## First-Line Anti-Sickling Agent **Key Point:** Hydroxyurea is the gold-standard disease-modifying therapy for sickle cell disease, approved by FDA and recommended by all major guidelines (NCCN, ASH, WHO). ### Mechanism of Action Hydroxyurea works by: 1. Increasing fetal hemoglobin (HbF) production via reactivation of γ-globin genes 2. HbF does not polymerize with sickle hemoglobin (HbS), preventing sickling 3. Reduces hemolysis and improves overall hemoglobin levels 4. Decreases white blood cell and reticulocyte counts (anti-inflammatory effect) ### Clinical Evidence **High-Yield:** The landmark MSH (Multicenter Study of Hydroxyurea) trial demonstrated: - 50% reduction in vaso-occlusive crises - 58% reduction in acute chest syndrome - 50% reduction in hospitalizations - Improved overall survival ### Dosing & Monitoring - Starting dose: 15 mg/kg/day orally - Titrate by 5 mg/kg/day every 12 weeks up to 35 mg/kg/day or MTD (maximum tolerated dose) - Monitor CBC, reticulocyte count, and HbF levels every 8–12 weeks - Target: HbF >20% or absolute reticulocyte count <100,000/μL ### Side Effects & Contraindications | Side Effect | Frequency | Management | |---|---|---| | Myelosuppression | Common | Dose reduction; monitor CBC | | Macrocytosis | Expected | Benign; indicates HbF rise | | Teratogenicity | Absolute | Contraindicated in pregnancy | | Leg ulcers (rare) | <5% | May worsen pre-existing ulcers | **Clinical Pearl:** Hydroxyurea is safe in children ≥2 years and is now recommended as preventive therapy in all patients with sickle cell disease, not just those with severe disease. **Warning:** Do NOT confuse hydroxyurea with other supportive measures (penicillin, folic acid, transfusion) — these are adjuncts, not disease-modifying. [cite:Harrison 21e Ch 104]
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