S. S. Lamba*, K. Y. Such and H. Lewis Ill Pages 366 - 375 ( 10 )
Recent biochemical and biophysical studies of sickle cell hemoglobin have provided valuable insight into the molecular basis of the sickling phenomenon in sickle cell disease. A large number of compounds have been examined for antisickling potential. These can be characterized as noncovalent or covalent in their mechanism of action. Examples of noncovalent agents include: alkylureas, dimethyl sulfoxide, dimethylforma mide, small peptides, etc. Examples of covalent agents include: nitrogen mustard, glyceraldehyde, aldehydic pyridoxal derivatives, dimethyladipimi date, etc. Also, acylating agents such as acylsalicylates have been investigated. lnspite of such advances and attempts, a useful agent has not been successfully produced. Thus, sickle cell disease continues to be a serious health problem for which there is no cure, and the treatment remains to be symptomatic.
Sickle cell disease includes a group of hereditary hemoglobin disorders characterized by red cells which undergo sickle shape transformation under hypoxic conditions. Due to the substitution of valine for glutamic acid in position 6 of the beta chain, sickle hemoglobin polymerizes when it is deoxygenated. The most clinically significant of these diseases is sickle cell anemia. Symptoms include dactylitis, painful crisis, splenic sequestration and the development of multi-organ damage and failure. Different clinical presentations of sickle cell anemia call for individualized management. The reason for such clinical variability is not known; although the patient's hemoglobin level as well as fetal hemoglobin (HbF) concentrations are important. New therapeutic approaches include the use of hydroxyurea which is reported to increase the level of fetal hemoglobin which interferes with polymer formation. Because fetal hemoglobin contains gammaglobin chains instead of beta chains, it is not affected by the genetic defect that causes sickle cell disease. Increased levels of fetal hemoglobin decrease the tendency toward intracellular polymerization of sickle hemoglobin that characterizes the disease.
This review provides information regarding the role of fetal hemoglobin (HbF) and sickling; methodology for an accurate quantitation of HbF; recent pharmacological interventions; and includes results of selected clinical trials reported in recent years.