hemoglobin S

**Genetics/Molecular basis** - Missense (point) mutation in the β-globin gene on chromosome 11: GAG (Glu) → GTG (Val) at codon 6. This replaces a hydrophilic, negatively charged residue with a hydrophobic, neutral one. - Autosomal recessive. HbSS = sickle cell anemia; HbAS = sickle cell trait; HbSC = compound heterozygote (HbC: Glu6Lys), usually milder disease. - HbS has reduced electrophoretic mobility toward the anode compared with HbA (a charge change), which is the basis for hemoglobin electrophoresis diagnosis (HbS migrates more slowly than HbA).

**Pathophysiology** - In the deoxygenated state, the hydrophobic valine forms a hydrophobic interaction with a pocket on an adjacent hemoglobin (Phe85, Leu88 on the β-chain), leading to polymerization of HbS into long rigid fibers. This distorts the RBC into a sickle shape. - Sickling is promoted by hypoxia, acidosis (↓pH, right shift), dehydration, ↑2,3-BPG, and increased HbS concentration (e.g., from deoxygenation or dehydration, leading to higher intracellular concentration). - Sickling is initially reversible; repeated cycles damage the membrane, causing irreversible sickled cells that undergo extravascular hemolysis (spleen, reticuloendothelial system) and some intravascular hemolysis. - Vaso-occlusion results from sickled cells, adhesion to endothelium, inflammation, and nitric oxide depletion by free hemoglobin. - HbF (α2γ2) inhibits HbS polymerization. Infants are protected for the first ~6 months, and symptoms appear as HbF falls. Hydroxyurea raises HbF.

**Clinical features of sickle cell disease** - Chronic hemolytic anemia: ↑indirect bilirubin, ↑LDH, ↓haptoglobin, ↑reticulocytes; pigmented gallstones; jaundice. - Vaso-occlusive (pain) crises: bones, chest, abdomen. Dactylitis (hand-foot syndrome) is often the earliest presentation in infants. - Acute chest syndrome: fever, chest pain, cough, hypoxia, new pulmonary infiltrate; a leading cause of death in adults. Treat with oxygen, analgesia, antibiotics, and transfusion or exchange transfusion. - Autosplenectomy (splenic infarcts, Howell-Jolly bodies on smear) leads to susceptibility to encapsulated organisms (*Streptococcus pneumoniae*, *Haemophilus influenzae*, *Neisseria meningitidis*). Children also develop *Salmonella* osteomyelitis (classic in sickle cell, vs. *S. aureus* in general). - Splenic sequestration crisis (children): sudden splenic enlargement, hypovolemia, ↓Hb. - Aplastic crisis: parvovirus B19 infection of erythroid precursors, causing reticulocytopenia and a sudden drop in Hb. - Stroke (children; screen with transcranial Doppler, treat high-risk with chronic transfusions), avascular necrosis of the femoral head, priapism, retinopathy, chronic kidney disease (papillary necrosis, hematuria, renal medullary carcinoma in trait), leg ulcers, pulmonary hypertension. - Peripheral smear: sickle cells (drepanocytes), target cells, Howell-Jolly bodies, polychromasia. Radiographs: "crew cut" skull appearance (marrow hyperplasia, extramedullary hematopoiesis).

**Sickle cell trait (HbAS)** - Usually asymptomatic with normal life expectancy. Sickling occurs only under extreme conditions (severe hypoxia, high altitude, extreme exertion/dehydration). - Complications: isosthenuria (inability to concentrate urine, as the renal medulla is hypoxic, hypertonic, and acidic), painless hematuria (papillary necrosis), renal medullary carcinoma, splenic infarction at altitude, and exertional rhabdomyolysis. - Heterozygote advantage: protection against *P. falciparum* malaria (balanced polymorphism, high frequency in sub-Saharan Africa and among African Americans).

**Diagnosis** - Newborn screening (hemoglobin electrophoresis or HPLC). Confirm with electrophoresis: HbSS shows mostly HbS with HbF and no HbA; trait shows ~HbA > HbS (roughly 60% A, 40% S). - Sodium metabisulfite test (induces sickling) is a screening test only and cannot distinguish trait from disease. - Solubility test (e.g., Sickledex) is also a screening test.

**Management** - Prevention: penicillin prophylaxis in early childhood, vaccinations (pneumococcal, meningococcal, Hib), folate supplementation. - Hydroxyurea: ↑HbF and decreases the frequency of crises and acute chest syndrome (first-line disease-modifying therapy). Other agents include L-glutamine, crizanlizumab (P-selectin inhibitor), and voxelotor (stabilizes oxygenated Hb, though it has been withdrawn from some markets). - Acute pain crisis: hydration, oxygen if hypoxic, and aggressive analgesia (opioids). - Transfusion for stroke, acute chest syndrome, and aplastic or sequestration crises (watch for alloimmunization and iron overload). - Curative options: hematopoietic stem cell transplant, and gene therapies (e.g., exagamglogene autotemcel/Casgevy, lovotibeglogene autotemcel/Lyfgenia). - Avoid triggers: dehydration, hypoxia, extreme cold.

**High-yield pearls** - Glu→Val at position 6 of the β-chain (HbS); Glu→Lys at the same position (HbC). - Sickle cell disease patients are functionally asplenic, so give encapsulated organism prophylaxis and vaccines. - *Salmonella* osteomyelitis is classic in sickle cell disease. - Hydroxyurea increases HbF. - Parvovirus B19 triggers aplastic crisis. - Renal medullary carcinoma is associated with sickle cell trait.