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Veterinary Spotlight: Abuse with unknown perils

Posted: Saturday, January 17, 2004

Performance-enhancer EPO could have deadly, far-reaching effects on a healthy horse

PERIODICALLY, some form of cheating rises to the surface to blemish the sport of horse racing. Few methods have been as blatantly abusive to the horse as blood doping with epoetin alfa, a synthetic form of the body's natural erythropoietin, which can be fatal when given to a healthy horse. Epoetin alfa is considered a life-saving drug for humans with severe anemia and is better known by the trademarks Epogen and Procrit.

Natural erythropoietin is a protein produced by the kidneys that circulates through the bloodstream to the bone marrow, where it stimulates production of red blood cells. Red blood cells carry oxygen throughout the body.

Muscles require oxygen to function properly. When muscles are used to such an extent that the cardiovascular system cannot keep up with the needed supply of oxygen, a waste product, lactic acid, is produced that causes muscle fatigue-the burning you feel when a muscle tires. The greater the amount of circulating red blood cells in the body, the greater is the body's capacity to deliver the needed oxygen; therefore, as long as the oxygen supply is able to keep up with oxygen demand, muscles do not tire.

Epogen was developed by the research company Amgen Inc. to aid humans with severe anemia caused by acute kidney failure or cancer treatment. Anemia is a decrease in red blood cells. Epogen synthetically stimulates the body to produce increased numbers of red blood cells, thereby increasing oxygen delivery to the body. This increased supply of oxygen promotes stamina by delaying the onset of fatigue.

While Epogen is a boon to human medicine, its off-label use in healthy horses as a performance enhancer is deadly.

Unknown hazards

"When you increase red blood cells, you increase aerobic capacity. The bone marrow cranks out more red blood cells. The problem is that you can't turn off the effects of Epogen," said Kenneth McKeever, Ph.D., associate professor of equine exercise physiology at Rutgers University in New Jersey, who collaborated with George Maylin, Ph.D., of Cornell University to develop the current test for antibodies to erythropoietin (EPO) in horses.

"One, EPO is a hazard to the integrity of the sport," McKeever said, "and, two, it is a hazard to the animal."

According to McKeever, the two most serious results of blood doping with Epogen are that it might cause the blood to thicken to a sludge or it could cause the body to shut down its own natural production of red blood cells, resulting in severe anemia. But these problems are just the direct results of Epogen abuse.

Although McKeever emphasized that he knows of no published research into the effects of Epogen abuse in horses, he speculated that thickening of the blood could cause problems anywhere in the horse's body where small blood vessels exist.

When blood is too thick, McKeever explained, it does not move well through the circulatory system and is more likely to form clots.

"You get blood that is very, very thick, and the thicker the blood, the harder it is to pump through the cardiovascular system," McKeever said. "In people that purportedly have died from Epogen misuse, their blood became so thick that they start either forming clots or blocking small blood vessels in places like the heart, the brain, kidneys, etc. That is one of the potential side effects.

"I don't know anyone who has reported it, but if there is small vessel damage within the digestive tract, colic is certainly something [to consider] ... that's putting two and two together, but I wouldn't rule it out. But, I wouldn't say there is definitely a cause and effect, either."

In the trials McKeever and his colleagues performed, they used a very low dose of Epogen, but the results were dramatic.

"We've had the packed cell volumes [hematocrit] of those horses wind up in the 70 range, and that is getting pretty close to pushing sludge," he reported. "That was with the minimal dose for a very short period of time. Some people are giving horses a longer course of treatment and a higher dose, so the effects could potentially be even more. Those horses would be prone to throwing clots or having vessels block off. If you block the vessels, then blood pressure is going to go up super high, and that could potentially be a cause of problems. "Now, if you want pure, wild speculation from there, one of the diseases that has a link to changes in blood pressure is [exercise-induced pulmonary hemorrhage]. So, if you affect the cardiovascular system in that way, we don't know what happens with EIPH in horses that get Epogen. Anything that would raise blood pressure through the roof potentially would have an effect there."

McKeever also speculated that the microcirculatory system of the hoof might be affected by thickening of the blood, setting the horse up for laminitis. "If you look at a horse cross-eyed, he'll founder," he said.

Douglas Byars, D.V.M., of Hagyard Davidson McGee Associates in Lexington, is board certified in veterinary internal medicine. Byars agreed with McKeever that the adverse effects of Epogen are still speculative.

"With these horses that are receiving it, the trainer just cares that they receive it because he thinks it might help," Byars said. "They are certainly not doing follow-up studies. We know about the adverse responses, but not the peripheral clinical entities."

Byars urged clinicians to consider Epogen abuse as a possible cause if they are presented with a performance horse that is anemic. "If you have an anemic racehorse-and there are a lot of different causes of anemia-but with low red [blood] cell counts and low hematocrits, the degree of anemia is more severe with EPO horses than with another natural immunological state called autoimmune hemolytic anemia," Byars said. "There are some cancers that can infiltrate the bone marrow, but that is pretty rare."

Testing is limited

Current testing for EPO abuse is limited in that it can only detect elevated levels of antibodies produced in response to the drug. According to McKeever, the drug itself has a half-life of just minutes, although its effects could last up to 120 days. This makes it virtually impossible to pinpoint when a horse was administered the drug and by whom.

According to Scot Waterman, D.V.M., executive director of the Racing Medication and Testing Consortium, most racing jurisdictions now are testing for telltale antibodies to EPO. However, the fact that the drug cannot be detected in a split sample places racing commissions in an awkward position.

"No disciplinary action is taken because our rules prohibit substances, not antibodies," said Paula Flowerday, executive secretary of the Texas Racing Commission.

The typical course of action is merely to notify the owner of the horse's test results and bar the horse from competition until it tests clean. Consequently, racing organizations are clamoring for a more definitive test for EPO abuse.

McKeever is working on a secondary test that he believes will be available in several months. The test focuses on detecting plasma transferrin receptor activity, which occurs within hours of administration of Epogen.

"The primary protein in red blood cells is hemoglobin, and hemoglobin has iron in it," McKeever explained. "To get that iron into the developing red blood cell, there are receptors that are floating around in the plasma. Think of a hand floating around, ready to grab an iron molecule. It takes that iron molecule into the bone marrow and into the cells that are being produced, and then shoves it in there to make hemoglobin. Then, those receptors go back out and get more iron. Those plasma transferrin receptors go off within hours of getting an increase in erythropoietin, via an injection, and they stay up for weeks afterward."

If the new test fulfills the expectations of racing commissions, it will provide them with a means to identify trainers who violate the rule prohibiting EPO use or at least hold them accountable if a horse receives the drug on their watch.