Sickle Cell Anemia

Definition & Epidemiology

Genetics & Molecular Basis

• Inheritance: Autosomal recessive
• Mutation: A single nucleotide substitution (GAG → GTG) at codon 6 of β-globin, resulting in valine replacing glutamic acid at position 6
• This produces sickle hemoglobin (HbS) = α₂β₂^S
• Normal adult Hb composition: ~96% HbA (α₂β₂), ~3% HbA2 (α₂δ₂), ~1% HbF (α₂γ₂)
• In HbSS patients, HbA is completely replaced by HbS; heterozygotes retain ~60% HbA

• Harriet Lane Handbook, 23rd ed., p. 479

Pathogenesis

• Reoxygenation initially reverses sickling
• Each sickling episode causes calcium influx → K⁺ and water loss → membrane skeleton damage
• Cumulative membrane damage creates irreversibly sickled cells prone to hemolysis

1. Level of non-HbS hemoglobin - HbA and HbF both inhibit HbS polymerization. HbF is especially protective; this is why neonates are asymptomatic until ~5-6 months of age when HbF declines to adult levels.
2. Intracellular HbS concentration - Dehydration raises intracellular Hb concentration and worsens sickling. Coexistent α-thalassemia (reduces Hb concentration) is actually protective.
3. Microvascular transit time - Sluggish flow (spleen, bone marrow, inflamed tissues) allows sickling to occur. Sickled cells are abnormally "sticky," further prolonging transit time.

• Robbins & Kumar Basic Pathology, p. 386-387

Peripheral Blood Smear

Two Main Pathologic Consequences

1. Chronic Hemolytic Anemia

• Mean RBC lifespan: ~20 days (vs. ~120 days normal) - one-sixth of normal
• Hematocrit: typically 18-30% (normal 38-48%)
• Associated with hyperbilirubinemia, compensatory reticulocytosis, and compensatory erythroid hyperplasia in bone marrow
• Bone marrow expansion causes bone resorption → prominent cheekbones, "crew-cut" appearance on skull X-ray
• Extramedullary hematopoiesis may occur in liver and spleen

2. Vasoocclusive Crises

Clinical Features

Vasoocclusive Crises

Organ Damage (Chronic)

• Autosplenectomy by adulthood: spleen reduced to fibrotic nubbin; renders patients functionally asplenic and susceptible to encapsulated bacteria (pneumococci, H. influenzae, meningococci)
• Hypoxia-induced fatty changes in heart, liver, renal tubules
• Renal: glomerulosclerosis, papillary necrosis, concentrating defect (isosthenuria)
• Chronic leg ulcers, avascular necrosis of femoral/humeral head
• Pulmonary hypertension
• Robbins & Kumar Basic Pathology, pp. 387-388

Diagnosis

• Newborn screening (mandatory in all 50 US states): Hemoglobin electrophoresis / HPLC on heel-stick blood
• Sickle preparation / Sickledex: Rapid tests positive for all sickle hemoglobinopathies (false negatives in neonates with high HbF)
• Prenatal diagnosis: Chorionic villus sampling or cell-free DNA testing; amniocentric fetal DNA analysis
• Transcranial Doppler (TCD): Screening begins at age 2 years, annually until age 16; velocity >200 cm/sec indicates high stroke risk requiring exchange transfusion
• Harriet Lane Handbook, 23rd ed.; Harrison's Principles 22e

Treatment

Disease-Modifying Drugs

• Mechanism: Induces HbF synthesis (heterocellularly), reducing HbS polymerization
• Indicated for all patients with HbSS and HbSβ⁰ thalassemia, regardless of symptoms
• In adults: raises HbF from ~5% to ~10%, increases Hb ~1 g/dL, reduces pain crises and ACS by ~50%, and after 17.5 years follow-up, reduces mortality by 49%
• In infants started at <1 year (~27 mg/kg): HbF rises to ~33%, hemoglobin ~10 g/dL, acute events markedly reduced
• Current recommendation: Start at 9 months of age at ~20 mg/kg, titrated to maximum tolerated dose based on neutrophil and platelet counts
• Contraindicated in pregnancy (teratogenic)

• Mechanism: Increases hemoglobin O₂ affinity, stabilizing the oxygenated conformation
• Dose 1500 mg/day: raises Hb ~1 g/dL in 59% of patients, reduces hemolysis biomarkers
• Additive to hydroxyurea; used when HU alone is insufficient

• Mechanism: Anti-P-selectin monoclonal antibody; blocks sickle cell-endothelial adhesion
• Given IV monthly; in the pivotal trial, reduced acute painful episodes by ~45%
• A follow-up trial did not replicate these results; role remains uncertain

• Reduces oxidative stress in sickle erythrocytes
• Phase 3 trial: 25% reduction in painful episodes, 33% reduction in hospitalization

Transfusion

• Simple transfusion for: symptomatic severe anemia, cardiopulmonary instability
• Exchange transfusion for: stroke, ACS with rapid progression/deterioration, multisystem organ failure, prior stroke, TCD >200 cm/sec
• Goal: lower HbS to <40%, target Hb ~10 g/dL; avoid hyperviscosity (keep Hct <30%)
• Prophylactic transfusions used in pregnancy to reduce vaso-occlusive crises

Curative Approaches

• HLA-identical related donor: event-free survival >95%
• Only ~15% of patients have a fully matched related donor
• Haploidentical transplant protocols improving outcomes

1. Lentiviral vector introducing a modified HbA gene (BT87Q mutation) that inhibits HbS polymerization
2. CRISPR/Cas9 disrupting BCL11A (the major HbF repressor), thereby reactivating HbF production Both achieve near-pancellular HbF or HbA^T87Q at 30-50%, total Hb >12 g/dL, and near-total prevention of acute vasoocclusive events. Long-term safety data are still accumulating.

• Harrison's Principles of Internal Medicine 22e (2025), p. 819

Preventive Care & Prophylaxis

Pregnancy Considerations

• Median life expectancy is now into the fifth decade; female fertility generally preserved
• Increased risk: preterm labor, PROM, infections, pain crises, thrombosis, pre-eclampsia, cesarean delivery
• 6-fold increased maternal mortality vs. controls
• Hydroxyurea is contraindicated in pregnancy (teratogenic)
• NSAIDs avoided after 30 weeks gestation
• Regional anesthesia preferred over general (reduces postpartum sickling complications)
• VTE risk 1.7-10x higher in pregnant SCD patients
• Rosen's Emergency Medicine, p. 3377