Erythropoietin (EPO), a glycoprotein (~30,400
daltons) produced primarily by the kidney, is the principal factor
regulating red blood cell production (erythropoiesis) in mammals.3
Renal production is regulated by changes in oxygen availability.
Normally, EPO levels vary inversely with hematocrit. Under conditions of
hypoxia, the level of EPO in the circulation increases, leading to
increased production of red blood cells. Conversely, a high hematocrit
should suppress the release of EPO.
The over-expression of EPO may be associated with certain pathophysiological conditions.4
Primary polycythemia (polycythemia vera) is a neoplastic (clonal) blood
disorder characterized by EPO-independent, autonomous production of
erythrocytic progenitors from abnormal bone marrow stem.5 The
majority of polycythemia vera cases are caused by oncogenic mutations
that constitutively activate the JAKSTAT signal transduction pathway,
such as JAK2V617F, or exon 12 mutations or LNK mutations. In most cases, decreased levels of EPO are found in the serum of affected patients.5 Conversely, various types of secondary polycythemias are associated with the production of elevated levels of EPO.5-8
The overproduction of EPO may be an adaptive response associated with
conditions that produce tissue hypoxia, such as living at a high
altitude, chronic obstructive pulmonary disease, cyanotic heart disease,
sleep apnea, high oxygen affinity hemoglobinopathy, smoking, or
localized renal hypoxia. In other instances, elevated EPO levels are the
result of production by neoplastic cells. Tumors that have been
associated with an inappropriate EPO production include cerebellar
hemangioblastomas, uterine leiomyomas, pheochromocytoma, renal cell
carcinoma, hepatocellular carcinoma, parathyroid adenomas, and
meningiomas.6
Deficient EPO production is found in conjunction with certain forms of anemia.9,10 These include anemia of renal failure, end-stage renal disease,11
hypothyroidism, and malnutrition. EPO levels are often measured in
patients with chronic kidney disease to assess the kidneys' continued
ability to produce erythropoietin. Anemias of chronic disease (chronic
infections, autoimmune diseases, rheumatoid arthritis, AIDS,
malignancies), are characterized by a blunted response of erythroid
progenitors to EPO. Other forms of anemia can be associated with
EPO-independent causes, and affected individuals show elevated levels of
EPO. These forms include aplastic anemias, iron deficiency anemias,
thalassemia, megaloblastic anemias, pure red cell aplasias, and
myelodysplastic syndromes.12
Recombinant human EPO
(rhEPO) is administered clinically to stimulate red cell production in
patients with chronic kidney disease, HIV-infected patients treated with
zidovudine, patients undergoing myelosuppressive chemotherapy
treatment, and other anemic patients (as an alternative to blood
transfusion.)13,14 Several investigators have reported that
in chemotherapy-treated cancer patients, baseline EPO levels of greater
than 500 mIU/mL predicts unresponsiveness to EPO therapy. Endogenous
serum erythropoietin levels are measured as a qualification criterion
for rhEPO treatment of anemia in HIV-infected patients taking
zidovudine.13
Pretransfusion erythropoietin levels
have also been used to predict patients with myelodysplastic syndromes
that are likely to respond to rhEPO treatment.12,15 rhEPO is
used by some athletes as a performance enhancing drug in an effort to
increase endurance and oxygen capacity by increasing the red blood cell
count.16 This inappropriate use of the drug can result in
adverse clinical consequences due to hypertension and increased blood
viscosity. Its use has been prohibited by most sports organizations.
