A 30-year-old patient with sickle cell disease is prescribed hydroxyurea to reduce vaso-occlusive crises. The primary mechanism of benefit is:

• A Direct inhibition of HbS polymerization by covalent binding to valine
• B Induction of fetal hemoglobin (HbF) synthesis by inhibiting ribonucleotide reductase and inducing gamma-globin gene expression via HbF inducers ✓
• C Reduction of sickling by increasing blood viscosity
• D Competitive inhibition of 2,3-BPG binding to deoxyhemoglobin

Explanation

Hydroxyurea induces HbF (alpha2-gamma2) synthesis through multiple mechanisms: inhibition of ribonucleotide reductase causes mild myelosuppression and subsequent erythroid regeneration during which gamma-globin genes are reactivated (similar to stress erythropoiesis); additionally, hydroxyurea generates nitric oxide (NO), stimulating cGMP → gamma-globin gene expression via epigenetic mechanisms. Elevated HbF dilutes HbS, raises the critical concentration threshold for HbS polymerization, and HbF chains (gamma) have reduced affinity for HbS (alpha2-betaS) hybrid polymer formation. This reduces sickling frequency and vaso-occlusive episodes. Hydroxyurea does not directly bind HbS or affect 2,3-BPG.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.