A 24-year-old woman with sickle cell anaemia (HbSS) is initiated on hydroxyurea. The PRIMARY mechanism by which hydroxyurea reduces sickle cell crises is:
- A Inducing fetal haemoglobin (HbF) synthesis through activation of soluble guanylate cyclase in erythroid progenitors ✓
- B Inhibiting polymerisation of HbS by directly binding to sickle haemoglobin
- C Reducing red cell dehydration by inhibiting the Gardos channel
- D Increasing 2,3-DPG levels to rightward shift the oxygen dissociation curve
Explanation
Hydroxyurea (hydroxycarbamide) increases HbF (foetal haemoglobin, α₂γ₂) production in erythroid progenitors by a mechanism involving S-nitrosylation and activation of soluble guanylate cyclase, increasing cGMP in BFU-E/CFU-E and promoting γ-globin gene expression. HbF dilutes HbS and directly inhibits the intracellular polymerisation of deoxygenated HbS, which is the molecular basis of sickling. HbF also reduces red cell density and adhesion molecule expression. Clinical benefits include reduced painful crises (MSH trial: 44% reduction), ACS, transfusion requirements, and improved survival. Voxelotor directly inhibits HbS polymerisation; senicapoc inhibits the Gardos channel.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.