A 5-year-old boy with β-thalassemia intermedia presents with extramedullary hematopoiesis causing splenomegaly and hepatomegaly. His hemoglobin is 7.5 g/dL and he is transfusion-dependent. Which agent is the drug of choice to reduce transfusion requirements by increasing fetal hemoglobin (HbF) production?

Question

Accepted Answer

B. Hydroxyurea. ## HbF Induction in Thalassemia Intermedia

**Key Point:** Hydroxyurea is the first-line pharmacological agent for increasing fetal hemoglobin (HbF) production in thalassemia intermedia and major, thereby reducing transfusion dependence.

### Mechanism of Hydroxyurea

**High-Yield:** Hydroxyurea induces HbF production by:
1. Reactivating γ-globin gene expression (silenced after birth)
2. Increasing erythroid progenitor proliferation
3. Reducing sickling and hemolysis (in sickle cell disease)
4. Improving hemoglobin levels by 1–3 g/dL in responders

### Efficacy in Thalassemia

| Outcome | Hydroxyurea | Splenectomy | Folic Acid | EPO |
|---------|-------------|-------------|-----------|-----|
| **HbF induction** | Yes (30–50% increase) | No | No | No |
| **Transfusion reduction** | Yes (50–80% of patients) | Modest | No | Minimal |
| **Mechanism** | γ-globin reactivation | Reduces splenic sequestration | Supports RBC production | Stimulates RBC production |
| **Onset** | 4–12 weeks | Immediate (post-op) | Weeks | Days–weeks |
| **First-line status** | Yes | Adjunctive | Supportive | Adjunctive |

**Clinical Pearl:** Hydroxyurea is particularly effective in β-thalassemia intermedia, where HbF induction can reduce or eliminate transfusion requirements. Responders show HbF levels rising from <5% to 15–30%, significantly improving oxygen-carrying capacity.

**Mnemonic:** **HYDROXYUREA = Helps Yield Reactivated Oxygen-carrying Hemoglobin (fetal), eXcels in Young patients, Useful for Reducing transfusion Exigency in Anemia**

### Monitoring During Hydroxyurea Therapy
- CBC (baseline, 2 weeks, then monthly)
- Renal function and LFTs (monthly)
- HbF level (at 4–12 weeks to assess response)
- Bone marrow reserve (assess for myelosuppression)

**Warning:** Hydroxyurea is teratogenic (Pregnancy Category D) and contraindicated in pregnant women. Counsel on contraception in reproductive-age patients. Myelosuppression is dose-limiting; monitor CBC closely.

Answer

A. Erythropoietin

Answer

C. Splenectomy

Answer

D. Folic acid supplementation

Explanation

HbF Induction in Thalassemia Intermedia

Mechanism of Hydroxyurea

Efficacy in Thalassemia

Monitoring During Hydroxyurea Therapy

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Outcome	Hydroxyurea	Splenectomy	Folic Acid	EPO
HbF induction	Yes (30–50% increase)	No	No	No
Transfusion reduction	Yes (50–80% of patients)	Modest	No	Minimal
Mechanism	γ-globin reactivation	Reduces splenic sequestration	Supports RBC production	Stimulates RBC production
Onset	4–12 weeks	Immediate (post-op)	Weeks	Days–weeks
First-line status	Yes	Adjunctive	Supportive	Adjunctive