Various hematinics or "blood-builders" have been administered to racing horses in an attempt to enhance their performance. These hematinics come in the form of nutrients (iron, copper, B12, thiamin, riboflavin and folic acid) and injected compounds, including recombinant human erythropoietin (rHuEPO), a potent drug that is used in human medicine to treat anemia of end-stage renal failure.
Products that do actually increase red cell production are unethical and potentially dangerous to the horse's health. In racehorses, the use of rHuEPO may have serious health effects, especially if administered in concert with furosemide.
Normal equine physiology
The main growth factor is erythropoietin, a hormone produced predominantly by the kidneys that stimulates the stem cells within the bone marrow to manufacture needed RBCs. It's a process that can take as few as two days, but more commonly five to seven.
Nutrients essential to erythropoesis, especially for oxygen-carrying hemoglobin production, are iron, copper, B12, thiamin, riboflavin and folic acid.
Enhanced RBC mobilization
Upon exercise, the horse's spleen contracts, adding a significant amount of red blood cells into the central circulation to meet the demand of maximal exercise. Maximal oxygen uptake (VO2max) in the horse is 110 to 180 ml/kg/min, achieved in part because of splenic contraction and mobilization of up to 12 L of extra red-cell-rich blood into central circulation during exercise. This innate ability to increase circulating blood volume makes the horse a "natural blood-doper."2
Horses have some protective physiological mechanisms, says Ken McKeever, PhD, FACSM, professor of equine exercise physiology at Rutgers University. "They can accommodate the huge amount of red cell volume that is squeezed in from the spleen at the onset of exercise. There are also differences in the way the red cells can bend," he says. "Equine red blood cells are more flexible and less fragile than human red blood cells, and they'll form up like a roll of coins when necessary in small vessels."
Use of rHuEPO in racing horses
The compound rHuEPO has saved many human lives and enhanced the quality of life for patients with chronic renal failure. But as soon as it was licensed for use in human medicine, the compound was being misused by individuals in both human and equine sports medicine.
"We began research not only on detection methods (to try to determine its illicit use), but on whether rHuEPO would affect aerobic capacity and athletic performance of horses," says McKeever. Some equine practitioners have questioned whether the human form of erythropoietin would have an effect in the horse.
McKeever and his colleagues started their research with very low doses of rHuEPO (15 IU/kg given three times a week for three weeks) in splenectomized horses to eliminate the possibility that splenic reserve was responsible for an increase in circulating red cell volume and increased performance.
"We showed that rHuEPO causes an increase in red cell mass, hematocrit and aerobic capacity," McKeever says. "But at the same time, we also saw an increase in blood viscosity, measured at different shear rates representative of different points in the cardiovascular system (i.e. aorta versus capillaries). The take-home message was that the recombinant human EPO worked in horses, as suspected. But our splenectomized study horses did not represent the intact racehorse."
McKeever, now at Rutgers Equine Science Center, did a followup study in standardbreds with intact spleens, following a similar protocol but with a higher dose of rHuEPO (50 IU/kg given three times a week for three weeks). The purpose: to show that rHuEPO increased red cell volume and aerobic capacity in an intact standardbred horse. But they also tried to detect antibodies to the compound.
"It was common for a certain number of horses to show a cross-reactivity problem, as if the horse was responding to a foreign protein," McKeever says. "After three injections of rHuEPO, the horses did show evidence of antibody production."
They also showed that the erythropoietin molecules were similar in humans and horses, that the erythropoietin is excreted fairly rapidly and that the red cells that develop stay in the system for quite a long time, as do the antibodies. (The antibody titer can therefore be used to detect rHuEPO, requiring horses to register a specific low level before they can race.)
Potential dangers of rHuEPO
"The horse has some protective mechanisms, but when we did our studies, we had a cutoff point for administering the rHuEPO," states McKeever. "We were worried about getting the blood too thick."
Thickening the blood could result in clotting, a reduction in cardiac output and the ability to transport oxygen since the horse is naturally losing fluids at exercise. Add the diuretic furosemide, which is commonly administered in racing horses, and you may exacerbate the problems.
"Not only do you have the cross-reactivity problem, but if the blood becomes too viscous, and you don't know where that occurs in the horse, you could potentially run into sludging problems—microvascular problems that could disrupt the function of very small vessels," McKeever says. "That is what they purportedly see in humans. With the thickening of fluid within small vessels and an increase in red blood cells, one may begin to develop blood clots. Then add the use of furosemide or aminocaproic acid, and you're asking for a disaster."
Despite rHuEPO's purported benefit, the horse's physiology remains extremely sensitive, fighting to maintain blood pressure, blood volume and blood tonicity.
"When we administered rHuEPO (as in some human studies), producing a short-term increase in red cell mass and blood volume, the body sensed that via its baroreceptors and signaled to get rid of some of that extra blood volume," McKeever says. "We actually saw a decrease in plasma volume. Therefore, although you've increased the red cell mass, you've maintained overall blood volume at the expense of plasma volume. This could have implications for normal regulation, since you no longer have the pool of water for sweat production."
In addition to rHuEPO, there are other hematinics that are available, as companies are working on other ways to stimulate red cell production, and there are numerous products that purport to increase red cell mass.
"If they work, they fall into the same nefarious category as rHuEPO," McKeever says. "If they don't work, then people are wasting money on useless, unethical products, despite their purported benefit."
Ed Kane, PhD, is a researcher and consultant in animal nutrition. He is an author and editor on nutrition, physiology and veterinary medicine with a background in horses, pets and livestock. Kane is based in Seattle.
1. Kirkham WW, Guttridge H, Bowden J, et al. Hematopoietic response to hematinics in horses. J Am Vet Med Assoc 1971;159(11):1316-1318.
2. McKeever KH, Agans JM, Geiser S, et al. Low dose exogenous erythropoietin elicits an ergogenic effect in standardbred horses. Equine Vet J Suppl 2006;36:233-238.
3. McKeever KH, Agans JM, Geiser S, et al. Effect of recombinant human erythropoietin administration on red cell volume, aerobic capacity and indices of performance in standardbred horses, in Proceedings. 16th Equine Nutr Physiol Symp 1999;163-164.