PharmacologyTier 2Medical Sciences concept

Hydroxyurea mechanism in sickle cell disease (HbF induction)

Core concept

Induces fetal haemoglobin (HbF) production - the principal disease-modifying mechanism in sickle cell disease
HbF (a2g2) does not co-polymerise with HbS - dilutes intracellular HbS concentration and interferes with polymer formation, the root cause of sickling
Also has independent nitric oxide donor properties contributing to vasodilation

Key detail

Also myelosuppressive (reduces neutrophil and reticulocyte counts) and increases red cell hydration/deformability - additional mechanisms reducing vaso-occlusion
Reduces vaso-occlusive crisis frequency, acute chest syndrome, transfusion requirement and mortality - genuinely disease-modifying
Requires regular FBC monitoring for myelosuppression; takes several months to reach maximal HbF response

Clinical relevance

First-line disease-modifying therapy for most patients with sickle cell disease, including many with only moderate symptom burden - not reserved for severe disease
Teratogenic - contraception counselling required; caution with pregnancy planning
Non-response or intolerance -> consider L-glutamine, crizanlizumab, or voxelotor as alternative/add-on agents

Correlations

Sickle cell disease pathophysiology and crises
Fetal haemoglobin and haemoglobin switching
Gene therapy approaches in haemoglobinopathy

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