Pharmacologic modulation of fetal hemoglobin

Fetal hemoglobin (HbF) inhibits the polymerization of sickle hemoglobin (HbS) and can substitute for normal adult hemoglobin in erythrocytes of patients with β thalassemia and sickle cell anemia. For these reasons, pharmacologic agents that can reverse the switch from γ- to β-globin chain synthesis (ψ-globin chains characterize HbF and sickle β-globin chains are present in HbS)or select adult erythroid precursors that maintain the ability to produce HbF are therapeutically useful. The first "hemoglobin switching" agent, a nucleoside analog, 5-azacytidine, was postulated to increase HbF by causing gene hypomethylation. Other drugs, of which hydroxyurea is the prototype, promote HbF production indirectly by perturbing the maturation of erythroid precursors. Short-chain fatty acids may directly affect HbF gene expression. Of all agents that modulate HhF gene expression, only hydroxyurea has been proven clinically effective in controlled clinical trials in patients with sickle cell anemia. Modulation of HbF production using hydroxyurea is a promising beginning for pharmacologic therapy of hemoglobinopathies. Still, in adults with sickle cell anemia its effects are not consistent, and the limit of increasing HbF with hydroxyurea alone may have been reached. In very young children its use is just starting and its ultimate value, and peril, when started early in life is still unknown.