Sickle Cell Disease

Hematology & Oncology

Description

Sickle cell disease comprises a group of inherited hemoglobinopathies in which a point mutation (β-globin gene GAG → GTG) substitutes valine for glutamic acid at position 6, producing hemoglobin S (HbS). Under de-oxygenating stress HbS polymerizes into tactoids, distorting erythrocytes into rigid, sickle-shaped cells that haemolyze prematurely and occlude the microvasculature, precipitating painful vaso-occlusive crises (VOCs) and chronic multiorgan injury. Genotypes include homozygous HbSS, compound heterozygotes HbSC, HbS/β-thalassemia, HbSD, and rare double variants, all sharing the pathobiology of polymerization and endothelial dysfunction.

Symptoms

Hallmark manifestations are recurrent VOC presenting as sudden, excruciating bone or visceral pain, often requiring opioid analgesia, and chronic hemolytic anemia with fatigue, scleral icterus, and gallstones. Acute complications encompass acute chest syndrome (new pulmonary infiltrate with chest pain and hypoxemia), ischemic or hemorrhagic stroke, splenic sequestration in childhood, aplastic crisis from parvovirus B19, priapism, renal papillary necrosis, and multi-organ failure. Progressive vasculopathy leads to avascular necrosis of femoral heads, pulmonary hypertension, proliferative sickle retinopathy, chronic kidney disease, cardiomyopathy, and pregnancy-related maternal and fetal morbidity.

Risk Factors

African, Afro-Caribbean, Middle-Eastern, Mediterranean, and South-Asian ancestry confer high allele frequency due to historic malaria selection. Co-existent α-thalassemia modulates hemolysis, whereas high HbF-promoter haplotypes (Senegal, Arab-Indian) temper severity. Environmental precipitants of VOC include extreme heat or cold, dehydration, hypoxia, high altitude, infection, uncontrolled asthma, menstruation, psychosocial stress, and cocaine or tobacco use.

Diagnosis

Newborn screening via isoelectric focusing or HPLC identifies HbS at birth; confirmatory DNA analysis or family electrophoresis defines genotype. In adults, hemoglobin electrophoresis or capillary HPLC quantifies HbS, HbA, HbF, and HbA₂ levels. Baseline CBC shows hemoglobin 6–9 g/dL, reticulocytosis, and Howell–Jolly bodies. Sickledex solubility tests are inadequate for genotype specification. Transcranial Doppler velocity ≥ 200 cm/s in cerebral arteries predicts pediatric stroke risk. Echocardiography estimates tricuspid-regurgitant velocity for pulmonary-hypertension screening. Serum ferritin and liver MRI T2* quantify transfusional iron.

Treatment

Disease-modifying therapy begins with hydroxyurea 15–20 mg/kg/day, titrated to mild myelosuppression, which elevates HbF, reduces VOCs, and prolongs survival. Oral L-glutamine lowers oxidative stress and diminishes pain events. Crizanlizumab, a P-selectin monoclonal antibody (5 mg/kg IV monthly), cuts annual VOCs by ~45 % and is approved for patients ≥ 16 years with or without hydroxyurea. Voxelotor 1 500 mg daily stabilizes oxygenated HbS, raises hemoglobin by ≥ 1 g/dL, and ameliorates hemolysis. Regular erythrocytapheresis prevents stroke recurrence and mitigates iron overload when combined with iron chelation (deferasirox). Allogeneic HLA-matched sibling hematopoietic-stem-cell transplantation offers > 90 % cure in children but is limited by donor availability and graft-versus-host disease. In December 2023 the FDA authorized two autologous gene therapies: exagamglogene autotemcel (Casgevy), a CRISPR/Cas9-edited BCL11A enhancer knockout that reactivates HbF and eliminated VOCs in 97 % of treated patients, and lovotibeglogene autotemcel (Lyfgenia), a lentiviral β-A-T87Q globin gene addition product restoring anti-sickling hemoglobin, both indicated for ≥ 12-year-olds with severe recurrent crises.

Outlook

Median survival in high-income nations now reaches the sixth decade, yet life expectancy remains 22–30 years below population norms. Hydroxyurea, prophylactic penicillin in children, vaccination, and aggressive VOC management have slashed childhood mortality, while gene therapies promise functional cure for selected individuals. Long-term challenges include chronic pain, organ failure, and health-care inequities that disproportionately burden marginalized communities.

Complications

Recurrent VOCs, avascular necrosis of femoral and humeral heads, chronic kidney disease and hyposthenuria, proliferative retinopathy leading to blindness, pulmonary hypertension, heart failure with preserved ejection fraction, cholelithiasis, leg ulcers, osteomyelitis by Salmonella species, thromboembolic events, pregnancy loss, and opioid dependence from chronic pain.

Prevention

Universal newborn screening, early vaccination (PCV15/20, MenACWY, Hib, influenza, COVID-19), penicillin prophylaxis, and education on fever protocols prevent infectious precipitants. Pre-operative exchange transfusion reduces peri-operative complications. Genetic counseling and carrier screening (HbS trait) inform reproductive decisions, and advanced prenatal diagnostics enable early intervention planning.

Support

Maintain hydration ≥ 3 L/day, adhere to hydroxyurea or disease-modifying regimen, take folic-acid 1 mg daily, and continue prophylactic penicillin until at least age five. Avoid high-altitude travel, pressurized airplane cabins without supplemental oxygen, and exposure to extreme temperatures. Engage in moderate regular aerobic exercise, ensure routine ophthalmic and dental care, and attend specialized sickle-cell comprehensive-care clinics. Family can assist with medication scheduling, early recognition of stroke FAST signs, and transport for transfusion appointments.