kinesiology
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Blood Reviews
journal homepage: www.elsevier.com/locate/blre
Review
Blood doping: Then and now. A narrative review of the history, science and efficacy of blood doping in elite sport
Thomas S. Atkinsona,b, Marc J. Kahna,⁎
a Department of Medicine, Section of Hematology/Medical Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA b Department of Medicine, Section of Hematology/Medical Oncology, Southeast Louisiana Veterans Health Care Systems, New Orleans, LA 70119, USA
A R T I C L E I N F O
Keywords: Blood doping Erythropoietin Sports hematology Oxygen delivery
A B S T R A C T
As the line between excellent and exceptional athletic performance narrows and as the financial remuneration for exceptional performance increases, unscrupulous athletes and their trainers will strive to enhance perfor- mance regardless of cost. One method of performance enhancement is by the augmentation of the oxygen- carrying capacity of the blood through blood doping. We discuss the science behind erythropoiesis and means by which these processes can be exploited to the potential advantage of the athlete. These include pre-sport transfusion practices as well as supplemental recombinant human erythropoietin (rHuEpo) and the use of newer erythropoietic agents, many of which have not received FDA approval. Finally, we discuss the data behind the efficacy of blood doping in an attempt to discern whether or not the practice actually works to improve athletic and competitive performance.
1. Introduction
As the pressure to improve athletic performance intensifies due to ever-increasing financial remuneration and the allure of prestige, un- scrupulous athletes will seek ways to beat the system. Blood doping has been intertwined with elite endurance athletics for roughly the past half-century. In recent memory, no single event stands out more than the 2018 Seoul Olympics where the entire Russian team was barred from participation due to systematic doping.
The term doping refers to a multitude of practices which seek to artificially improve athletic performance through augmentation of the oxygen-carrying capacity of the blood. Blood doping, broadly defined by the World Anti-Doping Agency (WADA) as “any form of intravascular manipulation of the blood or blood components by physical or chemical means [1],” includes such practices as transfusion, recombinant human erythropoietin (rHuEpo) administration, and administration of artificial stimulants of erythropoiesis.
Aside from blood transfusion, the use of rHuEpo is perhaps the most notorious and widely-studied method of blood doping. Athletes also have at their disposal other, more novel ways of blood doping: hypoxia inducible factor (HIF) stabilizers, and the use of artificial hemoglobin (i.e. “synthetic blood”) are other examples of means to increase oxygen carrying capacity and thus increase aerobic exercise capacity. Despite the intent of dopers to improve athletic performance, the true effects on
athletic performance are unknown. In what is inarguably the most notorious case of blood doping,
Lance Armstrong was stripped of his seven Tour de France titles in 2012 after exhaustive investigation showed that he had been blood doping since at least 1999. His methods of doping were extensive and included not only the use of anabolic steroids but also the use of rHuEpo and its derivatives, in combination with autotransfusion.
The true incidence of blood doping, which athletes go to great lengths to conceal, is unknown. One study estimates the prevalence of blood doping in endurance athletes to be between 15% and 22% based on results of testing and direct inquiry [2]. In addition to potential adverse health consequences of doping, doping also carries the risk of an athlete being suspended or banned from competition. When con- sidering the seriousness of these consequences, it is reasonable to pose the question: does blood doping actually work to improve sporting performance?
As governing bodies have instituted new rules and new means of detecting the use of performance-enhancing drugs, athletes and their trainers have devised ever-more sophisticated means of blood doping and strategies to avoid detection.
This paper will review blood doping techniques, blood doping de- tection methods, and will review the data regarding the effects blood doping has on performance.
https://doi.org/10.1016/j.blre.2019.100632
⁎ Corresponding author at: Tulane University School of Medicine, 1430 Tulane Ave, #8010, New Orleans, LA 70112, USA. E-mail address: mkahn@tulane.edu (M.J. Kahn).
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2. Physiology
Hemoglobin plays a central role in transporting oxygen throughout the body by increasing the oxygen carrying-capacity of the blood by approximately 70-fold [3]. Oxygen binds to hemoglobin under condi- tions of high oxygen concentration in the lungs and delivers oxygen to tissues where oxygen concentration is low. Oxygen unloading is pro- moted by decreased pH, which allows for increased oxygen delivery to metabolically active tissues. Alterations in the oxygen affinity of he- moglobin can have negative ramifications for aerobic performance if the affinity for oxygen by hemoglobin is increased, which results in decreased oxygen delivery to active tissues and is therefore not benefit the endurance athlete.
Free plasma hemoglobin has a host of toxic effects to the brain and kidney. Red blood cells, containing hemoglobin, are there essential for the safe delivery of oxygen to metabolically active cells. Consequently, an increase in red blood cell mass may be of benefit to the endurance athlete, for whom prolonged aerobic exercise requires efficient delivery of oxygen to muscle tissues.
Hypoxia is responsible for increased levels of erythropoietin pro- duction by the renal Epo-producing cells of the kidney [4]. In the athlete, periods of intense exercise decrease renal blood flow via splanchnic vasoconstriction [5], which may also be responsible for in- creased Epo production and secretion.
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that are responsible for inducing expression of the Epo gene under hypoxic conditions. In the absence of hypoxia, the HIF-alpha subunit is ubiquitinated by the von Hippel-Lindau/E3 ligase complex and subsequently rapidly degraded in the proteasome of Epo-producing cells [6]. However, when oxygen tension is low, this degradation ceases. The stable HIF dimer is then able to enter the nucleus, where it binds to promoter regions on DNA and results in increased transcription and translation of Epo [7].
Increased circulating erythropoietin from HIF expression results in increased binding of Epo to its receptor EPOR. EPOR is highly expressed on hematopoietic stem cells in the bone marrow. The Epo-EPOR in- teraction leads to intracellular signaling along the JAK2 and STAT5 pathways, to induce stem cell differentiation along the erythroid lineage. Early erythropoiesis occurs within the bone marrow. Reticulocytes are then released into the circulating blood where they shortly become mature erythrocytes.
The hematocrit has been observed to decrease with vigorous ex- ercise, but the phenomenon of “sports anemia” is a misnomer. To the contrary, athletes experience an increase in erythropoiesis as a result of vigorous exercise. However, rapid expansion of the plasma volume also follows heavy training [8]. This expansion of plasma volume and re- sultant hemodilution is responsible for the laboratory appearance of a decreased hematocrit and hemoglobin concentration. Thus, the total red cell mass is a more accurate indicator of total body hemoglobin in athletes [9].
3. Early history of blood doping
The study of altitude physiology and the story of blood doping are closely connected. The various effects of high altitude on human phy- siology have been described since antiquity [10]. However, the first detailed account of “mountain sickness” due to low inhaled partial pressure of oxygen is commonly accepted to have been first described in 1590, when the Spanish missionary Joseph de Acosta described the symptoms of shortness of breath, chest pain, cough, and vomiting that he experienced while crossing the Andes of Peru [11].
Almost 300 years later, the French physician Denis Jourdanet, who traveled for nearly two decades in the mountainous regions of Mexico, hypothesized that it was the hypoxemia of high elevation (as opposed to low barometric pressure) that was responsible for an increased blood viscosity of subjects living at altitude [12]. These observations were
then advanced by his countryman, Francois-Gilbert Viault, who corre- lated the increased viscosity to increased hematocrit by measuring an increase in his own red cell count after living for 23 days at altitude. Viault concluded: “So it seems that one of the first effects of a period spent by man in the high mountains consists of an increase in the normal function of hemapoiesis.” [13] This astute observation, pub- lished in 1890, presciently anticipated the widespread adoption of high- altitude training roughly three-quarters of a century before it became clear that such practices conferred benefits to athletes, as demonstrated at the 1968 Mexico City Olympics, where athletes, from high-altitude areas won most of the endurance races [14].
In the early 20th century, the widespread practice of canine ex- perimentation led to a vast expansion in our understanding of exercise physiology. A 1927 article by Barcroft and Stevens reported a series of experiments demonstrating that dogs increased their hematocrit by contracting their spleens prior to exercise, in effect autotransfusing in preparation for increased aerobic demand [15]. Natural experiments like this outlined a theoretical framework for the practice of auto- transfusion that would come into practice among elite athletes several decades later. Humans, however, incapable of such convenient means of autotransfusion, would initially rely upon allogeneic blood transfu- sions to gain a competitive advantage.
In 1945, Hurtado et al. demonstrated that the hypoxia of altitude (rather than decreased barometric pressure) triggered increased he- matopoiesis, supporting the notion that increased red cell mass could improve oxygen delivery [16]. This idea was given practical application when Pace proved that allogenic blood transfusion increased exercise tolerance under conditions of hypoxia [17].
Nearly 50 years after Barcroft and Stevens described canine splenic autotransfusion, the practice of autologous red cell transfusion to im- prove aerobic exercise efficiency in humans was demonstrated in the scientific literature. In August 1972, Ekblom et al. reported a series of experiments in which healthy subjects were phlebotomized and then later reinfused with their own blood prior to controlled exercise ex- periments. These results demonstrated that, all other things being (roughly) equal, increasing hemoglobin concentration does improve measures of aerobic capacity [18]. It was not until 1981 that the Fin- nish athlete Mikko Juhani Ala-Leppilampi was the first athlete to go on record admitting to having received a transfusion prior to competing in the 3000-m steeplechase at the 1972 Munich Olympics. Although un- placed in his event [19], Ala-Leppilampi's more renowned teammate Lasse Virén won two gold medals and set two world records at the same Games, and has been long-rumored to have also benefited from pre- event transfusions at those same Games.
Blood doping reached mainstream attention in 1984 after it was revealed that seven members of the American men's cycling team, four of whom had won medals, had been transfused before competing in that year's Olympics. This resulted in public outcry, including an editorial in the New England Journal of Medicine that unequivocally decried the practice [20]. Public and medical opinion notwithstanding, the practice of seeking a competitive edge at the most elite levels of sport continued and expanded with the FDA approval of recombinant human ery- thropoietin (rHuEpo) in 1989.
4. Transfusion
Allotransfusion was the earliest reported method of blood doping. While relatively safe when done under appropriate conditions, allo- transfusion is not without risk, and can cause volume overload or transfusion reactions in the setting of antigen mismatch between donor and recipient. Because of antigenic differences between donor and host, attempts at blood doping with homologous erythrocytes are relatively easy to detect via flow cytometric analysis, which can easily identify very low levels of homologous antigens. As such, this practice is un- common, with a recent article reporting that few athletes have tested positive for homologous blood [21].
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By contrast, autologous transfusion is both rampantly widespread and far more difficult to detect. And while considerably safer than al- lotransfusion when carried out in medical clinics, there have been re- ports of severe morbidity associated with autotransfusion in sport. In 2011, the Italian cyclist Riccardo Ricco fell critically ill following a transfusion of autologous blood he had kept in his own refrigerator. This highlights the covert and unsafe practices that accompany blood doping and illustrate how the necessity to keep the practice covert leads to significant safety concerns.
No single test is uniformly available to directly identify the presence of autologously transfused blood, however several biomarkers are under investigation for this purpose. Plasticizers involved in manu- facture of the bags and tubes used in the blood donation and storage process can be detected in the urine after re-transfusion, and can sug- gest recent doping [22]. Additional emerging detection methods in- clude analysis of circulating micro-RNA [23], changes in hepcidin (aka “ironomics”) [24], changes in transcriptomic biomarkers [25], and the analysis of RBC-microparticles [26]. While promising, these methods remain too premature for routine use, but if nothing else the number of analytical methods under development for detection of autologous transfusion highlights an area of critical need in the crusade against doping.
5. rHuEpo and ESAs
In 1985, the first erythropoietin stimulating agent (ESA) was syn- thesized, changing the world of blood doping from that point forward. Erythropoietin alfa (Epogen, Procrit) was FDA-approved for the treat- ment of anemia associated with kidney disease in 1989. It was subse- quently banned by the International Olympic Committee the following year [27]. Despite the ban, it took a decade to develop a method for the detection of rHuEpo in athletes [28]. Erythropoietin (Epo) is a glyco- protein and its glycosylation pattern varies depending on the cells in which it is cultured [29]. Recombinant human erythropoietin (rHuEpo) was initially transfected and cloned using Chinese hamster ovary cells, and subsequently produced in baby hamster kidney cells [30]. By ex- ploiting the differences in glycosylation patterns between endogenous human Epo and rHuEpo, a method of separation based on charge using isoelectric focusing was developed. This assay can detect nanogram amounts of rHuEpo in the urine [31]. Further refinements have been made which allow for detection of newer-generations of rHuEpo as well as other erythropoietin stimulating agents [32].
The first-generation rHuEpo agents have a short half-life of 8–24 h, requiring frequent dosing schedules. Darbepoetin alfa (Aranesp®) is a next-generation erythropoiesis-stimulating protein which was FDA-ap- proved in 2011. Darbepoetin-alfa is a modified version of Epo with significantly increased molecular mass. This increased mass allows for a three-fold increase in half-life, as well as increased potency. Due to its increased half-life, darbepoetin alfa also has a longer detection window, making it less appealing as an agent for use in blood doping. Nonetheless, three athletes tested positive for the drug at the 2002 Salt Lake City Winter Olympics; the drug's creator Amgen aided in the de- velopment of detection methods for the drug during those Games [33].
A PEGylated rHuEpo with an even longer half-life of approximately 130 h (Mircera®) was FDA-approved in 2007 [34]. Since it has the longest window of detection of all the ESAs, it is also considered to have a low risk of abuse in blood doping, and the drug's developer provided an ELISA for detection of the drug that was provided to WADA before the drug was even released [27]. Despite the assumption of the drug's low-risk status, in 2008 multiple athletes tested positive for it none- theless, including Bernard Kohl, the third overall finisher of that year's Tour de France.
The use of ESAs is associated with multiple risks. Elevated hema- tocrit from ESA use results in increased blood viscosity, which increases the risk of thromboembolic events such as stroke and MI [35]. ESA use also reduces endogenous Epo production via negative feedback, and it
has been reported that this negative feedback, and resultant anemia, may persist long after ESA withdrawal. Due to antibody formation to ESA with potential cross-reactivity to endogenous Epo, although rare, ESA abuse also has the ominous potential to induce pure red cell aplasia [36]. Finally, it has long been recognized that ESAs are associated with elevations in blood pressure.
A recent systematic review by Sgrò, et al. evaluated a series of clinical trials dating from 1991 to 2016 investigating the effects of Epo on exercise performance. They concluded that erythropoietin used in clinical dosages can lead to relative improvements of maximal aerobic power by 6%–8% [37], with positive effects on submaximal exercise performance as well. There seems little question at this point that Epo, by means of raising the red cell volume, improves aerobic exercise capacity.
But whether this improved aerobic capacity translates to improved sporting performance remains a contentious topic. A well-designed and executed, albeit controversial research article published in 2017, sug- gests not. Heuberger et al. carried out a double-blind, randomized placebo-controlled trial of well-trained amateur cyclists to evaluate the effects of rHuEpo on maximal, submaximal, and race performance [38]. Fourty-eight participants were randomized equally to receive either rHuEpo or placebo over the course of 8 weeks. Tests of maximal and submaximal exercise were obtained at baseline and periodically thereafter. Finally, at the end of the trial, all the participants competed in a race to the summit of Mont Ventoux in France.
Not surprisingly, the group receiving rHuEpo had significantly larger increases in their hemoglobin concentrations over the course of the study compared to the placebo arm. This study also showed sig- nificant increases in multiple variables associated with maximal ex- ercise performance in the treatment arm. However, there were no sig- nificant differences between the treatment group and the placebo group with measures of submaximal exercise performance. Most notably, there were no differences between the two groups in the average race times. It is also worth noting that participants were unable to correctly guess if they had received rHuEpo or placebo in either arm of the study.
Although limited by a relatively small study population, the Heuberger study supports decades of literature that have demonstrated the correlation between hemoglobin concentration and maximal ex- ercise performance. However, the study raises questions about the ef- fects of Epo on submaximal exercise capacity and its benefits to com- petitive performance. Unlike other studies with less stringent design, this paper did not demonstrate a difference between the two groups in submaximal exercise performance [39–41]. Part of these differences between studies may be due to differences in the methodology of how “submaximal” exercise was conducted. Heuberger et al. conducted submaximal exercise tests of 80% of maximal power lasting 45 min for their study, in order to more closely mimic the conditions of a race; other studies carried out shorter tests lasting from 3 to 30 min, arguably more closely mimicking tests of exhaustion than endurance (according to Heuberger). Professional athletes could not participate in the Heu- berger study for ethical reasons and so the study did not demonstrate to what effect blood doping modulates the performance of the most elite athletes. However, this study is perhaps the most comprehensive study to assess the effects of rHuEpo on actual sporting performance, and the evidence presented suggests the effect is not significant.
6. HIF stabilizers
Hypoxia-inducible factor-1 (HIF-1) is a dimeric molecule that is expressed in numerous tissues of the body. It is composed of an alpha subunit and a beta subunit. Within kidney cells, the alpha-subunit is rapidly degraded under conditions of normoxia, but under conditions of hypoxia, the dimer is stabilized and acts as a transcription factor to facilitate the production of erythropoietin. There exist several small- molecule agents which act as HIF stabilizers. By stabilizing HIF-1-alpha, renal cells are pharmacologically prompted to increase Epo production,
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resulting in increased hematocrit. Although none of the HIF stabilizers have FDA approval, some are in clinical trials. WADA added HIF sta- bilizers to the list of banned substances in 2011, suggesting that they have been available on the black market for some time. The first athlete to test positive for a HIF stabilizer was reported in 2016 [42].
Early clinical trial outcomes suggest these drugs may be safe for treatment of anemia in chronic kidney disease (CKD), however the study populations have generally not included healthy subjects without anemia. As such, the risks of HIF-stabilizers in the athlete is largely unknown. It would seem reasonable to conclude that any means of increasing the Epo level would share similar risks in the healthy, non- anemic patient, namely increased blood viscocity, hypertension, and cardiovascular adverse events. However the early trials in CKD appear to suggest that these risks are actually lower compared to exogenous Epo administration [43].
Furthermore, the role of HIF-1 in tumorigenesis has been recognized since at least 1999 [44], and there are theoretical concerns that in- creased activation of HIF via HIF stabilizers could potentially increase the incidence of various cancers [45,46].
Cobalt acts as an elemental HIF-alpha stabilizer and acts to prevents ubiquitination of the HIF-alpha subunit [47]. Cobalt has been used in the distant past for the purposes of stimulating erythropoiesis, however it is associated with numerous side effects including severe organ da- mage such as cardiotoxicity, which limit its use as a blood doping agent [48].
Xenon gas also increases the production of HIF-1a [49] with downstream effect of increasing Epo levels [50]. Xenon was added to the WADA list of banned substances in 2014. There have been widely- circulated claims that members of the Russian Winter Olympics team used xenon at the Sochi Olympics in 2014 [51].
7. Synthetic oxygen carriers
Free hemoglobin not encapsulated by the red blood cell (RBC) membrane is unstable and has a host of toxic effects, from vasocon- striction resulting from scavenging of free nitric oxide, to acute tubular necrosis of the kidneys leading to renal failure. Hemoglobin-based Oxygen Carriers (HBOCs) are a class of therapeutic agents which utilize modified forms of hemoglobin to circumvent these toxicities with the aim of improving oxygen delivery in the anemic patient. There are no currently FDA-approved HBOCs.
Hemopure™ is a bovine-derived, crosslinked acellular form of he- moglobin. Trials designed to evaluate the use of Hemopure™ to aug- ment athletic performance have failed to demonstrate a significant benefit [52], concluding that the adverse cardiovascular effects of hy- pertension potentially negate the benefits of improved oxygen delivery to tissues [53].
In addition to HBOCs, perfluorocarbon emulsions (PFCs), which are halogen-substituted carbon nonpolar oils, can carry and deliver oxygen. PFCs require a large concentration gradient to drive oxygen dissolution, which suggests that PFCs are only of benefit in the presence of sup- plemental oxygen. This would seem to limit the utility of PFCs in the realm of endurance sports [54].
Both HBOCs and perfluorocarbon-based compounds have been banned by WADA, and tests for their detection have been available since 2004 [55].
8. The athlete biological passport
At present, the only officially sanctioned method for detection of transfusion is the Athlete Biological Passport (ABP). The ABP is a pro- gram developed by WADA to detect doping by means of measuring changes in an athlete's unique biometric values over time, rather than from the detection of any particular substance itself. The program, implemented in 2009, contains multiple modules intended to detect doping in its numerous forms. The operating guidelines are regularly
updated and are currently in the sixth version [56]. Currently WADA can sanction athletes based on suspicious changes in the ABP alone.
The blood module of the ABP (Blood ABP) is built on years of work aimed at correlating changes in detectable serum markers of ery- thropoiesis and iron homeostasis to the administration of rHuEpo and other blood doping techniques. Early work around the turn of the new millennium demonstrated significant and predictable changes in he- matocrit, reticulocyte%, erythropoietin, and serum soluble transferrin receptor levels that resulted from rHuEpo use [57,58].
For example, recent Epo use is expected to result in an increase in hematocrit and reticulocyte count with an early spike in EPO levels (from exogenous administration), which is then expected to fall below the normal baseline in response to the increased RBC mass. Changes from an athlete's baseline for these parameters can raise the suspicion of blood doping even in absence of any detectable contraband substance. However, small changes in these values may be (mis)attributed to other causes, and the sensitivity and specificity of such changes in detecting autotransfusion remains uncertain [27].
Limitations of the early system led to refinements that both sim- plified detection and improved sensitivity of the algorithm, leading to the development of the so-called OFF-score (OFF-S) [59], which has proven valuable for its ability to detect the effects of rHuEpo beyond the window of detection of the actual doping substance itself. The OFF- S can be considered an “index of stimulation” that suggests recent Epo use even in absence of significantly elevated Epo levels, and is calcu- lated by the formula: OFF-S = Hb (g/L) – 60√(Reticulocyte%), with a normal range that falls between 85 and 95 [60].
Further work in this area led to the development of the Athlete Abnormal Blood Profile Score (ABPS), which is a multi-parametric test similarly designed to predict rHuEpo administration as well as blood transfusion [61]. The ABPS and the OFF-score compose the framework for the blood module of the ABP [62].
By following a strict protocol for blood collection, transportation, storage, and analysis, a set of eight values available on routine CBC measurements such as hemoglobin, hematocrit, MCV, RDW, and re- ticulocyte indices, the ABP is able to track changes in an athlete's he- matologic parameters over time. Bayesian Network analysis is then applied to detect abnormal values which may require additional testing or follow-up [63].
The Blood ABP represents the most powerful tool available at pre- sent to combat doping. In 2017, the most recent year for which records have been made available, over 29,000 ABP Blood Module samples were analyzed, marking an increase of 3% over the previous year [64].
9. Discussion
The Heuberger study suggests that Epo administration alone does not significantly improve submaximal sporting performance in well- trained athletes, even though it does improve some measures of ex- ercise capacity. It might be easy to imagine that an argument could be made to use this study to decriminalize the use of rHuEpo. However, in any randomized controlled trial, the clinical endpoints stand as the most clinically relevant factors—in other words, a study is only as useful as its endpoints. In practical terms, the benefit of illicit Epo abuse would best be shown by its ability to lead to victory in sporting per- formance. Other less important endpoints such as physiologic variables are less clinically relevant. What good is improving oxygen delivery if it doesn't help you win? Additionally, both the medical (i.e. thrombosis) risks and professional (i.e. expulsion from competition) risks, being as high as they are, cast doubt on the use of Epo to improve athletic performance, even if aerobic exercise is marginally improved. In other words: the proven benefit of Epo abuse—a 6%–8% improvement in maximal aerobic capacity—simply is not enough to justify its multi- tudinous drawbacks.
But if Epo doesn't improve sporting performance, why is its abuse in endurance sports so widespread? Epo abuse is only one ingredient in
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the recipe for blood doping. And the most important ingredient is the athlete themself. Due to ethical considerations, elite athletes have not been included in trials related to Epo abuse. And there have been no clinical trials that evaluate the rather elaborate blood doping regimens that are routinely employed by elite athletes. It is not unlikely that Epo, when used by an elite athlete in combination with additional doping methods, can confer an actual performance benefit, and that scant difference in performance between top elite athletes hinges upon the slightest of advantages. Even if that advantage is largely, or even en- tirely based on the placebo effect, if the athlete believes it can help them perform, the practice will persist and it will be difficult to elim- inate blood doping from sport. It seems unlikely that any clinical trial will ever—or could ever—be designed to test this hypothesis.
While the practice of blood doping is sure to continue long into the future, the utility and efficiency of the practice has only relatively re- cently begun to gain rigorous scientific and clinical investigation. Cynically, it may be logical to conclude that as long as competitive sports exist, athletes will seek to gain an advantage; unscrupulous athletes will continue to go to illicit measures to gain that advantage; and the crusade to ensure a level playing field will continue. Athletes and their trainers are frequently ahead of the curve when it comes to exploiting the science of performance enhancement and evading de- tection, and this trend seems unlikely to change.
10. Future considerations
The science behind athletic performance enhancement remains in its infancy. Despite this fact, elite athletes will undoubtedly continue to seek to gain a competitive edge over their rivals, even if the methods employed are not the subject of rigorous scientific scrutiny. As novel methods of blood doping emerge, novel methods of detection will be necessary to combat them. Better understanding the limits of human athletic performance could lead to better understanding of the normal aging process and could assist with injury and recovery.
11. Practice points
• Erythropoietin is capable of increasing the red blood cell volume and thus the aerobic capacity of athletes, however this increase comes with potential drawbacks such as cardiovascular and thromboembolic complications (e.g. hypertension, heart attack, and stroke).
• HIF stabilizers have the potential to increase Epo levels and hema- tocrit. These agents are not FDA approved and their safety in elite athletes is largely unknown.
11.1. Research agenda
• Analytical detection methods for autologous blood transfusion re- main an unmet need in the battle against blood doping.
Funding source
None.
Declaration of competing interest
Neither of the authors have any financial or other conflicts of in- terest to report. The work is original and has not been published else- where. Both authors have contributed substantially to the work.
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