Blood doping

In this Olympic year, Jeremy Windsor brings us an update on the performance enhancing use of blood doping

In 2007 the Tour de France made newspaper headlines around the world for all the wrong reasons. There was widespread condemnation of the rapidly growing number of cyclists who seemed to be failing drug tests as a result of blood doping. Instead of exciting pictures of super-human athletes sprinting breathlessly towards the finish line, the world’s media showered us with images of jeering spectators, booing and waving placards at the nervous competitors. Even the normally patriotic French media joined in, with Le Soir running a funeral notice for the tour and Liberacion arguing that the event should be stopped.

The seeds of the debacle were almost routine: the German rider Patrik Sinkewitz failed a drugs test a month before the start of the tour. Nothing was made of it, as he was soon forced out of the race because of injury. Shortly after, though, the pre-tour favourite Alexander Vinokourov was found guilty of using blood transfusions; days later the race leader Michael Rasmussen was withdrawn by the management of his Rabobank team after missing a series of anti-doping tests.

This was far from the first time the tour had been plunged into controversy. During the 1998 event, now commonly referred to as the Tour de Farce, members of both the Festina and TVM cycling teams were arrested when the French authorities found large quantities of illegal drugs in their hotel rooms.

In 2004 Philippe Gaumont, a rider with the Cofidis team, admitted to investigators that the use of drugs such as steroids, human growth hormone, amphetamines and erythropoietin (r-EPO) were endemic among competitors. More recently a series of high profile cases have confirmed Gaumont’s accusation, with previous tour winners such as Bjarne Riis, Jan Ullrich and Marco Pantani all being implicated in the illegal use of performance enhancing drugs.

Linking many of these cyclists together is their illegal use of either r-EPO or other blood products. Below we consider in more depth the effects these performance enhancers have, how they are detected, and what damage they can do.

Performance boosting

In order to explain how r-EPO and blood products can benefit an athlete, we need a clear understanding of ‘VO2max’. This widely used sports-training term simply refers to the maximum amount of oxygen an individual’s body can use over a given period of time. While you or I might have a VO2 max of two, three or four litres per minute, international endurance athletes enjoy a VO2 max of five, six or seven litres per minute. This vastly superior ability to utilise oxygen is invaluable in long-distance events as it allows the body to produce large quantities of adenosine triphosphate (ATP) – the fuel it needs to power its muscles.

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For every molecule of glucose, the body’s cells are capable of making 38 molecules of ATP if oxygen is present. But when the cells are deprived of oxygen, ATP production falls dramatically, so the body can only generate two ATP molecules per glucose molecule – and this at the cost of also producing large quantities of lactic acid.

In order to sustain high levels of exercise, it is therefore necessary to maximise the availability of oxygen by increasing the athlete’s VO2max. While training can certainly increase VO2max, those at the very highest levels of competition struggle to find room for improvement. One way to squeeze in that extra capacity is to turn to blood transfusions or the use of erythropoietin (r-EPO).

These work because the vast majority of oxygen that makes it into the muscles is delivered by haemoglobin molecules bound closely to red blood cells in the circulation. Seminal work from the 1950s showed that people with low concentrations of red blood cells and haemoglobin had a much lower VO2 max than individuals with normal levels (see Figure 1, above right) (1) .

In 1972, further work showed that when the body’s concentration of haemoglobin was raised from 14.5g to 16g per 100ml of blood, the improvement in oxygen carrying capacity resulted in an increase of up to 10% in VO2max (2) . This was shown to improve athletic performance, with a series of studies revealing that transfusions of up to 800ml of blood improved brief all-out run times by 35%, while competitive athletes managed to reduce their five-mile and 10km times by 45 and 69 seconds respectively (1) .

These findings soon led to a number of elite athletes using blood transfusions to improve their performance in a range of endurance sports, such as cycling, crosscountry skiing and long-distance running.

Then in 1987 came a breakthrough in the means by which an athlete could increase their concentration of circulating red cells. Instead of transfusing blood, athletes could instead administer an injection that would stimulate the release of large quantities of immature red cells (reticulocytes) from the body’s own bone marrow, which would subsequently mature in the circulation, increasing the total number of red cells.

Recombinant erythropoietin (r-EPO) is a synthetic copy of a hormone normally produced by the kidney and liver when the body’s tissues are faced with low levels of circulating oxygen (hypoxia). In 2000, scientists at the Hormone Laboratory in Oslo conducted a double-blind randomised controlled study on 20 male endurance athletes to assess the impact of r-EPO on athletic performance.

In the 10 athletes who received r-EPO (5,000 units three times a week), the proportion of red cells in the circulation (haematocrit) rose from 42.7% to 50.8%, while VO2max levels increased from 63.6 to 68.1 ml per kg body weight (3) . These changes were subsequently carried over into athletic performance, with a 9% increase in the time taken to reach exhaustion being noted in brief, incremental cycling tests for up to three weeks after r-EPO treatment (3) .

Many scientists now believe that r-EPO has a number of additional benefits beyond its role in increasing the concentration of the body’s circulating red cells. In theory, if r-EPO only works in the way I’ve described here, the benefits would only be noticed at the highest levels of aerobic activity. But recent work suggests that r-EPO can improve performance in events that do not rely upon high levels of oxygen delivery for success. This would suggest that r-EPO has another type of action which may resemble that of amphetamines, cortisone or anabolic steroids. At present it is still unclear exactly what is going on (4) , but this lack of scientific understanding has done little to deter large numbers of elite athletes from using r-EPO.

How to detect blood doping

EPO

Although r-EPO was swiftly outlawed by the World Anti-Doping Agency (WADA) in 1990, it was not until the 2000 Sydney Olympics that a test was introduced that could distinguish between r-EPO and the natural form of EPO produced by the body itself. Prior to the use of this test, sporting bodies had relied upon other means to identify r-EPO users.

A key weapon in the detection of performance-enhancing drugs has been the random searching of athletes’ homes and training facilities. On occasions this has proved effective, with the case of the Scottish cyclist David Millar being perhaps the most publicised example. In 2004, after the discovery at the cyclist’s home of two ampoules of Eprex, a commonly used form of r-EPO, Millar was stripped of his world time-trial title and banned from competitive cycling.

Several other indirect measurements of r-EPO use have also been deployed. Probably the best known is the policy adopted by the Union Cycliste Internationale (UCI), the professional union that oversees competitive cycling events across the world. The UCI imposes a 15-day suspension on any male cyclist who is shown to have a haematocrit of more than 50% and a haemoglobin concentration of greater than 17g per decilitre of whole blood (g/dl). Although a very small group of athletes will have naturally high concentrations of circulating red cells and haemoglobin because of their genetic make-up, the levels found in individuals taking r-EPO tend to fall over the course of a few weeks as the effects of the doping fade.

This testing regime has certainly stopped excessive use of r-EPO, but it has also tended to encourage users to ‘fly below the radar’ and either reduce the amount of r-EPO they use or dilute high concentrations of red cells and haemoglobin with intravenous fluids in the hours prior to a test. In response to this, WADA has outlawed a wide range of intravenous fluids (including albumin, dextran and hydroxyethyl starch) and detection of these agents carries a similar penalty to the detection of r-EPO itself.

In 2000, researchers at the National Doping Detection Laboratory in France published a report in the journal Nature describing the first reliable urine test to be able to distinguish between synthetic and naturally occurring ring EPO and behaves differently in an electric field. This allows researchers not only to distinguish between the two forms of EPO, but also the different r-EPO products currently available.

Despite its enormous promise, this test has two important limitations: l The half life of r-EPO is usually less than two weeks, so any test used to accurately identify r-EPO must be conducted soon after the administration of the drug. Most athletes are aware of this and stop using r-EPO in the days leading up to an event in order to avoid detection.

* After prolonged bouts of intensive exercise it is possible for the kidneys to excrete large volumes of protein in the urine (postexercise proteinuria). Two out of 10 samples collected from athletes competing in the 2005 Ironman Triathlon in Lanzarote were thought to contain r-EPO. But after a lengthy appeal process the athletes were reinstated, having argued successfully that the proteins in the urine were being ‘mis-read’ as r-EPO when in fact they were not.

Blood transfusions

Despite the limitations of the urinary r-EPO urine test, in many cases elite athletes have switched back to using blood transfusions in order to try to avoid detection. Two sources of blood are available. The first is through a transfusion service which matches the recipient’s blood to that of a donor (homologous transfusion), while the second method involves the athlete donating their own blood a month or so before a competition and receiving it again as a transfusion shortly before the event (autologous transfusion).

In the past the latter method has been difficult to detect, as the genetic material found in the red cells is obviously identical. However, more recently, scientists have sought to develop a ‘passport’ system that records baseline haematocrit, reticulocyte and haemoglobin levels and compares them regularly with random samples taken throughout an athlete’s competitive career (6) . This approach, although still at the experimental stage, has enormous potential, as it not only detects the presence of additional red blood cells in the circulation but can also identify the use of r-EPO by measuring levels of reticulocytes.

Hazards of blood doping

As we have already seen, an increase in the haematocrit clearly provides athletes with an advantage over their ‘clean’ fellow competitors. But this advantage comes at a considerable cost: 18 young professional European cyclists died suddenly from complications caused by r-EPO use after it became available in the late 1980s. In the past 20 years the numbers of r-EPO-related deaths have fallen, but the associated risks of harm remain considerable.

As concentrations of red cells rise and blood thickens, the heart is forced to work harder to circulate blood. This strain increases the risk of abnormal heart rhythms (cardiac arrhythmias) and heart attacks (myocardial infarction). The thicker blood also leads to an increase in the formation of blood clots and the development of life threatening pulmonary embolism (PE) and cerebral vascular accident (stroke) (7,8) .

Persistent users of r-EPO are also prone to develop anti-EPO antibodies. These are capable of rapidly destroying red cell stores in the bone marrow and over the course of hours and days can leave an individual with only a handful of red cells in their circulation. In addition to the dangers of PE, MI and CVA, blood transfusions also carry their own risks, including blood-borne infections (HIV, Hepatitis B and C) and a wide range of transfusion reactions that can occur if blood is not adequately matched to the recipient. Conclusion

As improvements in drug testing continue, it may soon become possible both to detect the presence of r-EPO and blood transfusions, and to use the tests as a discouragement to athletes contemplating their use. But the history of illegal drug use in sport suggests that new drugs and techniques will emerge that will prove even harder to identify. While the dark sides of the sports and pharmacology industries perpetuate this macabre tussle of innovation, we should remember that the ultimate losers are athletes who wreck their health and possibly their lives in pursuit of a distorted ideal.

References

1. Eichner ER. ‘Blood doping, infusions, erythropoietin and artificial blood’. Sports Med 2007; 37(4-5):389-91.

2. Elblom B, Goldberg AN, Gullbring B. ‘Response to exercise after blood loss and reinfusion’. J Appl Physiol 1972; 33:175-80.

3. Birkeland KI, Stray Gundersen J, Hemmersbach P. ‘Effect of rhEPO administration on serum levels of sTfR and cycling performance’. Med Sci Sports Exerc 1999; 32:1238-43.

4. Joyner MJ. ‘VO 2max, blood doping and erythropoietin’. Br J Sports Med. 2003; 37:190-1

5. Lasne F, de Ceaurriz J. ‘Recombinant erythropoietin in urine’. Nature 2000; 405:635.

6. Sharpe K, Ashenden MJ, Schumacher YO. ‘A third generation approach to detect erythropoietin abuse in athletes’. Haematologica 2006 Mar; 91(3):356-63.

7. Scott J, Phillips GC. ‘Erythropoietin in sports: a new look at an old problem’. Curr Sports Med Rep 2005; 4:224-6.

8. Robinson N, Giraud S et al. ‘Erythropoietin and blood doping’. Br J Sports Med 2006; 40 Suppl 1:i30-4.