Erythropoietin

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erythropoietin
Identifiers
Symbol	EPO
HUGO	3415
Entrez	2056
OMIM	133170
RefSeq	NM_000799
UniProt	P01588
Other data
Locus	Chr. 7 q21

Erythropoietin (IPA pronunciation: [ɪˌɹɪθ.ɹoˈpo.ɪ.tɪn], alternative pronunciations: [ɪˌrɪθroʊˈpɔɪtn, əˌrɪθroʊ-, əˌriθroʊ-]) or EPO is a glycoprotein hormone that is a cytokine for erythrocyte (red blood cell) precursors in the bone marrow. Also called hematopoietin or hemopoietin, it is produced by the kidney, and is the hormone regulating red blood cell production. Erythropoietin is available as a therapeutic agent produced by recombinant DNA technology in mammalian cell culture. It is used in treating anemia resulting from chronic renal failure or from cancer chemotherapy. Its use is also believed to be common as a blood doping agent in endurance sports such as bicycle racing, triathlons and marathon running.

1 Discovery and biological role
2 EPO as a therapeutic agent
3 EPO as a blood doping agent
4 Erythropoietin and Jehovah's Witnesses
5 Adverse effects
6 Safety advisories in anemic cancer patients
7 See also
8 References
9 External links

[edit] Discovery and biological role

The existence of a humoral factor regulating red blood cell production was first postulated in 1906^[1] based on transfusion experiments in rabbits. In 1950, the still unidentified erythropoietic factor was found to be stimulated in rats breathing a low-oxygen atmosphere, thus establishing the elements of its biological regulation. In the 1960s its source was identified as the kidneys. Human EPO was first purified from human urine by T. Miyake, C. K. Kung and E. Goldwasser at the University of Chicago in 1977.^[2] Limited quantitites of the native human protein were used experimentally to treat patients with anemia.

EPO has now been identified as a glycoprotein with a molecular mass of about 30,000 Daltons. It has a 165 amino acid chain with four oligosaccharide side chains and circulates in the blood plasma at a very low concentration (about 5 pmol/L).

In adult humans, EPO is produced primarily by peritubular cells in the kidneys, where its production is stimulated by low oxygen levels in the blood, also known as hypoxia. Some EPO is also produced by the liver, which is the primary source in the fetus.

EPO acts by binding to a specific erythropoietin receptor (EpoR) on the surface of red cell precursors in the bone marrow, stimulating them to transform into mature red blood cells. As a result the oxygen level in blood reaching the kidney rises and the amount of EPO produced decreases.

Because the kidneys are the primary source of erythropoietin, chronic kidney disease often results in a systemic deficiency of EPO and consequent anemia. Anemia can also occur in cancer patients, sometimes as a direct result of the malignancy but usually as an adverse effect of chemotherapy.

Also, in patients who may require a blood transfusion or undergo surgery where blood loss is expected, EPO is given in advance as a precaution. The bone marrow produces more red blood cells, and if blood is lost during the operation, there is still enough to sustain the patient.

[edit] EPO as a therapeutic agent

Therapeutic human EPO was initially isolated and purified from urine in 1977. In 1983, the gene coding for EPO was identified. In 1991 it was also approved for treating anemia resulting from cancer chemotherapy. Johnson & Johnson, an American pharmaceutical company, markets EPO under license from Amgen for cancer chemotherapy under the brand name Procrit. EPO is generally injected under the skin by the patient, although it may also be given intravenously. Several injections weekly are required for the original forms, but the long-acting forms may require injections only once every two weeks.By far the most common side-effect for any EPO products is fever. Also, use of EPO products can lead to an increased chance of the formation of blood clots. Headache, nausea, vomiting, and delirium are also common side-effects. All forms of EPO are expensive. A dialysis patient, who can expect to require lifelong EPO treatment, will pay up to $10,000 per year for the drug in the U.S. Cancer chemotherapy patients, who require EPO for shorter periods, pay about $1,000 per month in the U.S. Worldwide revenues for sales of EPO were over 'USD$10 billion in 2004.'

[edit] EPO as a blood doping agent

Although pharmaceutical EPO has benefited many thousands of anemic patients, it also has a converse side as a blood doping agent sometimes used by healthy athletes to gain a competitive advantage. By increasing the oxygen carrying capacity of the blood it increases the aerobic respiratory capacity of the muscles, making it appealing to participants in endurance sports such as cycling and long-distance running. It is considered to be especially valuable in multi-stage bicycle races, where it can offset the decrease in red blood cells that occurs over several weeks of racing. EPO doping probably became common in Grand Tour cycling after pharmaceutical EPO became available in the late 1980s, but there was at the time no way to prove its use in the absence of physical evidence of EPO possession. The deaths of a dozen or more elite cyclists in the early 1990s from heart failure while sleeping, were grim evidence of its overuse. Excessive use of pharmaceutical EPO can lead to so many red blood cells that the blood becomes thick enough to strain the heart, especially during sleep when the heart rate is low. Beyond a certain point, the increase in haematocrit is actually detrimental to the oxygen carrying capacity due to negative blood flow effects, and increases the likelihood of developing symptoms similar to chronic mountain sickness.The extent of the doping problem became undeniable after the Festina team scandal in the 1998 Tour de France, in which Willy Voet was apprehended with a huge cache of doping materials, including EPO. He and others later wrote about the widespread use of drugs in cycling. In the 2000 Tour de France, a laboratory test to detect residues of pharmaceutical EPO in urine was introduced for the first time as an anti-doping measure. It was developed by the French National Laboratory for Doping Detection. The test method relies on laboratory methods for distinguishing pharmaceutical EPO from the endogenous EPO normally present in an athlete’s urine after strenuous exercise. Because existing brands of pharmaceutical EPO are made in cell culture animal cells, they have a different pattern of residues than the native human form. Although widely applied, the test is controversial. In 2005, Rutger Beke, a Belgian triathlete successfully challenged his conviction for EPO doping by presenting scientific evidence that the test was unreliable in his case. Several other athletes have since made similar defenses. In the highest profile case to date, Spanish rider Roberto Heras was stripped of what would have been his fourth win of the Vuelta a España in 2005 after a positive urine test for pharmaceutical EPO. He has asserted his innocence and vowed to challenge the conviction based on the handling of his sample and alleged weaknesses in the test method.

[edit] Erythropoietin and Jehovah's Witnesses

Jehovah's Witnesses believe in the Bible's command at Acts 15:28,29 to "abstain from blood"; this belief results in the refusal to accept transfusions of whole blood or any of its four major components.

The use of erythropoietin to increase the number of red blood cells is one suggested alternative to a blood transfusion.

The presence of human albumin in the erythropoietin mixture may preclude its use by some Jehovah's Witnesses, although an alternative now exists: Darbepoetin alfa (marketed under the name Aranesp), a synthetic form of erythropoietin containing no blood fractions.

[edit] Adverse effects

Erythropoietin is associated with an increased risk of adverse cardiovascular complications if it is used to increase hemoglobin levels above 13.0 g/dl.^[3]

[edit] Safety advisories in anemic cancer patients

Amgen sent a "dear doctor" letter in January, 2007, that highlighted results from a recent anemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.

Amgen advised the United States FDA as to the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).

In response to these advisories, the FDA released a Public Health Advisory^[4] on March 9, 2007, and a clinical Alert^[5] for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents such as epogen and darbepoeitin. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.

In addition, on March 9, 2007, drug manufacturers agreed to new "black box" warnings about the safety of these drugs.

On March 22, 2007, a congressional inquiry into the safety of erythropoeitic growth factors was reported in the news media.^[6] Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.

[edit] See also

Amgen, producer of artificial EPO (Brand Names: Epogen and Aranesp)
Dynepo, trademark name for an erythropoiesis stimulating protein, by TKT
Blood doping, transfusions and EPO use as doping methods; testing and enforcement
Jehovah's Witnesses and blood transfusions