HbS point mutation causes a single amino acid replacement in β chain (substitution of glutamic acid with valine). Causes extravascular and intravascular hemolysis.- 8% of African Americans carry and HbS allele (resistance to malaria).

Low O₂, high altitude, or acidosis precipitates sickling (deoxygenated HbS polymerizes) → anemia and vaso-occlusive disease.

- Newborns are initially asymptomatic because of ↑ HbF and ↓ HbS.- Heterozygotes (sickle cell trait) also have resistance to malaria.

- "Crew cut" on skull x-ray due to marrow expansion from ↑ erythropoiesis (also seen in thalassemias).

Complications:- Aplastic crisis (due to parvovirus B19)- Autosplenectomy (Howell-Jolly bodies) → ↑ risk of infection by encapsulated organisms- Splenic infarct/sequestration crisis- Salmonella osteomyelitis- Painful crises (vaso-occlusive): dactylitis (painful swelling of hands/feet), priapism, acute chest syndrome, avascular necrosis, stroke- Renal papillary necrosis (↓ P_^O2 in papilla) and microhematuria (medullary infarcts)

Diagnosis: hemoglobin electrophoresis

Treatment: hydroxyurea (↑ HbF), hydration