INTRODUCTION

The beneficial effects of high levels of fetal hemoglobin (HbF) in sickle cell disease and β thalassemia have been recognized for many years. In 1948, Watson et al. noted that newborns with sickle cell disease do not suffer from the clinical complications of their disease until HbF declines to adult levels after the first 6 months of life. Later, it was shown that the majority of patients with sickle cell disease from some regions of Saudi Arabia and India who co-inherit another genetic determinant associated with high HbF levels, have a very mild sickling disorder. More recently, the Cooperative Study of Sickle Cell Disease, a large multicenter study of the natural history of sickle cell disease (see Chapter 19) demonstrated an inverse correlation between HbF levels and the frequency of painful crises and early death. These clinical and epidemiological observations are supported by laboratory studies that demonstrate a sparing effect of HbF on polymerization of deoxyhemoglobin S. Similarly, in β thalassemia, an increase in the synthesis of fetal γ-globin chains may decrease the imbalance between α- and non-α-globin chains and ameliorate the severity of the anemia. This appreciation of the beneficial effects of HbF in sickle cell disease and β thalassemia stimulated a great deal of interest in the development of therapeutic agents to increase HbF production in patients with these disorders.