A 25-year-old African-American male with sickle cell anemia has significantly fewer painful crises since starting hydroxyurea. The biochemical mechanism by which hydroxyurea reduces sickling is:

• A Direct alkylation of the valine-6 mutation site in HbS
• B Inhibition of 2,3-BPG synthesis, increasing oxygen affinity of HbS
• C Stimulation of red cell carbonic anhydrase, preventing pH-induced sickling
• D Induction of fetal hemoglobin (HbF, alpha2gamma2) synthesis, which inhibits HbS polymerization ✓

Explanation

Hydroxyurea is a ribonucleotide reductase inhibitor that also stimulates guanylate cyclase in erythroid progenitors, increasing cGMP and reactivating gamma-globin gene expression to produce fetal hemoglobin (HbF). Gamma-globin chains substitute for the mutant beta-S chains in the tetramer; HbF (alpha2gamma2) does not participate in the deoxy-HbS polymer and its presence dilutes HbS concentration, exponentially reducing the likelihood of polymer nucleation and erythrocyte sickling.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.