A patient with sickle cell disease is started on hydroxyurea. The mechanism by which hydroxyurea reduces sickling crises is:

• A Hydroxyurea inhibits ribonucleotide reductase, reducing HbS synthesis
• B Hydroxyurea increases HbF (fetal hemoglobin) production by reactivating the gamma-globin gene via HbF induction mechanisms, and HbF dilutes HbS polymer formation, reducing sickling ✓
• C Hydroxyurea directly alkylates HbS molecules preventing polymerization
• D Hydroxyurea increases 2,3-DPG, shifting the ODC right and improving oxygen delivery to tissues

Explanation

Hydroxyurea (hydroxycarbamide) reduces sickle cell crises primarily by stimulating production of fetal hemoglobin (HbF, containing gamma-globin chains). HbF does not participate in HbS polymerization; in fact, HbF is excluded from sickle hemoglobin polymer chains. Increased HbF dilutes HbS within the RBC, raising the concentration threshold for sickling, reducing polymer formation, and improving RBC deformability. The mechanism of HbF induction involves: ribonucleotide reductase inhibition → S-phase arrest → stress erythropoiesis → HbF gene reactivation (gamma-globin normally silenced after infancy by BCL11A and LRF/ZBTB7A). Hydroxyurea also reduces neutrophil counts (improving endothelial adhesion) and NO bioavailability. While it does inhibit ribonucleotide reductase (Option A is partially true mechanistically), the clinical benefit is via HbF induction, not HbS suppression.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.