In sickle cell disease, hydroxyurea reduces HbS polymerisation by increasing HbF. The molecular mechanism by which HbF inhibits sickling is:
- A HbF gamma chains sterically inhibit the incorporation of deoxyHbS into the polymer nucleus, disrupting fibre formation ✓
- B HbF gamma chains have higher oxygen affinity, reducing deoxyhaemoglobin
- C HbF reduces 2,3-DPG binding, shifting oxygen dissociation curve left
- D HbF activates adenylate cyclase, increasing membrane flexibility
Explanation
HbF (α2γ2) inhibits deoxyHbS polymerisation not merely by dilution but because γ-chains contain threonine instead of valine at position β87 (site critical for intermolecular contact in the HbS fibre). When HbF is incorporated into a growing HbS fibre, the γ-chain ends the polymer chain, preventing further addition — an 'axial interruption' mechanism. Thus HbF acts as an anti-polymerisation agent at the molecular level. Even 20–30% HbF is sufficient to markedly reduce sickling. Hydroxyurea increases HbF by activating γ-globin gene expression (through nitric oxide, stress erythropoiesis pathways).
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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