Sickle Cell Disease and Hydroxyurea
Sickle cell disease is an important genetic cause of hemolytic anemia, a form of anemia due to increased erythrocyte destruc-tion, instead of the reduced mature erythrocyte production seen with iron, folic acid, and vitamin B12 deficiency. Patients with sickle cell disease are homozygous for the aberrant β-hemoglobin S (HbS) allele or heterozygous for HbS and a second mutated β-hemoglobin gene such as hemoglobin C (HbC ) or β-thal-assemia. Sickle cell disease has an increased prevalence in individuals of African descent because the heterozygous trait confers resistance to malaria.In the majority of patients with sickle cell disease, anemia is not the major problem; the anemia is generally well compen-sated even though such individuals have a chronically low hema-tocrit (20–30%), a low serum hemoglobin level (7–10 g/dL), and an elevated reticulocyte count. Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization. Abnormal erythrocytes aggregate in the microvasculature—where oxygen tension is low and hemoglobin is deoxygenated—and cause veno-occlusive dam-age. The clinical manifestations of sickle cell disease reflect organ damage by veno-occlusive events. In the musculoskeletal system, this results in characteristic, extremely painful bone andjoint pain. In the cerebral vascular system, it causes ischemic stroke. Damage to the spleen increases the risk of infection, particularly by encapsulated bacteria such as Streptococcuspneumoniae. In the pulmonary system, there is an increased riskof infection and, in adults, an increase in embolism and pulmo-nary hypertension. Supportive treatment includes analgesics, antibiotics, pneumococcal vaccination, and blood transfu-sions. In addition, the cancer chemotherapeutic drug hydroxyu-rea (hydroxycarbamide) reduces veno-occlusive events. It isapproved in the United States for treatment of adults with recur-rent sickle cell crises and approved in Europe in adults and chil-dren with recurrent vaso-occlusive events. As an anticancer drug used in the treatment of chronic and acute myelogenous leuke-mia, hydroxyurea inhibits ribonucleotide reductase and thereby depletes deoxynucleoside triphosphate and arrests cells in the S phase of the cell cycle . In the treatment of sickle cell disease, hydroxyurea acts through poorly defined pathways to increase the production of fetal hemoglobin γ (HbF), which interferes with the polymerization of HbS. Clinical trials have shown that hydroxyurea decreases painful crises in adults and children with severe sickle cell disease. Its adverse effects include hematopoietic depression, gastrointestinal effects, and terato-genicity in pregnant women.