A 30-year-old man with homozygous sickle cell disease presents with acute sickle cell crisis. He was recently started on hydroxyurea 15 mg/kg/day, which is titrated up. Hydroxyurea reduces vaso-occlusive episodes primarily by which mechanism?

• A Direct anti-sickling by oxidising haemoglobin S polymer
• B Reducing red cell survival time by inducing haemolysis of HbS cells
• C Chelating iron to reduce oxidative stress on sickle RBCs
• D Increasing HbF production by activating HbF-promoting transcription (BCL11A inhibition, p38 MAPK activation) ✓

Explanation

Hydroxyurea (hydroxycarbamide) exerts its anti-sickling effect primarily by increasing fetal haemoglobin (HbF/α2γ2) production. HbF inhibits the polymerisation of deoxy-HbS — HbF cannot participate in the asymmetric HbS polymer and 'dilutes' the intracellular HbS concentration. The molecular mechanism involves: ribonucleotide reductase inhibition causing DNA damage response, activation of stress-kinase pathways (p38 MAPK), and downstream upregulation of gamma-globin gene expression (including potential epigenetic effects). BCL11A is a transcriptional repressor of gamma-globin; hydroxyurea effects are partially mediated via this pathway. The Multicenter Study of Hydroxyurea (MSH) trial confirmed 44% reduction in painful crises with hydroxyurea.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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Written and medically reviewed by the StethoPrep medical team.