A 35-year-old man with sickle cell disease presents with severe bone pain (vaso-occlusive crisis). He has been on hydroxyurea 35 mg/kg/day for 18 months with suboptimal response (HbF 8%, still having 4 crises/year). What is the mechanism by which hydroxyurea reduces sickling, and what alternative newer therapy has demonstrated reduction in vaso-occlusive crises through P-selectin inhibition?
- A HU increases HbF by activating globin gene methylation; rivipansel blocks pan-selectin
- B HU increases HbF by inhibiting ribonucleotide reductase (reactivating gamma-globin); crizanlizumab blocks P-selectin ✓
- C HU reduces HbS polymerisation by directly acetylating haemoglobin; voxelotor blocks selectin
- D HU increases HbF by inducing BCL11A; inclacumab is the anti-P-selectin agent
Explanation
Hydroxyurea (hydroxycarbamide) increases foetal haemoglobin (HbF) production by inhibiting ribonucleotide reductase, creating S-phase cytotoxicity in erythroid progenitors that selects for erythropoietic stress responses — ultimately reactivating gamma-globin gene expression and increasing HbF. HbF inhibits HbS polymerisation. Crizanlizumab (Adakveo) is a humanised anti-P-selectin monoclonal antibody that prevents P-selectin on activated endothelium from binding to PSGL-1 on sickle cells and WBCs, blocking the cell-cell interactions that initiate vaso-occlusion. The SUSTAIN trial demonstrated a 45% reduction in vaso-occlusive crisis rate. Voxelotor increases HbS oxygen affinity to prevent sickling. Rivipansel was a pan-selectin inhibitor that failed in Phase 3 (RESET trial).
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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Written and medically reviewed by the StethoPrep medical team.