Clinical Information

Erythropoietin (EPO), a large (193 amino acid residue) glycoprotein hormone secreted by the kidney, regulates red blood cell (RBC) production. Normally, EPO levels vary inversely with hematocrit. Hypoxia stimulates EPO release, which, in turn, stimulates bone marrow erythrocyte production. High blood levels of RBC, hemoglobin, hematocrit, or oxygen suppress the release of EPO.

Primary polycythemia (polycythemia vera) is a neoplastic (clonal) blood disorder characterized by autonomous production of hematopoietic cells. Increased RBCs result in compensatory suppression of EPO levels. Findings consistent with polycythemia vera include hemoglobin greater than 18.5 g/dL, persistent leukocytosis, persistent thrombocytosis, unusual thrombosis, splenomegaly, and erythromelalgia (dysesthesia and erythema involving the distal extremities).

Secondary polycythemias may either be due to an appropriate or an inappropriate increase in red cell mass. Appropriate secondary polycythemias (eg, high-altitude living and pulmonary disease) are characterized by hypoxia and a compensatory increase in red cell mass. EPO production is increased in an attempt to increase the delivery of oxygen by increasing the number of oxygen-carrying RBCs. Some tumors secrete EPO or EPO-like proteins; examples include tumors of the kidney, liver, lung, and brain. Such increases result in inappropriate secondary polycythemias.

Abnormal EPO levels also may be seen in renal failure. The majority of EPO production is in the kidneys. Therefore, chronic kidney failure may result in decreased EPO production and, subsequently, anemia. In addition to the kidneys, the liver also produces a small amount of EPO. Thus, patients who are anephric have a residual amount of EPO produced by the liver.

Patients in chronic kidney failure, as well as patients with anemia due to a variety of other causes including chemotherapy, HIV/AIDS, and some hematologic disorders, may be candidates for treatment with recombinant human EPO. Recombinant EPO compounds used to treat anemia include epoetin alpha and darbepoetin. Epoetin alpha is a 165 amino acid glycoprotein produced in mammalian cells and has an identical amino acid sequence to natural human EPO. It has 3 oligosaccharide chains and a molecular mass of 30.4 kDa. Darbepoetin alpha is a 165 amino acid glycoprotein that is also produced in mammalian cells. It has 2 additional N-linked oligosaccharide chains and a molecular mass of 37 kDa. There are no specific assays for measuring recombinant EPO compounds. Drug levels can only be roughly estimated from the cross reactivity of the compounds in EPO assays. According to in-house studies, epoetin and darbepoetin show approximately 58% and 36% cross-reactivity, respectively, in the EPO assay.