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[[image:erythropoietin.png|thumb|320px|Erythropoietin]]
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'''Erythropoietin''' ({{IPAc-en|ɪ|ˌ|r|ɪ|θ|r|oʊ|ˈ|p|ɔɪ|.|ᵻ|t|ɪ|n|,_|-|r|ə|-|,_|-|p|ɔɪ|ˈ|ɛ|t|ɪ|n|,_|-|ˈ|iː|t|ɪ|n}};{{refn|{{MerriamWebsterDictionary|Erythropoietin}}}}{{refn|{{Dictionary.com|Erythropoietin}}}}{{refn|{{cite web |url=https://www.oxforddictionaries.com/definition/english/erythropoietin |title=erythropoietin – definition of erythropoietin in English from the Oxford dictionary |publisher=[[OxfordDictionaries.com]] |access-date=2016-01-20 }}}} '''EPO'''), also known as '''hematopoietin''' or '''hemopoietin''', is a [[glycoprotein]] [[cytokine]] secreted by the kidney in response to cellular [[Hypoxia (medical)|hypoxia]]; it stimulates [[red blood cell]] production ([[erythropoiesis]]) in the bone marrow. Low levels of EPO (around 10 mU/mL) are constantly secreted sufficient to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include any [[anemia]], and  [[hypoxemia]] due to chronic lung disease.
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Erythropoietin is produced by interstitial [[fibroblast]]s in the kidney in close association with the [[peritubular capillary]] and [[proximal convoluted tubule]].  It is also produced in [[Perisinusoidal space|perisinusoidal]] cells in the [[liver]]. Liver production predominates in the fetal and perinatal period; renal production  predominates in adulthood.


{{Editor Join}}
[[Exogeny|Exogenous]] erythropoietin, '''recombinant human erythropoietin''' (rhEPO) is produced by [[recombinant DNA technology]] in [[cell culture]] and are collectively called [[erythropoiesis-stimulating agent]]s (ESA): two examples are [[epoetin alfa]] and [[epoetin beta]]. ESAs are used in the treatment of [[anemia]] in [[chronic kidney disease]], anemia in [[myelodysplasia]], and in anemia from [[cancer]] [[chemotherapy]]. Risks of therapy include death, [[myocardial infarction]], [[stroke]], [[venous thromboembolism]], and tumor recurrence.  Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided.


'''Erythropoietin''' ({{pronEng|ɨˌrɪθoʊˈpɔɪɨtɨn}}, {{IPA|/ɨˌrɪθroʊˈpɔɪtən/}}, or {{IPA|/ɨˌriːθroʊ-/}}) 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]] that regulates the red blood cell production.  
rhEPO has been used illicitly as a [[performance-enhancing drug]].<ref name="PEDs in sports review">{{cite journal | vauthors = Momaya A, Fawal M, Estes R | title = Performance-enhancing substances in sports: a review of the literature | journal = Sports Medicine | volume = 45 | issue = 4 | pages = 517–31 | date = April 2015 | pmid = 25663250 | doi = 10.1007/s40279-015-0308-9 }}</ref> It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of [[posttranslational modification]].


== History ==
==Pharmacology==
[[Hematologist]] Dr. John Adamson and nephrologist Dr. [[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.
EPO is highly [[glycosylation|glycosylated]] (40% of total molecular weight), with half-life in blood around 5&nbsp;h. 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).
== Function ==


In the 1980s, Adamson, Eschbach and others helped lead a clinical trial at the [[Northwest Kidney Centers]] for a synthetic form of the hormone, [[Epogen]] produced by [[Amgen]]. The trial was successful; its results were published in The [[New England Journal of Medicine]] in January 1987. The study authors were Dr. Adamson, Dr. [[Joseph W. Eschbach]], Dr. Joan C. Egrie, Dr. Michael R. Downing and Dr. Jeffrey K. Browne.
=== Red blood cell production ===
Erythropoietin is an essential hormone for red blood cell production. Without it, definitive [[erythropoiesis]] does not take place. Under [[hypoxia (medical)|hypoxic]] conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting [[CFU-E]], pro[[erythroblast]] 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]], or cell death.


In 1989, the Food and Drug Administration approved the hormone, called Epogen, which remains in use.
Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., [[interleukin 3|IL-3]], [[Interleukin 6|IL-6]], [[glucocorticoid]]s, and [[stem cell factor|SCF]]) involved in the development of [[erythroid]] lineage from [[stem cell|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.


==Regulation==
=== Nonhematopoietic roles ===
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.<ref name="pmid22848149">{{cite journal | vauthors = Elliott S, Sinclair AM | title = The effect of erythropoietin on normal and neoplastic cells | journal = Biologics | volume = 6 | issue =  | pages = 163–89 | year = 2012 | pmid = 22848149 | pmc = 3402043 | doi = 10.2147/BTT.S32281 }}</ref> 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. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on the deep peroneal, superficial peroneal, tibial and sural nerves.<ref>{{cite journal | vauthors = Hosseini-Zare MS, Dashti-Khavidaki S, Mahdavi-Mazdeh M, Ahmadi F, Akrami S | title = Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure | journal = Clinical Neurology and Neurosurgery | volume = 114 | issue = 6 | pages = 663–7 | date = July 2012 | pmid = 22296650 | doi = 10.1016/j.clineuro.2012.01.007 }}</ref>


EPO is produced mainly by peritubular fibroblasts of the [[renal cortex]]. It is synthesized by renal peritubular cells in adults, with a small amount being produced in the liver.<ref name="Jacobson1957">{{wikicite|id=Jacobson1957|reference=Jacobson LO, Goldwasser E, Fried W, Plzak L. Role of the kidney in erythropoiesis. Nature 179:633. (1957)}}</ref><ref name="Fisher1996">{{wikicite|id=Fisher1996|reference=Fisher JW, Koury S, Ducey T, Mendel S. Erythropoietin (Epo) production by interstitial cells of hypoxic monkey kidneys. Br J Jaematol 95:27-32. (1996)}}</ref> Regulation is believed to rely on a feed-back mechanism measuring blood oxygenation. Constitutively synthesized transcription factors for EPO, known as [[hypoxia inducible factors]] (HIFs), are hydroxylated and proteosomally digested in the presence of oxygen.<ref name="pmid17253966">{{cite journal |author=Jelkmann, W |title=Erythropoietin after a century of research: younger than ever |journal=Eur J Haematol. |volume=78 |issue=3 |pages=183–205 |year=2007 |pmid=17253966|doi=10.1111/j.1600-0609.2007.00818.x}}</ref> It binds to the erythropoietin receptor (EpoR) on the red cell surface and activates a JAK2 cascade. This receptor is also found in a large number of tissues such as bone marrow cells, lymphocytes, and peripheral/central nerve cells, many of which activate intracellular biological pathways upon binding with Epo.  
== Mechanism of action ==
Erythropoietin has been shown to exert its effects by [[protein-protein interaction|binding]] to the [[erythropoietin receptor]] (EpoR).<ref name="pmid10318834">{{cite journal | vauthors = 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 | title = Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide | journal = The Journal of Biological Chemistry | volume = 274 | issue = 20 | pages = 14163–9 | date = May 1999 | pmid = 10318834 | doi = 10.1074/jbc.274.20.14163 }}</ref><ref name="pmid9808045">{{cite journal | vauthors = 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 | title = An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation | journal = Nature Structural Biology | volume = 5 | issue = 11 | pages = 993–1004 | date = November 1998 | pmid = 9808045 | doi = 10.1038/2965 }}</ref> EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a [[janus kinase 2|JAK2]] signalling cascade. This initiates the [[STAT5]], [[Phosphoinositide 3-kinase|PIK3]] and [[MAPK/ERK pathway|Ras MAPK]] pathways. This results in differentiation, survival and proliferation of the erythroid cell.<ref>{{Cite book|url=https://books.google.com/?id=orVuGH_nrSMC&pg=PP1|title=The Cytokine Handbook, Two-Volume Set|last=Thomson|first=Angus W.|last2=Lotze|first2=Michael T.|date=2003-04-22|publisher=Gulf Professional Publishing|isbn=9780080518794|language=en}}</ref> SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal.<ref>{{cite journal | vauthors = Hodges VM, Rainey S, Lappin TR, Maxwell AP | title = Pathophysiology of anemia and erythrocytosis | journal = Critical Reviews in Oncology/Hematology | volume = 64 | issue = 2 | pages = 139–58 | date = November 2007 | pmid = 17656101 | doi = 10.1016/j.critrevonc.2007.06.006 }}</ref> 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.{{citation needed|date=April 2016}}


===Primary Role in Red Cell Blood Line===
== Synthesis and regulation ==
Erythropoietin has its primary effect on red blood cells by promoting red blood cell survival through protecting these cells from [[apoptosis]]. It also cooperates with various growth factors involved in the development of precursor red cells. It has a range of actions including vasoconstriction-dependent [[hypertension]], stimulating [[angiogenesis]], and inducing proliferation of [[smooth muscle]] fibers.
Erythropoietin levels in blood are quite low in the absence of anemia, at around 10&nbsp;mU/mL. However, in hypoxic stress, EPO production may increase up to 1000-fold, reaching 10&nbsp;000&nbsp;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,<ref name=Jacobson1957>{{cite journal | vauthors = Jacobson LO, Goldwasser E, Fried W, Plzak L | title = Role of the kidney in erythropoiesis | journal = Nature | volume = 179 | issue = 4560 | pages = 633–4 | date = March 1957 | pmid = 13418752 | doi = 10.1038/179633a0 | bibcode = 1957Natur.179..633J }}</ref><ref name=Fisher1996>{{cite journal | vauthors = Fisher JW, Koury S, Ducey T, Mendel S | title = Erythropoietin production by interstitial cells of hypoxic monkey kidneys | journal = British Journal of Haematology | volume = 95 | issue = 1 | pages = 27–32 | date = October 1996 | pmid = 8857934 | doi = 10.1046/j.1365-2141.1996.d01-1864.x }}</ref><ref name=sinharaja2002>{{cite book |editor1-first=Kim E. |editor1-last=Barrett |editor2-first=Susan M. |editor2-last=Barman |editor3-first=Scott |editor3-last=Boitano |editor4-first=Heddwen |editor4-last=Brooks |title=Ganong's review of Medical Physiology |edition=24th |publisher=McGraw Hill |isbn=978-1-25-902753-6 |page=709 }}</ref> and the [[pericytes]] in the [[brain]].<ref>{{cite journal | vauthors = Ji P | title = Pericytes: new EPO-producing cells in the brain | journal = Blood | volume = 128 | issue = 21 | pages = 2483–2485 | date = November 2016 | pmid = 27884833 | doi = 10.1182/blood-2016-10-743880 }}</ref> Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability.<ref name=pmid17253966>{{cite journal | vauthors = Jelkmann W | title = Erythropoietin after a century of research: younger than ever | journal = European Journal of Haematology | volume = 78 | issue = 3 | pages = 183–205 | date = March 2007 | pmid = 17253966 | doi = 10.1111/j.1600-0609.2007.00818.x }}</ref> Constitutively synthesized transcription factors for EPO, known as [[hypoxia-inducible factors]], are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia [[GATA2]] inhibits the promoter region for EPO. [[GATA2]] levels decrease during hypoxia and allow the promotion of EPO production.<ref>{{cite journal | vauthors = Jelkmann W | title = Regulation of erythropoietin production | journal = The Journal of Physiology | volume = 589 | issue = Pt 6 | pages = 1251–8 | date = March 2011 | pmid = 21078592 | pmc = 3082088 | doi = 10.1113/jphysiol.2010.195057 }}</ref>


==Uses==
== Medical uses ==
{{main article|Erythropoiesis-stimulating agent}}
Erythropoietins available for use as [[Biologic medical product|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 [[ulcerative colitis]])<ref>{{cite journal | vauthors = Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J | title = Efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease: a prospective cohort study | journal = Nutrition in Clinical Practice | volume = 28 | issue = 1 | pages = 120–7 | date = February 2013 | pmid = 23064018 | doi = 10.1177/0884533612462744 }}</ref> and [[Myelodysplastic syndrome|myelodysplasia]] from the treatment of [[cancer]] ([[chemotherapy]] and [[radiation]]). The [[package insert]]s include [[boxed warning]]s of increased risk of death, [[myocardial infarction]], [[stroke]], [[Venous thrombosis|venous thromboembolism]], and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11&nbsp;g/dL to 12&nbsp;g/dL.<ref name="url_Epogen_Procrit _FDA">{{cite web |url=http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm267698.htm |title=Safety Labeling Changes: Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa) |work=MedWatch: The FDA Safety Information and Adverse Event Reporting Program |date=August 11, 2011 |publisher=United States Food and Drug Administration }}</ref>


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 kidney disease]], from the treatment of [[cancer]] ([[chemotherapy]] & [[radiation]]) and from other critical illnesses ([[heart failure]]).
== History ==
 
In 1905, [[Paul Carnot]] proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to [[bloodletting]], Carnot and his graduate student [[Clotilde-Camille Deflandre]] <ref>{{cite journal|last1=Carnot|first1=P|last2=Deflandre|first2=Cl|title=Sur l'activite hematopoietique du serum au cours de la regeneration du sang|journal=Compt. Rend. Acad. Sci.|date=1906|volume=143|pages=384–386}}</ref> attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev  demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase [[hematocrit]]. This substance was purified and confirmed as erythropoietin.<ref name="pmid17253966" /><ref>{{cite book |first=Ahmet |last=Höke |name-list-format=vanc |title=Erythropoietin and the Nervous System |publisher=Springer |location=Berlin |year=2005 |pages= |isbn=978-0-387-30010-8 |oclc=64571745 }}{{page needed|date=April 2016}}</ref>
===Anemia due to chronic kidney disease ===
 
In patients who require dialysis (have stage 5 [[chronic kidney disease]](CKD)), iron should be given with erythropoietin.<ref name="pmid8914038">{{cite journal |author=Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE |title=A randomized controlled study of iron supplementation in patients treated with erythropoietin |journal=Kidney Int. |volume=50 |issue=5 |pages=1694-9 |year=1996 |pmid=8914038 |doi=}}</ref> People in the US and on dialysis are most often given Epogen®, outside the US other brands of epoetin may be used.
 
Outside of people on dialysis, erythropoietin is used most commonly to treat anemia in people with chronic kidney disease and not on dialysis (those in stage 3 or 4 CKD and those living with a kidney transplant). There are two types of erythropoietin (and three brands) for people with anemia due to chronic kidney disease (not on dialysis), these are:
* epoetin (Procrit®(also known as Eprex®), NeoRecormon®)
* darbepoetin (Aranesp®).
 
=== Anemia due to treatment for cancer ===
 
In March 2008 a panel of advisers for the [[Food and Drug Administration]] (FDA) supported keeping ESAs from [[Amgen]] and [[Johnson & Johnson]] on the market for use in cancer patients. The FDA has focused its concern on study results showing an increased risk of death and [[tumor]] growth in chemo patients taking the anti-anaemia drugs. According to the FDA increases have been seen in various types of cancer, including breast, lymphoid, cervical, head and neck, and the "non-small cell" type of lung cancer.<ref>[http://money.cnn.com/2008/03/13/news/companies/amgen/?postversion=2008031317]CNN Money article</ref>
 
===Anemia in critically ill patients===
There are two types of erythropoietin (and three brands) for people with anemia, due to critical illness. These are:
* epoetin (Procrit®(also known as Eprex®), NeoRecormon®)
* darbepoetin (Aranesp®).
 
In a recent [[randomized controlled trial]]<ref>Howard L. Corwin et al., “Efficacy and Safety of Epoetin Alfa in Critically Ill Patients,” N Engl J Med 357, no. 10 (September 6, 2007): 965-976, http://content.nejm.org/cgi/content/abstract/357/10/965 (accessed September 6, 2007).</ref>, erythropoietin was shown to not change the number of blood transfusions required by critically ill patients. A surprising finding in this study was a small mortality benefit in patients receiving erythropoietin.  This result was [[Statistical significance|statistically significant]] after 29 days but not at 140 days.  This mortality difference was most marked in patients admitted to the ICU for trauma. The authors speculate several hypothesis of potential etiologies for reduced mortality, but given the known increase in thrombosis and increase benefit in trauma patients as well as marginal nonsignificant benefit (adjusted hazard ratio of 0.9) in surgery patients, one might speculate that some of the benefit might be secondary to the procoagulant effect of erythropoetin.  Regardless, this study suggests further research may be necessary to see which critical care patients, if anyone, might benefit from administration of erythropoeitin. Any benefit of erythropoetin must be weighed against the 50% increase in [[thrombosis]], which has been well substantiated by numerous trials.
 
===Blood doping===


It has a history of usage as a [[blood doping]] agent in endurance sports such as cycling, triathlons and marathon running.
In 1977, Goldwasser and Kung purified EPO.<ref name="pmid18467">{{cite journal | vauthors = Miyake T, Kung CK, Goldwasser E | title = Purification of human erythropoietin | journal = The Journal of Biological Chemistry | volume = 252 | issue = 15 | pages = 5558–64 | date = August 1977 | pmid = 18467 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18467 }}</ref> Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.<ref name="pmid17253966" /> Synthetic EPO was first successfully used to correct anemia in 1987.<ref name="pmid3537801">{{cite journal | vauthors = Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW | title = Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial | journal = The New England Journal of Medicine | volume = 316 | issue = 2 | pages = 73–8 | date = January 1987 | pmid = 3537801 | doi = 10.1056/NEJM198701083160203 }}</ref> In 1985, Lin ''et al'' isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO.<ref name="pmid3865178">{{cite journal | vauthors = Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z | title = Cloning and expression of the human erythropoietin gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 22 | pages = 7580–4 | date = November 1985 | pmid = 3865178 | pmc = 391376 | doi = 10.1073/pnas.82.22.7580 | bibcode = 1985PNAS...82.7580L }}</ref> In 1989, the [[US Food and Drug Administration]] approved the hormone [[Epogen]] for use in certain anemias.<ref>{{cite web|url=http://pi.amgen.com/united_states/epogen/epogen_pi_hcp_english.pdf|title=Epogen Prescribing Information}}</ref>


==Adverse effects==
==Usage as doping product==
EPO has been banned since the early 1990s, but a first test was not available until the [[2000 Summer Olympics]].<ref name="WADA">{{cite web|url=https://www.wada-ama.org/en/questions-answers/epo-detection|title=EPO DETECTION|publisher=[[World Anti-Doping Agency]]|date=December 2014}}</ref> Before this test was available, no athletes were sanctioned after positive tests, but it happened that they were sanctioned after confessing to having used EPO, for example in the [[Festina affair]], when a car with doping products for the Festina cycling team was found.


Erythropoietin is associated with an increased risk of adverse cardiovascular complications in patients with kidney disease if it is used to increase [[hemoglobin]] levels above 13.0 g/dl.<ref name="pmid17108342">{{cite journal |author=Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A |title=Normalization of hemoglobin level in patients with chronic kidney disease and anemia |journal=N. Engl. J. Med. |volume=355 |issue=20 |pages=2071-84 |year=2006 |pmid=17108342 |doi=10.1056/NEJMoa062276}}</ref>
The first doping test in cycling was used in the [[2001 La Flèche Wallonne]]. The first rider to test positive in that race was [[Bo Hamburger]], although he was later acquitted because his B-sample was not conclusive.<ref>{{Cite news|url=http://news.bbc.co.uk/sport2/hi/other_sports/1483975.stm|publisher=BBC|date=10 August 2001|title=Hamburger cleared of EPO use}}</ref>


===Safety advisories in anemic cancer patients===
A 2007 study showed that EPO has a significant effect on exercise performance,<ref>{{cite journal | vauthors = Thomsen JJ, Rentsch RL, Robach P, Calbet JA, Boushel R, Rasmussen P, Juel C, Lundby C | title = Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity | journal = European Journal of Applied Physiology | volume = 101 | issue = 4 | pages = 481–6 | date = November 2007 | pmid = 17668232 | doi = 10.1007/s00421-007-0522-8 }}</ref><ref name="PEDs in sports review" /> but a 2017 study showed that the effects of EPO administered to amateur cyclists was not distinguishable from a placebo.<ref>{{cite journal | vauthors = Heuberger JA, Rotmans JI, Gal P, Stuurman FE, van 't Westende J, Post TE, Daniels JM, Moerland M, van Veldhoven PL, de Kam ML, Ram H, de Hon O, Posthuma JJ, Burggraaf J, Cohen AF | title = Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial | journal = The Lancet. Haematology | volume = 4 | issue = 8 | pages = e374-e386 | date = August 2017 | pmid = 28669689 | doi = 10.1016/S2352-3026(17)30105-9 }}</ref>
 
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 use|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<ref>{{cite web |url=http://www.fda.gov/cder/drug/advisory/RHE2007.htm |title=FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp) |format= |work=}}</ref> on March 9, 2007, and a clinical alert<ref>{{cite web |url=http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE2007HCP.htm |title=Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA) |format= |work=}}</ref> for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents such as [[epogen]] and [[darbepoetin]].  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 warning]]s 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.  Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.


== See also ==
== See also ==
* [[Amgen]], producer of artificial EPO (Brand Names: Epogen and Aranesp)
* [[Hemopoietic growth factors]]
* [[Dynepo]], trademark name for an erythropoiesis stimulating protein, by [[Transkaryotic Therapies|TKT]]
* [[Blood doping]], transfusions and EPO use as doping methods; testing and enforcement
* [[Jehovah's Witnesses and blood transfusions]]
* [[Jehovah's Witnesses and blood transfusions]]
* The german company AplaGen Biopharmaceuticals[http://www.aplagen.com] has developed a new EPO-mimetic peptide, HemoMer™. The active compound is bound to a polysacharid-based polymeric carrier ([[Hydroxyethylstarch]]). Half-Life is increased by increase of molecular weight above the filtration threshold of the kidney, comparable to PEGylation.  The so-called supravalence concept has significant advantages to PEGylation, because Half-Life and efficacy are improved simultaneously but not of the cost of the each other.  The drug is completely biodegradable and can thus be eliminated even by dialysis patients. At the moment the drug is still preclinical.<ref>[http://www.aplagen.com]</ref>
==Additional images==
<gallery>
Image:EPO Hämatopoese.png|EPO [[hematopoiesis]] (German)
Image:JAK-STAT-Signaltransduktion nach EPO-Bindung.png|[[JAK-STAT signaling pathway]]
Image:EPO.png|EPO structure
Image:EPO sales.png|EPO sales
Image:Epo-Blotting.png|Epo blotting
</gallery>


==References==
== References ==
{{Reflist|2}}
{{Reflist|30em}}


 
== Further reading ==
==Further reading==
{{refbegin|35em}}
{{refbegin | 2}}
* {{cite journal | vauthors = Takeuchi M, Kobata A | title = Structures and functional roles of the sugar chains of human erythropoietins | journal = Glycobiology | volume = 1 | issue = 4 | pages = 337–46 | date = September 1991 | pmid = 1820196 | doi = 10.1093/glycob/1.4.337 }}
{{PBB_Further_reading
* {{cite journal | vauthors = Semba RD, Juul SE | title = Erythropoietin in human milk: physiology and role in infant health | journal = Journal of Human Lactation | volume = 18 | issue = 3 | pages = 252–61 | date = August 2002 | pmid = 12192960 | doi = 10.1177/089033440201800307 }}
| citations =
* {{cite journal | vauthors = Ratcliffe PJ | title = From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway | journal = Blood Purification | volume = 20 | issue = 5 | pages = 445–50 | year = 2002 | pmid = 12207089 | doi = 10.1159/000065201 }}
*{{cite journal | author=Takeuchi M, Kobata A |title=Structures and functional roles of the sugar chains of human erythropoietins. |journal=Glycobiology |volume=1 |issue= 4 |pages= 337-46 |year= 1992 |pmid= 1820196 |doi= }}
* {{cite journal | vauthors = Westenfelder C | title = Unexpected renal actions of erythropoietin | journal = Experimental Nephrology | volume = 10 | issue = 5-6 | pages = 294–8 | year = 2002 | pmid = 12381912 | doi = 10.1159/000065304 }}
*{{cite journal | author=Semba RD, Juul SE |title=Erythropoietin in human milk: physiology and role in infant health. |journal=Journal of human lactation : official journal of International Lactation Consultant Association |volume=18 |issue= 3 |pages= 252-61 |year= 2002 |pmid= 12192960 |doi= }}
* {{cite journal | vauthors = Becerra SP, Amaral J | title = Erythropoietin--an endogenous retinal survival factor | journal = The New England Journal of Medicine | volume = 347 | issue = 24 | pages = 1968–70 | date = December 2002 | pmid = 12477950 | doi = 10.1056/NEJMcibr022629 }}
*{{cite journal | author=Ratcliffe PJ |title=From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway. |journal=Blood Purif. |volume=20 |issue= 5 |pages= 445-50 |year= 2003 |pmid= 12207089 |doi= }}
* {{cite journal | vauthors = Genc S, Koroglu TF, Genc K | title = Erythropoietin and the nervous system | journal = Brain Research | volume = 1000 | issue = 1-2 | pages = 19–31 | date = March 2004 | pmid = 15053948 | doi = 10.1016/j.brainres.2003.12.037 }}
*{{cite journal | author=Westenfelder C |title=Unexpected renal actions of erythropoietin. |journal=Exp. Nephrol. |volume=10 |issue= 5-6 |pages= 294-8 |year= 2003 |pmid= 12381912 |doi= }}
* {{cite journal | vauthors = Fandrey J | title = Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 286 | issue = 6 | pages = R977-88 | date = June 2004 | pmid = 15142852 | doi = 10.1152/ajpregu.00577.2003 }}
*{{cite journal | author=Becerra SP, Amaral J |title=Erythropoietin--an endogenous retinal survival factor. |journal=N. Engl. J. Med. |volume=347 |issue= 24 |pages= 1968-70 |year= 2002 |pmid= 12477950 |doi= 10.1056/NEJMcibr022629 }}
* {{cite journal | vauthors = Juul S | title = Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models | journal = Clinics in Perinatology | volume = 31 | issue = 1 | pages = 129–42 | date = March 2004 | pmid = 15183662 | doi = 10.1016/j.clp.2004.03.004 }}
*{{cite journal | author=Genc S, Koroglu TF, Genc K |title=Erythropoietin and the nervous system. |journal=Brain Res. |volume=1000 |issue= 1-2 |pages= 19-31 |year= 2004 |pmid= 15053948 |doi= 10.1016/j.brainres.2003.12.037 }}
* {{cite journal | vauthors = Buemi M, Caccamo C, Nostro L, Cavallaro E, Floccari F, Grasso G | title = Brain and cancer: the protective role of erythropoietin | journal = Medicinal Research Reviews | volume = 25 | issue = 2 | pages = 245–59 | date = March 2005 | pmid = 15389732 | doi = 10.1002/med.20012 }}
*{{cite journal | author=Fandrey J |title=Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. |journal=Am. J. Physiol. Regul. Integr. Comp. Physiol. |volume=286 |issue= 6 |pages= R977-88 |year= 2004 |pmid= 15142852 |doi= 10.1152/ajpregu.00577.2003 }}
* {{cite journal | vauthors = Sytkowski AJ | title = Does erythropoietin have a dark side? Epo signaling and cancer cells | journal = Science's STKE | volume = 2007 | issue = 395 | pages = pe38 | date = July 2007 | pmid = 17636183 | doi = 10.1126/stke.3952007pe38 }}
*{{cite journal | author=Juul S |title=Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models. |journal=Clinics in perinatology |volume=31 |issue= 1 |pages= 129-42 |year= 2004 |pmid= 15183662 |doi= 10.1016/j.clp.2004.03.004 }}
*  {{cite book |last=Goldwasser |first=Eugene |title=A Bloody Long Journey: Erythropoietin and the Person Who Isolated It |publisher=Xlibris |date=2011 |isbn=978-1-4568-5737-0}}{{Self-published inline|certain=yes|date=December 2017}}
*{{cite journal | author=Buemi M, Caccamo C, Nostro L, ''et al.'' |title=Brain and cancer: the protective role of erythropoietin. |journal=Med Res Rev |volume=25 |issue= 2 |pages= 245-59 |year= 2005 |pmid= 15389732 |doi= 10.1002/med.20012 }}
*{{cite journal | author=Sytkowski AJ |title=Does erythropoietin have a dark side? Epo signaling and cancer cells. |journal=Sci. STKE |volume=2007 |issue= 395 |pages= pe38 |year= 2007 |pmid= 17636183 |doi= 10.1126/stke.3952007pe38 }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* [http://query.nytimes.com/gst/fullpage.html?res=9B0DE2D81138F93BA35752C0A961948260&sec=&spon=&partner=permalink&exprod=permalink NYT] 1987 announcement of Epogen's clinical success
{{Wikiquote}}
* [http://www.epogen.com/ Patient information on Epogen]
* {{Cite news |last=Schmeck |first=Harold M., Jr. |date=January 8, 1987 |title=Synthesized Drug Eases Kidney Ills |url=https://query.nytimes.com/gst/fullpage.html?res=9B0DE2D81138F93BA35752C0A961948260 |work=[[The New York Times]] |page=A00021 |access-date=7 August 2018 |postscript=. (Announcement of Epogen's clinical success)}}
* [http://www.aranesp.com/ Patient information on Aranesp]
* [http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000372/WC500054472.pdf "European Public Assessment Report (EPAR): Dynepo: EPAR summary for the public" (EMEA/H/C/372)] (PDF)—[[European Medicines Agency]]
* [http://www.procrit.com/ Patient information on Procrit]


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[[Category:Cytokines]]
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Latest revision as of 13:04, 4 January 2019

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Erythropoietin (/ɪˌrɪθroʊˈpɔɪ.ɪtɪn, -rə-, -pɔɪˈɛtɪn, -ˈiːtɪn/;[1][2][3] EPO), also known as hematopoietin or hemopoietin, is a glycoprotein cytokine secreted by the kidney in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO (around 10 mU/mL) are constantly secreted sufficient to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10 000 mU/mL) include any anemia, and hypoxemia due to chronic lung disease.

Erythropoietin is produced by interstitial fibroblasts in the kidney in close association with the peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood.

Exogenous erythropoietin, recombinant human erythropoietin (rhEPO) is produced by recombinant DNA technology in cell culture and are collectively called erythropoiesis-stimulating agents (ESA): two examples are epoetin alfa and epoetin beta. ESAs are used in the treatment of anemia in chronic kidney disease, anemia in myelodysplasia, and in anemia from cancer chemotherapy. Risks of therapy include death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence. Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided.

rhEPO has been used illicitly as a performance-enhancing drug.[4] It can often be detected in blood, due to slight differences from the endogenous protein; for example, in features of posttranslational modification.

Pharmacology

EPO is highly glycosylated (40% of total molecular weight), with half-life in blood around 5 h. 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).

Function

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, or cell death.

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.

Nonhematopoietic roles

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.[5] 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. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on the deep peroneal, superficial peroneal, tibial and sural nerves.[6]

Mechanism of action

Erythropoietin has been shown to exert its effects by binding to the erythropoietin receptor (EpoR).[7][8] EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a JAK2 signalling cascade. This initiates the STAT5, PIK3 and Ras MAPK pathways. This results in differentiation, survival and proliferation of the erythroid cell.[9] SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal.[10] 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.[citation needed]

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,[11][12][13] and the pericytes in the brain.[14] Regulation is believed to rely on a feedback mechanism measuring blood oxygenation and iron availability.[15] Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors, are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia GATA2 inhibits the promoter region for EPO. GATA2 levels decrease during hypoxia and allow the promotion of EPO production.[16]

Medical uses

Main article: Erythropoiesis-stimulating agent

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 ulcerative colitis)[17] 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 g/dL to 12 g/dL.[18]

History

In 1905, Paul Carnot proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to bloodletting, Carnot and his graduate student Clotilde-Camille Deflandre [19] attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase hematocrit. This substance was purified and confirmed as erythropoietin.[15][20]

In 1977, Goldwasser and Kung purified EPO.[21] Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.[15] Synthetic EPO was first successfully used to correct anemia in 1987.[22] In 1985, Lin et al isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO.[23] In 1989, the US Food and Drug Administration approved the hormone Epogen for use in certain anemias.[24]

Usage as doping product

EPO has been banned since the early 1990s, but a first test was not available until the 2000 Summer Olympics.[25] Before this test was available, no athletes were sanctioned after positive tests, but it happened that they were sanctioned after confessing to having used EPO, for example in the Festina affair, when a car with doping products for the Festina cycling team was found.

The first doping test in cycling was used in the 2001 La Flèche Wallonne. The first rider to test positive in that race was Bo Hamburger, although he was later acquitted because his B-sample was not conclusive.[26]

A 2007 study showed that EPO has a significant effect on exercise performance,[27][4] but a 2017 study showed that the effects of EPO administered to amateur cyclists was not distinguishable from a placebo.[28]

See also

References

  1. ↑ "Erythropoietin". Merriam-Webster Dictionary.
  2. ↑ "Erythropoietin". Dictionary.com Unabridged. Random House.
  3. ↑ "erythropoietin – definition of erythropoietin in English from the Oxford dictionary". OxfordDictionaries.com. Retrieved 2016-01-20.
  4. ↑ 4.0 4.1 Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Medicine. 45 (4): 517–31. doi:10.1007/s40279-015-0308-9. PMID 25663250.
  5. ↑ Elliott S, Sinclair AM (2012). "The effect of erythropoietin on normal and neoplastic cells". Biologics. 6: 163–89. doi:10.2147/BTT.S32281. PMC 3402043. PMID 22848149.
  6. ↑ Hosseini-Zare MS, Dashti-Khavidaki S, Mahdavi-Mazdeh M, Ahmadi F, Akrami S (July 2012). "Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure". Clinical Neurology and Neurosurgery. 114 (6): 663–7. doi:10.1016/j.clineuro.2012.01.007. PMID 22296650.
  7. ↑ 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.
  8. ↑ 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 (November 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.
  9. ↑ Thomson, Angus W.; Lotze, Michael T. (2003-04-22). The Cytokine Handbook, Two-Volume Set. Gulf Professional Publishing. ISBN 9780080518794.
  10. ↑ Hodges VM, Rainey S, Lappin TR, Maxwell AP (November 2007). "Pathophysiology of anemia and erythrocytosis". Critical Reviews in Oncology/Hematology. 64 (2): 139–58. doi:10.1016/j.critrevonc.2007.06.006. PMID 17656101.
  11. ↑ Jacobson LO, Goldwasser E, Fried W, Plzak L (March 1957). "Role of the kidney in erythropoiesis". Nature. 179 (4560): 633–4. Bibcode:1957Natur.179..633J. doi:10.1038/179633a0. PMID 13418752.
  12. ↑ Fisher JW, Koury S, Ducey T, Mendel S (October 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.
  13. ↑ Barrett, Kim E.; Barman, Susan M.; Boitano, Scott; Brooks, Heddwen (eds.). Ganong's review of Medical Physiology (24th ed.). McGraw Hill. p. 709. ISBN 978-1-25-902753-6.
  14. ↑ Ji P (November 2016). "Pericytes: new EPO-producing cells in the brain". Blood. 128 (21): 2483–2485. doi:10.1182/blood-2016-10-743880. PMID 27884833.
  15. ↑ 15.0 15.1 15.2 Jelkmann W (March 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.
  16. ↑ Jelkmann W (March 2011). "Regulation of erythropoietin production". The Journal of Physiology. 589 (Pt 6): 1251–8. doi:10.1113/jphysiol.2010.195057. PMC 3082088. PMID 21078592.
  17. ↑ Liu S, Ren J, Hong Z, Yan D, Gu G, Han G, Wang G, Ren H, Chen J, Li J (February 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.
  18. ↑ "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. August 11, 2011.
  19. ↑ Carnot, P; Deflandre, Cl (1906). "Sur l'activite hematopoietique du serum au cours de la regeneration du sang". Compt. Rend. Acad. Sci. 143: 384–386.
  20. ↑ Höke A (2005). Erythropoietin and the Nervous System. Berlin: Springer. ISBN 978-0-387-30010-8. OCLC 64571745.[page needed]
  21. ↑ Miyake T, Kung CK, Goldwasser E (August 1977). "Purification of human erythropoietin". The Journal of Biological Chemistry. 252 (15): 5558–64. PMID 18467.
  22. ↑ Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (January 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.
  23. ↑ Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z (November 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. Bibcode:1985PNAS...82.7580L. doi:10.1073/pnas.82.22.7580. PMC 391376. PMID 3865178.
  24. ↑ "Epogen Prescribing Information" (PDF).
  25. ↑ "EPO DETECTION". World Anti-Doping Agency. December 2014.
  26. ↑ "Hamburger cleared of EPO use". BBC. 10 August 2001.
  27. ↑ Thomsen JJ, Rentsch RL, Robach P, Calbet JA, Boushel R, Rasmussen P, Juel C, Lundby C (November 2007). "Prolonged administration of recombinant human erythropoietin increases submaximal performance more than maximal aerobic capacity". European Journal of Applied Physiology. 101 (4): 481–6. doi:10.1007/s00421-007-0522-8. PMID 17668232.
  28. ↑ Heuberger JA, Rotmans JI, Gal P, Stuurman FE, van 't Westende J, Post TE, Daniels JM, Moerland M, van Veldhoven PL, de Kam ML, Ram H, de Hon O, Posthuma JJ, Burggraaf J, Cohen AF (August 2017). "Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial". The Lancet. Haematology. 4 (8): e374–e386. doi:10.1016/S2352-3026(17)30105-9. PMID 28669689.

Further reading

  • Takeuchi M, Kobata A (September 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 (August 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 (2002). "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 (December 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 (March 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 (June 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 (March 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 (March 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 (July 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 (2011). A Bloody Long Journey: Erythropoietin and the Person Who Isolated It. Xlibris. ISBN 978-1-4568-5737-0.[self-published source]

External links

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