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  • 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 ).

figure 1

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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  • Sickle cell anemia

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ISSN: 1756-8722

sickle cell anemia essay title

Sickle Cell Anemia

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

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

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

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Sickle cell anemia

Sickle cell anemia is one of a group of inherited disorders known as sickle cell disease. It affects the shape of red blood cells, which carry oxygen to all parts of the body.

Red blood cells are usually round and flexible, so they move easily through blood vessels. In sickle cell anemia, some red blood cells are shaped like sickles or crescent moons. These sickle cells also become rigid and sticky, which can slow or block blood flow.

The current approach to treatment is to relieve pain and help prevent complications of the disease. However, newer treatments may cure people of the disease.

Symptoms of sickle cell anemia usually appear around 6 months of age. They vary from person to person and may change over time. Symptoms can include:

  • Anemia. Sickle cells break apart easily and die. Typical red blood cells usually live for about 120 days before they need to be replaced. But sickle cells usually die in 10 to 20 days, leaving a shortage of red blood cells. This is known as anemia. Without enough red blood cells, the body can't get enough oxygen. This causes fatigue.

Episodes of pain. Periodic episodes of extreme pain, called pain crises, are a major symptom of sickle cell anemia. Pain develops when sickle-shaped red blood cells block blood flow through tiny blood vessels to the chest, abdomen and joints.

The pain varies in intensity and can last for a few hours to a few days. Some people have only a few pain crises a year. Others have a dozen or more a year. A severe pain crisis requires a hospital stay.

Some people with sickle cell anemia also have chronic pain from bone and joint damage, ulcers, and other causes.

  • Swelling of hands and feet. Sickle-shaped red blood cells block blood circulation in the hands and feet, which can cause them to swell.
  • Frequent infections. The spleen is important for protecting against infections. Sickle cells can damage the spleen, raising the risk of developing infections. Babies and children with sickle cell anemia commonly receive vaccinations and antibiotics to prevent potentially life-threatening infections, such as pneumonia.
  • Delayed growth or puberty. Red blood cells provide the body with the oxygen and nutrients needed for growth. A shortage of healthy red blood cells can slow growth in babies and children and delay puberty in teenagers.
  • Vision problems. Tiny blood vessels that supply blood to the eyes can become plugged with sickle cells. This can damage the portion of the eye that processes visual images, called the retina, and lead to vision problems.

When to see a doctor

See your healthcare professional right away if you or your child has symptoms of sickle cell anemia, including fever or stroke.

Infections often start with a fever and can be life-threatening. Because children with sickle cell anemia are prone to infections, seek prompt medical attention for a fever greater than 101.5 degrees Fahrenheit (38.5 degrees Celsius).

Seek emergency care for symptoms of stroke, which include:

  • One-sided paralysis or weakness in the face, arms or legs.
  • Difficulty walking or talking.
  • Sudden vision changes.
  • Unexplained numbness.
  • Severe headache.

Sickle cell anemia is caused by a change in the gene that tells the body to make hemoglobin. Hemoglobin is the iron-rich compound in red blood cells that allows these cells to carry oxygen from the lungs to the rest of the body. The hemoglobin associated with sickle cell anemia causes red blood cells to become rigid, sticky and misshapen.

For a child to have sickle cell anemia, both parents must carry one copy of the sickle cell gene and pass both copies to the child.

If only one parent passes the sickle cell gene to the child, that child will have the sickle cell trait. With one typical hemoglobin gene and one sickle cell gene, people with the sickle cell trait make both typical hemoglobin and sickle cell hemoglobin.

Their blood might contain some sickle cells, but they generally don't have symptoms. They're carriers of the disease. That means they can pass the gene to their children.

Risk factors

For a baby to have sickle cell anemia, both parents must carry a sickle cell gene. In the United States, sickle cell anemia most commonly affects people of African, Mediterranean and Middle Eastern descent.

Complications

Sickle cell anemia can lead to a host of complications, including:

  • Stroke. Sickle cells can block blood flow to the brain. Signs of stroke include seizures, weakness or numbness of the arms and legs, sudden speech difficulties, and loss of consciousness. If your child has any of these signs or symptoms, seek medical treatment right away. A stroke can be fatal.
  • Acute chest syndrome. A lung infection or sickle cells blocking blood vessels in the lungs can cause this life-threatening complication. Symptoms include chest pain, fever and difficulty breathing. Acute chest syndrome might need emergency medical treatment.
  • Avascular necrosis. Sickle cells can block the blood vessels that supply blood to the bones. When the bones don't get enough blood, joints may narrow and bones can die. This can happen anywhere but most often happens in the hip.
  • Pulmonary hypertension. People with sickle cell anemia can develop high blood pressure in their lungs. This complication usually affects adults. Shortness of breath and fatigue are common symptoms of this condition, which can be fatal.
  • Organ damage. Sickle cells that block blood flow to organs deprive the affected organs of blood and oxygen. In sickle cell anemia, blood also is low in oxygen. This lack of oxygen-rich blood can damage nerves and organs, including the kidneys, liver and spleen, and can be fatal.
  • Splenic sequestration. Sickle cells can get trapped in the spleen, causing it to enlarge. This may cause abdominal pain on the left side of the body and can be life-threatening. Parents of children with sickle cell anemia can learn how to locate and feel their child's spleen for enlargement.
  • Blindness. Sickle cells can block tiny blood vessels that supply blood to the eyes. Over time, this can lead to blindness.
  • Leg ulcers. Sickle cell anemia can cause painful open sores on the legs.
  • Gallstones. The breakdown of red blood cells produces a substance called bilirubin. A high level of bilirubin in the body can lead to gallstones.
  • Priapism. Sickle cell anemia can cause painful, long-lasting erections, known as priapism. Sickle cells can block the blood vessels in the penis, which can lead to impotence over time.
  • Deep vein thrombosis. Sickled red blood cells can cause blood clots, increasing the risk of a clot lodging in a deep vein, known as deep vein thrombosis. It also increases the risk of a blood clot lodging in a lung, known as pulmonary embolism. Either can cause serious illness or even death.
  • Pregnancy complications. Sickle cell anemia can increase the risk of high blood pressure and blood clots during pregnancy. It also can increase the risk of miscarriage, premature birth and low birth weight babies.

If you carry the sickle cell trait, it can help to see a genetic counselor before you get pregnant. A counselor can help you understand your risk of having a child with sickle cell anemia. You also can learn about possible treatments, preventive measures and reproductive options.

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5 Facts You Should Know About Sickle Cell Disease

Infographic: 5 facts you should know about sickle cell disease

5 Facts You Should Know About Sickle Cell Disease [PDF – 198 KB] Also available in: Spanish [PDF – 288 KB] | French [PDF – 303 KB]

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Title: 5 facts you should know about sickle cell disease, a child gets sickle cell disease (scd) when he or she receives two sickle cell genes*—one from each parent..

A child who inherits only one sickle cell gene has sickle cell trait (SCT). If both parents have either SCD or SCT, it is important for them to discuss this information with each other and with a doctor when making decisions about family planning.

*Genes, which are passed down from a parent to child, are instructions in each of our cells that determine a person’s traits such as eye color, blood type, and risk of disease.

SCD has many faces.

The disease affects millions of people worldwide and is especially common among people who come from and whose ancestors come from the following regions highlighted in red:

SCD can be cured for certain patients.

A bone marrow transplant, which involves collecting healthy cells from a donor’s bone marrow and transferring them into a patient, can cure SCD. However, a bone marrow transplant may not be the best choice for all patients because it comes with serious risk. A bone marrow transplant expert can advise patients about whether or not it is a good choice for them.

Anemia is a common effect of SCD, but it can be treated.

In someone with SCD, red blood cells die early and not enough are left to carry oxygen throughout the body, causing anemia. Infection or enlargement of the spleen, an organ that stores red blood cells, may make anemia worse. Blood transfusions are used to treat severe anemia.

A person with SCD can live a long and high quality life.

More than 95% of newborns with SCD in the United States will live to be adults. People with SCD can lower their chances of difficulties from the disease and enjoy many normal activities by

  • Getting regular checkups with their doctor.
  • Following treatments prescribed by their doctor, such as taking medication called hydroxyurea.
  • Preventing infections by taking simple steps including washing their hands.
  • Practicing healthy habits like drinking 8 to 10 glasses of water per day and eating healthy food.

For more information about SCD, visit: www.cdc.gov/ncbddd/sicklecell

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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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StatPearls [Internet].

Hematopoietic stem cell transplantation in sickle cell disease.

Damilola Ashorobi ; Kushal Naha ; Ruchi Bhatt .

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Last Update: July 19, 2023 .

  • Continuing Education Activity

Since the Sickle Cell Anemia Act, steady progress has been made in the screening and treatment of sickle cell disease. Despite the development of new medical therapies, sickle cell disease remains an incurable condition for most affected individuals. Hematopoietic stem cell transplantation represents the only currently available curative option for individuals living with sickle cell disease. Hematopoietic stem cell transplantation may be autologous, requiring genetic modification of the patient's stem cells to correct the genetic mutation characteristic of sickle cell disease, or allogeneic, involving replacement of the defective stem cells with healthy stem cells from a suitable donor. Although HSCT is curative for most patients, the procedure is associated with significant toxicities and occasionally fatal complications. Care must be exercised when selecting patients for HSCT. This activity reviews the therapeutic role of HSCT in sickle cell disease and highlights the role of the interprofessional team in caring for patients who undergo the procedure.

  • Identify patients with sickle cell disease who may be candidates for hematopoietic stem cell transplantation based on their clinical history.
  • Assess and manage the complications of hematopoietic stem cell transplantation in sickle cell disease.
  • Effectively counsel patients with sickle cell disease and their caregivers about the risks and benefits of hematopoietic stem cell transplantation.
  • Develop and implement interprofessional team strategies to improve outcomes for patients with sickle cell disease undergoing hematopoietic stem cell transplantation.
  • Introduction

Sickle cell disease (SCD) is the most common hemoglobinopathy in the United States. SCD affects about 100,000 Americans, mostly of African descent. [1]  Approximately 20 million individuals worldwide are affected by SCD. The molecular basis of SCD was poorly understood when the disease was first described in the early 1900s. It was not until 1949 when Dr. Linus Pauling carried out a landmark study, that it was determined that this condition is caused by abnormal hemoglobin that sickles when exposed to a low-oxygen environment. The abnormal form of hemoglobin in SCD arises from a single amino acid mutation in the beta-globin gene called hemoglobin S. [2]

Because SCD is an autosomal recessive disorder, both beta-globin genes must be mutated for an individual to develop overt disease. When only a single copy of the gene is mutated, the resulting phenotype is termed sickle cell trait. Sickle cell trait is usually benign, but affected persons may develop sickled cells when exposed to exceptionally low pressures of oxygen.

Since 1949, scientists have made steady progress in understanding the complex molecular pathology of SCD. However, until about two decades ago, no known cure for this genetic disorder existed. According to Dr. Mary T. Basset, a physician during the American civil rights movement, SCD research, screening, and treatment received little to no funding and was neglected because patients were primarily of African descent. [3]  One of the significant achievements of the civil rights movement in the 1970s was the establishment of the Sickle Cell Disease Association of America and the creation of the Sickle Cell Anemia Act of 1972. Since then, there has been greater public awareness of SCD and incrementally more funding towards finding a cure, culminating in the first bone marrow stem cell transplant for SCD. 

The Sickle Cell Anemia Act also improved screening processes for SCD. Today, in most parts of the United States, sickle cell screening is performed before discharging neonates from the hospital. This screening allows for early medical intervention and reduces morbidity and mortality from SCD. Treatment of SCD has improved, incorporating penicillin prophylaxis for children younger than 5, hydroxyurea to boost fetal hemoglobin levels, prophylactic blood transfusions, and pain medications, including opioids. Unfortunately, most of these treatments are palliative, and patients continue to experience poor quality of life because of recurrent pain episodes, end-organ damage, and a reduced life expectancy, underscoring the importance of seeking a cure for this condition.

In September 2018, the National Heart, Lung, and Blood Institute (NHLBI) launched the Cure Sickle Cell Initiative. Under this initiative, efforts are being made to develop new genetic approaches to cure SCD. [4] [5]  Advancement in gene therapy techniques has shown promising results in preclinical and clinical trials, but formal approval by the United States Food and Drug Administration (FDA) is still awaited. [2] [3] [6] [7]

  • Anatomy and Physiology

Sickle cell disease is a genetic disorder inherited in an autosomal recessive manner. The hallmark mutation of SCD affects the sixth amino acid in the hemoglobin beta-chain, replacing the normal glutamate residue with valine. This point mutation results in hemoglobin polymerization in a hypoxic environment leading to the deformation of red blood cells and occlusion of the microvasculature. The resulting organ ischemia produces multiple organ damage typical of sickle cell disease. [2]

  • Indications

Although hematopoietic stem cell transplantation (HSCT) remains the only available curative therapy for SCD, not all affected individuals are eligible for such therapy, primarily because of the significant toxicities associated with the procedure. HSCT is currently indicated in persons with severe SCD with complications including stroke, acute chest syndrome, recurrent pain crisis, nephropathy, retinopathy, osteonecrosis of multiple joints, and priapism. [6]  The decision to proceed with HSCT is complex and must include a discussion of potential benefits and risks, such as infection, graft-versus-host disease (GVHD), and organ injury from the conditioning regimen. In addition, HSCT can have unpredictable effects on preexisting heart, lung, and kidney diseases. Transplantation is only indicated when the benefits outweigh these risks. [8] [9] [10]

HSCT should ideally be performed in children with SCD at high risk for severe disease before the onset of complications. Unfortunately, without effective and validated biomarkers, predicting when such individuals might develop complications is challenging. The development of effective medical therapies has also complicated decisions regarding HSCT, as there are no prospective head-to-head comparisons of these medical therapies against HSCT. Thus, HSCT is more likely to benefit individuals who do not wish to utilize chronic medical therapy. The uncertainty around HSCT in SCD is reflected in the 2014 guidelines issued by the NHLBI, acknowledging that additional research was required for patient and donor selection and to determine the optimal transplantation regimen before HSCT could be made widely available as a curative procedure for SCD. [11]

It is generally agreed that HSCT is indicated in children with progressive organ dysfunction, such as worsening cardiac, renal, and pulmonary function, recurrent stroke, and recurrent priapism, despite the institution of optimal medical therapy. HSCT can also be considered in older adolescents and young adults who can make an informed decision regarding the risks and benefits of the procedure. Regardless of the patient's age, the availability of a suitable donor, such as a fully matched sibling, is an essential requirement. [12]  Alternate donors, such as haploidentical and matched unrelated donors, may be considered in selected cases. [13]

The optimal age for receiving HSCT has not been established. However, several retrospective studies have shown improved survival after HSCT in children compared to adults, especially in children below the age of 10. [14] [15]  Similarly, the optimal source of donor stem cells is unclear. Donor stem cells can be derived from umbilical cord blood, bone marrow, or mobilized peripheral blood. Of these sources, umbilical cord blood and bone marrow are expected to have the best outcomes; stem cells from these sites are associated with a lower risk of GVHD than peripheral blood. However, at least one study of HSCT in SCD did not show a lower incidence of GVHD with cord blood and bone marrow stem cells, although overall survival was superior with these sources compared to peripheral blood stem cells. [15]

  • Preparation

Hematopoietic stem cell transplantation is a complicated process involving multiple tests and extensive preparation. Routine laboratory testing must be performed, including a complete blood count, comprehensive metabolic profile, and 24-hour urine protein and creatinine. Brain magnetic resonance imaging and magnetic resonance angiography (MRI/MRA) is necessary to determine the extent of brain infarcts and vascular abnormalities. An echocardiogram must be performed to estimate pulmonary arterial pressures. Dental clearance and pulmonary function tests are also a part of pretransplant testing.

Most importantly, HLA-typing must be performed to identify a suitable donor. The red cell phenotype of the recipient and donor is obtained. Screening for donor-directed antibodies is undertaken because of the risk of pure red cell aplasia after HSCT. [16] [17]  Hydroxyurea must be discontinued before HSCT, and exchange transfusion is often initiated to minimize the risk of complications. Patients and their families should be counseled about the risk of infertility; options for fertility preservation should be offered before initiating the transplantation process.

  • Technique or Treatment

Bone marrow transplantation is more accurately described as hematopoietic stem cell transplantation (HSCT). HSCT is broadly categorized into two types, autologous, where an individual receives their own stem cells, and allogeneic, where an individual receives stem cells from another individual, termed the donor. Autologous HSCT is typically not helpful in SCD unless the stem cells have been modified by genetic techniques to correct the underlying genetic mutation. Allogeneic HSCT is more widely used; the donor must be matched and can be a sibling or unrelated donor, although matched sibling donors are preferred. Matching refers to human leukocyte antigen (HLA); donors and recipients are considered fully matched if they have identical sequences at 8 out of 8 HLA loci.

Hematopoietic stem cell transplantation techniques have been developed and refined continuously since the first transplant was performed in 1984. The HSCT technique requires a conditioning or preparative regimen of chemotherapy to ablate the stem cells of the recipient. The aplastic marrow is repopulated by healthy donor stem cells. The preparative regimen of the first HSCT in 1984 included cyclophosphamide at 120 mg/kg and fractionated total body irradiation. [18] The patient then received GVHD prophylaxis consisting of a short course of methotrexate and methylprednisolone. Since then, significant strides have been made with conditioning regimens, including developing lower-intensity treatments such as nonmyeloablative and reduced-intensity conditioning regimens that induce cytopenias to allow donor cell engraftment but do not completely ablate the marrow. [19]  Administration of cyclophosphamide after HSCT is another advancement that has markedly improved outcomes in allogeneic HSCT, but its use is typically limited to patients receiving haploidentical stem cells. [20] [21]

Myeloablative regimens that combine cytotoxic chemotherapy and total body irradiation are typically used for HSCT in SCD. Examples of commonly employed regimens include busulfan plus cyclophosphamide or busulfan plus fludarabine. One study described the combination of thiotepa, fludarabine, and treosulfan with excellent long-term results. [22]  Once the conditioning regimen has been administered and the donor stem cells have been transfused, the patient is assessed for engraftment and donor chimerism, the proportion of hematopoietic cells derived from the donor. Donor chimerism of ≥20% is needed to assure the production of enough non-HbS hemoglobin that sickling will not occur, thus producing a clinical cure. [12]  Care should be taken to avoid using granulocyte-colony stimulating factor after transplantation because of reports of fatal cases of sickle cell crises with this agent. [23]  Recipients should receive immunizations after the transplant procedure per standard protocols for bone marrow transplantation. Prophylaxis against GVHD and opportunistic infections must be initiated similarly to other indications for HSCT.

  • Complications

Since the first HSCT was performed in 1984, over 1200 cases have been described. Complications arising from transplantation can be grouped into medical complications from the conditioning regimen, the transplantation itself, the immunosuppressive therapy used after transplantation, or financial toxicity.

Conditioning regimens are highly toxic and can be associated with short-term organ injury and long-term effects such as infertility and secondary malignancies. [24] [25] Transplantation itself is associated with a high risk of morbidity and mortality, especially if there is a mismatch. HSCT is safest when a matched donor is available, but unfortunately, only a few transplant candidates have such donors. Even with a suitable donor, there is still a 9% risk of graft rejection and a 15% risk of chronic GVHD. [15] The immunosuppressive therapy needed to suppress GVHD predisposes patients to opportunistic infections, which can occasionally be fatal. Nonhealing leg wounds in some patients compound the risk of infection, although this is not necessarily a barrier to HSCT. [26] Finally, significant financial costs associated with HSCT can be burdensome, especially for patients from socioeconomically disadvantaged backgrounds. [27]

The potential for one or more of these complications should be carefully considered when evaluating an individual with SCD for HSCT. The patient and their caregivers should be educated about these complications to make an informed decision. Moreover, with appropriate counseling, the patient and their caregivers are better prepared to deal with complications, ultimately improving outcomes. Mitigation strategies for these complications vary depending on the circumstances.

Complications in the immediate period during and after transplantation, such as infections, organ injury from the conditioning regimen, and acute GVHD, are usually managed by the transplant team with protocols similar to those used in patients receiving HSCT for other indications. However, more long-term complications, such as late secondary malignancies, are often managed with close screening, the burden of which is shared between the transplant team and other health professionals. Infertility should be managed preemptively with counseling regarding fertility preservation options before the transplantation procedure.

  • Clinical Significance

HSCT currently represents the only curative option for SCD, which is otherwise a chronic and incurable condition with complications that affect multiple organs leading to reduced quality of life and shortened survival. HSCT is associated with excellent overall and event-free survival and improvement in vaso-occlusive phenomena. [28] However, HSCT does carry a risk of significant toxicity, which limits its use in clinical practice to young patients with good organ function but at high risk of complications. This represents only a small portion of the population living with SCD.

Allogeneic HSCT also requires the identification of a suitable donor, typically a matched sibling. Thus allogeneic HSCT is not an option for most patients with SCD, despite the advances that have been made in this field. Autologous stem cell transplantation with genetically modified stem cells is expected to overcome some of these limitations. Although not commercially available, several gene therapy treatments are awaiting FDA approval. [7]

  • Enhancing Healthcare Team Outcomes

Sickle cell disease is a complex disorder affecting multiple organ systems that requires care coordination among various teams of healthcare professionals to ensure optimal outcomes. HSCT is a highly specialized field requiring a team of trained physicians, nurses, pharmacists, stem cell technicians, and other services such as infectious disease and intensive care teams. Close coordination among these teams is critical for successful outcomes; HSCT procedures are only performed at tertiary care centers with adequate experience and infrastructure.

However, optimizing these outcomes requires extending this effort beyond the transplant center to pediatric and adult hematologists working in the community so that affected individuals are referred at the appropriate time for evaluation for HSCT. Creating awareness of this therapeutic option among hematologists caring for individuals living with SCD is critical. Expanding access to HSCT and continuing research into improving the safety and efficacy of HSCT in patients with SCD represent the measures most likely to improve patient safety and outcomes. 

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Disclosure: Damilola Ashorobi declares no relevant financial relationships with ineligible companies.

Disclosure: Kushal Naha declares no relevant financial relationships with ineligible companies.

Disclosure: Ruchi Bhatt declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

  • Cite this Page Ashorobi D, Naha K, Bhatt R. Hematopoietic Stem Cell Transplantation in Sickle Cell Disease. [Updated 2023 Jul 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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sickle cell anemia essay title

Researching the Sickle Cell Anaemia Essay

Sickle cell anaemia is a hereditary disease passed down from parents to their children. The red blood cells, which are typically disc-shaped, take an abnormal shape and form a crescent or sickle form. The disease shortens the lifespan of the people infected by weakening the body’s immunity system thereby making one vulnerable to diseases. Sickle cell anaemia has a high prevalence among people of African descent as well as those in the Mediterranean. In America, African Americans have a high prevalence rate (National Heart Lung and Blood Institute, 2010). The disease has increased in Europe in recent years (Roberts and Montalembert, 2007).

The symptoms of the disease start showing after a baby reaches four months. Nearly, all the patients suffering from sickle cell experience painful crises, which vary in length. Sickle cell anaemia leads to two kinds of pains -acute and chronic. Acute pain is very common and lasts for hours or days. The chronic pain is severe and can last for months. It is difficult to bear and limits one’s functionality. The symptoms related to pain or crises are a pain in the bones, chest and joints. The crises occur because the sickle-shaped red blood cells clog becoming sticky and prevents blood from flowing smoothly in the blood vessels. The restriction of blood flow causes pain and eventually leads to the damage of organs, for instance, the spleen. Other symptoms are associated with anaemia. It means that some people exhibit mild symptoms while others exhibit severe symptoms. The commonest symptom of sickle cell anaemia is fatigue where patients generally feel very weak and tired. Other signs and symptoms are dizziness, running out of breath, paleness, headaches, fever and cold feet and hands. Sickle cell anaemia leads to health problems such as eye problems, gallstones, priapism in males or unwanted erections, ulcers that appear on the legs, stunted growth in children and strokes (Vorvick, 2010).

The red blood cells are responsible for carrying oxygen. They contain hemoglobin- a protein that helps to carry oxygen. The red color of the blood comes from hemoglobin. However, in a person with sickle cell anaemia there is an abnormality caused by an abnormal type of protein known as hemoglobin S. The hemoglobin distorts the figure of the red blood cells giving them a sickle cell form due to low exposure to oxygen (Vorvick, 2010). The sickle-shaped cells are fragile and carry less oxygen. The abnormal Sickle cells clog very easily forming clumps and disintegrating into pieces thus interfering with the normal blood flow. Normally, the red blood cells, which have the shape of a disc, move easily through the blood cells transporting oxygen to the rest of the body through the blood vessels but the sickle cells become sticky and stiff hence cannot move easily through the blood vessels as shown in appendix 1 (Lab Tests Online, 2010).

The mode of sickle cell inheritance is X-linked and is carried on chromosomes. Thus, a person can be a carrier of a genetic diseases trait without even being aware and passing it to their children. Sickle cell anaemia is passed down to generations when they inherit two defective genes from each parent or become carriers of the trait if they inherit only one defective gene from one of the parents see appendix 2.

Haemoglobin F is produced during the gestation period by a fetus. After birth hemoglobin F is replaced by hemoglobin A. The variations in hemoglobin result from gene mutations. Other hemoglobin variants are available but few are common. The changes in the hemoglobin give rise to variants such as hemoglobin C, hemoglobin S and beta-thalassemia (Lab Tests Online, 2010).

People with hemoglobins and a normal hemoglobin gene copy produce 20-40% of hemoglobins and do not generally exhibit any health problems because they manufacture adequate hemoglobin A. Such people have a single altered copy of hemoglobin (heterozygous) and they only carry a trait of sickle cell anaemia. The carriers of sickle cell anaemia have a recessive gene that when passed to the offspring causes the disease. On the contrary, the homozygous- people who carry two mutated hemoglobin genes have hemoglobin S and are thus victims of sickle cell anaemia. The homozygous does not produce the normal hemoglobin A (Lab Tests Online, 2010).

The mutated hemoglobin S produces a less soluble type of hemoglobin and fluid that forms polymers during the process of oxygen transport within the red blood cells. The polymers are responsible for altering the shape of the red blood cells giving them a crescent or sickle shape. The shape altering occurs in low oxygen environments, which causes problems for the blood circulatory system (Lab Tests Online, 2010).

The disease has no cure but can be managed through various treatments, which should be given even during crises free periods. The patients need to take folic acid supplements that help in the production of red blood cells as the sickle cells are short-lived and last between 10-20 days instead of the normal span of 120 days (Vorvick, 2010). The treatments help to reduce the occurrences of crises and control the symptoms. Pain medicines are administered during pain crises. Drinking fluids also help to reduce dehydration, which leads to crises. In periods of crisis, non-narcotic drugs may be used but some patients require the use of narcotic drugs in large doses. Another drug like hydroxyurea is used to alleviate pain and difficulties in breathing. In children, vaccines and antibiotic drugs are used to avoid bacterial infections. In severe cases, blood transfusions are done regularly to prevent occurrences of strokes. When kidney damage occurs dialysis can be done or a kidney transport. Surgery can be performed on patients with priapism. Gall bladder removal in case a patient has gallstone disease. Eye operations for those with eye problems and wound care for the ulcers on the legs. Moreover, bone marrow transplants can be done but involve many risks such as infections or rejection (Vorvick, 2010). Patients need to see a doctor frequently.

Lab Tests Online. 2010. Sickle cell Anaemia . Web.

National Heart Lung and Blood Institute. 2010. Sickle cell Anaemia . Web.

Roberts, I. and Montalembert, M., 2007. Sickle cell disease as a paradigm of immigration haematology: new challenges for haematologists in Europe. Haematological, 92 (7), pp. 865–71.

Vorvick, L., 2010. Sickle cell anaemia . Web.

Source: National Heart Lung and Blood Institute

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  22. Researching the Sickle Cell Anaemia

    Sickle cell anaemia is a hereditary disease passed down from parents to their children. The red blood cells, which are typically disc-shaped, take an abnormal shape and form a crescent or sickle form. The disease shortens the lifespan of the people infected by weakening the body's immunity system thereby making one vulnerable to diseases.

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