Sickle Cell Anemia: Genetics, Pathophysiology, Complications, and Modern Management

Genetics

• Autosomal recessive: β-globin gene (HBB) point mutation (Glu6Val) → hemoglobin S (HbS).
• Both parents must be carriers (sickle cell trait) for affected child (25% chance).

Pathophysiology

• Deoxygenated HbS polymerizes → rigid, sickle-shaped RBCs.
• Vaso-occlusion → ischemia, reperfusion injury, inflammation.
• Chronic hemolysis → anemia, bilirubin, NO scavenging → endothelial dysfunction.

Clinical Manifestations

• Vaso-occlusive crises (VOC): Severe pain (bones, chest, abdomen); recurrent.
• Acute chest syndrome: Infiltrate + fever + respiratory symptoms – leading cause of death.
• Stroke: Overt (10% by age 20) or silent infarcts.
• Splenic dysfunction: Auto-splenectomy → encapsulated organism sepsis risk.
• Organ damage: Nephropathy, retinopathy, avascular necrosis, priapism.

Diagnosis

• Newborn screening (HPLC, isoelectric focusing).
• Hemoglobin electrophoresis / HPLC confirms HbS.

Treatment

• Hydroxyurea: ↑HbF, ↓VOC, ↓transfusions, ↑survival.
• Voxelotor: Inhibits HbS polymerization.
• Crizanlizumab: Anti-P-selectin → ↓adhesion/VOC.
• Transfusion: Acute (stroke, ACS) or chronic (stroke prevention).
• Curative: Allogeneic HSCT (matched sibling best); gene therapy (lentiviral β-globin, CRISPR) emerging.

Survival

With comprehensive care, median survival now >50 years in high-resource settings. Newborn screening, penicillin prophylaxis, vaccines, hydroxyurea, stroke screening (TCD) transformed outcomes.