A 30-year-old woman with sickle cell disease presents with acute chest syndrome. The pathophysiology of sickling under hypoxia involves primarily which molecular event?

• A Oxidation of heme iron from Fe2+ to Fe3+, forming methemoglobin that polymerises
• B Polymerization of deoxygenated HbS via hydrophobic interaction of valine substituted at position 6 of beta-globin ✓
• C Lipid peroxidation of red cell membrane phospholipids causing spherocyte formation
• D Autoimmune destruction triggered by sickling-induced neoantigen exposure

Explanation

In HbS, glutamic acid at position 6 of beta-globin is replaced by valine, creating a hydrophobic 'sticky patch' on the deoxygenated molecule. This allows deoxygenated HbS molecules to polymerize into long rigid fibers, distorting the RBC into the characteristic sickle shape. Repeated sickling damages the membrane, causing irreversible sickle cells. Elevated HbF (fetal hemoglobin) inhibits polymerization, which is the basis for hydroxyurea therapy. Methemoglobin formation is a separate oxidative pathway not involved in sickling.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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