Blood Builders (Hematinics)
Administration of hematinics (also known as "blood builders") to horses, either in the form of dietary supplements or as injectable compounds, is commonly practiced by owners, trainers, and veterinarians. The general objective in using these compounds is to increase a horse's supply of nutrients essential for the synthesis of hemoglobin and red blood cells (RBCs) and, in doing so, "build the blood" by increasing the number of RBCs. The basis for this practice seems obvious--the higher the number of RBCs, the better exercise performance will be.
Unfortunately, life is never that simple.
Yes, hematinics do supply nutrients that are essential for the production of RBC. However, their administration does not necessarily result in "blood boosting," and the need for hematinics depends on a number of factors, particularly the make-up of the horse's overall diet.
I am sure that many of you are aware of the current furor in human athletics concerning use of the doping agent erythropoietin (EPO). EPO, a hormone pro-duced by the kidneys, stimulates RBC production. With the advent of genetic engineering, human EPO became commercially available and, inevitably, human athletes looked to this drug as a means to boost performance. We also know that EPO has been used in horses, and currently there is concern among the racing authorities regarding illegal use of this drug (i.e., doping) in racehorses.
Before we further discuss the use of hematinics and EPO in horses, it is important to understand some basics concerning the production of RBCc, the role the spleen plays in boosting circulating RBC numbers during exercise, and the tools available to assess the adequacy of RBC numbers and iron stores.
Production Of Red Cells
Blood is a combination of cells (red cells, white cells, and platelets) and plasma; the latter is a combination of water, proteins, and a small amount of certain fats. Blood cells are produced by the bone marrow, a tissue located in the center of bones. Blood volume is about 8% of body weight--that is, a 500-kilogram (1,100-pound) horse has about 40 liters (11 to 12 gallons) of blood.
Within the bone marrow, special cells known as stem cells support production of red and white blood cells. Production of RBCs is dependent on growth factors and an adequate supply of essential nutrients. The main growth factor involved is EPO, which stimulates stem cells, instigating the process that results in the maturation of a new RBC. Normally, this process takes about five to seven days, although under conditions of very high demand new RBCs can be churned out in as little as two days.
The nutrients essential for normal erythropoiesis (red blood cell production) include iron, copper, vitamin B12, and folic acid (another type of B-vitamin). These nutrients mostly are required for the synthesis of hemoglobin, the special protein that carries oxygen in the blood. Iron is a critical component of hemoglobin, and iron deficiency will slow production of hemoglobin and RBC and, in turn, result in anemia. It is for this reason that iron is the principle component of most hematinics.
RBC production is an ongoing process. These cells have a limited lifespan, usually about 140 to 160 days. Aged red cells are removed by the spleen, and the iron contained within these cells is used in the synthesis of new red cells. This is an important point; the body is very efficient in its use of iron, and supply of iron is very rarely a limiting factor for erythropoiesis.
Normally, new RBCs are produced at a rate that closely matches the rate of removal of aged RBCs, so that red cell numbers remain con-stant. However, this might not be true under certain disease states, the end result being the development of anemia. Anemia can occur under three main circumstances: 1) when production by the bone marrow fails to keep pace with demand; 2) with loss of blood from the body (hemorrhage); and 3) following destruction of RBCs.
The most common reason for inadequate RBC production is chronic illness (e.g., a bacterial infection). Hemorrhage can be either acute or chronic--serious injuries are a common cause of acute hemorrhage. For example, a deep cut to the forearm or penetrating wound to the chest causes blood loss. Chronic hemorrhage implies a slow "leak" of RBCs from the body. A good example is gastric ulceration. Horses with gastric ulcers can be slightly anemic due to hemorrhage in the stomach.
Assessment Of Red Cell Numbers
In athletic horses, much attention is directed toward evaluation of the "blood count." The three main parameters usually assessed (as part of a complete blood count or CBC) are: hematocrit, RBC count (the number of red cells per unit volume of blood), and hemoglobin concentration. Hematocrit or PCV (packed cell volume) provides a measure of the number of RBC relative to the total volume of blood. For example, if the PCV is 40%, this indicates that RBC represent 40% of the total blood volume, the remainder being other cellular constituents and plasma fluid.
What are so-called "normal values" for PCV, RBC count, and hemoglobin concentration? Most veterinary laboratories have established reference ranges for these parameters--this database is established by taking blood samples from a large number of healthy horses and using their laboratory equipment to measure PCV, etc. Then, when patient samples are analyzed, the results are compared to this reference range. If these numbers fall within the reference range, we can be reasonably assured that the results are "normal" (see Table 1 on page 74).
Racehorse trainers routinely use the "blood count" as a means to assess fitness and readiness to race. For example, some trainers consider that a hemoglobin concentration of 16 to 18 grams per deciliter (g/dL) is desirable for optimal racing performance. However, there are a few pitfalls in this approach. The main problem is the very large reservoir of RBCs that is stored in the spleen.
This reservoir of RBCs plays an important role during exercise. At the start of exercise, the spleen contracts and releases the stored red cells into general circulation. In fact, up to one-third of the horse's red cells are stored within the spleen. One of the main functions of red cells is to transport oxygen from the lung to other parts of the body. Therefore, the increase in blood volume associated with splenic contraction provides a tremendous boost in the horse's capacity to transport oxygen.
Indeed, this high capacity for oxygen transport contributes to the high athleticism of the horse. We know this to be true because following removal of the spleen, horses suffer a sharp decline in athletic ability.
Splenic contraction and release of stored red cells can occur under other circumstances--for example, when the horse is excited or in pain. Therefore, values for PCV and hemoglobin concentration can vary greatly depending on the horse's demeanor, degree of excitement, and exercise state. If the horse is excited or agitated at the time of blood sampling, the blood count probably will not reflect a true resting state. Galloping exercise will result in the largest increase in PCV, with values as high as 65%-70%, while PCV often is in the range of 45%-55% after a period of slower exercise (trotting). The PCV will gradually decline during a one- to two-hour period after exercise as RBC return to storage in the spleen.
The bottom line is that blood sampling is best done early in the morning with the horse resting in its stall (and before feeding). The PCV of a quiet, resting horse is typically 32%-46%. When values are greater than 45%, chances are the horse was excited at the time of sampling. For an individual horse, values for PCV and hemoglobin will fall within a fairly narrow range. Therefore, providing the conditions at the time of blood sampling are similar, repeated blood count evaluations can be a useful health monitoring tool.
For example, a decrease in PCV (e.g., from 38% to 28%) might explain poor exercise performance and will prompt your veterinarian to investigate the cause of this reduction in red cell number.
Hematinics, or blood builders, commonly are administered to horses. Although the make-up of these preparations can vary, iron is the principle ingredient, with lesser amounts of copper, zinc, and some of the B-vitamins (folic acid, vitamin B12, thiamin, and riboflavin) usually included.
The misconception is that the hematinic will stimulate RBC production, and therefore the treatment enhances a horse's performance by improving its ability to transport oxygen from the lung to working muscles.
Very few studies have examined the effectiveness of hematinics. However, studies of growing ponies and of Thoroughbred horses in light training found no change in PCV, RBC count, or hemoglobin concentration after eight to 12 weeks of supplementation (see Kirkham et al. 1971; Lawrence et al. 1987). It is important to emphasize that these studies were done in healthy animals with normal blood counts--a different response might be seen in horses which are anemic or under heavy performance stress. These animals probably could benefit from the nutrients provided in a typical hematinic.
It also is important to realize that iron deficiency is very rare in the horse. By comparison, women athletes are at high risk for iron deficiency anemia because of a combination of menstrual losses and inadequate dietary intake.
Obviously, the situation is different in horses--unless a horse is suffering from chronic blood loss, such as that caused by a bleeding ulcer, body iron stores will be adequate and certainly well maintained by regular use of a hematinic (see Carlson 1992).
If you are feeding supplements to your horse, try to avoid "doubling-up" on the nutrients provided--it is common for horses to receive multiple supplements that contain similar nutrients. One iron supplement is more than adequate, and helps avoid giving the horse too much iron. In addition, some studies have shown that high levels of dietary iron can interfere with the absorption of other minerals in the diet.
In human athletics, concern over the use of synthetic EPO (trade name Epogen) has reached fever pitch the past couple of years. First, there was the scandal during the 1998 Tour de France cycling race in which a number of cyclists (and teams) were required to withdraw because of allegations con-cerning doping with EPO. This incident sparked a flurry of research into the performance-enhancing effects of EPO and the development of test procedures for detecting illegal doping. This year, the International Olympic Committee (IOC) introduced new testing procedures for use at the Sydney Olympics.
Epogen first was developed for treatment of life-threatening anemia in humans with kidney failure--in those patients, production of erythropoietin is greatly reduced and results in suppression of RBC production. Administration of Epogen to those patients corrects the anemia and greatly improves their quality of life. For the same reason, Epogen has been used in some veterinary patients with kidney failure, particularly dogs and cats.
The problem with Epogen relates to its use as a performance-enhancing agent. Studies in human athletes have shown up to 10% improvements in endurance performance after treatment with the drug. Middle distance runners, swimmers, and cyclists will benefit most. The reason for this performance boost is simple--there is a 15%-20% increase in blood count that results in a large increase in oxygen-carrying capacity, and about a 6%-8% increase in maximum aerobic capacity (VO2max) (see Birkland et al. 2000).
Diagnosis of EPO doping is difficult because the erythropoietin in the drug is identical to the erythropoietin produced in the body. Newer testing procedures have improved detection of illicit drug use; however, these methods are by no means fail-safe. More importantly, the effects of EPO on endurance performance outlast changes in any marker of illicit drug use. For now, abuse of EPO by human athletes is likely to continue.
There are similar concerns regarding illicit use of EPO in athletic horses, particularly racehorses. As detailed in the June 3, 2000, issue of The Blood-Horse, the Association of Racing Commissioners International, the National Thoroughbred Racing Association, and the Thoroughbred Horsemen's Association have instigated research aimed at the development of a test for detection of doping with Epogen. This research is being led by Ken McKeever, PhD, MS, at Rutgers University.
At this stage, the jury is still out regarding the potential for Epogen to enhance performance in horses. However, recent studies in McKeever's laboratory (see McKeever et al. 1999) have demonstrated that a short course of Epogen treatment (50 IU/kg three times weekly for three weeks) results in a 10%-12% increase in the VO2max of unfit Standardbred mares. This effect could result in performance enhancement.
Whether or not a similar increase in aerobic capacity occurs in fit horses remains to be determined. Remember that horses are natural "blood dopers" in that the spleen injects a large number of red cells into circulation at the start of exercise, providing a huge boost in aerobic power. It is possible that the effects of Epogen on performance in horses are less marked than those documented in human endurance athletes.
Regardless of these theoretical arguments, use of Epogen in horses for the purposes of performance enhancement is unethical and, worse, places the horse at risk for serious health problems. There have been reports of severe anemia, and even death in horses receiving repeated Epogen treatments. Epogen contains human erythropoietin, a substance that the horse's immune system recognizes as foreign. Therefore, the immune system responds by producing antibodies to destroy it. However, human and equine erythropoietin have a very similar structure, and it is likely that these "anti-Epogen" antibodies also destroy the horse's own erythropoietin.
The take-home message is that Epogen should not be used in horses for the purposes of performance enhancement.
Birkland, K.I.; Stray-Gundersen, J.; Hemmersbach, P.; Hallén, J.; Haug, E.; Bahr, R. Effect of rhEPO administration on serum levels of sTfR and cycling performance. Medicine and Science in Sports and Exercise 2000; 7: 1238-1243.
Carlson, G.P. Hematology and body fluids in the equine athlete: A review. In Gillespie, J.R., and Robinson, N.E. (eds): Equine Exercise Physiology 2. Davis, ICEEP Publications, 1987, 393-425.
Carlson, G.P. A survey of the iron status of Thoroughbred horses in race training. In Proceedings of the 10th Forum of the American College of Veterinary Internal Medicine, San Diego, Calif., 1992, 448-449.
Geor, R.J.; Weiss, D.J. Drugs affecting the hematologic system of the performance horse. Veterinary Clinics of North America: Equine Practice 1993; 9: 649-667.
Kirkham, W.W.; Guttridge, H.; Bowden, J.; Edds, G.T. Hematopoietic responses to hematinics. Journal of the American Veterinary Medical Association 1971; 159: 1316-1319.
Lawrence, L.M.; Ott, E.A.; Asquith, R.L.; Miler, G.J. Influence of dietary iron on growth, tissue mineral composition, apparent phosphorus absorption, and chemical properties of bone. In Proceedings of the 10th Equine Nutrition and Physiological Society Symposium, Lexington, Ky., 1987, 563-571.
McKeever, K.H.; Agans, J.M.; Geiser, S.; Scali, R.; Guirnalda, P.D.; Kearns, C.F.; Lorimer, P.J. Effect of recombinant human erythropoietin administration on red cell volume, aerobic capacity, and indices of performance in Standardbred horses. In Proceedings of the 16th Equine Nutrition and Physiological Society Symposium, Raleigh, N.C., 1999, 163-164.
Piercy, R.J.; Swardson, C.J.; Hinchcliff, K.W. Erythroid hypoplasia and anemia following administration of recombinant human erythropoietin to two horses. Journal of the American Veterinary Medical Association 1998; 212: 244-247.
About the Author
Ray Geor, BVSc, PhD, Dipl. ACVIM, is professor and chairperson of Large Animal Clinical Sciences at the College of Veterinary Medicine at Michigan State University
POLL: University Equine Hospitals