sickle cell research paper

• Open access
• Published: 03 March 2022

Advances in the diagnosis and treatment of sickle cell disease

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

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

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

Introduction

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

Molecular basis and pathophysiology

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

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

Acute and chronic pain

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

Diagnosis of acute and chronic pain

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

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

Management of acute and chronic pain

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

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

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

Cardiopulmonary disease

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

Diagnosis of cardiopulmonary disease

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

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

Management of cardiopulmonary disease

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

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

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

Central nervous system (CNS) complications

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

Diagnosis of CNS complications in SCD

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

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

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

Management of CNS complications

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

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

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

Kidney disease

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

Diagnosis of kidney disease in SCD

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

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

Management of kidney disease

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

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

Disease-modifying therapies in SCD

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

l -glutamine

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

Crizanlizumab

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

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

Curative therapies in SCD

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

Advancing research in SCD

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

Conclusions

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

Availability of data and materials

Not applicable.

Abbreviations

Six-minute walk distance

Angiotensin-converting enzyme inhibitor

Angiotensin receptor blockade

Cognitive behavioral therapy

Chronic kidney disease

Chronic opioid therapy

Echocardiogram

End stage renal disease

Fluid-attenuated inversion recovery

Glomerular filtration rate

Graft-versus-host disease

Hemoglobin S

Hematopoietic stem cell transplant

Nonsteroidal anti-inflammatory drugs

N-terminal pro-brain natriuretic peptide

New York Heart Association

Pulmonary arterial hypertension

Pulmonary function test

Pulmonary hypertension

Positive predictive value

Patient-reported outcomes

Randomized controlled trial

• Sickle cell disease

Serotonin and norepinephrine reuptake inhibitors

Tricyclic antidepressants

Transcranial Doppler

Tissue plasminogen activator

Tricuspid regurgitant jet velocity

Visual Analog Scale

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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

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Research in Sickle Cell Disease: From Bedside to Bench to Bedside

Gabriel salinas cisneros, swee lay thein.

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Correspondence: Swee Lay Thein ( [email protected] ).

Corresponding author.

Received 2021 Apr 13; Accepted 2021 Apr 17; Collection date 2021 Jun.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Sickle cell disease (SCD) is an exemplar of bidirectional translational research, starting with a remarkable astute observation of the abnormally shaped red blood cells that motivated decades of bench research that have now translated into new drugs and genetic therapies. Introduction of hydroxyurea (HU) therapy, the only SCD-modifying treatment for >30 years and now standard care, was initiated through another clinical observation by a pediatrician. While the clinical efficacy of HU is primarily due to its fetal hemoglobin (HbF) induction, the exact mechanism of how it increases HbF remains not fully understood. Unraveling of the molecular mechanism of how HU increases HbF has provided insights on the development of new HbF-reactivating agents in the pipeline. HU has other salutary effects, reduction of cellular adhesion to the vascular endothelium and inflammation, and dissecting these mechanisms has informed bench—both cellular and animal—research for development of the 3 recently approved agents: endari, voxelotor, and crizanlizumab; truly, a bidirectional bench to bedside translation. Decades of research to understand the mechanisms of fetal to adult hemoglobin have also culminated in promising anti-sickling genetic therapies and the first-in-human studies of reactivating an endogenous (γ-globin) gene HBG utilizing innovative genomic approaches.

Introduction

Sickle cell disease (SCD) can trace its first description in the Western literature to a case report in 1910 by Herrick 1 of a young dental male student from Grenada with severe malaise and anemia. Hallmarks of the disease were noted then: “healing ulcers” predominantly on the legs that lasted about a year; anemia with a “hemoglobin (Dare) 40 per cent” and jaundice (“tinge of yellow in the sclerae”), and a disease with “acute exacerbations.” Herrick 1 , 2 also made a remarkable observation that the “red corpuscles varied much in size,” and that “the shape of the reds was very irregular,” but what especially attracted his attention was “the large number of thin, elongated, sickle-shaped and crescent-shaped forms.” He surmised “that some unrecognized change in the composition of the corpuscle itself may be the determining factor” (Figure 1 ).

The first documented observation of sickle-shaped red blood cells. Historical figure from 1910, taken from the publication by Herrick 1 with title “Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.” (Reproduced with permission from JAMA Intern Med . 1910;6:517–521. Copyright © 1910 American Medical Association. All rights reserved.)

It was not until almost 40 years later in 1949 when Pauling and his collaborators 3 discovered that the “…unrecognized change in the composition of the corpuscle” was due to an altered hemoglobin (Hb) structure, thus SCD became the first disease to be understood at a molecular level. The abnormal Hb was later shown to result from the substitution of glutamic acid by valine at position 6 of the β-globin chain of Hb 4 that arose from an A>T base change (Table 1 ). 5 Genetic simplicity of the sickle mutation in a compact gene encoding an abnormal Hb that was relatively accessible through a simple blood draw has lent SCD to many proof-of-principle and validation experiments for many years. This was facilitated by the globin genes among the first to be cloned and fully analyzed by DNA sequencing. 6 , 7 SCD became a role model for molecular genetics, leading the way in breakthrough discoveries in areas of DNA diagnostics, population and epidemiological genetics, and more recently, genetic therapies. 8 , 9 Certainly for the last century, studies of SCD and genetics of Hb have contributed and benefited other medical conditions more than SCD itself. In the last 10 years, however, we have gained a much better understanding of the sickle pathophysiology. We have also gained incredible insights on the switch from fetal to adult Hb 10 with identification of key regulating factors such as B-cell lymphoma/leukemia 11A (BCL11A) 11 , 12 that together, with major advances in genetic and genomic technologies, 13 , 14 have translated into genetic-based approaches for treating SCD.

Terminology.

HbA = hemoglobin A; HbD = hemoglobin D; HbE = hemoglobin E; HbF = hemoglobin F; HbS = hemoglobin S; HbSC = hemoglobin SC; HbSS = hemoglobin SS.

Here we take readers through the key discoveries, which showcases the bidirectional bench to bedside research in SCD highlighting the leaps in our understanding that have contributed to new therapeutic options in its management.

The history of SCD pathophysiology—from bench to bedside to bench

After building an electrophoresis machine, Pauling 3 was able to separate normal adult hemoglobin (α2β2, HbA) from abnormal sickle hemoglobin (α2β2 S , HbS) and describe SCD at a molecular level for the first time. But, many questions remained unanswered, such as how HbS lead to the formation of these “thin, elongated sickle-shaped” red cells, the key phenotype in sickle pathophysiology, motivating an enormous amount of basic science studies on the Hb polymer structure, 15 thermodynamics, 16 , 17 and kinetics 18 of HbS polymerization. Since polymerization of HbS can only occur when HbS is deoxygenated, 19 increasing HbS oxygen affinity as a therapeutic approach has been discussed for many years, culminating in the development of oxygen affinity modifying drugs such as voxelotor (also known as Oxbryta or GBT440). Importantly, increasing oxygen binding to HbS could also compromise oxygen delivery, as first discussed by Beutler, 20 an effect that is detrimental in a disease characterized by tissue/organ damage due to oxygen deprivation.

A key bedside observation that fetal Hb (HbF) had beneficial effects was first hypothesized by the pediatrician Watson 21 in 1948, who noted that African American infants with SCD were less prone to have “sickling” events in the first few months of life during which HbF gradually disappears from the blood (Table 1 ). Since then, multiple observational studies between 1970s and 1990s demonstrating a milder form of SCD in those patients with higher levels of HbF have been published. Clinical and population studies elucidated that the level of HbF in adults is under 2 levels of genetic control. 22 Common genetic variation, historically referred to as heterocellular hereditary persistence of fetal hemoglobin (HPFH), is characterized by modest increases of HbF (1%–4% of total Hb) that are unevenly distributed among the red blood cells (RBCs). Although the HbF increases are modest in healthy adults, co-inheritance of heterocellular HPFH on a background of stress erythropoiesis, such as SCD, leads to increases in HbF levels as high as 25% with immense clinical benefits. Although familial, the inheritance pattern of heterocellular HPFH was not clear until 20 years ago, when genetic studies showed that common HbF variation behaved as a quantitative trait and the levels are predominantly genetically controlled. 23 To date, 3 quantitative trait loci are known: the hemoglobin gene complex ( HBB ) on chromosome 11p ( Xmn 1-Gγ site), the BCL11A gene on chromosome 2, and the HBS1L-MYB intergenic region on chromosome 6q. 24 In contrast, rare variants, historically referred to as pancellular HPFH, are inherited in a Mendelian fashion as alleles of the HBB complex. Carriers for pancellular HPFH have substantial increases in HbF levels of 15% to 30% that are homogeneously distributed among the RBCs. Pancellular HPFH is caused by substantial DNA deletions within the HBB cluster or specific single base changes in the promoters of the γ-globin genes. 25 Persistence of HbF production has no clinical consequences in healthy adults, but ameliorate symptoms of SCD. Indeed, inheritance of a Mendelian form of HPFH in trans to a β S allele (HbS/HPFH) may eliminate clinical consequences of SCD, motivating enormous research on understanding how fetal HbF is repressed in adults. 26

Translating clinical benefits of hydroxyurea to an improved understanding of sickle pathophysiology

The beneficial effect of HbF led to the first study of hydroxyurea (HU) in 2 patients with the HbSS form of SCD, also referred to as sickle cell anemia (see Table 1 ) in 1984, in which measurable and sustainable increases in HbF could be achieved with minimal toxicity, but no change in clinical course could be observed in the short period of study. 27 Nonetheless, these encouraging preliminary results motivated numerous clinical trials of HU, first in adults 28 and then in pediatric patients with SCD 29 ; its overall safety profile and efficacy led to US Food and Drug Administration (FDA) approval of HU for treatment of SCD in adults in 1998 and in children in 2017.

Our understanding of sickle pathophysiology has also been greatly helped by the use of humanized sickle mouse models, which has provided new insights on adhesion, inflammation, and interactions of the sickled RBCs with their microenvironment—vasculature, neutrophils, monocytes, platelets, and the upregulation of vasculature cyto-adhesion molecules. 30 , 31 Molecules such as P- and E-selectin, fundamental in the adhesion and activation of white blood cells, specially neutrophils, to the vasculature have been found to represent an important component of the pain crisis pathophysiology and have become therapeutic targets. 32

As polymerization of deoxy-HbS is the key event that triggers the downstream consequences of SCD, several therapeutic approaches have focused on mitigation of this root cause, utilizing both genetic and pharmacological anti-sickling strategies. The best-established strategy is induction of HbF synthesis borne out not only by the plentiful clinical and epidemiological studies, but also by the kinetics and thermodynamics of the polymerization process itself. Studies of HbS polymerization kinetics posit that the delay time relative to the transit time through the microcirculation is a major determinant of whether polymerization results in irreversible sickling and hence severity in SCD. The amino acid sequence of γ-globin chain is sufficiently different from β S such that little or no γ-globin takes part in the fiber formation, so the primary effect of HbF (α2γ2) is to simply dilute the intracellular concentration of HbS. 19 Because HbS polymerization is highly sensitive and dependent on intracellular HbS concentration, 33 even a small decrease in HbS concentration is therapeutic because more cells can escape the small vessels before sickling occurs. Strategies that reduce HbS intracellular concentration, such as increasing HbF or the red cell volume (ie, mean corpuscular volume [MCV]), increase the delay time to sickling, while strategies that reduce adherence and shorten transit time should be therapeutic. HU inhibits ribonucleotide reductase causing reversible myelosuppression. Although the exact mechanism of HbF induction is unclear, a primary mechanism relates to the subsequent recovery or “stress erythropoiesis” and release of early erythroid progenitors that synthesize more HbF. This causes the uneven distribution of HbF among the RBCs, 34 one of the reasons proposed for the variable clinical response between SCD patients. 35 , 36 Otherwise, HU-induced HbF increase would be much more effective.

Advances in our understanding of the molecular mechanisms regulating the fetal to adult Hb switch have led to the generation of new agents that do not rely on causing “stress erythropoiesis” and they fall into 2 main groups: those that affect chromatin regulators (such as decitabine on DNA methylation and histone deacetylase [HDAC] inhibitors) and others that affect DNA-binding transcription factors. Contemporaneous genome-wide association studies 11 , 12 identified BCL11A as the first key repressor protein for silencing of the fetal (γ) globin genes joined later by zinc finger and BTB domain-containing protein 7A (ZBTB7A), also known as leukemia related factor (LRF). 37 In 2018, key studies by 2 groups showed that BCL11A and ZBTB7A each bind to a cognate recognition site within the γ-globin promoter. 38 , 39 Besides its role as γ-globin repressor, BCL11A is also essential for B-lymphoid development. 40 Identification of the key erythroid-specific enhancer elements 41 was critical and important in the development of the clinical trials aimed at downregulating BCL11A using 2 different genetic approaches—lentiviral short hairpin RNA (shRNA) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease-9 (Cas-9) editing. 42 , 43 Another genetic approach for reactivating endogenous γ-globin to produce high HbF is to mimic the naturally occurring HPFH variants in the γ-globin promoters by genome-editing to disable binding of BCL11A or ZBTB7A/LRF repressors. 10 , 44 In theory, correcting the sickle mutation ( rs334 ) is the most direct approach, as the same base change is present in all β S alleles, but homology-directed DNA repair is limited by the efficiency at which the correction is achieved and the concomitant generation of insertions/deletions and conversion of the β S gene to a β-thalassemia allele. 45

New therapeutic drug targets that have evolved from molecular dissection of SCD pathophysiology

HU was originally an anti-neoplastic agent in the treatment of patients with myeloproliferative diseases, in whom it has been shown to induce variable moderate increases in HbF and MCVs, 46 but HU is now probably best known as standard therapeutic agent for SCD. 47 , 48 While the clinical efficacy of HU relates predominantly to the level of HbF increase, it also has other salutary therapeutic effects—such as reducing cellular adhesion, hemolysis, and inflammation. 49 Molecular dissection of these mechanisms led to new insights on the pathophysiology of SCD (Figure 2 ) and new therapeutic targets on vaso-occlusion (endari), HbS polymerization (voxelotor), and vascular adhesion (crizanlizumab) that were approved by the FDA in the last 5 years (Table 2 ).

Pathophysiology of SCD. Polymerization of HbS under a state of deoxygenation is the fundamental event in the pathophysiology of SCD. These sickled RBCs become activated and interact via pro-inflammatory cytokines with the endothelium, WBCs, especially neutrophils/monocytes, and platelets. There is increased expression of pro-adhesive molecules (selectins) in the endothelial vasculature, which promote the adhesion of WBC, a key component of vaso-occlusion physiology. Platelet activation promotes further cytokine release and inflammation and also a hypercoagulable state by secreting coagulation and tissue factors. These damaged “sickle” RBCs are prone to destruction, leading to the continual release of cell-free hemoglobin which leads to depletion of hemopexin and haptoglobin. Consequently, the bioavailability of nitric oxide is reduced, leading to vascular dysfunction and end-organ damage. Both pathways triggered by the polymerization of HbS perpetuate the chronic state of inflammation seen in SCD facilitating end-organ damage. ESL-1 = E-selectin ligand-1; HbS = hemoglobin S; NET = neutrophil extracellular trap; RBC = red blood cell; ROS = reactive oxygen species; SCD = sickle cell disease; WBC = white blood cell.

Medications Approved and in the Pipeline for Sickle Cell Disease.

2,3-DPG= 2,3-diphosphoglycerate; ASH = American Society of Hematology; cGMP= cyclic guanosine monophosphate; FDA = Food and Drug Administration; HbF = hemoglobin F; HbS = hemoglobin S; HDAC= histone deacetylase; IL-1β = interleukin 1 beta; iNKT = invariant natural killer T cell; NAD = nicotinamide adenine dinucleotide; NADH = NAD + hydrogen (H); PK = pyruvate kinase; SCD = sickle cell disease.

Endari (L-glutamine)

L-glutamine is an essential amino acid that evolved as an anti-sickle agent through its role as a precursor for the synthesis of glutathione, nicotinamide adenine dinucleotide (NAD), and arginine, all of which protect erythrocytes from oxidative damage and indirectly maintain vascular tone. 50 , 51 Early studies by Nihara et al 52 in 7 SCD patients showed significant increases in nicotinamide adenine dinucleotide - hydrogen (NADH) and NAD redox potential, but no change in Hb concentration. In a follow-up study, erythrocytes from SCD patients who were administered L-glutamine decreased endothelial adhesion in vitro; findings interpreted as glutamine having a role in maintaining RBC membrane integrity and its interaction with the blood vessels and adhesion molecules. 53 In 2017, L-glutamine became the second drug to be licensed by the FDA for patients 5 years or older with SCD (Table 2 ). The approval was based on a double-blind phase III trial in which 230 children and adults with either HbSS or HbS/β 0 thalassemia were randomized to receive L-glutamine or placebo for 48 weeks. Compared to placebo, L-glutamine was associated with 25% reduction in the number of vaso-occlusive crisis (VOC) events (median 3.0 versus 4.0; P = 0.005), 30% lower hospitalization rates (median 2.0 versus 3.0; P = 0.005), and reduced number of episodes of acute chest syndrome, respectively. Although there were significant increases in NADH and NAD redox potential, and decreased endothelial adhesion of ex vivo treated sickle erythrocytes, there were no changes in Hb or reticulocyte counts. 54 To date, however, L-glutamine has been rejected by the European Medicines Agency because of its relatively small therapeutic effects, and concerns on the high drop-out rate of 36% in the treatment arm, and 24% in the placebo arm.

L-glutamine appears to be reasonably well tolerated, but adherence is poor due to its taste and route of administration (twice daily as oral powder). As it is an amino acid, one should be cautious in its use among SCD patients in whom renal and hepatic dysfunction are not uncommon.

Voxelotor (Oxbryta/GBT440)

Voxelotor (also known as Oxbryta or GBT440) is the second anti-sickling agent that was approved by the FDA in November 2019 for the treatment of SCD in patients aged 12 years and older (Table 2 ). Voxelotor is anti-sickling because it stabilizes the oxygenated state of Hb through reversible binding to the amino terminus of alpha chain of Hb. 55 The phase III Hemoglobin Oxygen Affinity Modulation to inhibit HbS Polymerization (HOPE) study (ClinicalTrials.gov: NCT03036813 ) was a randomized, placebo-control study of 274 patients of all SCD genotypes, age 12–65 years, in which voxelotor showed dose-dependent increase in Hb and decrease hemolysis markers, suggestive of decreased sickling. 56 Although these findings did not correlate with a decrease in the number of pain crises in patients with SCD, the promising findings led to FDA approval in November 2019 for patients older than 12 years old with SCD. There is some concern, however, that Hb molecules with the drug bound are in a conformation that delivers very little oxygen, especially detrimental in a disease characterized by decreased oxygen delivery, 57 in which case, the increase in Hb needs to be about the same as the concentration of the drug-bound, nonoxygen delivering Hb. Hopefully, these concerns are addressed in current multicenter phase III clinical studies in both adults (ClinicalTrials.gov: NCT03036813 ) and children (ClinicalTrials.gov: NCT02850406 ). In the meanwhile, it remains important to continue to monitor closely the patients while on this medication, particularly in those with prior stroke and silent cerebral infarcts. It should also be noted that HbS-voxelotor complexes, while useful in monitoring voxelotor therapy, causes interference with determination of HbS fraction in routine laboratory techniques—isoelectric-focusing gel, high-performance liquid chromatography, and capillary zone electrophoresis—of Hb fractionation. 58

Crizanlizumab

Adhesion of the sickle erythrocytes and neutrophils with the vascular endothelium leads to upregulation of endothelial adhesion molecules—vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E and P selectins, facilitating vaso-occlusion. Crizanlizumab is a humanized monoclonal antibody that selectively inhibits P-selectin. The study to assess safety and impact of SelG1 with or without hydroxyurea therapy in sickle cell disease patients with pain crises (SUSTAIN) was a phase II multicenter, randomized, placebo-controlled double-blind study in which crizanlizumab was tested in 198 patients with SCD (on or not on HU) for its ability to reduce VOCs over a period of 52 weeks. Results showed a significant reduction of sickle cell-related pain crises per year in the high dose arm (5 mg/kg) as compared to the placebo (1.63 versus 2.98), and a low incidence of adverse events. Patients on the treatment arm also had an increased time-to-first VOC compared with placebo. Although side effects were relatively fewer in patients on crizanlizumab, 1 patient had an intracranial bleed. A phase III is currently ongoing to assess safety and efficacy of crizanlizumab, as this medication may alter platelet function. In November 2019, crizanlizumab (Adakveo) was FDA approved for reduction of VOCs in patients with SCD, 16 years or older (Table 2 ). 59 , 60 It should be noted that crizanlizumab is a preventive therapy, administered intravenously over 30 minutes on week 0, 2, and every 4 weeks thereafter. There are recent concerns with crizanlizumab due to the increased reports of serious infusion and post-infusion reactions ( https://www.crizanlizumab.info/ ), causing hematologists to discontinue therapy. 61

Promising medications in the pipeline

Rivipansel (also known as GMI1070) is another agent targeting cell adhesion (Table 2 ), which was developed as a pan-selectin inhibitor, but has greatest activity against E-selectin. A phase II, randomized, placebo-controlled multicenter study in adolescents and adults showed the drug to be safe, and markedly reduced use of opioids during hospitalization (83% reduction compared to placebo) as well as a trend toward a faster resolution of VOC (41 versus 63 h). 62 A phase III study of rivipansel in patients 6 years and older hospitalized for a pain crisis (ClinicalTrials.gov: NCT02187003 ) was recently completed, and although the drug did not reach its primary or key secondary endpoints, analyses suggested that early administration of rivipansel in vaso-occlusive events may reduce hospital stay and intravenous opioid use in pediatric and adult patients ( https://doi.org/10.1182/blood-2020-134803 ). Although interesting, the clinical impact of rivipansel and its timely use as a preventive medication may be limited for the general SCD population.

All SCD patients have elevated pro-inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor alpha [TNFα], and IL-1β), neutrophils, heme and other molecules with inflammatory potential, referred to as damage-associated molecular patterns. 32 A number of anti-inflammatory agents have been investigated including corticosteroids and regadenoson, an adenosine A 2A receptor agonist. Humanized sickle mouse demonstrated elevated levels of invariant natural killer T cells (iNKT) implicating their role in the pathogenesis of ischemia-reperfusion injury. 63 Reduction of this subset of T cell (iNKT) activity ameliorated the inflammatory injury in the lungs in sickle mice, 64 prompting studies in patients with SCD. 65 , 66 Unfortunately, results showed that low-dose infusion of regadenoson was not sufficient to produce a statistically significant reduction in the activation of iNKT cells or in measures of clinical efficacy. 66 Another study utilized the anti-iNKT cell monoclonal antibody NKTT120. High intravenous doses of NKTT120 were shown to decrease iNKT cells in adults with SCD. It should be noted, however, that the subjects in the study were in steady-state when iNKT cell activation was significantly lower compared to VOC. 65 The implication is that, to be effective in VOC, much higher doses of NKTT120 (NKT Therapeutics, Inc.) may be needed.

IL-1β is a cytokine that is central in the inflammatory response and has also been shown to be elevated in subjects with SCD. 67 , 68 Canakinumab is a humanized monoclonal antibody targeting IL-1β and has been approved by the FDA for treatment of rheumatological disorders in 2009. Its broader role as an inflammatory agent was demonstrated in subjects with previous myocardial infarcts, 69 motivating an ongoing randomized double-blind placebo-controlled phase II study of subcutaneous canakinumab in patients with SCD aged 8–20 years old (ClinicalTrials.gov: NCT02961218 ) (Table 2 ). Preliminary results suggest that canakinumab improves pain scores, sleep, and school/work attendance ( https://doi.org/10.1182/blood-2019-123355 ).

Despite high levels of HU-induced HbF, some patients continue to have sickle-related manifestations, which has been attributed to the uneven distribution of HbF among the RBCs. An alternative to increasing HbF synthesis that does not mimic stress erythropoiesis is to increase access of the transcription factors to the γ-globin genes by manipulation of the chromatin regulators (such as decitabine on DNA methylation and HDAC inhibitors). Hypermethylation of the upstream γ-globin promoter sequences is believed to be important in the Hb switch during which the γ genes are silenced by DNA methyltransferase 1 (DNMT1). 70 This led to the use of 5-azacytidine, a first generation DNMT1 inhibitor, but it was quickly abandoned due to its toxicity and carcinogenicity. 70 Decitabine, an analogue 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: NCT01685515 ). A phase I study showed that decitabine-THU led to the inhibition of DNMT1 protein with induction HbF increase, and more importantly, HbF-enriched RBCs (F cells) increased to 80%. These agents did not induce cytoreduction but increased platelets count, which can be problematic in SCD patient and require further evaluation. 71

HDACs are another group of regulatory molecules involved in epigenetic silencing of the γ-globin genes and have been considered as therapeutic targets for HbF induction (Table 2 ). Panobinostat is a pan HDAC inhibitor currently being tested in adult patients with SCD as a phase I study (ClinicalTrials.gov: NCT01245179 ). Increasing cellular cyclic guanosine monophosphate (cGMP) levels has also been proposed as one mechanism of HbF increase by HU. 72 Phosphodiesterase 9 (PDE9) degrades cGMP, and it has been shown to be present in activated RBCs and neutrophils of patients with SCD. PDE9 inhibitors have been studied in clinical trials in patients with SCD with interesting results demonstrating elevation of HbF without deleterious effects in the bone marrow. 73

Exciting drugs in the pipeline with anti-sickling properties have also been derived from a combination of bench and clinical observations. HbS polymerizes only when deoxygenated and its oxygenation is influenced by a few factors. One key factor influencing Hb oxygenation is the concentration of 2,3-diphosphoglycerate (2,3-DPG) in the RBC. Increased intracellular 2,3-DPG decreases oxygen binding and stabilizes the deoxygenated form (T form) of Hb, promoting sickling. 19 It has been noted more than 50 years ago that 2,3-DPG levels in RBCs from SCD patients were significantly higher than that in healthy RBCs, 74 and that adding 2,3-DPG to both healthy and SCD RBCs reduces Hb oxygen affinity. 74 Decreasing 2,3-DPG as a therapeutic target has long been proposed by Poillon et al 75 when they showed that considerable reduction of 2,3-DPG in sickle erythrocytes significantly reduced the sickling tendency. 2,3-DPG is an intermediate substrate in the glycolytic pathway, the only source of ATP production in RBCs. As pyruvate kinase (PK) is a key enzyme in the final step of glycolysis, enhancing its activity in red cells presents a very attractive therapeutic anti-sickling strategy as this leads to a decrease in 2,3-DPG, which increases Hb oxygenation with inhibition of the sickling process. Additionally, the concomitant increase in ATP levels restores ATP depletion in sickled RBCs and improves RBC membrane integrity. Currently, there are 3 ongoing phase I/II clinical studies of PK activation in SCD: 2 studies utilizing Mitapivat/AG-348 in HbSS patients in steady-state (ClinicalTrials.gov: NCT04000165 ; NCT04610866 ), and another (FT-4202) in healthy subjects and SCD patients (ClinicalTRials.gov: NCT03815695 ) ( https://doi.org/10.1182/blood-2020-134269 ). Preliminary data showed that AG-348 data was well-tolerated and safe in subjects with SCD, and support dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation accompanied by increases in Hb level and decreases in hemolytic markers ( https://doi.org/10.1182/blood-2019-123113 ).

Mitapivat is also currently in phase II/III clinical trials in humans with PK deficiency 76 (ClinicalTrials.gov: NCT02476916 , NCT03548220 , NCT03559699 ), as well as in an ongoing phase II study in subjects with nontransfusion-dependent thalassemia (ClinicalTrials.gov: NCT03692052 ).

Evolution of the curative approaches for SCD

Allogeneic transplantation.

Hemopoietic stem cell transplantation (HSCT) had not been considered as a therapeutic option for SCD until 1984, prompted by the successful reversal of SCD in an 8-year-old SCD child who developed acute myeloid leukemia (AML). 77 The patient received HSCT for the AML from a HLA-matched sister who was a heterozygous carrier for HbS (hemoglobin AS [HbAS]) (Table 1 ). She was cured of her leukemia and at the same time, her sickle cell complications also resolved. 77 , 78 This successful HSCT demonstrated that reversal of SCD could be achieved without complete reversal of the hematological phenotype to normal hemoglobin genotype (HbAA), and as long as stable mixed hemopoietic chimerism after HSCT can be achieved. 79

The outcomes for both children and adults who receive HLA-matched sibling donor hematopoietic stem cells (HSCs) are now excellent. 80 , 81 Key milestones in making HLA-matched sibling donor HSCT an accepted curative option include: (1) the development of less intense conditioning regimens expanding allogeneic transplantation to adult patients who otherwise would not be able to tolerate the intense myeloablative conditioning 82 and (2) that to reverse the sickle hematology, regardless of whether donors have normal hemoglobin genotype, HbAA, or are carriers for HbS (HbAS), only a minimum of myeloid chimerism of 20% is sufficient. 83 Transplantation of HLA-matched sibling donor HSCs cures SCD, but to date, relatively few (~2000) patients with an average age of 10 years have benefited; the vast majority is excluded due to donor availability, toxicity related to myeloablative conditioning, and graft-versus-host disease (GvHD). 81 , 84 , 85

To enable allogeneic HSCT as a therapeutic option to more patients with SCD, there is a major need to expand alternative donor sources of HSCs that include related haploidentical HSCs, matched unrelated donors, and cord blood. Of these, the most promising is related haploidentical allogeneic HSCT due to donor availability; post-transplantation cyclophosphamide has also improved safety with increased cure rates. 86 – 88

While the overall survival was 94% in a study of unrelated cord blood transplantation for pediatric patients with SCD and thalassemia, the disease-free survival was not so good at about 50% in the SCD population. 89 Compared to unrelated cord blood transplantation, related cord blood transplantation offers a better probability of success with a 2-year disease-free survival of 90% and a low risk of developing acute GvHD (11%) or chronic GvHD (6%) in pediatric patients with SCD. 90

There are multiple clinical trials ongoing at this point at ClinicalTrials.gov that are assessing different techniques to improve the outcome of patients with SCD undergoing allogeneic HSCT. For more details of the different allogeneic HSCTs, we refer to a recent review. 91

Autologous transplantation and genetic therapies

The genetic simplicity of the sickle mutation affecting an HSC lends itself to genetic therapies, an approach that eliminates the need to find a donor and thus, available to all patients (Table 3 ). Since these are the patient’s own stem cells, there is no need for immunosuppression, avoiding the risks of GvHD and immune-mediated graft rejection. Following gene modification in vitro, the patient’s own stem cells are reinfused after chemotherapy conditioning. Currently, there are 3 broad approaches: (1) Addition of lentiviral vectors (LVs) that express different versions of non- or anti-sickling genes, or a γ-globin coding sequence in a β-globin gene to increase HbF levels and decrease HbS; (2) addition of a LV that expresses erythroid-specific shRNA for BCL11A to downregulate its expression, thereby increasing γ-globin expression; and (3) editing of the BCL11A gene to delete the regulatory element controlling its expression in erythroid cells.

Gene Editing and Gene Therapies for Sickle Cell Disease.

a Currently not recruiting due to 2 long-term follow-up patients developed myeloid malignancies.

b Currently suspended due to findings of NCT02140554 .

βAS3 = anti-sickling beta globin gene βAS3; BCL11A = B-cell lymphoma/leukemia 11A; CRISPR/Cas-9 = clustered regularly interspaced short palindromic repeats/CRISPR (C) associated nuclease-9; DSMB = Data and Safety Monitoring Board; hHSPCs = human hematopoietic stem and progenitor cells; SCD = sickle cell disease; shRNA = short hairpin RNA.

A critical component in autologous HSCT is the amount and quality of CD34 + cells that can be obtained from the patient. Historically, granulocyte colony-stimulating factor (GCS-F) had been used to obtain such cells in non-SCD patients, but the elevated white cell counts from GCS-F mobilization of CD34 + in SCD patients increases the risk of triggering acute severe pain, acute chest syndrome, and even death, and is thus contra-indicated in patients with SCD. Bone marrow harvest is another source, but CD34 + cells obtained from bone marrow harvests are suboptimal in quantity and quality, thus requiring multiple harvests, each harvesting procedure increasing the risk of triggering acute pain crisis. Development of plerixafor as an alternative approach has been crucial in optimization of CD34 + collection in patients with SCD. Plerixafor blocks the binding between chemokine CXC-receptor 4 and the stromal cell triggering mobilization of CD34 + cells into the peripheral blood stream without the uncontrolled increase of total white blood cells. Plerixafor in association with hyper-transfusion therapy has become the preferred way of mobilizing HSCs in patients with SCD. 92 – 96

Two clinical trials (Table 3 ) have evolved from preclinical studies in SCD mice that showed that erythroid-specific down regulation of BCL11A is feasible and that it resulted in therapeutic elevation of HbF. One approach utilizes an shRNA embedded in a microRNA contained within a LV to limit knockdown of BCL11A to erythroid precursors. 42 Of 6 patients with a median 18 months (range 7–29 mo) post-therapy, stable HbF induction of 20.4% to 41.15% was observed and the HbF was broadly distributed among the erythrocytes with F cells of 59% to 94%. Sickle complications were reduced or absent in all patients. 42 The other approach utilized CRISPR-Cas editing to disrupt the key erythroid-specific enhancer in BCL11A leading to near normal Hb in 3 patients with HbF of >40% that was distributed pancellularly. 43

Among the ongoing clinical trials on genetic therapy (Table 3 ), the most promising with the largest clinical experience relies on a lentivirus expressing a mutated β-globin β T87Q (LentiGlobin BB305) with anti-sickling properties. 97 ( https://ash.confex.com/ash/2020/webprogram/Paper134940.html ) At the time of this review, 47 patients with SCD have been treated in 2 related clinical trials (ClinicalTrials.gov: NCT02140554 and NCT04293185 ). 98 Unfortunately, reports of myelodysplasia and AML in 3 patients led to a temporary pause in enrolment; the clinical trial was allowed to resume when further investigation demonstrated integration of the LV to a nononcogenic gene with no disruption in expression of other genes in the vicinity. The conclusion was that the LV is unlikely to be implicated in cancer development. 98 , 99 Exclusion of busulfan and insertional mutagenesis in these therapy-related leukemias, isolated reports of leukemias in SCD patients, with or without HU, pre-or post-transplantation, 100 suggests that SCD patients may have a relatively increased risk of AML or myelodysplasia due to damage to hemopoietic stem cells related to chronic stress erythropoiesis. If so, it may be prudent to prescreen individuals with SCD for preleukemic progenitor cells as well as somatic mutations in genes involved in epigenetic regulation (DNMT3A, TET2, ASXL1), which are associated with an increased risk of developing blood cancers, referred to as clonal hematopoiesis of indeterminate potential (CHIP) origin. It has also been suggested that curative therapies should be performed in younger patients prior to acquisition of such CHIP variants or all patients should be screened for such variants prior to undergoing marrow conditioning.

Worldwide impact of SCD

SCD may have first appeared in the Western literature in 1910, but the clinical spectrum of SCD has been recognized in West Africa for centuries 101 and probably existed in American slaves during the slavery period before 1910. 102 Due to migration patterns, SCD is now worldwide, affecting millions globally, and the numbers are increasing. 103 , 104 Nevertheless, SCD remains drastically more prevalent in historically malaria-endemic areas, such as sub-Saharan Africa, where carriers (HbAS) for the sickle mutation have a substantial protection against Plasmodium malariae infection. In a recent meta-analysis of SCD prevalence in subjects <5 years old, the birth prevalence of HbAS was estimated at >16,000 per 100,000 live births in Africa; much higher when compared to 800 per 100,000 live births in Europe. 105 – 107

In 2010, an estimated 300,000 newborns were affected—projected to increase to 400,000 in 2050—of which more than 75% is in Africa. Unfortunately, 50%–80% of the infants born annually with SCD in Africa will not reach their fifth birthday. In the Republic of Congo, almost 12.5% of the pediatric patients hospitalized have SCD and the estimated annual cost of care for each of these patients is above 1000 United States dollars (USD). 108 Trained personnel, access to vaccines, antibiotic prophylaxis, implementation of newborn screening, and blood products—all fundamental for the care and management of patients with SCD—are still limited resources in developing countries. 109 The socioeconomic burden of SCD in Africa, and worldwide, will continue to increase with growth of the world’s population and human migration.

Although groundbreaking research is being performed in developed countries, access to the new medications—L-glutamine, voxelotor, and crizanlizumab—is limited in developing countries. In the meanwhile, studies have shown that HU is safe in malaria-endemic sub-Saharan Africa with no difference in incidence of malaria between children either on or off HU. The overall clinical benefit from HU therapy may even protect the recipients from severe effects of malaria. 110 – 112 It should be noted, however, that prior to these studies, HU has already been demonstrated to be safe and effective as an alternative to regular blood transfusion therapy for prevention of secondary stroke in children with sickle cell anemia. 113

Conclusions

SCD epitomizes the bidirectional translational research common to many other diseases. An astute observation of “elongated, sickle-shaped and crescent-shaped” RBCs has spurred the way to the uncovering of the first disease at a molecular level. Since then, SCD has been at the forefront of human genetic discovery, which has now translated into the first-in-human studies of reactivating an endogenous (γ-globin) gene utilizing innovative genomic approaches. A cure for this debilitating disease through HSCT and gene therapies is now within reach, but likely to remain available to a minority of the patients for the next few decades. A major unmet need for the vast majority now is a small molecule that targets the root cause of the disease and that can be taken orally. As new drugs and treatments are developed, it is essential that we find ways to make them accessible to all patients in both high- or low-resource countries.

Disclosures

The authors have no conflicts of interest to disclose.

Sources of funding

This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute and National Institutes of Health (SLT).

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Sickle cell anemia.

Ankit Mangla ; Moavia Ehsan ; Nikki Agarwal ; Smita Maruvada .

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Last Update: September 4, 2023 .

• Continuing Education Activity

Sickle cell anemia is an inherited disorder of the globin chains that causes hemolysis and chronic organ damage. Sickle cell anemia is the most common form of sickle cell disease (SCD), with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage. Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. This activity reviews the pathophysiology, presentation, complications, diagnosis, and treatment of sickle cell anemia and also highlights the role of the interprofessional team in the management of these patients.

• Describe the pathophysiology of sickle cell anemia.
• Summarize the epidemiology of sickle-cell anemia.
• List the management options for sickle cell anemia.
• Outline the importance of cooperation among healthcare professionals to educate the patients on getting vaccinated, remaining hydrated, and timely follow-up to prevent the development of complications in those with sickle cell disease.
• Introduction

Sickle cell disease (SCD) refers to a group of hemoglobinopathies that include mutations in the gene encoding the beta subunit of hemoglobin. The first description of SCA 'like' disorder was provided by Dr. Africanus Horton in his book The Disease of Tropical Climates and their Treatment (1872). However, it was not until 1910 when Dr. James B Herrick and Dr. Ernest Irons reported noticing 'sickle-shaped' red cells in a dental student (Walter Clement Noel from Grenada). [1] In 1949, independent reports from Dr. James V Neel and Col. E. A. Beet described the patterns of inheritance in patients with SCD. In the same year, Dr. Linus Pauling described the molecular nature of sickle hemoglobin (HbS) in his paper 'Sickle Cell Anemia Hemoglobin.' Ingram Vernon, in 1956, used a fingerprinting technique to describe the replacement of negatively charged glutamine with neutral valine and validated the findings of Linus Pauling. [2]   

Within the umbrella of SCD, many subgroups exist, namely sickle cell anemia (SCA), hemoglobin SC disease (HbSC), and hemoglobin sickle-beta-thalassemia (beta-thalassemia positive or beta-thalassemia negative). Several other minor variants within the group of SCDs also, albeit not as common as the varieties mentioned above. Lastly, it is essential to mention the sickle cell trait (HbAS), which carries a heterozygous mutation and seldom presents clinical signs or symptoms. Sickle cell anemia is the most common form of SCD, with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage. [3]  

Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. In 1984, Platt et al. first reported the use of hydroxyurea in increasing the levels of HbF. [4]  Since then, the treatment of sickle cell has taken to new heights by introducing several new agents (voxelotor, crizanlizumab, L-glutamine) and, most recently, gene therapy.

Hemoglobin (Hb) is a significant protein within the red blood cell (RBC). It comprises four globin chains, two derived from alpha-globin (locus on chromosome 16) and two from beta-globin (locus on chromosome 11). There are many subtypes of Hb. The most common ones that are found in adults without hemoglobinopathies are listed here:

• HbA1- comprises two chains of the alpha-globin and two chains of the beta-globin (a2b2) - This constitutes 95% of the adult hemoglobin.
• HbA2- comprises two chains of the alpha-globin and two chains of the delta-globin (a2d2) - This constitutes less than 4% of the adult hemoglobin.
• HbF- comprises two chains of the alpha-globin and two chains of the gamma-globin (a2g2) - This Hb is more prevalent in the fetus (due to the high oxygen binding affinity that helps extract oxygen from maternal circulation).

The sickle cell mutation occurs when negatively charged glutamate is replaced by a neutral valine at the sixth position of the beta-globin chain. The mutation is transmitted via Mendelian genetics and is inherited in an autosomal codominant fashion. [5]  A homozygous mutation leads to the severest form of SCD, ie, SCA- also called HBSS disease. The coinheritance of beta-naught thalassemia and sickle cell mutation leads to HBS-Beta-0 disease, which phenotypically behaves like HBSS disease.

A heterozygous inheritance leads to HbAS. Patients with HbAS are not considered within the spectrum of SCD as most of them never present with typical symptoms of SCA. They might only be detected during childbirth, blood donation, or screening procedures. 

Several other compound heterozygotes exist where a single copy of the mutated beta-globin gene is coinherited with a single copy of another mutated gene. The second most common variant of SCD is the HbSC disease, where the sickle cell gene is coinherited with a single copy of the mutated hemoglobin C gene. HbC is formed when lysine replaces glutamine at the sixth position on the beta-globin chain. HbSC disease accounts for 30% of patients in the United States. 

• Epidemiology

The epidemiological data on SCD is scarce. It is well known that SCD and HbAS are more prevalent in sub-Saharan Africa, where the carrier of HbAS is afforded natural protection against severe Plasmodium falciparum malaria. It is estimated that ~230,000 children were born with SCA, and more than 3.5 million neonates were born with HbAS in sub-Saharan Africa in 2010. an estimated 75% of SCD-related births take place in sub-Saharan Africa. West Africa is home to the largest population of individuals with HbSC disease. [3]

The United States (US) Center for Disease Control (CDC) estimates that approximately 100,000 Americans have SCD. The CDC also estimates that 1 in 13 babies born to African-American parents have sickle cell trait, and 1 in 365 African-Americans have SCD. The estimated ratio of Hispanic Americans with SCD is 1 in 16,300. Children and adolescents make up to 40% of all SCD patients in the US. The incidence varies by state and geographical concentration of ethnicities. Besides, migration within the country and immigration from foreign countries alter the prevalence of SCD and HbAS. This is true for several countries where patients with SCD and SCA are living. Genetic studies in Brazil have also tied the origin of such patients to the slave trade originating from West Africa (Mina Coast and Angola). [6]  With the improvement in technology and ease of international migration, the incidence of SCA is predicted to rise. It is estimated that the annual number of newborns with SCA will exceed 400,000 by 2050.

There is also a stark difference in mortality and morbidity in high-income and low-income countries. Adopting vaccination guidelines for children with SCD and intensive screening procedures has sharply reduced the mortality of kids with SCD between 0 to 4 years (68% drop noted from 1999 to 2002 compared to 1983 to 1986). On the other hand, in sub-Saharan Africa, 50 to 90% of children born with SCD will die before their fifth birthday. Improving the care afforded in high-income countries and targeted training of healthcare providers have improved life expectancy. However, it still lags by decades compared to matched non-SCD cohorts (54 versus 76 years - projected life expectancy, and 33 years versus 67 years- quality-adjusted life expectancy). [7]

HbSC disease accounts for 30% of all patients with SCD in the US. As with HbAS, patients with the Hb C trait (heterozygous mutation) also remain asymptomatic for most of their lives. Although considered a milder variant of SCD, HbSC disease may present with severe morbidities. [8]

• Pathophysiology

Sickle cell anemia is characterized by two major components: Hemolysis and vaso-occlusive crises (VOC). The defect in the beta-globin gene makes the sickle hemoglobin (HbS) molecule susceptible to converting into rigid, elongated polymers in a deoxygenated state. The sickling process is cyclical initially, where sickle erythrocytes oscillate between the normal biconcave shape and the abnormal crescent shape (acquired under low oxygen pressure). However, there comes a time when the change becomes irreversible, and the sickle erythrocytes develop a permanent sickle shape, increasing the risk for hemolysis and VOC. All variants of SCD share the same pathophysiology leading to polymerization of the HbS component. [3]  

Multiple factors inherent to sickle erythrocytes, like the low affinity of HbS for oxygen, physiologically high 2,3-diphosphoglycerate, and increased sphingokinase-1 activity, lead to deoxygenation, which promotes the polymerization of HbS. In addition to this, a high concentration of HbS, abnormal activity of the Gados channel leading to dehydration, and repeated damage to the red blood cell (RBC) membrane also increase the risk of polymerization of HbS.

Oxidative stress contributes to hemolysis by auto-oxidation of HbS, leading to erythrocyte cell membrane damage. The increased expression of xanthine dehydrogenase, xanthine oxidase, and decreased expression of NADPH oxidase increase the oxidative stress within sickle RBC. A hemolyzed cell releases free hemoglobin (scavenges nitrous oxide) and arginase 1 (competes for L-arginine) that prevent the action and formation of nitrous oxide and contribute to oxidative stress and vascular remodeling (arginase-1 converts arginine to ornithine). [3]   

Besides the polymerization of the HbS and intravascular hemolysis, several other factors also contribute to vaso-occlusion. For example, the sickle RBC (expresses several adhesion molecules on the surface), free heme and Hb, reactive oxygen species, and endothelium interact with each other and with neutrophils and platelets to promote vaso-occlusion and thrombosis.  

• Histopathology

In patients with SCA, peripheral blood smear shows elongated RBC with tapering ends that look like a sickle (also called drepanocytes). Additional findings are present in a few patients. 

• Howell-Jolly bodies- Remnants of DNA are seen in the RBC and commonly seen in patients in whom the spleen has been removed. Therefore, patients with SCA have auto-splenectomy.
• Target cells (Leptocytes)- Most commonly seen in patients with Thalassemia. They are seen frequently in sickle-thalassemia syndromes and are sometimes noted in patients with SCA.
• Polychromatic cells - these are reticulocytes that signify marrow response to hemolysis. 
• Nucleated red blood cells can sometimes be visible on the peripheral smear. 

None of these findings are confirmatory. Confirmation is obtained only through hemoglobin electrophoresis, high-performance liquid chromatography, or isoelectric focusing. DNA-based techniques are not used routinely. Instead, they are used in patients with uncertain diagnoses. Pre-natal fetal testing involves using fetal DNA obtained through amniocentesis. Techniques to capture the fetal DNA in maternal blood remain investigational.

• History and Physical

Most patients with HbSS phenotype do not present with classical 'sickle cell crises' soon after birth. HbF is still present in the blood, helping maintain adequate tissue oxygenation, and it takes around 6-9 months to wean off completely. Not all SCAs have the same phenotype, and multiple phenotypes exist that can either co-exist or present as a spectrum of the disease. [3]  

• Vaso-occlusive subphenotype - Distinguished by higher hematocrit (Hct) compared to other SCA. A higher Hct leads to higher viscosity that promotes frequent vaso-occlusive crises and acute chest syndrome. 
• Higher risk of gallstones, pulmonary hypertension, ischemic stroke, priapism, and nephropathy
• Severe anemia increases cardiac workload and blood flow through organs, making them susceptible to damage.
• Higher free heme and Hb in blood vessels cause oxidative damage
• High Hb F subtype- A 10 to 15% level of HbF alleviates the symptoms of SCA. However, the distribution of HbF is not consistent throughout the body.
• Pain-sensitive subphenotype- Altered neurophysiology amongst various individuals makes them susceptible to pain. Some individuals are more susceptible to pain compared to others with SCA.

The patients with SCA present with acute or chronic complications associated with the disease. The most common acute complication of SCA is vaso-occlusive crisis (VOC). The treatment section below discusses the management of acute and chronic issues. 

Important points to be noted in the history of patients with SCA

• All patients with SCA will experience VOC during their lives. The earliest presentation is dactylitis in kids as young as six months of age.
• Any body organ can develop VOC (head, eyes, etc.), although extremities and the chest are most commonly involved. If a VOC pain sounds atypical, obtain a history to rule out other causes.
• When was the last pain crisis, and how many times in the previous year have they been admitted to the hospital with pain crises?
• If they take analgesics daily, it is prudent to know the type and quantity of the analgesic (opioid or non-opioid), the last use of analgesics, and whether they take the analgesics before coming to the ER/office.
• History of taking disease-modifying drugs (hydroxyurea, voxelotor, crizanlizumab, etc.) 
• A history of substance abuse, psychiatric disorders, and use of psychotropic medications must be obtained. 
• History of receiving blood transfusions and exchange transfusions- helps assess the risk of iron overload, presence of alloantibodies (multiple transfusions in the past can lead to the development of alloantibodies, which will help assess the risk of transfusion reactions), and previous transfusion reactions. 
• History of any other diseases that may or may not be associated with SCA - previous history of stroke, thrombosis, priapism, etc.
• It is also advised to get in touch with the primary hematologist taking care of the patient- it is valuable to have their input in understanding the patient's normal physiology. 
• History of previous surgeries.
• History of life-threatening crises in the past- if present, should alert the clinician to ensure that a similar event is not occurring again. For example, fat embolism may occur more frequently in patients with SCA. 

The physical exam should focus on the general system exam to determine the need for oxygen requirements, pain management, and blood/exchange transfusion. However, a focused exam is necessary to rule out any organ-specific problem. For example, a rapidly enlarging liver or spleen should alert the physician about sequestration crises. 

Patients with SCA are usually diagnosed in childhood. Intensive newborn screening programs in developed countries can identify patients in the neonatal stage. In the US, universal screening for SCA was implemented in all states by 2007. High-performance liquid chromatography and isoelectric focusing are the methods used in the US. In Europe, most countries deploy targeted screening in high-risk areas (where SCA is more common) and not a universal screen. In sub-Saharan Africa, no country has adopted a screening program. In India, the solubility test is used as the first step- if positive, then high-performance liquid chromatography is used to confirm at the reference center. [3]

Acute Complications in Patients with SCA

Acute Chest Syndrome (ACS):  ACS is the most common complication of SCA. It is also the most common cause of death and the second most common cause of hospital admission. A patient can either present with ACS or may develop it during hospitalization for any other reason. Hence, it is prudent to monitor all patients with SCA admitted to the hospital for ACS. It is important to recognize ACS early and act upon it to prevent respiratory failure.

• The risk factors for ACS include a previous history of ACS, asthma, or recent events like recent surgical procedures, pulmonary embolism, fluid overload, infection, etc.
• The clinical features include sudden onset of cough and shortness of breath. Fever may or may not be a part of the spectrum of presentation. If present, then it usually points towards infection.
• Laboratory evaluation includes a complete blood count with differential chemistries, including liver and kidney evaluation, blood cultures, and sputum cultures.
• Chest X-ray shows a new pulmonary infiltrate- this is a quintessential feature of defining ACS. CT and perfusion mismatch scans are only used if there is a strong clinical suspicion of pulmonary or fat embolism. Therefore, they are not usually helpful in acute settings.

Sequestration Crises: This can either be hepatic or splenic sequestration.

• Patients experience rapid spleen enlargement associated with pain in the left upper quadrant. In children with SCA, it is common in children between 1 to 4 years of age, as the spleen is still intact.
• Patients with non-SCA variants (HbSC, HbS-beta+ thalassemia) are not prone to 'auto-splenectomy' commonly seen in patients with SCA. Hence, they can develop splenic sequestration later in life. Such patients may have baseline splenomegaly, causing hypersplenism. Parents and patients must receive counseling regarding the signs and symptoms of an enlarging spleen.
• Younger patients present with acute anemia and hypovolemic shock due to smaller circulating volumes, whereas adults may present with a more insidious onset.
• Pain occurs due to stretching of the splenic capsule and new infarcts.
• Blood count shows a drop in Hb by more than 2gm/dL, increased reticulocyte count, and nucleated red blood cells. 
• Hepatic sequestration: Hepatic sequestration can occur across all phenotypes of SCA. Like the spleen, patients may have a baseline enlargement of the liver. Hepatic sequestration is also defined as rapid enlargement of the liver with stretching of the capsule. The hemoglobin shows a drop of more than 2gm/dL. Liver enzymes may not get elevated.

Acute Stroke:  Stroke is the most devastating complication of SCA. Since the advent of transcranial Doppler (TCD) and the institution of primary prevention programs, the incidence of stroke has gone down in patients with SCA. In the absence of primary prevention, ~10% of children suffer from overt stroke, and approximately 20 to 35% have silent cerebral infarcts. TCD is not useful for adults. 

• Severe headache, altered mental status, slurred speech, seizures, and paralysis- are signs of stroke. 
• Urgent neurological consultation and CT scan followed by MRI/MRA must be done. 

Aplastic crises:  It is usually precipitated by parvovirus B-19 and is defined as a rapid drop in Hb at least 3 to 6 gm/dL below the baseline. Patients present with severe fatigue, anemia, shortness of breath, and even syncope. Blood counts show severely low hemoglobin with near-absent reticulocytes. Bone marrow biopsy shows arrest in the pro-normoblast stage in patients with acute parvovirus infections. [9]

Acute intrahepatic cholestasis (AIC):  Presents with sudden onset right upper quadrant pain. Physical exam shows worsening jaundice, enlarging and tender liver, and clay-colored stools. Labs show very high bilirubin levels, elevated alkaline phosphatase, and coagulopathy. The hemolysis parameters may be normal. AIC is a medical emergency.

Infections in patients with SCA can be a harbinger of infection with Streptococcus pneumoniae infection or osteomyelitis.

• The use of prophylactic antibiotics and pneumococcal vaccinations has reduced their incidence. However, loss of splenic function in SCA patients puts them at risk of invasive bacterial species.
• Osteomyelitis can be unifocal or multifocal- Staphylococcus aureus , Salmonella , and other enteric organisms can cause osteomyelitis in SCA patients. 

Priapism  is defined as a sustained, unwanted, painful erection lasting more than 4 hours. It is a common condition among patients with SCA, affecting 35% of all men/boys. 

Acute Ocular Complications

• The complication presents similarly in patients with SCA and sickle cell trait.
• The low oxygen pressure and acidotic nature of the aqueous humor promote sickling of the RBC, which leads to blockage of the trabecular network and an acute rise in intraocular pressure (IOP). 
• High IOP is poorly handled in patients with SCA - which can lead to CRAO and secondary hemorrhages. 
• Central retinal artery occlusion (CRAO)- Results from thrombus formation in the retinal artery leading to infarction of the retina, macular ischemia, or macular infarction. CRAO can occur spontaneously or secondary to increased IOP (from hyphema), Moyamoya syndrome, or ACS in patients with SCA. 
• Patients present with proptosis, local pain, and edema of the lid or orbit.
• The exam shows reduced extraocular motility and decreased visual acuity.
• CT scan helps in distinguishing this from orbital cellulitis/ infection. 
• Orbital Compression Syndrome (OCS) - also called orbital apex syndrome, is characterized by ophthalmoplegia and vision loss secondary to events occurring at the orbital apex. Cranial nerves II, III, IV, VI, and the first division of CN V can be involved. MRI of the orbits is the best modality for diagnosis. 

Chronic Complications in Patients with SCA

Iron Overload:  Iron (Fe) overload is a common problem in SCA patients due to repeated transfusions and chronic hemolysis. Each unit of packed RBC contains 200 to 250 mg of iron. Excessive iron mainly affects the heart, lungs, and endocrine glands. [10]  Hepatic cirrhosis from excessive iron is a major cause of death in patients with SCA. Clinical trials in patients with thalassemia have shown that systemic iron load correlates directly with survival and cardiac incidents. [11]

Avascular Necrosis (AVN) of Joints:  AVN of the femoral head is a common cause of chronic pain and disability in SCA patients. Although the hip joint is the most common joint to be involved, other joints can also be affected. AVN occurs at the distal portion of the bone, where collateral circulation is poor. The capillaries get occluded by sickle RBCs, leading to hypoxia and bone death. Risk factors for AVN of the femoral head include age, frequency of painful episodes, hemoglobin level, and alpha-gene deletion. In patients with HbSS, the overall prevalence is 50 percent by age 33. HbSS-alpha thalassemia and HbSS-Beta-0 thalassemia are at higher risk of developing AVN early in life. 

Leg Ulcers : More common in SCA compared to other SCD genotypes. Approximately 2.5% of patients with SCA above ten years of age have leg ulcers. Leg ulcers are more common in men and older people and less common in people with high total hemoglobin, alpha-gene deletion, and high levels of HbF. Trauma, infections, and severe anemia also increase the risk of leg ulcers. The ulcers occur more commonly on the medial and lateral surfaces of the ankles. They vary in size and depth, and chronic ulcers may lead to osteomyelitis, especially if they are deep enough to expose the bone.

Pulmonary Artery Hypertension (PAH) : Affects 6 to 11% of patients with SCA. PAH in SCA is classified under World Health Organization (WHO) group V. However, chronic hemolysis leads to pulmonary vascular changes classified under WHO group 1 in up to 10% of all SCA patients. PAH in SCA can also occur due to left heart dysfunction (Group II), chronic lung disease from SCA (Group III), chronic thromboembolism (Group IV), or extrathoracic causes (Group V). 

The patient may complain of dyspnea on exertion, swelling in the legs, or present with symptoms of underlying disease (like a history of thrombosis, heart failure, etc.). An echocardiogram helps in estimating the tricuspid regurgitant jet velocity (TRV). Elevated TRV is associated with increased mortality in adults. However, TRV can be transiently elevated during acute chest syndrome. Serum NT-pro-BNP is directly correlated with mortality as well. The final diagnosis is made with a right heart catheterization.  

Renal complications: Chronic kidney disease (CKD) occurs in approximately 30% of adult patients with SCA. The acidotic, osmotic, and hypoxic environment of the kidney increases the risk of polymerization of HbS, leading to the sickling of RBC. SCA patients secrete excessive creatinine in their proximal tubules. Hence, it becomes challenging to identify early signs of kidney disease, as creatinine takes a longer time to rise. Microalbuminuria (30-300mg albumin in 24-hour urine collection) is often the first manifestation of CKD. Spot urine-creatinine ratio is not validated in SCA patients due to hypersecretion of creatinine.

• Hypoesthenuria- Inability to concentrate urine due to loss of deep juxtamedullary nephrons. It is the most common complication in SCA patients. It leads to frequent urination and increases the risk of dehydration. It also increases the risk of enuresis in children.
• Renal papillary necrosis occurs due to obstruction of the vessels supplying the vasa recta, resulting in medullary infarction. It presents with hematuria. It is more common in patients with HbSC disease.
• Asymptomatic Proteinuria: It is present in 15 to 50% of patients. It develops early in life due to hyperfiltration and loss of selectivity for albumin.

Ophthalmologic Complications: Chronic eye complications are more common in patients with HbSC and HbSS disease. They are found in up to 50% of patients.

• Proliferative Sickle Retinopathy occurs due to vaso-occlusion of vitreal arterioles, leading to ischemia which leads to neovascularization. Neovascular tissue is predisposed to hemorrhage and vitreal traction forces, resulting in vitreal hemorrhage (the most severe complication of proliferative sickle retinopathy). 
• Treatment / Management

Patients with SCA present with acute and chronic complications. 

Management of Acute Complications

Pain management is a critical part of SCA. It is challenging for clinicians to accurately assess patients' needs, especially if they meet them for the first time. Patients with SCA often suffer from the stigma of requiring high doses of opioids for pain control, which leads to them being labeled as 'opioid abusers,' 'manipulators,' or even' drug seekers.'  [12]

• Analgesic administration starts simultaneously with evaluating the cause, ideally within 30 minutes of triage and 60 minutes of registration.
• Develop individualized pain management plans - this should be made available to the emergency room and should be implemented each time the patient presents with VOC and pain.
• NSAIDs are used in patients with mild to moderate pain who report prior episodes of relief with NSAIDs
• Any patient presenting with severe pain- preferably used parenteral opioids. An intravenous route is preferred; however, if access is difficult, use the subcutaneous route.
• The dose of parenteral opioids is calculated based on the total dose of short-acting oral opioids taken at home.
• Pain should be reassessed every 15 to 30 minutes, and readminister opioids if needed. The escalation of opioids is done in 25% increments.
• Patient-controlled analgesia (PCA) is preferred. If an "on-demand" setting is used in PCA, then continue long-acting analgesia.
• When pain control is achieved, "wean off" parenteral opioids before converting to oral medications.
• Calculate the inpatient analgesic requirement at discharge and adjust home doses of short and long-acting opioids accordingly.
• Meperidine is not used in managing VOC-related pain unless this is the only medication that controls the pain.
• Antihistamines only help in controlling opioid-related itching. When required, use oral formulations only—readminister every 4 to 6 hours as needed.
• Incentive spirometry
• Intravenous hydration
• Supplemental oxygen is needed only if saturation drops below 95% on the room air.

Management of Chronic Pain

Chronic pain management in SCA patients focuses on the safe and adequate use of pain medications, particularly opioids. A comprehensive assessment of the patient's ailment, the kind and doses of pain medicine required to control pain, and the functional outcomes of using these medications are made at each encounter. The process involves collaboration with multiple specialties, like psychiatry, social work, etc., to administer the right pain medicine in the proper doses. 

The strategy adopted in the clinic to prescribe pain medicine involves:

• One person must be assigned to prescribe long-term opioids. They should document all encounters extensively involving the physical exam, lab work, etc. 
• Assess each patient for non-SCA-related pain and treat/refer to the appropriate specialty for managing this pain.
• Limit prescribing pain medicines without meeting the patient- every patient must be physically assessed every 2 to 3 months or sooner.
• Develop an individualized pain management plan for each patient, reassess this plan annually, and modify it accordingly.
• Encourage patients to explore alternative methods of controlling pain, like direct massage, self-hypnosis, and music therapy.

Acute Chest Syndrome (ACS):  It is an emergency regardless of the sickle cell disease phenotype. It can lead to respiratory failure and death if not managed as an emergency.

• All patients must be hospitalized-
• Upon admission, start treatment with antibiotics, including coverage for atypical bacteria.
• Supplemental oxygen is provided to those with oxygen saturation of less than 95% at room air.
• "Early" administration of simple blood transfusion is recommended for hypoxic patients. However, exchange transfusion is recommended at the earliest opportunity.
• Close monitoring for worsening respiratory status, increasing oxygen requirement, worsening anemia, and bronchospasm (use of beta-adrenergic dilators is encouraged in asthmatics) must be done. Intensive care units must be on standby to receive such patients who experience worsening respiratory status.
• Closely monitor predictors of severity- increasing respiratory rate, worsening hypoxia, decreasing hemoglobin or platelet count, multilobar involvement on chest X-ray, and developing neurological complications.
• Incentive spirometry and hydration (intravenous or oral) must always be encouraged. 
• ACS is a strong indicator for initiating disease-modifying therapy (hydroxyurea, etc.) or starting the patient on a chronic blood transfusion program.

Sequestration Crises

• Intravenous fluids for hydration, pain control, and simple/exchange blood transfusion are central to managing sequestration crises.
• Never correct anemia completely- when the crises resolve, and the organs shrink, the sequestered blood re-enters the circulation, leading to increased hematocrit and viscosity, increasing the risk of thrombotic and ischemic events.
• Splenectomy is recommended for patients with life-threatening episode splenic sequestration crises or with recurrent splenic sequestration. It is also offered to those who have baseline hypersplenism.
• Instruct patients and parents in monitoring the size of the liver and spleen regularly.

Acute Stroke:  Urgent neurology and transfusion medicine consultation are needed to provide optimal care and prevent long-term damage.

• Simple or exchange blood transfusion emergently.
• Start a program of chronic exchanges or blood transfusion. 
• Where blood transfusion cannot be used (iron overload, excessive alloantibodies) or is unavailable, start on long-term disease-modifying therapy. SWiTCH trial demonstrated that chronic transfusions are a better way to manage patients with stroke.

Aplastic Crises:  Parvovirus infections cause a transient drop in hemoglobin. Humoral immunity develops within 7 to 10 days that stays for life. The patient is extremely susceptible to developing ACS or stroke during the acute period. Initiate exchange/simple transfusion to bring Hb to a safe level, not necessarily to normal/baseline level.

Infections presenting with fever:  Oral empiric antibiotics are given promptly while evaluating the reason for the fever. For ill-appearing patients, admit them and administer intravenous antibiotics.

Priapism: Early recognition is the key to management. Delayed management can lead to impotence. Urologists need to be involved early on in the care of such patients. 

• Conservative measures include using analgesics, hydration, and sedation - which usually leads to detumescence and retains potency. Most experts would call for upfront urologic management rather than losing time trying conservative measures. [13]
• Urologists can perform penile aspiration or irrigation of corpora cavernosa with alpha-adrenergic drugs.
• Blood transfusion/ exchange transfusion is not useful - few authors have reported neurological complications with the use of blood transfusion (ASPEN syndrome). Hence it is best to avoid blood transfusion.

Acute ocular Complications:  All ocular complications must be managed in consultation with ophthalmologists and hematologists to prevent vision loss. 

• Hyphema- Anterior chamber paracentesis or surgical intervention to manage the thrombus must be done promptly.
• Reducing intraocular pressure helps prevent CRAO and other compression issues. 
• Infections are managed with prompt administration of antibiotics. 
• Corticosteroids are used to relieve excessive pressure in patients with OCS.

Chronic Complications

Avascular Necrosis:  About 40 to 80% of cases of hip joint AVN are bilateral; therefore, both joints should be investigated simultaneously. Pain management and physical therapy are to be initiated as early as possible. Advanced cases may require hip arthroplasty.

Leg Ulcer: Conservative measures involve wound care, wet-to-dry dressings, and pain control. Hydroxyurea is avoided in patients with open leg ulcers, as it may prevent healing. Frequent evaluation for the stage of healing or lack of infection, osteomyelitis must be done. Local and systemic antibiotics are used for infected ulcers.

Pulmonary Hypertension:  Patients with higher TRV are referred to pulmonologists for management. Small studies have shown increased mortality with sildenafil.

Renal Complications: Refer SCA patients with micro- or microalbuminuria to nephrologists for detailed workup and consideration of angiotensin-converting enzyme inhibitor (ACE-inhibitor). Follow patients closely who have modest elevation in creatinine (>0.7 mg/dL in children, >1.0 mg/dL in adults), and refer to a nephrologist at the earliest sign of worsening creatinine.

Ophthalmologic Complications: Refer SCA patients regularly for ophthalmologic evaluation, especially if they complain of slow vision changes. Direct and indirect ophthalmoscopy, slit-lamp biomicroscopy, and fluorescein angiography are used to evaluate SCA patients. Laser photocoagulation therapy is used to manage proliferative sickle retinopathy. A vitrectomy or retinal repair may be needed in the rare event of vitreal hemorrhage or retinal detachment. 

Iron Overload

Unlike hemochromatosis, phlebotomy is not an option in patients with SCA. Preventing iron overload with good transfusion practices is the best way to deal with iron overload. Patients with SCA need not follow the rule of having hemoglobin close to 7gm/dL. Packed RBC transfusion should be restricted to the management of symptoms. Choosing exchange transfusion over simple transfusion also helps to reduce/prevent iron overload.

Indications to start iron chelation therapy

• A liver iron concentration (LIC) greater than 3 mg iron (Fe)/gm dry weight
• Cardiac T2* < 20 milliseconds
• Serum ferritin greater than 1000 on two different occasions 15 days apart
• Age greater than two years
• Expected survival beyond one year
• Number of transfusions of packed RBC in 1 year- > 10 in pediatric patients OR > 20 in adults. 

Goals of therapy

• Serum ferritin < 1000 mcg/L,
• LIC <7mg Fe/gm dry weight
• Cardiac T2* > 20 milliseconds

When do patients need modification of treatment?

• Treatment needs to be intensified if LIC > 15 mg Fe/gm dry weight and deescalated when LIC < 3 mg Fe/gm dry weight.
• Treatment needs to be intensified if serum ferritin > 2500 IU/L and deescalated when serum ferritin < 300 IU/L
• Treatment needs to be intensified when cardiac MRI shows T2* < 15 milliseconds or when cardiac symptoms occur (like heart failure, arrhythmias)

Iron Chelators

• Disperse tab formulation: Initial dose: 10mg/kg/day. Maximum dose: 20mg/kg/day
• Tablet or granule formulation: Initial dose: 7mg/kg/day. Maximum dose: 14mg/kg/day
• It does not interfere with the pharmacodynamics of hydroxyurea; hence it can be used simultaneously.
• Adverse effects- gastrointestinal intolerance, dose-dependent rise in serum creatinine, liver dysfunction.
• Daily subcutaneous infusions via portable infusion pump given over 8 to 24 hours; 1 to 2 gm/day 
• It can be given as a daily IV infusion also. 40 to 50 mg/kg/day (max dose 60 mg/kg/day) over 8 to 12 hours (max rate 15 mg/kg/hour) 
• IM route is acceptable for children but not preferred for adults. 0.5 to 1mg/day
• Adverse effects- Injection site reactions, cardiovascular shock (if administered too fast), blood dyscrasias, growth retardation.  
• Adverse effects - agranulocytosis, hepatotoxicity, gastrointestinal symptoms, and arthralgia.

Blood transfusion:  Blood transfusions form an integral part of the management of SCA. The goal of transfusion is to increase the oxygen-carrying capacity of blood and reduce the HbS component. A blood transfusion (simple or exchange) is given to keep the HbS level below 30% (STOP 1 and 2 trials). [14]  In patients receiving regular exchange transfusions (history of stroke, intolerance, or contraindication to hydroxyurea), a more practical target for HbS is 25% to prevent a rise of HbS beyond 30%.

What types of blood transfusion are used in SCA?

• Simple transfusion: Transfusion of matched packed red blood cells (PRBC)
• Exchange transfusion: Transfusion of PRBC while removing blood from the patient at the same time.

Who should receive blood transfusions?

• Hb < 7gm/dL or drop of >2 gm/dL from baseline- consider simple or exchange transfusion. 
• Twin pregnancy- consider prophylactic exchange transfusion
• Hb less than 9 gm/dL- Simple transfusion
• Hb more than 9gm/dL- Partial exchange transfusion

What kind of transfusion practice should be followed?

• Severe ACS - oxygen saturation less than 90% even when started on supplemental oxygen. 
• Multiorgan Failure
• Acute ischemic stroke
• Splenic sequestration - never corrects the anemia completely.
• Acute anemia

Complications from Chronic Transfusions

• Alloimmunization- increases the risk of transfusion reactions, especially delayed hemolytic transfusion reactions. 
• Iron overload
• Transmission of blood-borne diseases like hepatitis B, C, and HIV; extremely low risk due to intensive screening of donors and blood products.
• Differential Diagnosis

In general, globin gene mutations affecting hemoglobin are common and affect 7% of the entire world population. [15]  Over 1000 variations of hemoglobin exist. However, only a handful of variations are significant clinically. 

Common Variants of SCA or HbSS Disease

• Hemoglobin S-beta-0 thalassemia (Clinically behaves exactly like HbSS disease)
• Hemoglobin SC (a milder variant of SCD) - can have a phenotypic presentation of sickle cell anemia.
• Hemoglobin S-beta+ thalassemia (a milder variant of SCD)

Several other hemoglobin variants are present that can mimic SCA if they are inherited along with HbS.

• Hemoglobin Jamaica-Plain (beta-68 [E12] Leu -> Phe)
• Hemoglobin Quebec-Chori (beta-87 [F3] Thr > Ile)
• Hemoglobin D-Punjab (beta-globin, codon 121, glutamine to glutamic acid)
• Hemoglobin O-Arab
• Hemoglobin E

Other conditions that can present with hemolysis, where SCA can be ruled out with history, examination, hemoglobin electrophoresis, and study of the peripheral smear

• Antibody-mediated autoimmune hemolytic anemia (both warm and cold antibodies)
• Other hemoglobinopathies- alpha or beta-thalassemia
• Paroxysmal nocturnal hemoglobinuria
• RBC-membrane defects (hereditary spherocytosis, hereditary elliptocytosis)
• Enzyme defects (pyruvate kinase deficiency, glucose-6-phosphate deficiency)
• Drug-induced hemolysis
• Transfusion-related hemolysis (acute or delayed hemolytic reaction)
• Microangiopathic hemolytic anemia (atypical or typical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura)
• Infectious causes (malaria, babesiosis, Rickettsia , Clostridia , Bartonella )
• Vasculitis-induced hemolysis
• Medical Oncology

The goal of disease-modifying therapy in sickle cell anemia is to reduce the frequency of vaso-occlusive crises (VOC) and pain crises and prevent organ damage. These medications usually do not have a role "during" acute crises. Hydroxycarbamide, or hydroxyurea, was the first drug approved by the FDA for use in patients with SCA. However, the USFDA approved hydroxyurea for pediatric patients two years and above only in 2017 (based on the ESCORT HU trial).   

Disease-Modifying Drugs/Therapy

The goal of disease-modifying therapy in patients with SCA is to alter the kinetics of sickle erythrocytes. Hydroxyurea does this by increasing the concentration of fetal hemoglobin (HbF).

Hydroxyurea:  This is a ribonucleotide reductase inhibitor that increases the concentration of HbF in patients with SCD. It not only increases the intracellular concentration of HbF but also increases the number of erythrocytes containing HbF. In addition to this, hydroxyurea also reduces the number of circulating reticulocytes and leukocytes, raises the volume of an RBC (high MCV is noted in patients receiving hydroxyurea), reduces the deformability of RBC, improves the flow of blood through capillaries, and alters the expression of adhesion molecules hence preventing vaso-occlusive crises. The initial trials with hydroxyurea (Phase-III Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH)) demonstrated a clear benefit over placebo in reducing the incidence of pain crises and the cost of care. Long term, the MSH study also showed a mortality benefit. In the pediatric age group, two seminal trials (HUG-KIDS-Phase I/II and BABY HUG-phase III) demonstrated good tolerability and led to the drug's approval. [16] [17]  

• Having three or more sickle cell-associated moderate to severe pain crises within a 12-month period; treat with hydroxyurea.
• Those with sickle cell-associated pain that interferes with daily activities of living and quality of life
• History of severe and/or recurrent ACS
• Severe symptomatic chronic anemia that interferes with daily activities or quality of life
• Infants 9 months of age and older, children, and adolescents with SCA offer hydroxyurea regardless of clinical severity to reduce SCA-related complications (e.g., pain, dactylitis, ACS, anemia)
• For those with chronic kidney disease, taking erythropoietin and hydroxyurea can be added to improve anemia.
• DO NOT give hydroxyurea to pregnant women and lactating mothers who choose to breastfeed their babies.
• Dosing for adults: Start with 15 mg/kg/day. Round up to the closest 500 mg. For patients with CKD- start at 5 to 10 mg/kg/day. 
• Dosing for infants and children: start at 20 mg/kg/day
• Target absolute neutrophil count (ANC) above 2000/microL and platelet count above 80,000/microL. In younger patients, an ANC of 1250/microL is allowed if baseline counts are low.
• Monitor blood counts every four weeks when increasing the dose of hydroxyurea.
• Clinical response takes 3 to 6 months to develop. Hence, a minimal trial of 6 months of daily continued use of hydroxyurea is conducted before considering alternative therapies. 
• Daily adherence is a must. It must be emphasized to the patient.
• If a positive response is seen, then hydroxyurea must be continued indefinitely. 
• Myelotoxicity is the most common and most substantiated adverse effect of hydroxyurea. The rest of the adverse effects reported in the literature, especially carcinogenesis and leukemia, have never been demonstrated in large studies. 
• Avoid the use of hydroxyurea in patients with leg ulcers.

Voxelotor:  Voxelotor acts by inhibiting the polymerization of HbS and increasing the affinity for oxygen. It is dosed at 1500 mg by mouth daily and is approved for SCA treatment in patients 12 years of age and older. Voxelotor can be given with or without hydroxyurea. USFDA approved it in 2019 based on the results of the phase 3 HOPE trial (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) evaluating voxelotor (1500 mg versus 900 mg versus placebo in 1:1:1 design). [18] [19]  

The most common adverse reactions are headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia. Voxelotor interferes with high-performance liquid chromatography (HPLC). Hence, the hemoglobin quantification is not accurate when the patient is on voxelotor. HPLC should be done when the patient is off therapy. Also, the use of voxelotor may increase the Hb, but there is no evidence to suggest discontinuation of exchange transfusion in patients receiving this for stroke prophylaxis.

Crizanlizumab:  A humanized immunoglobulin G2-Kappa monoclonal antibody inhibits P-selectin, thereby blocking its interaction with P-selecting glycoprotein-1. This leads to reduced interaction between activated endothelium, platelets, leukocytes, and sickled RBCs, leading to reduced VOC. [20]  The phase II SUSTAIN trial demonstrated a clinical benefit of Crizanlizumab by demonstrating a reduction in pain crises, VOC, emergency room visits, and increased median time to first crises. Although the hospitalization rate was numerically lower in the intervention group, the difference was not statistically significant compared to the placebo group. [21]

It is approved for the treatment of SCA in patients 16 years of age and older. It is dosed as a 5 mg/kg intravenous infusion administered over 30 minutes at weeks 0 and 2 and then every four weeks. The most common adverse reactions are nausea, arthralgia, back pain, and pyrexia. Infusion-related reactions can occur. Crizanlizumab can interfere with platelet counts; send the blood immediately before administration or in citrated tubes. 

L-Glutamine:  Glutamine is the most abundant amino acid in the body. It is not an essential amino acid under normal circumstances, but in patients with SCA, a high hemolysis rate increases the demand for glutamine. L-glutamine is available in a medical formulation. The exact mechanism of action of L-glutamine remains anecdotal. It is believed to work by scavenging for reactive oxygen species and acting as a substrate for the regeneration of nitrous oxide, NAD, and NADH. [22]  The USFDA approved L-glutamine in 2017 after positive results from the phase III trial. The authors demonstrated a statistically lower number of pain crises, fewer hospitalizations, fewer cumulative days in the hospital, prolonged time to first and second pain crises, and a reduced number of ACS. [23]  Adverse events include constipation, nausea, headache, abdominal pain, cough, extremity pain, back pain, and chest pain. There is an additional concern that L-glutamine may increase mortality and the rate of multiorgan failure. However, these are yet exploratory. 

Hematopoietic Stem Cell Transplant

Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative option in SCA patients where cure rates approach approximately 90%. Improving the quality of life and reducing the cost of managing long-term complications trumps the cost of performing allogeneic HSC. Pre-school age is considered the best time to perform HSCT, with increased mortality recorded in older patients. A myeloablative or a non-myeloablative regimen can be used; however, myeloablative regimens are not recommended for adults. A matched sibling donor is preferred for performing allogeneic HSCT. Due to the lack of matched sibling donors, other approaches like a matched unrelated donor, umbilical cord blood transplant, and haploidentical transplant are also being explored. [24] [25]

Potential barriers to performing allogeneic HSCT

• Alloimmunization due to repetitive transfusions (exchange of blood)
• Organ dysfunction due to SCA (possibly a reason why younger patients do better)
• Lack of matched sibling donors/ insurance.

Indications for performing allogeneic HSCT

• Stroke (most common and strongest indication to perform allogeneic HSCT.
• Abnormal transcranial doppler
• Acute chest syndrome
• Recurrent VOC not controlled with medical therapy or chronic transfusions

The complications with allogeneic HSCT:

• Transplant-related mortality approaches 7 to 10%, comparable with SCD-related mortality
• Graft rejection OR graft failure - less with myeloablative regimens (7 to 11%) compared to non-myeloablative regimens (11 to 50%)
• Graft-versus-host disease and related morbidity
• Transplant-related complications like lung injury, endocrine, and metabolic adverse events

The recent approvals of newer agents and the emergence of gene-editing techniques have expanded the options for SCA patients. Also, extending the benefit of HSCT to low-income countries remains a significant challenge. 

Future Perspectives

Gene editing is a new therapy focus whereby researchers attempt to increase the HbF level in patients with SCA. This technique is being developed alongside HSCT. Many approaches to gene editing are in clinical trials right now. [26] [27]

• Viral gene addition using lentivirus: The technique aims to add a modified beta or gamma-globin gene to reduce the HbS component and increase the HbA (beta-globin gene) or the HbF (gamma-globin gene).
• CRISPR (Clustered regularly interspaced short palindromic repeats): Targets the expression of BCL11A, which normally downregulates gamma-globin expression. By introducing insertions and deletions in the BCL11A erythroid lineage-specific enhancer on chromosome 2, BCL11A is downregulated, resulting in increased expression of the gamma-globin gene, which subsequently increases HbF.

Cost Factor

The annual cost of the voxelotor is approximately $125,000. Each vial of crizanlizumab costs approximately $2400, with a yearly cost of $84,852 and $113,136 per year for most patients. The monthly cost of the L-glutamine formulation is $3000 for adults and up to $1000 for the pediatric age group. A myeloablative regimen for HSCT can lead to a cost of approximately $280,000 at 100 days of care/admission. [28]  In addition, the advanced level of expertise and dedicated infrastructure required to deliver such care also comes at a considerably high cost. Considering such high costs for the newer therapies, bringing them to lower-income regions like sub-Saharan Africa is a challenge, where approximately 6 million suffer from sickle cell anemia. 

Most of the survival data in patients with SCA does not factor in the advent of new medications. The Cooperative Study of Sickle Cell Disease (CSSCD) (between 1978-88) reported the median age of death for women and men as 42 and 48 years, respectively. This study also showed that acute chest syndrome, renal failure, seizures, high leukocyte count, and low levels of HbF were associated with an increased risk of early death in patients with SCA. [29]  More recent studies have shown that elevated tricuspid regurgitant jet velocity on echocardiography, prolonged QTc interval, pulmonary hypertension, high N-terminal pro-brain natriuretic peptide, history of asthma and/or wheezing, history of end-stage renal disease requiring dialysis, and the severity of hemolysis are independent risk factors towards early death in patients with SCA. [30]

More recent data combining nine studies from Europe and North America (evaluating 3257 patients) listed the following as predictors of mortality:

• Age (per 10-year increase in age)
• Tricuspid regurgitant jet velocity 2.5 m/s or more
• Reticulocyte count
• Log(N-terminal-pro-brain natriuretic peptide)
• Fetal hemoglobin [30]

With the approval of newer drugs (voxelotor and crizanlizumab) in 2019, increased use of hematopoietic stem cell transplant, and exploration of newer techniques like gene therapy, survival is bound to increase along with the quality of life. 

• Complications

SCA can lead to acute complications and chronic complications

Acute complications: Most acute complications are associated with occlusion of the small to medium-sized vessels (sometimes large-sized vessels) due to polymerization of HbS and hemolysis. 

• Sequestration crises: splenic or hepatic sequestration
• Fat embolism
• Bone infarction/necrosis
• Coagulopathy: increases the risk of both arterial and venous clots- stroke, myocardial infarction, venous thrombosis
• Ophthalmic: vitreous hemorrhage, retinal detachment, retinal artery/vein occlusion
• Aplastic crises: in association with parvovirus infection
• Papillary necrosis
• Delayed growth and development and growth retardation
• Cardiac: cardiomegaly, cardiomyopathy, left ventricular hypertrophy, arrhythmia, congestive heart failure
• Pulmonary: pulmonary edema, sickle cell lung disease, pulmonary hypertension
• Hepatobiliary: hepatomegaly, intrahepatic cholestasis, cholelithiasis, viral hepatitis
• Splenic complications: splenomegaly, hyposplenia, asplenia
• Renal: acute and chronic renal failure, pyelonephritis, renal medullary carcinoma
• Musculoskeletal: degenerative changes, osteomyelitis, septic arthritis, osteonecrosis, osteopenia/osteoporosis
• Neurologic: aneurysm, mental retardation
• Ophthalmic: proliferative sickle retinopathy, vitreous hemorrhage, retinal detachment, nonproliferative retinal changes
• Endocrine: primary hypogonadism, hypopituitarism, hypothalamic insufficiency
• Iron overload due to repeated transfusions and chronic hemolysis
• Deterrence and Patient Education

SCA is a debilitating disease that affects a patient physically and has significant emotional and psychiatric consequences. The stigma of being diagnosed with SCA has been well documented. Many SCA patients are inaccurately labeled as drug seekers and opioid abusers due to the need for an inordinately high amount of opioids for pain control. In addition, frequent interactions with different providers (in the emergency rooms, hospital admissions, etc.) can lead to inconsistent care. In such a scenario, the patients need to be an advocate for themselves. The following points can act as a guide for patient education.

• Show consistency in outpatient clinics and show up for your appointments. Regularity in visits to your providers helps to build trust within the system.
• Discuss pain requirements for pain medications with your provider with an open mindset- They may appear restrictive in prescribing pain medications, especially opioids. Still, they are trying to help you by protecting you against overdosing. 
• Use the same emergency room, or at least the ER within the same hospital system. It is useful and helps in developing familiarity with the people who work in that ER. It also allows easy access to your individualized plan of care, which your provider develops for such situations. 
• Adherence to disease-modifying therapy will help reduce the events of pain crises and prevent long-term organ damage. 
• Always be receptive to alternative ways of getting control over pain - including music therapy, self-hypnosis, and deep muscle relaxation. 
• Patients can adopt protective measures- stay warm and avoid exposure to extreme temperatures, adequate hydration, and breathing exercises at home. 
• Enhancing Healthcare Team Outcomes

SCA is a systemic disorder that affects the entire body. The disease not only manifests with physical symptoms (pain crises, organ damage, etc.) but also has numerous psycho-social implications. Most patients with SCA belong to the African-American community and a minority to Hispanic and other communities, which makes them prone to certain prejudices. Besides, the high demand for opioids to manage chronic pain makes the situation even more challenging. [31]  All providers must keep aside their inherent prejudice when caring for a patient with SCA, working collaboratively as an interprofessional team. Almost all specialties need to be involved in managing patients with SCA. However, the hematology team dedicated to taking care of SCA patients must be the primary physicians for these patients.

Specialties like ophthalmology, orthopedics, psychiatry, gastroenterology, and cardiovascular medicine interact closely with SCA patients. However, this does not diminish the importance of other specialties. Pharmacy and nursing also play a vital role. With the advent of newer drugs and infusions and SCA affecting liver and kidney function, pharmacists and nursing experts are required to ensure safe dosage and medication delivery to the patient. 

The data presented here is derived mostly from large and small randomized clinical trials. [Level 1 and 2] Few aspects of care presented here are from cohort and case-control studies. [Level 3]

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Sickle Cell Anemia, Hemoglobin C Contributed by Ed Uthman (CC BY 2.0 https://creativecommons.org/licenses/by/2.0)

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

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

Disclosure: Nikki Agarwal declares no relevant financial relationships with ineligible companies.

Disclosure: Smita Maruvada declares no relevant financial relationships with ineligible companies.

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• Cite this Page Mangla A, Ehsan M, Agarwal N, et al. Sickle Cell Anemia. [Updated 2023 Sep 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Sickle Cell Disease: A Review

Affiliations.

• 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.
• PMID: 35788790
• DOI: 10.1001/jama.2022.10233

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.

Publication types

• Anemia, Sickle Cell* / complications
• Anemia, Sickle Cell* / diagnosis
• Anemia, Sickle Cell* / therapy
• Antibodies, Monoclonal, Humanized / therapeutic use
• Antisickling Agents / therapeutic use
• Benzaldehydes / therapeutic use
• Glutamine / therapeutic use
• Hematologic Agents / therapeutic use
• Hematopoietic Stem Cell Transplantation
• Hydroxyurea / therapeutic use
• Infant, Newborn
• Neonatal Screening
• Pain / drug therapy
• Pain / etiology
• Pyrazines / therapeutic use
• Pyrazoles / therapeutic use
• Transition to Adult Care
• United States / epidemiology
• Antibodies, Monoclonal, Humanized
• Antisickling Agents
• Benzaldehydes
• Hematologic Agents
• crizanlizumab
• Hydroxyurea