Essay: Erythropoietin

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  • Erythropoietin
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Erythropoietin (EPO) is a type of glycoprotein that is produced by both the kidneys and the liver (1). Its main role is to regulate the number of red blood cells that are produced, which in turn regulates the amount of hemoglobin (1, 4). Hemoglobin is essential for the transport of oxygen to tissues (4). Oxygen availability plays an important role in the function of cells (4). Hypoxic conditions stimulate the production of EPO (9). EPO stimulates the production of red-blood cells by binding to certain sites on erythroid progenitor cells (9). This triggers the differentiation of the cells into mature red-blood cells (9). While EPO is naturally produced by both the kidneys and liver, methods exist in order to produce EPO artificially as well (2, 4, 9). Synthetic EPO has approved uses in medicine that come with benefits and potential risks (1, 3, 4, 5, 10, 11). Endurance athletes also illegally use synthetic EPO in order to boost athletic performance (6, 7, 8, 12).
Synthetic EPO is produced through the isolation and cloning of the gene associated with EPO production (2, 4, 9). In a study done by Lin et al. (1985), the authors isolated the EPO gene by using a genomic phage library (9). They isolated the gene from the library using a mixture of oligonucleotide probes (9). According to the authors, the entire region of the gene that codes for amino acids is kept in a fragment that is 5.4 kilobases long (9). The EPO gene has four introns that include 1562 base pairs and five exons that include 582 base pairs (9). Once the authors isolated the EPO gene from the sample library, they introduced the gene into the ovary cells of Chinese hamsters (9). This produced a form of EPO that is active biologically both in vitro and in vivo (9). The EPO gene’s successful cloning resulted in the production of recombinant human EPO (4). This type of EPO later was approved for the treatment of different medical conditions (4).
One condition synthetic EPO is approved for is the treatment of cardiovascular disease (5, 11). Acute myocardial infarction is considered to be one of the leading causes of death in the United States and other developed countries (11). This is due to the ischemia/reperfusion injury, which is the irreversible damage of myocytes caused by infarction (11). Myocytes undergo the processes of apoptosis or necrosis due to the deregulation of the mitochondrial membrane (11). One factor that contributes to the death of myocytes include the fluctuation of reactive oxygen species, which increases oxidation (11). Other factors include the deregulation of transport across the mitochondrial membrane, abnormal activity of caspase-3, and the uncontrolled flux of calcium ions (11). EPO is believed to have cardioprotective effects by inhibiting these factors (11). EPO may maintain calcium homeostasis and the membrane potential within the mitochondrial membrane (11). EPO may also reduce the production of ROS and inhibit caspase-3 activity within cells (11).
Arrhythmias resulting from myocardial infarction may also be reduced through the use of EPO as well (5). According to a study by Gholamzadeh et al. (2015), higher doses of EPO were found to reduce the incidence of arrhythmias in myocardial infarction patients who underwent successful primary percutaneous coronary intervention (PCI) and anticoagulant treatments (5). EPO does this by decreasing the size of the infarction and improving left ventricular function following an infarction (5).
Another clinical use for EPO includes the treatment of glucose intolerance (1). According to a study done by Caillaud et al. (2015), EPO was found to significantly improve fasting blood glucose levels and overall tolerance of glucose (1). It was found to restore the activation of insulin-stimulated AKT partially and reduce total systemic inflammation, which contributes to more efficient metabolism of glucose (1).
EPO is also used in the treatment of anemia due to chemotherapy in cancer treatment and conditions such as chronic renal failure (3, 4, 9). In a study done by Doleschel et al. (2015), the author’s tested the use of EPO in the treatment of non-small-cell lung cancer (3). They found that EPO acts on the endothelium of tumors and increases the density, diameter, and number of endothelial vessels (3). This leads to slower tumor growth by more efficient anticancer drug delivery (3). Tumors undergo increased apoptosis as a result (3). The use of EPO is also effective at increasing the levels of hemoglobin in patients suffering from anemia due to chemotherapy treatment and end-stage renal failure (4, 9). It can reduce the need for blood transfusions and improve patient’s energy levels (4). Tolerance for exercise is also improved due to increased oxygen transport (4). EPO is also effective for improving cognitive function and overall sense of well-being for patients (4).
The use of EPO in the treatment of anemia also comes with certain risks (4, 10). EPO treatment can result in increased blood clotting (4). It can also cause hypertension and thromboembolisms due to increased blood viscosity from the increased number of red blood cells (4). EPO treatment can also result in excess blood iron levels, which can cause increased oxidative damage to tissues and increase the risk of cardiovascular disease (4). Patients undergoing EPO treatment may also display EPO resistance and do not adequately respond to EPO (10). They either require higher doses of EPO in order to maintain the recommended level of hemoglobin or do not respond to EPO at all (10). Because of the risks involved, EPO treatment is limited to only certain populations of patients (4). EPO dosage amount and frequency and hemoglobin levels must be monitored carefully in order to minimize the potential risk, while maximizing the benefits of the treatments (4).
Illegal use of EPO and blood transfusions in competitive endurance athletes is an issue as well (4, 6, 7, 8, 12). Endurance athletes use EPO in order to increase hemoglobin levels and enhance performance (4, 6, 7, 8, 12). However, blood doping comes with serious risks (4, 12).
Many of the risks associated with blood doping are the same as the use of EPO for medical purposes (4, 12). The elevated levels of hemoglobin increase the viscosity of blood (4, 12). Combined with dehydration and hyperthermic exercise conditons, this can lead to hypertension and increased risks of thromboembolisms, heart attacks, and stroke (4, 12). Blood doping may also cause the development of varicosities in peripheral veins (4).
Inappropriate storage and the mishandling EPO also contribute to the risk of blood doping (4). Improper storage and handling of EPO may cause degradation of the product and affect both its quality and the safety (4). Other risks of blood doping include the development of seizures and hypertensive encephalopathy (6). Blood flow and oxygen supply to the brain may also be restricted (6). One more risk associated with blood doping includes the development of red cell aplasia, which is a rare condition that results in the formation of anti-erythropoietin antibodies (6).
Blood doping is often difficult to detect in that red blood cells added through transfusion cannot be traced through reinfusion (7). Also, proteins from synthetic EPO can only be detected within a certain time period between the use of the drug and the test to detect it (7). Different hematological and biochemical tests are used for blood doping detection (12). One type of test includes the measurement of microRNA (miRNA) circulation in blood plasma (8). miRNAs are smaller RNA molecules that are non-coding which regulate different biological processes (8). They are used as a biomarker for the detection of red blood cell transfusion (8). Subjects that engage in transfusion have different patterns of circulating miRNA in blood plasma compared to normal subjects (8). Urine tests are also used in the detection of blood doping (12). These tests are based on electrophoretic mobility differences between synthetic EPO and EPO produced normally by the kidneys (12). Synthetic EPO and normal human EPO have different patterns of glycosylation and isoelectric points (12). Urine tests are used to separate the two forms of EPO based on the isoelectric point (12). Blood-doping is also detected by monitoring other biomarkers of EPO over time, such as hemoglobin and hematocrit (7, 12). Any non-physiological changes in these biomarkers raises the suspicion of blood doping (7, 12).
The use synthetic EPO is controversial (10). While many studies demonstrate the benefits of EPO in the treatment of anemia resulting from different medical conditions, other studies showed little benefit and even reported cases of mortality from EPO treatment (10). EPO treatment may present a number of benefits, but also carries potentially serious risks (4, 10). The risks are especially dangerous in illegal blood doping by endurance athletes (4, 6, 7, 8, 12). More research is required in order to determine the effectiveness of EPO as a treatment for different medical conditions.
References
1. Caillaud C , Mechta M, Ainge H, Madsen A, Ruell P, Mas E, Bisbal C, Mercier J, Twigg S, Mori T, Simar D, Barr??s R. (2015). Chronic erythropoietin treatment improves diet-induced glucose intolerance in rats. Journal of Endocrinology, 225, 77-88.
2. Chen S, Cressman S, Mao F, Shao H, Low D, Beilan H, Cagle E, Carnevali1 M, Gueriguian V, Keogh P, Porter H, Stratton S, Wiedeke M, Savatski L, Adamson J, Bozzini C, Kung A, Kent S, Bradburne J, Kochendoerfer G. (2005). Synthetic Erythropoietic Proteins: Tuning Biological Performance by Site-Specific Polymer Attachment. Chemistry and Biology 12(3): 371-383.
3. Doleschel D, Rix A, Arns S, Palmowski K, Gremse F, Merkle R, Salopiata F, Klingm??ller U, Jarsch M, Kiessling F, Lederle1 W. (2015). Erythropoietin Improves the Accumulation and Therapeutic Effects of Carboplatin by Enhancing Tumor Vascularization and Perfusion. Theranostics 5(8): 905-918.
4. Elliott S. (2008). Erythropoiesis-Stimulating Agents and Other Methods to Enhance Oxygen Transport. British Journal of Pharmacology 154(3): 529-541.
5. Gholamzadeh A, Amini S, Mohammadpour A, Vahabzadeh M, Fazelifar A, Fazlinezhad A, Dehghani M, Moohebati M, Dastani M, Malaekeh-Nikouie B, Falsoleiman H. (2015). Erythropoietin Reduces Post-PCI Arrhythmias in Patients With ST-elevation Myocardial Infarction. Journal of Cardiovascular Pharmacology 65(6): 555-561.
6. Heuberger J, Tervaert J, Schepers F, Vliegenthart A, Rotmans J, Daniels J, Burggraaf J, Cohen A. (2013). Erythropoietin doping in cycling: lack of evidence for efficacy and a negative risk’benefit. British Journal of Clinical Pharmacology 75(6): 1406-1421.
7. Jelkmann W, Lundby C. (2011). Blood doping and its detection. Blood 118(9): 2395-2404.
8. Leuenberger N, Schumacher Y, Pradervand S, Sander T, Saugy M, Pottgiesser T. (2013). Circulating microRNAs as Biomarkers for Detection of Autologous Blood Transfusion. PLOS One 8(6): e66309.
9. Lin F, Suggs S, Lin C, Browne J, Smalling R, Egrie J, Chen K, Fox G, Martin F, Stabinsky Z, Badrawi S, Lai P, Goldwasser E. (1985). Cloning and Expression of the Human Erythropoietin Gene. Proceedings of the National Academy of Sciences of the United States of America 82(22):7580-7584.
10. McCook O, Georgieff M, Scheuerle A, M??ller P, Thiemermann C, Radermacher P. (2012). Erythropoietin in the critically ill: do we ask the right questions?. Critical Care 16(5): 319.
11. Parvin A, Pranap R, Shalini U, Devendran A, Baker J, Dhanasekaran1 A. (2014). Erythropoietin Protects Cardiomyocytes from Cell Death during Hypoxia/Reperfusion Injury through Activation of Survival Signaling Pathways. PLOS One 9(9): e107453.
12. Pope H, Wood R, Rogol A, Nyberg F, Bowers L, Bhasin S. (2014). Adverse Health Consequences of Performance-Enhancing Drugs: An Endocrine Society Scientific Statement. Endocrine Reviews 35(3): 341-375.

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