What Is Erythropoietin?

The media article 'Performance-enhancing drug hurts brain' published in United Press International on 15 December 2011, highlights the consequences of Erythropoietin (EPO) use on cerebral circulation in healthy individuals. It argues that ethical and health risks associated with EPO use as a performance-enhancing drug outweigh the benefits, placing concern for healthy athletes that are not only gaining an unfair advantage but are also putting their lives at risk. The article summaries results of the study by Peter Rasmussen and colleagues, who found that in healthy individuals both short and long-term use of EPO restricts the amount of blood travelling to the brain. Contradicting evidence suggests that EPO has been an effective early treatment for patients dealing with ischemic stroke; however this is not included in the article. From the article it is infered that EPO should be used to treat 'sick people' to restore their haemoglobin levels back to normal, while it will have deleterious effects on an individual who is already producing a normal amount of red blood cells. Other than stroke, EPO has a history of treating anaemia caused by specific chronic diseases or chemotherapy medications (Jelkmann 2007) and is recommended for use as a therapeutic drug in Australia. For nonmedical uses, such as a performance-enhancing substance, purchasing EPO without a prescription is illegal and banned under the Olympic Movement's World Anti-Doping Code Prohibited Classes of Substances and Prohibited Methods (National Drug Strategy).

What is Erythropoietin?

EPO, produced by the kidneys, is a glycoprotein hormone that has its receptors in the hormonal system, as well as the paracrine and autocrine systems. Therefore, not only does it regulate red blood cell production but has an array of activity in the human body (Lappin 2003). By crossing the blood-brain barrier at high doses, EPO plays a neuroprotective role to injury, (Siren et al. 2001) assists in healing wounds (Haroon et al. 2003) and is able to prevent cell death by producing anti-apoptotic and cell proliferative actions (Chauhan N.B & Gatto 2010). In 1989 recombinant EPO (r-RHuEPO) was created to enhance aerobic capacity in chronically anaemic patients with kidney diseases (National Drug Strategy). For more than two decades cancer and HIV patients have benefited from EPO treatment. Lappin (2003) found that EPO receptors are located in cancer cells but not in surrounding healthy breast tissue. He therefore suggests that one day drugs can be targeted to tumours by these receptors, without harming healthy tissue. When the body experiences hypoxia, or inadequate oxygen supply, it will release EPO from kidney cells. EPO circulates in the plasma where it binds to elytroid progenitor cells (EPCs) (Erslev & Gabuzda 1985) initiating the proliferating signalling cascade. One of the classes of EPCs, BFU-E cells, proliferates into proerythroblasts that then grow and become erythroblasts and then reticulocytes. Reticulocytes then develop into red blood cells in the peripheral circulation (Lappin 2003).

Endurance sports require an efficient oxygen delivery system, which is why EPO has been used as a blood doping agent by athletes. As EPO has no effect on enhancing body image, the main reason athletes' use it is to boost their number of blood cells, improve oxygen delivery to muscles, reduce fatigue and enhance their endurance capability (Balestra & Germonpré 2010). As extra red blood cells are able to carry more nutrients and oxygen, EPO is believed to enhance muscles' healing process and increase metabolism (National Drug Strategy). In a recently published study, Max Gassmann et. al (2012) proved that injection of EPO causes immediate improvement in motivation in the brain, unaffecting red-blood cell count. New technologies have made it possible for a single injection of EPO to induce the body to naturally produce its own red blood cells, replacing the act of blood transfusions (Johnson 2006). As EPO increases red blood cell mass and haematocrit, in healthy individuals this could increase levels to the point where increased viscosity causes reduction of blood flow to the brain, resulting in clotting, thrombosis and stroke (Stohlawetz et al. 2000). Dehydration may also contribute to increased blood viscosity in healthy people who use EPO. At rest the body attempts to combat dehydration by "holding on" to more water. It does this by using water from the blood-stream during difficult exercise causing hematocrit (packed cell volume) levels to rise, and as a result the blood becomes more viscous (Jenkins 2005). Therefore, EPO should be used for those patients whose red blood cell levels are below normal, as opposed to increasing levels above normal and risking cerebral damage. With the worst case being death, other issues experienced by EPO users include convulsions, influenza-like symptoms, skin reactions, liver or pancreatic damage, increased blood pressure, etc. The black market contains 'fake' EPO that may contain only a small number of active ingredients and may even be contaminated. Transmission of viruses may occur through the sharing of equipment such as needles, infection and inflammation may occur where the skin has not been disinfected or cleaned and can even cause thrombosis (National Drug Strategy).

Elevated levels of EPO may produce a condition known as polycythaemia, when there is an elevated amount of red-blood cells causing the blood to become viscous enough to cause brain damage via stroke. The more vicious blood is, the greater the risk of developing blood vessel damage from coagulation and forming of unwanted blood clots, blocking blood flow to the heart or brain. As early as 1974, Erwin et al found that high blood viscosity impairs blood movement in the cerebral circulatory system while Stohlawetz et al. (2000) found that EPO effectively enhances endothelial activation and platelet reactivity, eventually leading to blood clot formation. EPO increases blood pressure by constricting blood vessels. Blood pressure is a measurement of the force of blood pumping on the arterial walls, and if you have high blood pressure - hypertension - the circulatory system is strained from the increased pumping of blood. Hypertension may eventually lead to atherosclerosis and arterial thickening which can can cause the occlusion of small blood cells in the brain. These blood cells can also be weakened by high blood pressure, causing them to rupture, a condition known as haemorrhagic stroke (Wong et al. 2011).

Past research

This is the first study to have shown a direct link between EPO and cerebrovascular events. The effect of EPO on hypertension, which is a precursor to many cerebrovascular diseases, has been investigated in many