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Hydroxyurea and other disease-modifying therapies in sickle cell disease

Griffin P Rodgers, MD
Section Editors
Stanley L Schrier, MD
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD


The major causes of morbidity and mortality in sickle cell disease (SCD) are the acute and long-term consequences of vasoocclusion, many of which cannot be reversed (eg, tissue infarction). (See "Overview of the clinical manifestations of sickle cell disease".)

The development of vasoocclusion is the result of a number of factors, beginning with the polymerization of deoxyhemoglobin S (HbS) and ending with the subsequent interactions between the sickled erythrocyte and the vascular endothelium. Factors that influence such hemoglobin polymerization include cellular dehydration, which increases the concentration of HbS and the sickling process; the level of gamma globin chains, which inhibit the polymerization of HbS; intracellular acidosis; and oxygen saturation. (See "Sickle hemoglobin polymer: Structure and functional properties" and "Mechanisms of vasoocclusion in sickle cell disease".)

Hydroxyurea and other agents that have been employed to decrease these processes and prevent irreversible complications of SCD will be reviewed here. Overviews of the treatment of SCD, the use of transfusion in SCD, and hematopoietic cell transplantation, the only curative treatment for SCD, are presented separately. (See "Overview of the management and prognosis of sickle cell disease" and "Hematopoietic cell transplantation in sickle cell disease" and "Red blood cell transfusion in sickle cell disease".)


Rationale for using disease-modifying therapies — A definitive cure is not currently available for most patients with sickle cell disease (SCD), and therapies directed at symptom relief do not alter the natural history of the disease. Thus, therapies are needed that prevent complications without subjecting patients to the morbidity and mortality of highly aggressive approaches such as hematopoietic cell transplantation (HCT).

Gene therapy for SCD is especially formidable, due to the necessity for erythroid-specific, high level, and balanced globin gene expression and the difficulty in transducing hematopoietic stem cells. As a result, increasing attention has been focused on the use of HCT. (See 'Gene therapy' below and 'Hematopoietic cell transplantation' below and "Hematopoietic cell transplantation in sickle cell disease".)


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