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#SICKLE CELL DISEASE — PATHOLOGY REVISION NOTES --- 1. DEFINITION & GENETICS Sickle cell disease (SCD) is an inherited chronic haemolytic anaemia caused by a point mutation in the β-globin gene on chromosome 11 . Mutation: Single nucleotide substitution (GAG → GTG) → Glutamic acid replaced by Valine at position 6 of the β-globin chain (β⁶Glu→Val). Inheritance: Autosomal recessive. Genotypes: HbSS — Sickle cell anaemia (most severe, most common form) HbAS — Sickle cell trait (carrier; generally asymptomatic) HbSC — Milder disease; target cells predominate HbS/β⁰-thalassaemia — Clinically similar to HbSS (no normal β-globin) HbS/β⁺-thalassaemia — Milder; some normal HbA present --- 2. PATHOPHYSIOLOGY A. Molecular Basis of Sickling On deoxygenation , HbS undergoes conformational change → exposes a hydrophobic patch on the βs-globin chain at the site of β6 valine. This binds a complementary hydrophobic site on another Hb tetramer → triggers polymerization . Polymers form 21 nm diameter helical fibres (1 inner + 6 peripheral double strands). Process follows the double nucleation model: Homogeneous nucleation → tetramers form a nucleus → expands into a fibre Heterogeneous nucleation → existing fibre surfaces nucleate further fibres Polymerization has a delay period that is extremely sensitive to deoxy-HbS concentration — even small increases dramatically shorten the delay. B. Factors That Promote Sickling ↓ Oxygenation (hypoxia) ↑ Intracellular HbS concentration (dehydration) Acidosis ↑ 2,3-DPG (reduces O₂ affinity → more deoxyHbS) Fever, infection, cold, stress C. Factors That Inhibit Sickling HbA — dilutes HbS (sickle trait is relatively protected) HbF — more potent inhibitor; greater amino acid disparity between βs and γ-globin chains → disrupts polymer formation. This is the mechanism exploited by hydroxyurea. D. Effect on Red Blood Cells Deoxygenation → sickling → reversible initially upon reoxygenation Repeated/prolonged sickling → irreversible membrane damage → irreversibly sickled cells (ISCs) Membrane damage → K⁺ and water efflux via Gardos pathway and K⁺-Cl⁻ co-transport → cellular dehydration → ↑ intracellular Hb concentration → shorter delay time → more sickling (vicious cycle) Phosphatidylserine abnormally appears on outer membrane leaflet (normally inner) → increased coagulability Red cells become abnormally adherent to endothelium via VCAM-1, thrombospondin, fibronectin Comparison: Feature Normal RBC Sickle RBC --- --- --- Shape Biconcave disc Sickle/elongated Deformability High Rigid Lifespan 120 days ≤20 days --- 3. CONSEQUENCES — HAEMOLYSIS & VASO-OCCLUSION These are the two pillars of SCD pathology. Haemolysis → anaemia (Hb typically 6–9 g/dL in HbSS), jaundice, pigment gallstones, raised reticulocyte count (~10%), raised bilirubin, raised LDH, low haptoglobin. Vaso-occlusion → rigid sickle cells obstruct microvasculature → tissue hypoxia → pain and organ damage. Releases free Hb and haem → scavenges nitric oxide (NO) → endothelial dysfunction → ↑ adhesion molecules, oxidant generation, platelet & coagulant activation, vasculopathy. --- 4. CLINICAL FEATURES Acute Manifestations Vaso-occlusive (painful) crisis — most common; affects bones, chest, abdomen. Triggered by infection, cold, dehydration, hypoxia. Dactylitis (hand-foot syndrome) — earliest presentation in infants; painful swelling of hands/feet Acute Chest Syndrome (ACS) ⚠️ — new pulmonary infiltrate + fever/respiratory symptoms; leading cause of death. Due to infection, fat embolism, in-situ sickling. Stroke ⚠️ — large vessel occlusion; occurs in ~11% of HbSS patients by age 20 Splenic Sequestration Crisis ⚠️ — sudden massive splenic enlargement with rapid fall in Hb; mainly in young children Aplastic Crisis ⚠️ — due to Parvovirus B19 infecting erythroid precursors → sudden drop in Hb + absent reticulocytes Bacterial Sepsis/Meningitis ⚠️ — Streptococcus pneumoniae , Haemophilus influenzae , Salmonella (osteomyelitis). Due to functional asplenia. Priapism — prolonged painful erection; can cause erectile dysfunction Haematuria/Papillary necrosis — due to renal medullary sickling Chronic Manifestations Anaemia (chronic haemolytic) Jaundice (unconjugated hyperbilirubinaemia) Functional asplenia → susceptibility to encapsulated organisms → auto-infarction of spleen by ~5 years in HbSS; Howell-Jolly bodies on blood film Splenomegaly (early childhood; later atrophies) Cardiomegaly + functional murmurs (high-output state) Pulmonary hypertension ⚠️ Avascular necrosis (AVN) — femoral/humeral head Proliferative retinopathy — particularly in HbSC Hyposthenuria (inability to concentrate urine) → enuresis → renal failure Proteinuria/Nephrotic syndrome Cholelithiasis (pigment stones — bilirubin) Leg ulcers (medial malleolus) Delayed growth and sexual maturation Restrictive lung disease ⚠️ Transfusional haemosiderosis ⚠️ (in heavily transfused patients) --- 5. DIAGNOSIS Peripheral Blood Film HbSS: Normocytic normochromic anaemia; many ISCs, polychroma