Genetics and Pathophysiology, visit https://www.nhlbi.nih.gov/science/sickle-cell-genetics-and-pathophysiology .    

Related Health Topics

Related news & features.