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Erythropoietin (EPO) is a large glycoprotein hormone that regulates red blood cell production. More than 90% of circulating EPO is produced by the kidney and 10% by the liver. Normally, EPO levels vary inversely with hemoglobin or hematocrit. Hypoxia stimulates EPO release, which, in turn, stimulates bone marrow erythropoiesis. Elevated levels of RBC, hemoglobin, hematocrit or oxygen suppress the release of EPO.


Patients with uncomplicated EPO-independent anemia have elevated concentrations of EPO that are appropriate for the level of anemia. Their EPO value falls within the hatched area of graph. Examples include iron deficiency, aplastic anemia, sickle cell anemia, thalassemia, megaloblastic anemia, and myelodysplastic syndromes.

Chronic renal failure may result in decreased renal EPO synthesis and, subsequently, anemia. In addition to renal failure, other conditions such as chronic infections (e.g. AIDS), chronic inflammation (e.g. rheumatoid arthritis & inflammatory bowel disease) malignancies (e.g. solid tumors, multiple myeloma & lymphoma) and prematurity are associated with anemia and deficient serum EPO levels. Patients suffering from EPO-deficient anemias have erythropoietin levels that are inappropriately low for the degree of anemia. Their EPO values fall within the darker shaded area of the graph. These patients may benefit from therapy with recombinant EPO.

Polycythemia vera is a neoplastic clonal blood disorder with autonomous proliferation of red blood cells. Increased red blood cells result in a negative feedback suppression of EPO. Patients with polycythemia vera have extremely elevated hemoglobin or hematocrit and decreased serum erythropoietin level.

Secondary polycythemia is associated with disorders that cause tissue hypoxia such as living at high altitude, chronic obstructive pulmonary disease, cyanotic heart disease, sleep apnea, high affinity hemoglobinopathy, smoking, or localized renal hypoxia. In secondary polycythemia, EPO production is increased in an attempt to increase oxygen delivery to tissues by increasing the number of oxygen carrying red blood cells. Patients with secondary polycythemia have elevated hemoglobin or hematocrit and higher than normal serum EPO level.

Some tumors secrete EPO or EPO-like proteins and cause erythrocytosis. Examples include renal cell carcinoma, Wilm’s tumor, hepatoma, cerebellar hemangioblastoma, adrenal tumors, and leiomyoma.

In the work up of polycythemia, an EPO assay is indicated if the hemoglobin level is greater than 18.5 g/dL in men or 16.5 g/dL in women, or if there is a lesser degree of hemoglobin elevation associated with polycythemia vera-related features. A low serum EPO level indicates that polycythemia vera is very likely. If the EPO level is elevated, the diagnosis is probably secondary erythrocytosis.

Reference range is 4 – 20 mIU/mL using an Immulite 2000 analyzer. Specimen requirement is a plain red top or SST tube of blood. This assay cannot distinguish between endogenous and exogenous EPO.

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