This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sickle cell disease or sickle cell anemia is a hereditary disorder of hemoglobin that affects approximately 1 in 500 births in black families in the United States. The abnormality of the hemoglobin molecule was recognized in 1949 making this disorder the first disease understood at a molecular level. We now know that the disease results from a single amino acid chain - the substitution of glutamic acid by valine at the eighth amino acid of the beta hemoglobin chain. This substitution leads to polymerization of hemoglobin S (Hb S) that results in gelation or crystallization of the Hb S tetramer when it unloads oxygen in the tissues. The gelation of the Hb S results in an abnormally shaped red cell that is sickle shaped and poorly deformable. The disease is manifested by three clincally important phenomena of vasocclusion that results in either: a) chronic organ damage (resulting in kidney failure, etc.); b) acute crises which may involve a specific site such as the lungs (acute chest syndrome), the brain (stroke), generalized symptoms mainly manifested as extremities and chest pain (pain crisis); and hemolytic anemia. Pain crises are the most frequent causes of hospitalization, they are also the most significant cause of morbidity, loss of work, and social difficulties that sickle patients encounter. Infants born with sickle cell disease are asymptomatic because of the presence of fetal hemoglobin (HbF) that even in small amounts inhibit polymerization of Hb S; they become symptomatic by the age of 6 months when HbF is substituted for adult hemoglobin. Hydroxyurea has emerged as an effective agent in the treatment of patients with sickle cell disease who have frequent pain crises. Hydroxyurea's beneficial effects include an increase in the HbF level, and an increase in the number of erythrocytes that contain HbF cells. Hydroxyurea may also work by decreasing the number of circulating reticulocytes, white blood cells, and platelets, which may participate in the pathogenesis of sickle crises. It is possible to augment the effect of hydroxyurea on HbF by treatment with recombinant human erythropoietin (rHuEPO), thus reducing the likelihood of sickling. The reported trials of rHuEPO in sickle cell disease showed mixed results because the effect of erythropoietin (EPO) appeared to be schedule-dependent. A newly developed erythropoiesis stimulating protein, darbepoetin alfa (ARANESP), manufactured by Amgen Inc., differs from rHuEPO in several ways and may offer advantages in the treatment of sickle cell disease. Darbeoetin alfa is heavily glycosylated, having up to 22 sailic acid residues per molecule (compared to 14 in rHuEPO). The greater carbohydrate content results in a significant prolonation of the half-life (49 hours) of the protein in the circulation. Phase I and II studies demonstrated efficacy and safety in the treatment of anemia during cancer chemotherapy. No antibodies to darbeopoetin alfa have been discovered in over 7,000 patients treated to date. As with rHuEPO, co-administration of iron may be required to achieve an optimal effect. The chief advantage in these treatment situations appears to be the ability to treat weekly and possibly every three weeks comparted to 3 times per week as required for rHuEPO.
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