Fetal hemoglobin, sickling, and sickle cell disease

Abstract

Increased numbers of F cells and large amounts of Hb F/F cell appear to produce clinical benefit in rare variants of sickle cell disease and probably in more commonly encountered patients. Fetal hemoglobin interferes with polymerization of Hb S in vitro, but laboratory studies carried out with homogeneous hemoglobin solutions are inadequate models of events in vivo, because RBCs are heterogeneous in their MCHC and Hb F content. Studies of hemoglobin switching in sheep, in tissue culture, and then in baboons led to use of 5-azacytidine for induction of increased Hb F synthesis in SS patients. Drug trials were successful but the theory that led to them was not. An alternate theory, not without flaws, led to the use of hydroxyurea. Chronic administration of the drug can lead to very impressive increases in Hb F synthesis and apparent clinical benefit. It is not clear that such clinical benefit is real rather than a placebo effect. Nor is it entirely clear that all of the effect of hydroxyurea can be related to increased production of F cells and increased F/F cell. Controlled clinical trials and studies of the properties of RBCs from treated patients may answer those questions. It is also likely that they will not only raise still other questions but probably show that our current understanding of the biology and treatment of sickle cell disease is far from complete.