A 12-year-old girl with β-thalassemia intermedia presents with growth retardation, delayed puberty, and hypogonadism. She has never received regular transfusions. Which drug is indicated to reduce transfusion dependence and improve hemoglobin levels in this patient?

Explanation

## Hydroxyurea in Thalassemia Intermedia **Key Point:** Hydroxyurea is the first-line pharmacologic agent to reduce transfusion dependence and improve hemoglobin in thalassemia intermedia by increasing fetal hemoglobin (HbF) production. ### Mechanism of Action Hydroxyurea: 1. Inhibits ribonucleotide reductase → increases deoxyribonucleotides → DNA synthesis 2. Reactivates γ-globin gene expression → increases HbF production 3. HbF (α₂γ₂) is less prone to polymerization than HbS/HbA₂, reducing hemolysis 4. Increases RBC mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) ### Clinical Benefits in Thalassemia Intermedia | Outcome | Effect | |---------|--------| | Hemoglobin level | ↑ 1–3 g/dL | | HbF percentage | ↑ 15–30% | | Transfusion requirement | ↓ or eliminated | | Hemolysis | ↓ (fewer RBC transfusions) | | Splenomegaly | ↓ | | Growth & puberty | Improved (reduced iron overload) | **High-Yield:** Hydroxyurea is preferred in thalassemia intermedia (not major) because: - Patients have residual β-globin production → HbF induction is effective - Reduces transfusion dependence → delays iron overload - Improves quality of life and growth - Cost-effective ### Dosing & Monitoring - **Starting dose:** 15–20 mg/kg/day - **Target:** 20–35 mg/kg/day (titrate to HbF >20% or Hb >10 g/dL) - **Monitor:** CBC (watch for myelosuppression), reticulocyte count, LFTs, renal function - **Response timeline:** 3–6 months for maximal HbF elevation ### Side Effects - **Myelosuppression:** dose-limiting (reversible) - **Teratogenicity:** contraindicated in pregnancy - **Carcinogenicity:** rare, long-term risk - **Leg ulcers:** in some patients (especially sickle cell disease) **Clinical Pearl:** Hydroxyurea is also the drug of choice in sickle cell disease for the same mechanism — HbF inhibits polymerization of deoxygenated HbS. ### Why Not Splenectomy? While splenectomy reduces hemolysis in thalassemia intermedia, it is: - A surgical intervention (not pharmacologic) - Associated with post-splenectomy sepsis risk - Reserved for patients with massive splenomegaly or severe hemolysis despite medical therapy - Not first-line in this clinical scenario [cite:Harrison 21e Ch 104; KD Tripathi 8e Ch 12]