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Erythropoietin, also known as erythropoetin or erthropoyetin (//, //, and //) or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine (protein signaling molecule) for erythrocyte (red blood cell) precursors in the bone marrow. Human EPO has a molecular weight of 34 kDa.
Also called hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and tubular epithelial tubule. It is also produced in perisinusoidal cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. In addition to erythropoiesis, erythropoietin also has other known biological functions. For example, it plays an important role in the brain's response to neuronal injury. EPO is also involved in the wound healing process.
When exogenous EPO is used as a performance-enhancing drug, it is classified as an erythropoiesis-stimulating agent (ESA). Exogenous EPO can often be detected in blood, due to slight differences from the endogenous protein, for example, in features of posttranslational modification.
Primary role in red blood cell production
Erythropoietin is an essential hormone for red cell production. Without it, definitive erythropoiesis does not take place. Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting CFU-E, proerythroblast and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone marrow in humans) by promoting their survival through protecting these cells from apoptosis.
Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., IL-3, IL-6, glucocorticoids, and SCF) involved in the development of erythroid lineage from multipotent progenitors. The burst-forming unit-erythroid (BFU-E) cells start erythropoietin receptor expression and are sensitive to erythropoietin. Subsequent stage, the colony-forming unit-erythroid (CFU-E), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it.
Additional nonhematopoietic roles
Erythropoietin has a range of actions including vasoconstriction-dependent hypertension, stimulating angiogenesis, and inducing proliferation of smooth muscle fibers. It can increase iron absorption by suppressing the hormone hepcidin.
EPO also affects neuronal protection during hypoxic conditions (stroke, etc.). Trials on human subjects are not yet reported; if proven to be a viable treatment of heart attack and stroke patients, it could improve the outcome and quality of life. The reasoning behind such a proposal is that EPO levels of 100 times the baseline have been detected in brain tissue as a natural response to (primarily) hypoxic damage.
Multiple studies have suggested that EPO improves memory. This effect is independent of its effect on hematocrit. Rather, it is associated with an increase in hippocampal response and effects on synaptic connectivity, neuronal plasticity, and memory-related neural networks. EPO may also be an effective treatment for depression.
Mechanism of action
EPO is highly glycosylated (40% of total molecular weight), with half-life in blood around five hours. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections). EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a JAK2 signaling cascade. Erythropoietin receptor expression is found in a number of tissues, such as bone marrow and peripheral/central nervous tissue. In the bloodstream, red cells themselves do not express erythropoietin receptor, so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis.
Synthesis and regulation
Erythropoietin levels in blood are quite low in the absence of anemia, at around 10 mU/ml. However, in hypoxic stress, EPO production may increase 1000-fold, reaching 10,000 mU/ml of blood. EPO is produced mainly by peritubular capillary lining cells of the renal cortex, which are highly specialized, epithelial-like cells. It is synthesized by renal peritubular cells in adults, with a small amount being produced in the liver. Regulation is believed to rely on a feedback mechanism measuring blood oxygenation. Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen.
Erythropoietins available for use as therapeutic agents are produced by recombinant DNA technology in cell culture, and include Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa); they are used in treating anemia resulting from chronic kidney disease, inflammatory bowel disease (Crohn's disease and ulcer colitis) and myelodysplasia from the treatment of cancer (chemotherapy and radiation), but include boxed warnings of increased risk of death, myocardial infarction, stroke, venous thromboembolism, tumor recurrence, and other severe off-target effects.
Recombinant EPO has a variety of glycosylation patterns giving rise to alfa, beta, delta, and omega forms:
Darbepoetin alfa is a form created by five substitutions (Asn-57, Thr-59, Val-114, Asn-115 and Thr-117) that create two new N-glycosylation sites.
More recently, a novel erythropoiesis-stimulating protein (NESP) has been produced. This glycoprotein demonstrates anti-anemic capabilities and has a longer terminal half-life than erythropoietin. NESP offers chronic renal-failure patients a lower dose of hormones to maintain normal hemoglobin levels.
Erythropoiesis-stimulating agents (ESAs) have a history of use as blood doping agents in endurance sports, such as horseracing, boxing, cycling, rowing, distance running, race walking, snowshoeing, cross country skiing, biathlon, and triathlon. The overall oxygen delivery system (blood oxygen levels, as well as heart stroke volume, vascularization, and lung function) is one of the major limiting factors to muscles' ability to perform endurance exercise. Therefore, the primary reason athletes may use ESAs is to improve oxygen delivery to muscles, which directly improves their endurance capacity. With the advent of recombinant erythropoietin in the 1990s, the practice of autologous and homologous blood transfusion has been partially replaced by injecting erythropoietin such that the body naturally produces its own red cells. ESAs increase hematocrit (% of blood volume that is red cell mass) and total red cell mass in the body, providing a good advantage in sports where such practice is banned. In addition to ethical considerations in sports, providing an increased red cell mass beyond the natural levels reduces blood flow due to increased viscosity, and increases the likelihood of thrombosis and stroke. Due to dangers associated with using ESAs, their use should be limited to the clinic where anemic patients are boosted back to normal hemoglobin levels (as opposed to going above the normal levels for performance advantage, leading to an increased risk of death).
Though EPO was believed to be widely used in the 1990s in certain sports, there was no way at the time to directly test for it, until in 2000, when a test developed by scientists at the French national antidoping laboratory (LNDD) and endorsed by the World Anti-Doping Agency (WADA) was introduced to detect pharmaceutical EPO by distinguishing it from the nearly identical natural hormone normally present in an athlete's urine.
In 2002, at the Winter Olympic Games in Salt Lake City, Dr. Don Catlin, the founder and then-director of the UCLA Olympic Analytical Lab, reported finding darbepoetin alfa, a form of erythropoietin, in a test sample for the first time in sports. At the 2012 Summer Olympics in London, Alex Schwazer, the gold medalist in the 50-kilometer race walk in the 2008 Summer Olympics in Beijing, tested positive for EPO and was disqualified.
Since 2002, EPO tests performed by US sports authorities have consisted of only a urine or "direct" test. From 2000–2006, EPO tests at the Olympics were conducted on both blood and urine. However, several compounds have been identified that can be taken orally to stimulate endogenous EPO production. Most of the compounds stabilize the hypoxia-inducible transcription factors which activate the EPO gene. The compounds include oxo-glutarate competitors, but also simple ions such as cobalt(II) chloride. 
Synthetic EPO is believed to have come into use in cycling about 1990. In theory, EPO use can increase VO2max by a significant amount, making it useful for endurance sports like cycling. Italian antidoping advocate Sandro Donati has claimed that the history of doping in cycling can be traced to the Italian Dr Francesco Conconi at the University of Ferrara. Conconi had worked on the idea of giving athletes tranfusions of their own blood in the 1980s. Donati felt this work "opened the road to EPO . . . because blood doping was a trial to understand the role of EPO".
Dr Michele Ferrari, a former student and mentee of Conconi, had a controversial interview mentioning the drug in 1994, just after his Gewiss-Ballan team had a remarkable performance in the La Flèche Wallonne race. Ferrari told l'Equipe journalist Jean-Michel Rouet that EPO had no "fundamental" effect on performance and that if his riders used it, it wouldn't "scandalize" himself. After the journalist pointed out several riders were suspected of dying from EPO, Ferrari said EPO was not dangerous, and only abuse of it was dangerous, saying, "It's also dangerous to drink 10 liters of orange juice." The 'orange juice' comment has been widely misquoted. Ferrari was fired shortly after, but continued to work in the industry. That same year, Sandro Donati, working for the Italian National Olympic Committee, presented a report accusing Conconi of being linked to the use of EPO in the sport.
In 1997, the Union Cycliste Internationale (UCI) instituted a new rule that riders testing above 50% haematocrit were not allowed to race. Robert Millar, former racer, later wrote for Cycling News that the 50% limit was "an open invitation to dope to that level", pointing out that normally haematocrit levels would start "around 40-42%" and drop during the course of a "grand tour", but after EPO, they were staying at 50% for "weeks at a time". By 1998, EPO use had become widespread, and the Festina affair tarnished the 1998 Tour de France. One manager offered a 270,000-franc-per-month raise to Christophe Bassons if he would use EPO, but Bassons refused.
In the 1998 Tour de France Stuart O'Grady won one stage, held the Tour de France yellow jersey for three days, and came second in the points classification with the assistance of EPO. In 2010, Floyd Landis admitted to using performance-enhancing drugs, including EPO, throughout his career as a professional cyclist. In 2012, the USADA released a report on its investigation into the US Postal Service cycling team and blood doping. The report contained affidavits from numerous riders on the team, including Frankie Andreu, Tyler Hamilton, George Hincapie, Floyd Landis, Levi Leipheimer, and others, outlining that they, and Lance Armstrong, used a cocktail of performance-enhancing substances for the Tour de France, most notably EPO, during the 1999 tour. Armstrong was later stripped of his seven tour wins by USADA, and the UCI concurred with the decision. Tour organisers have removed Armstrong's name and results from the race's history. Witnesses testified that code words used for EPO included "Edgar", "Poe", "Edgar Allen Poe", and "Zumo" (Spanish for 'juice').
In 1905, Paul Carnot, a professor of medicine in Paris, and his assistant, Clotilde Deflandre, proposed the idea that hormones regulate the production of red blood cells. After conducting experiments on rabbits subject to bloodletting, Carnot and Deflandre attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto continued to study red cell production and later called the hemopoietic substance 'erythropoietin'. Further studies investigating the existence of EPO by K.R. Reissman (unknown location) and Allan J. Erslev (Thomas Jefferson Medical College) demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase hematocrit. This substance was finally purified and confirmed as erythropoietin, opening doors to therapeutic uses for EPO in diseases such as anemia.
Haematologist John Adamson and nephrologist Joseph W. Eschbach looked at various forms of renal failure and the role of the natural hormone EPO in the formation of red blood cells. Studying sheep and other animals in the 1970s, the two scientists helped establish that EPO stimulates the production of red cells in bone marrow and could lead to a treatment for anemia in humans. In 1968, Goldwasser and Kung began work to purify human EPO, and managed to purify milligram quantities of over 95% pure material by 1977. Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated. Later, an NIH-funded researcher at Columbia University discovered a way to synthesize EPO. Columbia University patented the technique, and licensed it to Amgen. Controversy has ensued over the fairness of the rewards that Amgen reaped from NIH-funded work, and Goldwasser was never financially rewarded for his work.
In the 1980s, Adamson, Joseph W. Eschbach, Joan C. Egrie, Michael R. Downing and Jeffrey K. Browne conducted a clinical trial at the Northwest Kidney Centers for a synthetic form of the hormone, Epogen, produced by Amgen. The trial was successful, and the results were published in the New England Journal of Medicine in January 1987.
In 1985, Lin et al isolated the human erythropoietin gene from a genomic phage library and were able to characterize it for research and production. Their research demonstrated the gene for erythropoietin encoded the production of EPO in mammalian cells that is biologically active in vitro and in vivo. The industrial production of recombinant human erythropoietin (RhEpo) for treating anemia patients would begin soon after.
In 1989, the US Food and Drug Administration approved the hormone Epogen, which remains in use today.
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