A 28-year-old man with sickle cell disease presents with recurrent vaso-occlusive crises. Which drug is the first-line agent for reducing the frequency and severity of these crises?

Question

Accepted Answer

B. Hydroxyurea. ## 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]

Answer

A. Deferasirox

Answer

C. Penicillin V

Answer

D. Folic acid

A 28-year-old man with sickle cell disease presents with recurrent vaso-occlusive crises. Which drug is the first-line agent for reducing the frequency and severity of these crises?

Explanation

First-Line Anti-Sickling Agent

Mechanism of Action

Clinical Evidence

Dosing & Monitoring

Side Effects & Contraindications

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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