|Symbols||; EP; MVCD2|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Erythropoietin (// or /, , , /; from Greek: ἐρυθρός, erythros 'red' and ποιεῖν, poiein 'make'), also known as 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 proximal convoluted 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.
Exogenous erythropoietin is produced by recombinant DNA technology in cell culture. Several different pharmaceutical agents are available with a variety of glycosylation patterns, and are collectively called erythropoiesis-stimulating agents (ESA). The specific details for labelled use vary between the package inserts, but ESAs have been used in the treatment of anemia in chronic kidney disease, anemia in myelodysplasia, and in anemia from cancer chemotherapy. Boxed warnings include a risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence. Exogenous erythropoietin has been used illicitly as a performance-enhancing drug; it can often be detected in blood, due to slight differences from the endogenous protein, for example, in features of posttranslational modification.
Red blood cell production
Erythropoietin is an essential hormone for red blood 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.
Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis including vasoconstriction-dependent hypertension, stimulating angiogenesis, and promoting cell survival via activation of Epo receptors resulting in anti-apoptotic effects on ischemic tissues. However this proposal is controversial with numerous studies showing no effect. It is also inconsistent with the low levels of Epo receptors on those cells. Clinical trials in humans with ischemic heart, neural and renal tissues have not demonstrated the same benefits seen in animals.
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. High level erythropoietin receptor expression is localized to erythroid progenitor cells. While there are reports that EPO receptors are found in a number of other tissues, such as heart, muscle, kidney and peripheral/central nervous tissue, those results are confounded by nonspecificity of reagents such as anti-EpoR antibodies. In controlled experiments, EPO receptor is not detected in those tissues. 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 up to 1000-fold, reaching 10,000 mU/ml of blood. In adults, EPO is synthesized mainly by interstitial cells in the peritubular capillary bed of the renal cortex, with additional amounts being produced in the liver. Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability. Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen and iron.
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, chemotherapy induced anemia in patients with cancer, inflammatory bowel disease (Crohn's disease and ulcer colitis) and myelodysplasia from the treatment of cancer (chemotherapy and radiation). The package inserts include boxed warnings of increased risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 to 12 g/dl.
Recombinant erythropoietin has a variety of glycosylation patterns giving rise to alpha, beta, delta, and omega forms:
Darbepoetin alfa, which early literature during its development often termed as novel erythropoiesis-stimulating protein (NESP), 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. This glycoprotein has a longer terminal half-life, meaning it is possible to administer it less frequently.
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, Mixed Martial Arts 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. The first EPO-doping cases were found by the Swiss Laboratory for Doping Analyses.
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.
Inhalation of a xenon/oxygen mixture activates production of the transcription factor HIF-1-alpha, which leads to increased production of erythropoietin and improved performance. It has been used for this purpose in Russia since at least 2004.
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 protege 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 with top riders, allegedly including Lance Armstrong. 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 only immediately disqualified, but banned from racing for two weeks. 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 massive doping by the US Postal Service cycling team under the leadership of Lance Armstrong. 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 Armstrong used a cocktail of performance-enhancing substances for the Tour de France, most notably EPO, during Armstrong's seven consecutive Tour wins. It detailed how Armstrong and the Postal manager, Johan Bruyneel, forced other team members to dope as well. It also went to the root of their doping network, targeting the shadowy doctors and back room enablers who helped cyclists procure and administer drugs as well as highly placed executives who helped to avoid doping controls and hide positive test results. Armstrong was subsequently stripped of all of his victories from 1998 onward—including his Tour wins and his performance in the 2000 Summer Olympics. The UCI concurred with the decision. While several of the doping offenses took place outside the normal eight-year statute of limitations for doping offenses, USADA contended the statute of limitations did not apply due to Armstrong's "fraudulent concealment" of his doping. Longstanding precedent in U.S. law holds that the statute of limitations does not apply in cases of fraudulent conduct by a defendant. In accordance with this decision, Tour organizers removed Armstrong's name and results from the race's history.
Dynepo is the brand name for a form of EPO developed by Shire Pharmaceuticals. The first development steps were performed by HMR and Aventis. Aventis obtained the license in Europe in 2002. The company expected to launch the product in Europe in 2006, although patents held by the American biotechnology company Amgen, Inc. may have precluded its sale in the United States.
Dynepo was made in cultured human cells. It was therefore expected to have an authentic human form of sialic acid and other oligosaccharide residues. It was hoped that this would make a longer-acting product than existing brands. There were concerns that such production would also make Dynepo undetectable in the urine tests for EPO used, at that time, to detect doping by athletes. Dynepo was withdrawn from European markets on 17 February 2009 for commercial reasons. On July 1, 2009, professional cycling team Silence–Lotto announced that Thomas Dekker was tested positive for Dynepo on a test taken on December 24, 2007, while Dekker was riding for Rabobank.
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.
- "Erythropoietin". Merriam-Webster Dictionary.
- "Erythropoietin". Dictionary.com Unabridged. Random House.
- "erythropoietin - definition of erythropoietin in English from the Oxford dictionary". OxfordDictionaries.com. Retrieved 2016-01-20.
- "Safety Labeling Changes: Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa)". MedWatch: The FDA Safety Information and Adverse Event Reporting Program. United States Food and Drug Administration. 2011-08-11.
- Middleton SA, Barbone FP, Johnson DL, Thurmond RL, You Y, McMahon FJ, Jin R, Livnah O, Tullai J, Farrell FX, Goldsmith MA, Wilson IA, Jolliffe LK (May 1999). "Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide". The Journal of Biological Chemistry 274 (20): 14163–9. doi:10.1074/jbc.274.20.14163. PMID 10318834.
- Livnah O, Johnson DL, Stura EA, Farrell FX, Barbone FP, You Y, Liu KD, Goldsmith MA, He W, Krause CD, Pestka S, Jolliffe LK, Wilson IA (Nov 1998). "An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation". Nature Structural Biology 5 (11): 993–1004. doi:10.1038/2965. PMID 9808045.
- Jacobson LO, Goldwasser E, Fried W, Plzak L (Mar 1957). "Role of the kidney in erythropoiesis". Nature 179 (4560): 633–4. doi:10.1038/179633a0. PMID 13418752.
- Fisher JW, Koury S, Ducey T, Mendel S (Oct 1996). "Erythropoietin production by interstitial cells of hypoxic monkey kidneys". British Journal of Haematology 95 (1): 27–32. doi:10.1046/j.1365-2141.1996.d01-1864.x. PMID 8857934.
- Barret KE. Ganong's review of Medical Physiology. McGraw Hill. p. 709. ISBN 978-1-25-902753-6.
- Jelkmann W (Mar 2007). "Erythropoietin after a century of research: younger than ever". European Journal of Haematology 78 (3): 183–205. doi:10.1111/j.1600-0609.2007.00818.x. PMID 17253966.
- Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J (Feb 2013). "Efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease: a prospective cohort study". Nutrition in Clinical Practice 28 (1): 120–7. doi:10.1177/0884533612462744. PMID 23064018.
- "Aranesp(darbepoetin alfa)". Amgen.com. Retrieved 2009-04-29.
- "Procrit (Epoetin alfa)". Ortho Biotech Products. Archived from the original on 2009-10-26. Retrieved 2009-04-29.
- Macdougall IC (Jul 2000). "Novel erythropoiesis stimulating protein". Seminars in Nephrology 20 (4): 375–81. PMID 10928340.
- "Boxing Scandals". Bleacher Report. December 2011. Retrieved 2011-12-22.
- Jelkmann W, Lundby C (Sep 2011). "Blood doping and its detection". Blood 118 (9): 2395–404. doi:10.1182/blood-2011-02-303271. PMID 21652677.
- History of the Swiss Laboratory for Doping Analyses, www.doping.chuv.ch (page visited on 11 June 2014).
- Steeg JL (2007-02-28). "Catlin has made a career out of busting juicers - USATODAY.com". USA TODAY. Retrieved 2009-03-31.
- "Ousted Olympic race walk champion says he bought EPO in Turkey, hid it in refrigerator at home"[dead link] Associated Press story in the Washington Post (August 8, 2012)
- Lasne F, Martin L, Crepin N, de Ceaurriz J (Dec 2002). "Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones". Analytical Biochemistry 311 (2): 119–26. doi:10.1016/S0003-2697(02)00407-4. PMID 12470670.
- Kohler M, Ayotte C, Desharnais P, Flenker U, Lüdke S, Thevis M, Völker-Schänzer E, Schänzer W (Jan 2008). "Discrimination of recombinant and endogenous urinary erythropoietin by calculating relative mobility values from SDS gels". International Journal of Sports Medicine 29 (1): 1–6. doi:10.1055/s-2007-989369. PMID 18050057.
- Jelkmann W (2012). "The disparate roles of cobalt in erythropoiesis, and doping relevance.". Open Journal of Hematology 3: 3–6. doi:10.13055/ojhmt_3_1_6.121211.
- "Breathe it in". The Economist. 8 February 2014.
- Lodewijkx HF, Brouwer B (Dec 2011). "Some empirical notes on the epo epidemic in professional cycling". Research Quarterly for Exercise and Sport 82 (4): 740–54. doi:10.5641/027013611X13275192112069. PMID 22276416.
- Lundby C, Robach P, Boushel R, Thomsen JJ, Rasmussen P, Koskolou M, Calbet JA (Aug 2008). "Does recombinant human Epo increase exercise capacity by means other than augmenting oxygen transport?". Journal of Applied Physiology 105 (2): 581–7. doi:10.1152/japplphysiol.90484.2008. PMID 18535134.
- Harrison C (2003-03-01). "The Man Who Knows Too Much". Sport Monthly. chrisharrisonwriting.
- Gifford B (Jan–Feb 2006). "Paging Doctor Ferrari". Bicycling: 50–59.
- Maloney T (2003). "An Interview With Dr. Michele Ferrari, part two: That l'Equipe Interview". by Jean-Michel Rouet, from l'Equipe, 1994, reprinted excerpt. Cycling News.
- 10 liters of orange juice: see the article on Water intoxication, for example.
- Juliet Macur: Cycle of Lies: The Fall of Lance Armstrong
- Martin DT, Ashenden M, Parisotto R, Pyne D, Hahn AG (March–April 1997). "Blood testing for professional cyclists: What's a fair hematocrit limit?". Sports Science.
- "Pantani: Future 'in doubt'". BBC. 5 June 1999. Retrieved 30 June 2011.
- Millar R (2003-10-23). "The Bare Minimum". Cycling News.
- Startt J (2012-10-15). "Christophe Bassons Interview: 'People Now See I Wasn't Lying'". This Just In. Bicycling.com.
- "Stuart O'Grady admits to doping at 1998 Tour de France". Theaustralian.com.au. 2013-07-25. Retrieved 2013-07-25.
- "Landis admits to illegal drug use". BBC News. 2010-05-20.
- United States Anti Doping Agency. "Report on proceedings under the world anti-doping code and the usada protocol united states anti-doping agency, claimant, v. lance armstrong, respondent. reasoned decision of the united states anti-doping agency" (PDF). USADA. Retrieved 2012-10-28.
- "A lifetime ban: Does the time fit the crime?" Velo News, 12/16/13
- "U.S. Postal Service Pro Cycling Team Investigation". Statement From USADA CEO Travis T. Tygart Regarding The U.S. Postal Service Pro Cycling Team Doping Conspiracy. USADA. 2012-10-10.
- Chapman M (2012-10-15). "Cycling's Dirty Truth". Sport, Peddlers. BBC Radio 5. Archived from the original on October 16, 2012.
- Wathion, Noël. "Public statement on Dynepo (epoetin delta)" (PDF). European Medicines Agency. Retrieved 31 August 2015.
- Bauer K (2011). Ride a Stage of the Tour De France The Legendary Climbs and How to Ride Them. London: A & C Black. p. 35. ISBN 978-1-4081-3333-0.
- Höke A (2005). Erythropoietin and the Nervous System. Berlin: Springer. ISBN 0-387-30010-4. OCLC 64571745.
- Miyake T, Kung CK, Goldwasser E (Aug 1977). "Purification of human erythropoietin". The Journal of Biological Chemistry 252 (15): 5558–64. PMID 18467.
- Angell M (2005). The Truth About the Drug Companies : How They Deceive Us and What to Do About It. New York: Random House Trade Paperbacks. p. 60. ISBN 0-375-76094-6.
- Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (Jan 1987). "Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial". The New England Journal of Medicine 316 (2): 73–8. doi:10.1056/NEJM198701083160203. PMID 3537801.
- Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z (Nov 1985). "Cloning and expression of the human erythropoietin gene". Proceedings of the National Academy of Sciences of the United States of America 82 (22): 7580–4. doi:10.1073/pnas.82.22.7580. PMC 391376. PMID 3865178.
- Takeuchi M, Kobata A (Sep 1991). "Structures and functional roles of the sugar chains of human erythropoietins". Glycobiology 1 (4): 337–46. doi:10.1093/glycob/1.4.337. PMID 1820196.
- Semba RD, Juul SE (Aug 2002). "Erythropoietin in human milk: physiology and role in infant health". Journal of Human Lactation 18 (3): 252–61. doi:10.1177/089033440201800307. PMID 12192960.
- Ratcliffe PJ (2003). "From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway". Blood Purification 20 (5): 445–50. doi:10.1159/000065201. PMID 12207089.
- Westenfelder C (2002). "Unexpected renal actions of erythropoietin". Experimental Nephrology 10 (5-6): 294–8. doi:10.1159/000065304. PMID 12381912.
- Becerra SP, Amaral J (Dec 2002). "Erythropoietin--an endogenous retinal survival factor". The New England Journal of Medicine 347 (24): 1968–70. doi:10.1056/NEJMcibr022629. PMID 12477950.
- Genc S, Koroglu TF, Genc K (Mar 2004). "Erythropoietin and the nervous system". Brain Research 1000 (1-2): 19–31. doi:10.1016/j.brainres.2003.12.037. PMID 15053948.
- Fandrey J (Jun 2004). "Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 286 (6): R977–88. doi:10.1152/ajpregu.00577.2003. PMID 15142852.
- Juul S (Mar 2004). "Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models". Clinics in Perinatology 31 (1): 129–42. doi:10.1016/j.clp.2004.03.004. PMID 15183662.
- Buemi M, Caccamo C, Nostro L, Cavallaro E, Floccari F, Grasso G (Mar 2005). "Brain and cancer: the protective role of erythropoietin". Medicinal Research Reviews 25 (2): 245–59. doi:10.1002/med.20012. PMID 15389732.
- Sytkowski AJ (Jul 2007). "Does erythropoietin have a dark side? Epo signaling and cancer cells". Science's STKE 2007 (395): pe38. doi:10.1126/stke.3952007pe38. PMID 17636183.
- Goldwasser, Eugene. A Bloody Long Journey: Erythropoietin and the Person Who Isolated It. Xlibris, 2011. ISBN 978-1-4568-5737-0
- NYT - 1987 announcement of Epogen's clinical success
- Dynepo EPAR (European Public Assessment Report), PDF format , credit European Medicines Agency