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09-SEPTEMBER-2008 02:07:44 - Erythropoietin Erythropoietin Available structures: 1buy, 1cn4, 1eer Identifiers Symbols EPO; EP; MGC138142 External IDs OMIM: 133170 MGI: 95407 HomoloGene: 624 Gene ontology Molecular function: erythropoietin receptor binding hormone activity Cellular component: extracellular region extracellular space Biological process: response to hypoxia signal transduction cell-cell signaling multicellular organismal development circulation erythrocyte differentiation erythrocyte maturation RNA expression pattern More reference expression data Orthologs Human Mouse Entrez 2056 13856 Ensembl ENSG00000130427 ENSMUSG00000029711 Uniprot P01588 Q0VED9 Refseq NM_000799 mRNA NP_000790 protein NM_007942 mRNA NP_031968 protein Location Chr 7: 100.16 - 100.16 Mb Chr 5: 137.71 - 137.71 Mb Pubmed search 2 3 Erythropoietin pronounced /ɨˌɹɪθɹoʊˈpɔɪɨtɨn/, /ɨˌɹɪθɹoʊˈpɔɪtÉ™n/, or /ɨˌɹiË?θɹoÊŠ-/ or EPO is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine for erythrocyte red blood cell precursors in the bone marrow. Also called hematopoietin or hemopoietin, it is produced by the liver and kidney, and is the hormone that regulates red blood cell production. It also has other known biological functions. For example, erythropoietin plays an important role in the brain's response to neuronal injury.1 EPO is also involved in the wound healing process.2 When exogenous EPO is used as a performance enhancing drug, it is classed as an Erythropoiesis Stimulating Agent ESA. Exogenous EPO can often be detected in blood, due to slight difference from the endogenous protein, for example in features of posttranslational modification. Contents 1 History 2 Regulation 2.1 Primary Role in Red Cell Blood Line 3 Uses 3.1 Anaemia due to chronic kidney disease 3.2 Anaemia due to treatment for cancer 3.3 Anaemia in critically ill patients 3.4 Blood doping 3.5 Neurodegenerative diseases 4 Adverse effects 4.1 Safety advisories in anaemic cancer patients 5 See also 6 Additional images 7 References 8 Further reading 9 External links History In 1906 Paul Carnot, a Professor of Medicine in Paris, and his assistant DeFlandre proposed the idea that erythropoiesis was regulated by hormones. After conducting experiments on rabbits subject to bloodletting, Carnot and DeFlandre attributed an increase in red blood cells in rabbit subjects to a hemotopic 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 Reissman and Erslev demonstrated that a certain substance circulated in the blood was 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 like anemia.34 Haematologist 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 anaemia in humans. 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. In 1985, Lin et al. isolated the human erythropoietin gene from a genomic phage library and were able to characterize it for research and production5 Their research demonstrated that the gene for erythropoietin encoded the production of Epo in mammalian cells that is biologically active in vitro and in vivo. This opened up the door for the industrial production of recombinant erythropoietin RhEpo for treating anemia patients. In 1989, the Food and Drug Administration approved the hormone, called Epogen, which remains in use. More recently a novel erythropoiesis stimulating protein NESP has been produced.6 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. Regulation 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.78 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.9 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. Primary Role in Red Cell Blood Line 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. Uses Erythropoietin is available as a therapeutic agent produced by recombinant DNA technology in mammalian cell culture. It is used in treating anaemia resulting from chronic kidney disease, from the treatment of cancer chemotherapy radiation, and from other critical illnesses heart failure. Anaemia due to chronic kidney disease In patients who require dialysis have stage 5 chronic kidney diseaseCKD, iron should be given with erythropoietin.10 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 anaemia in people with chronic kidney disease who are 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 anaemia due to chronic kidney disease not on dialysis, these are: epoetin Procritalso known as Eprex, NeoRecormon darbepoetin Aranesp. PDpoetinan erythropoietin produced in Iran by Pooyesh Darou Pharmaceuticals Brands available in the USA include: epoetin Procrit and Epogen Anaemia due to treatment for cancer Please help improve this section by expanding it. Further information might be found on the talk page or at requests for expansion. November 2007 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.11 Anaemia in critically ill patients There are two types of erythropoietin and three brands for people with anaemia, due to critical illness. These are: epoetin Procritalso known as Eprex, NeoRecormon darbepoetin Aranesp epoetin delta Dynepo PDpoetinan erythropoietin produced in Iran by Pooyesh Darou pharmaceuticals In a recent randomized controlled trial,12 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 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 ESAs have a history of usage as a blood doping agent in endurance sports such as cycling, rowing, distance running, cross country skiing, biathlon, triathlons, and most recently, billiards.13 Neurodegenerative diseases Erythropoietin has been shown to be beneficial in certain neurodegenerative diseases like schizophrenia14. Adverse effects Erythropoietin is associated with an increased risk of adverse cardiovascular complications in patients with kidney disease if it is used to increase haemoglobin levels above 13.0 g/dl.15 Early treatment with erythropoietin has been shown to significantly increase the risk of Retinopathy of prematurity in premature infants, and is not recommended. 16 Safety advisories in anaemic cancer patients Amgen sent a dear doctor letter in January 2007, that highlighted results from a recent anaemia of cancer trial, and warned doctors to consider use in that off-label indication with caution. Amgen advised the United States FDA as to the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp p=0.01. In response to these advisories, the FDA released a Public Health Advisory17 on March 9, 2007, and a clinical alert18 for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents ESAs 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 warnings about the safety of these drugs. On March 22, 2007, a congressional inquiry into the safety of erythropoeitic growth factors was reported in the news media. Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients. Several recent publications and FDA communications have increased the level of concern related to adverse effects of ESA therapy in selected groups. In a revised Black Box Warning FDA notes significant risks associated with use. ESAs should only be used in patients with cancer when treating anemia specifically caused by chemotherapy and not for other causes of anemia. Further, it states that ESAs should be discontinued once the patient's chemotherapy course has been completed. For more information visit the FDA website at: http://www.fda.gov/medwatch/safety/2007/safety07.htm#ESA2, http://www.fda.gov/cder/foi/label/2007/103234s5158lbl.pdf, http://www.fda.gov/cder/foi/label/2007/103951s5164lbl.pdf and http://www.fda.gov/cder/drug/infopage/RHE/default.htm. See also Erythropoiesis Amgen, producer of artificial EPO Brand Names: Epogen and Aranesp Dynepo, trademark name for an erythropoiesis stimulating protein, by TKT Blood doping, transfusions and EPO use as doping methods; testing and enforcement Jehovah's Witnesses and blood transfusions The German company AplaGen Biopharmaceuticals4 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.19 Additional images EPO hematopoiesis German JAK-STAT signaling pathway EPO structure EPO sales Epo blotting References ^ Siren AL et al. 2001. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 98: 4044-4049. doi:10.1073/pnas.051606598. PMID 11259643. ^ Haroon ZA et al. 2003. A novel role for erythropoietin during fibrin-induced wound-healing response. Am J Pathol 163: 993-1000. ^ Jelkmann, Wolfgang. Erythropoietin after a century of research: younger than ever European Journal of Haematology 78 3, 183-205. 2007 ^ Hoke, A, and Hoke AE. Erythropoietin and the Nervous System: Novel Therapeutic Options for Neuroprotection. Published by Springer. 2006 ^ Lin FK et al. Cloning and Expression of the Human Erythropoietin Gene. Proceedings of the National Academy of Science. 8222:7580-7584. 1985 ^ Macdougall, IC. Novel erythropoiesis stimulating protein. Semin Nephrology 20:375-381. 2000 ^ Jacobson LO, Goldwasser E, Fried W, Plzak L. Role of the kidney in erythropoiesis. Nature 179:633. 1957 ^ 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 ^ Jelkmann, W 2007. Erythropoietin after a century of research: younger than ever. Eur J Haematol. 78 3: 183-205. doi:10.1111/j.1600-0609.2007.00818.x. PMID 17253966. ^ Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE 1996. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 50 5: 1694-9. doi:10.1038/ki.1996.487. PMID 8914038. ^ 1CNN Money article ^ 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. ^ Cueless: Billiards Player a Real Dope. Chicago Tribune/Associated Press, March 18, 2008. ^ H. Ehrenreich et al, Erythropoietin: a candidate compound for neuroprotection in schizophrenia., Mol Psychiatry. 2004 Jan;91:42-54., http://physiologie.univ-lyon1.fr/enseignement/coursLB/Ehrenreich2004.pdf accessed august 4th, 2008. ^ Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A 2006. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N. Engl. J. Med. 355 20: 2071-84. doi:10.1056/NEJMoa062276. PMID 17108342. ^ Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004863. PMID 16856062 ^ FDA Public Health Advisory: Erythropoiesis-Stimulating Agents ESAs: Epoetin alfa marketed as Procrit, Epogen, Darbepoetin alfa marketed as Aranesp. Retrieved on 2007-06-05. ^ Information for Healthcare Professionals: Erythropoiesis Stimulating Agents ESA. Retrieved on 2007-06-05. ^ AplaGen Biopharmaceuticals - About AplaGen Further reading Takeuchi M, Kobata A 1992. 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 2002. Erythropoietin in human milk: physiology and role in infant health.. Journal of human lactation : official journal of International Lactation Consultant Association 18 3: 252-61. PMID 12192960. Ratcliffe PJ 2003. From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway.. Blood Purif. 20 5: 445-50. doi:10.1159/000065201. PMID 12207089. Westenfelder C 2003. Unexpected renal actions of erythropoietin.. Exp. Nephrol. 10 5-6: 294-8. doi:10.1159/000065304. PMID 12381912. Becerra SP, Amaral J 2002. Erythropoietin--an endogenous retinal survival factor.. N. Engl. J. Med. 347 24: 1968-70. doi:10.1056/NEJMcibr022629. PMID 12477950. Genc S, Koroglu TF, Genc K 2004. Erythropoietin and the nervous system.. Brain Res. 1000 1-2: 19-31. doi:10.1016/j.brainres.2003.12.037. PMID 15053948. Fandrey J 2004. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression.. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286 6: R977-88. doi:10.1152/ajpregu.00577.2003. PMID 15142852. Juul S 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, et al. 2005. Brain and cancer: the protective role of erythropoietin.. Med Res Rev 25 2: 245-59. doi:10.1002/med.20012. PMID 15389732. Sytkowski AJ 2007. Does erythropoietin have a dark side? Epo signaling and cancer cells.. Sci. STKE 2007 395: pe38. doi:10.1126/stke.3952007pe38. PMID 17636183. External links NYT 1987 announcement of Epogen's clinical success Patient information on Epogen Patient information on Aranesp Patient information on Procrit v d e Endocrine system: hormones/endocrine glands Peptide hormones, Steroid hormones Hypothalamic-pituitary Hypothalamus: TRH, CRH , GnRH, GHRH, somatostatin, dopamine - Posterior pituitary: vasopressin, oxytocin - Anterior pituitary: α FSH, LH, TSH, GH, prolactin, POMC ACTH, MSH, endorphins, lipotropin Adrenal axis Adrenal medulla: epinephrine, norepinephrine - Adrenal cortex: aldosterone, cortisol, DHEA Thyroid axis Thyroid: thyroid hormone T3 and T4 - calcitonin - Parathyroid: PTH Gonadal axis Testis: testosterone, AMH, inhibin - Ovary: estradiol, progesterone, inhibin/activin, relaxin pregnancy Other end. glands Pancreas: glucagon, insulin, somatostatin - Pineal gland: melatonin Non-end. glands Placenta: hCG, HPL, estrogen, progesterone - Kidney: renin, EPO, calcitriol, prostaglandin - Heart atrium: ANP - Stomach: gastrin, ghrelin - Duodenum: CCK, GIP, secretin, motilin, VIP - Ileum: enteroglucagon - Adipose tissue: leptin, adiponectin, resistin - Thymus: Thymosin - Thymopoietin - Thymulin - Skeleton: Osteocalcin - Liver/other: Insulin-like growth factor IGF-1, IGF-2 Target-derived NGF, BDNF, NT-3 v d e Urinary system, physiology: renal physiology and acid base physiology Filtration Renal blood flow - Ultrafiltration - Countercurrent exchange Hormones affecting filtration Antidiuretic hormone ADH - Aldosterone - Atrial natriuretic peptide Secretion/clearance Pharmacokinetics - Clearance of medications Reabsorption Solvent drag - Na+ - Cl- - urea - glucose - oligopeptides - protein Endocrine Renin - Erythropoietin EPO - Calcitriol Active vitamin D - Prostaglandins Assessing Renal function/ Measures of dialysis Glomerular filtration rate - Creatinine clearance - Renal clearance ratio - Urea reduction ratio - Kt/V - Standardized Kt/V - Hemodialysis product - PAH clearance Effective renal plasma flow - Extraction ratio Acid base physiology Fluid balance - Darrow Yannet diagram - Body water - Interstitial fluid - Extracellular fluid - Intracellular fluid/Cytosol - Plasma - Transcellular fluid - Base excess - Davenport diagram - Anion gap - Arterial blood gas Buffering/compensation Bicarbonate buffering system - Respiratory compensation - Renal compensation v d e Cytokines, glycoproteins: colony-stimulating factors Numbered Macrophage colony-stimulating factor - Granulocyte macrophage colony-stimulating factor - Granulocyte colony-stimulating factor Unnumbered Erythropoietin - Thrombopoietin - Interleukin 3 Retrieved from http://en..org/wiki/Erythropoietin Categories: Genes on chromosome 7 | Human proteins | Growth factors | Hormones of the kidneys | Amgen | Drugs in sport | Erythropoiesis-stimulating agentsHidden categories: Articles to be expanded since November 2007 | All articles to be expanded Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages العربية Bosanski ÄŒesky Dansk Deutsch Þ‹Þ¨ÞˆÞ¬Þ€Þ¨Þ„Þ¦Þ?Þ° Español Esperanto Français Italiano עברית Lietuvių МакедонÑ?ки Nederlands 日本語 ‪Norsk bokmÃ¥l‬ Polski Português РуÑ?Ñ?кий Simple English SlovenÅ¡Ä?ina Åšlůnski Suomi Svenska Türkçe ä¸æ–‡ This page was last modified on 29 August 2008, at 03:52
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