Erythropoietin: Difference between revisions

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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.
|genericName=Erythropoietin
 
|aOrAn=a
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.
|drugClass=glycoprotein hormone
|indicationType=treatment
|hasBlackBoxWarning=Yes
|adverseReactions=hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion, and upper respiratory tract infection, cough, rash, and injection site irritation, nausea, vomiting, myalgia, stomatitis, cough, weight decrease, leukopenia, bone pain, hyperglycemia, insomnia, headache, depression, dysphagia, hypokalemia, and thrombosis, pruritus, headache, injection site pain, chills and deep vein thrombosis
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE</span>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Chronic Kidney Disease:: </span></i>


* In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL.
[[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&nbsp;g/dL to 12&nbsp;g/dL: this is to be avoided.
*No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
*Use the lowest PROCRIT dose sufficient to reduce the need for red blood cell (RBC) transfusions.


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]].


<i><span style="color:#FF0000;">Cancer:</span></i>
==Pharmacology==
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 ==


*ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.
=== Red blood cell production ===
*Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense PROCRIT to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance.
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.
*To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions.
*Use ESAs only for anemia from myelosuppressive chemotherapy.
*ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
*Discontinue following the completion of a chemotherapy course.


<i><span style="color:#FF0000;">Perisurgery:</span></i>
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.


*Due to increased risk of Deep Venous Thrombosis (DVT), DVT prophylaxis is recommended.
=== 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>


<!--Adult Indications and Dosage-->
== 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}}


<!--FDA-Labeled Indications and Dosage (Adult)-->
== Synthesis and regulation ==
|fdaLIADAdult=====Anemia Due to Chronic Kidney Disease====
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>


PROCRIT is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and not on dialysis to decrease the need for red blood cell (RBC) transfusion.
== 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>


* Dosing Information
== 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>


:* Dosage
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>


====Anemia Due to Zidovudine in HIV-infected Patients====
==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.


PROCRIT is indicated for the treatment of anemia due to zidovudine administered at ≤ 4200 mg/week in HIV-infected patients with endogenous serum erythropoietin levels of ≤ 500 mUnits/mL.
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>


* Dosing Information
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>


:* Dosage
== See also ==
* [[Hemopoietic growth factors]]
* [[Jehovah's Witnesses and blood transfusions]]


====Anemia Due to Chemotherapy in Patients With Cancer====
== References ==
{{Reflist|30em}}


PROCRIT is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.
== Further reading ==
{{refbegin|35em}}
* {{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 }}
* {{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 }}
* {{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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 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}}
{{refend}}


* Dosing Information
== External links ==
{{Wikiquote}}
* {{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.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]]


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====Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery====
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PROCRIT is indicated to reduce the need for allogeneic RBC transfusions among patients with perioperative hemoglobin > 10 to ≤ 13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery. PROCRIT is not indicated for patients who are willing to donate autologous blood pre-operatively.
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{{Hormones}}
* Dosing Information
{{Renal physiology}}
 
{{Colony-stimulating factors}}
:* Dosage
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{{Growth factor receptor modulators}}
====Limitations of Use====
{{Cytokine receptor modulators}}
 
*PROCRIT has not been shown to improve quality of life, fatigue, or patient well-being.
 
*PROCRIT is not indicated for use:
 
:*In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
:*In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
:*In patients scheduled for surgery who are willing to donate autologous blood.
:*In patients undergoing cardiac or vascular surgery.
:*As a substitute for RBC transfusions in patients who require immediate correction of anemia.
 
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[[Category:Drug]]
[[Category:Cytokines]]
[[Category:Growth factors]]
[[Category:Hormones of the kidneys]]
[[Category:Nephrology procedures]]
[[Category:World Anti-Doping Agency prohibited substances]]

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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