Editorial, comments & views haematologica 2002; 87:225-234 http://www.haematologica.ws/2002_03/225.htm

effective strategies to address and deter the entire A strategy to deter blood doping gamut of blood doping practices. The aim of this in sport paper is to inform the scientific community of the issues faced by the group, and to publicize a novel approach to deter blood doping that may serve to Blood doping is unacceptable on many levels. If stimulate further debate on this topic. practised naively it endangers the life of the athlete, and if medically supervised defies the Hippocratic Introduction Oath of the physician. Blood doping is an unde- In order to conceive an effective deterrent to served blemish on sport, its administrators and blood doping, it is first necessary to identify the sponsors, and inevitably stains the reputation of techniques prone to abuse, and when and how an innocent competitors. It is unconscionable from a athlete might use these methods. Then careful moral standpoint, since the use of a banned sub- examination of the likely hematologic/physiologic stance or practice violates the rules of the sport consequences of these practices, together with a and therefore makes redundant any subsequent knowledge of the strengths and weaknesses of sporting contest witnessed by the public. Finally, it available detection strategies, may reveal congru- can permit an athletic imposter to dethrone a wor- encies that represent feasible opportunities to thy champion. Despite the biological complexity of detect and thereby deter blood doping. A tenable blood, the goal of blood doping is relatively solution must also be cognizant of the logistical straightforward and singular – to increase circulat- difficulties associated with implementing test ing hemoglobin levels. This increases the oxygen strategies. This article will apply this logic to known concentration of arterial blood and therefore aero- doping strategies, with an emphasis on the abuse bic capacity. Although generally associated with of recombinant human erythropoietin that reflects endurance events, an enhanced oxygen carrying the prevalence of its abuse in the sporting commu- capacity can bestow a marked advantage in events nity. lasting as little as 45 seconds, as well as recovery from intermittent efforts and general training drills. Three classes of blood doping and their Therefore it is prudent to consider most sports (indi- mode of abuse vidual and team) at risk of blood doping. Erythropoietic stimulants Three accessible options for the athlete to boost The most widely abused erythropoietic stimulant circulating hemoglobin levels can be identified: 1) (EPS) to date has been recombinant human ery- use of various pharmacologic products such as thropoietin (r-HuEPO). Immoral athletes use r-HuE- recombinant human erythropoietin to stimulate PO to accelerate the rate of red cell production in over-production of red cells in the bone marrow; 2) the bone marrow. But r-HuEPO is an expensive drug, autologous or homologous blood transfusion; and and to obtain maximum benefit an athlete would 3) administration of hemoglobin-based oxygen car- need to inject r-HuEPO every 2-3 days over a 3-4 riers (HBOCs). week period. This would be accompanied by some The implementation of testing methods for a sin- form of exogenous iron administration (intravenous, gle technique or class of blood doping merely allows intramuscular or oral) to ensure sufficient iron is cheats to move to another effective but unde- available for haem synthesis. Because it takes sev- tectable approach, and it has been argued that this eral weeks before the full effect is realised, injec- does not answer the needs of a Fair competitor.1 tions must commence around one month prior to a The Science and Industry Against Blood doping major competition or season. The r-HuEPO is rapid- (SIAB) project is a multinational collaboration ly removed from the bloodstream with a half-life of between scientific researchers, pharmaceutical 4-12 hours, but a small amount is detectable companies and hematologists, dedicated to con- unchanged in the urine for 24-96 hours after each ducting research to assist the implementation of injection. Once the red cell mass has been boosted,

haematologica vol. 87(3):march 2002 226 Editorial, comments & views the athlete can substantially reduce the dosage of Blood transfusions r-HuEPO, since the erythropoietic rate need only In contrast to the 3-4 weeks required before an match the basal rate of red cell destruction to main- EPS will boost circulating hemoglobin by a physi- tain the circulating hemoglobin levels. During this ologically significant amount, infusion of exoge- maintenance phase it is difficult to discern the nously-derived hemoglobin will provide an imme- hematologic profile of a maintenance user from that diate improvement in oxygen carrying capacity. of a non-user. One notable characteristic may be an Although there are serious health risks associated elevated serum ferritin level associated with exoge- with transfusing blood obtained from a donor nous iron administration. (homologous) or from self (autologous), these con- Instead of maintaining the elevated red cell mass, cerns have been largely ignored by immoral ath- the athlete may cease using r-HuEPO if the goal letes seeking a performance advantage. was only to peak for a single competition. The body’s Because infused red cells that survive the first 24- homeostatic mechanisms will immediately seek to hour period persist in the circulation for the lifespan revert to the normal red cell mass. Because there is of a normal red cell (up to 120 days), an athlete no active means of removing mature red cells, its choosing to infuse homologous red cells could elect goal is achieved by a shutdown of reticulocyte pro- to administer the hemoglobin days or even weeks duction. This is reflected in a dramatic reduction in prior to arrival at the competition site, experiencing both endogenous erythropoietin (EPO) production a performance benefit commensurate with the per- (and therefore serum EPO levels) and reticulocyte centage of biologically-active infused red cells that release (and therefore reticulocyte count). The shut- remain in circulation at the time of competition. A down will be maintained until the red cell mass is partial agglutination reaction test performed on a returned to normal, which will take several weeks blood sample, although not yet instigated by (depending upon the nature and extent of the ini- authorities, could serve as a powerful deterrent tial stimulation). During this time the athlete will against the use of homologous blood transfusions. However the situation is more complicated if the experience a performance benefit commensurate athlete chooses to harvest their own red cells with the excess red cell mass still present. (autologous) and store the cells until they are to be Whilst EPO is the major humoral regulator of red re-infused. Storage techniques for erythrocytes per- cell production, there is a plethora of hormones that mit a shelf life of 35-42 days if stored at 4°C or up also influence the rate of erythropoeisis, and any one to 10 years if stored at -65°C in glycerol. If the ath- of these might be abused if a specific test method lete elects to store cells at 4°C, they must be har- accelerates the likelihood of the use of other phar- vested within 42 days of a major competition. This macologic interventions. High demand and a lucra- means that an athlete will experience a period of tive market have led pharmaceutical companies to reduced aerobic capacity during the several weeks develop several permutations (α, β, ω) of recombi- the bone marrow requires to replenish the harvest- nant human erythropoietin. The range of EPSs also ed cells. From an exercise physiology perspective, include mimetic peptides that emulate the erythro- this does not constitute an ideal preparation for a poietic effect of EPO. One such product, Aranesp, has major competition. However the alternative of recently been approved for human use and is a more freezing erythrocytes at -65°C and thawing is time stable and potent stimulant than r-HuEPO.2 Its man- consuming and the cost of equipment, materials ufacturer is cooperating with SIAB not only to pro- and skilled technologist’s time considerable. vide technical advice on possible detection meth- Although practical issues associated with blood ods, but also to facilitate timely access to the prod- transfusion makes this class of blood doping prob- uct together with blood and urine samples required lematic (and this perhaps explains the anecdotal to validate detection methodologies. reports of athletes avoiding transfusions when r- It is also prudent to recognise that alternative HuEPO became available) there is substantial approaches, such as gene-activated erythropoietin research into improving the viability and shelf life (currently in phase III clinical trials) or adeno-asso- of stored erythrocytes which may eventually ren- ciated viral vectors able to deliver an EPO gene, der this process more suitable to doping practices. could further expand the range of EPSs. Anti-dop- It is also likely that athletes would overcome the ing strategies relying solely on direct detection of a technical difficulties associated with harvesting specific molecule may be subverted if athletes begin and storing hemoglobin (as they did prior to the using products for which no direct test has been appearance of r-HuEPO) if testing strategies for validated. other approaches leave blood transfusion as the haematologica vol. 87(3):march 2002 Editorial, comments & views 227 only option for blood doping. For this reason a developing tests to deter illegitimate use of their deterrent must also address transfusion as a pos- products, and their cooperation is a cornerstone of sible avenue of blood doping. SIAB’s research efforts. These companies are Hemoglobin-based oxygen carriers unequivocally supportive of SIAB’s goals and are An alternative means of immediately increasing negotiating how best to direct their assistance. circulating hemoglobin levels is to infuse a hemo- Strengths and limitations of detection globin-based oxygen carrier (HBOC). These prod- strategies ucts have been the focus of intense research and development in recent years to serve as a blood Blood tests substitute that may ease the burden on blood Whilst the shortcomings of (as yet non-existent) donor supplies required in surgical settings and deterrents for HBOC or blood transfusion abuse are transfusion emergencies. self-evident, deterring the abuse of r-HuEPO and Hemoglobin can be easily extracted from red other EPSs is problematic on several fronts. blood cells, but breaks down in the body and also Because of the inherent difficulty associated with causes toxicity. HBOCs are obtained by chemical detecting abuse of a naturally occurring hormone, sterilization of hemoglobin extracted from a vari- and in the absence of a definitive test to identify ety of sources (bovine, expired donor, recombinant r-HuEPO, initial efforts to deter r-HuEPO abuse by human, and transgenic human hemoglobins). elite athletes focused on the end result of r-HuE- Biotechnological cross-linking, recombinant mod- PO abuse – an increased red cell mass as indicat- ifications and micro-encapsulation not only stabi- ed by elevated hemoglobin (Hb) and/or hematocrit lize the hemoglobin molecule but provide a range (Hct). The so-called Hematocrit rule results in the of different blood substitutes with a variety of clin- athlete being ruled ineligible to compete because ical benefits. The recent approval for human use of of health concerns associated with elevated one product is accompanied by several other prod- Hct/Hb. ucts at advanced stages of clinical trials. It is The concept of an arbitrary limit as incorporat- expected that investigators will be driven by the ed by the Hematocrit rule has since attracted crit- perceived market for alternatives to donor red cells icism because a significant proportion of athletes to focus on second and third generation products.3 (up to 5%) may exceed the threshold because of HBOCs are free of RBC blood group antigens and genetic factors and be unfairly banned from com- can be stored for a long time as a stable solution. petition. It may also permit athletes to titrate their Although this offers obvious advantages over Hb/Hct to approach but not exceed the limits obtaining hemoglobin via transfusion, the current adopted by their sport, or to expand plasma volume generation of products are rapidly removed from and thus remain below allowable limits. circulation by the reticuloendothelial system Several research groups have attempted to resulting in a half-life of 12-24 hours (dependent improve upon the Hematocrit rule by including addi- on the pharmacokinetics of individual products). tional hematologic parameters (for example percent Therefore in order to experience the benefits of reticulocytes, percent macrocytes, serum transferrin enhanced oxygen carrying capacity, an athlete receptor, serum EPO) that are known to be perturbed would need to infuse the HBOC shortly before during the accelerated erythropoeisis induced by r- competition. The physiologically-significant bene- HuEPO administration. The rationale is to reduce the fits would only be experienced in the interim before likelihood of an individual with a single parameter the HBOC was cleared from the system. out of range being removed from competition or It is pertinent to note that because HBOCs do being falsely accused of r-HuEPO abuse. Australian not appear in the urine, it would not be possible to scientists extended this concept and validated an identify the abuse of this class of product defini- algorithm that combined five hematologic parame- tively unless a blood sample was obtained, prefer- ters sensitive to accelerated erythropoiesis,4 and this ably within several hours (before or after compe- test was eventually adopted by the International tition) of administration. Olympic Committee (IOC) as part of the EPO test Unless deterrents are put in place, it would used at the Sydney 2000 Olympic Games. appear inevitable that HBOCs are liable to be However debate surrounding whether a blood abused by immoral athletes. The pharmaceutical test that is sensitive to accelerated erythropoiesis companies which develop these products for clin- is ideally suited to deter r-HuEPO abuse has yet to ical use have been approached to participate in be resolved. Altitude/training/genetic factors may

haematologica vol. 87(3):march 2002 228 Editorial, comments & views also be associated with a transient increase in ery- greatest challenge facing officials is the uniqueness thropoiesis (albeit of a much smaller magnitude) of the blood matrix. which might lead to mistakenly accusing an ath- Unlike urine, blood is not suitable for freezing lete when no drug was taken. Or the magnitude of and therefore cannot be transported long dis- the disturbance caused by r-HuEPO (or other EPS) tances. A blood sample must be drawn in a loca- administration may be small compared with the tion that is within close proximity to a testing site. range of values encountered in a normal popula- Because federations cannot dictate where an ath- tion – and disturbances associated with mainte- lete may live and train, out-of-competition blood nance doses may be virtually indistinguishable from testing is therefore limited by the proximity of the normal. Such a test may fail to identify a sophisti- athlete’s training venue to an accredited testing cated athlete who had deliberately titrated their laboratory. Furthermore the test adopted by the dosage to minimize the hematologic disturbance. IOC, although scientifically excellent, includes It seems that evidence of accelerated erythro- parameters that can only be measured using poiesis will remain an extremely useful screening sophisticated analyzers, and the cost and logistics tool to identify potential drug abusers rather than of having access to a properly calibrated analyzer serve as definitive proof of r-HuEPO abuse. must be taken into account. Unfortunately a qual- Urine tests ity control system to ensure that results are com- It appears that the French test able to identify parable when analyzed in separate locations is both isoforms of r-HuEPO in the urine5 has already been essential and a convoluted process to instigate. associated with a significant deterrent effect. It is SIAB is consulting with a multinational analytical expected that further refinement and widespread instrument manufacturer with the twin objectives adoption of a urine-based test that directly iden- of minimizing analytical error in critical analytes, tifies r-HuEPO will continue to be a powerful deter- and harnessing their accrued expertise to develop rent. However the expense and time required to calibration protocols that minimize inter-labora- conduct the assay, combined with the exhaustive tory variation between instruments. validation procedures required for a test that dif- A global strategy to deter blood doping ferentiates between naturally and recombinant- A strategy that effectively deters the abuse of all derived molecules, has so far limited the applica- known blood doping methods is necessarily multi- tion of this assay. Nor is the expertise required to faceted and extensive. The following proposal is a conduct the assay always readily available. consensus of opinion distilled from the intellectu- However the major drawback of the urine-based al expertise within SIAB, and is intended to seed test, which is seemingly inevitable and directly further debate on this complicated topic. attributable to the pharmacodynamic characteristics Out-of-competition testing of r-HuEPO, is the disappearance of measurable lev- The essential characteristic of any antidoping els of r-HuEPO from the urine soon after injections strategy is the ability to sanction an athlete based cease. Urine tests are useful during, but not after, r- upon identification of a banned substance. Because HuEPO use. Therefore if testing is announced, or EPS abuse will occur in the weeks preceding an occurs at major events, it is likely that athletes will event, the athlete must be subject to random, escape sanction by ceasing r-HuEPO injections sev- unannounced testing during the weeks they are eral days prior to testing. Because of the short half- likely to boost their red cell production. Because of life of r-HuEPO, all traces of the drug would have left the difficulties associated with storage/transport the system when the urine sample is collected, of blood samples from remote locations, it seems despite the athlete retaining the physiologic bene- this must be in the form of a urine-based test capa- fits associated with an elevated red cell mass. ble of directly identifying known EPSs. A crucial Logistical difficulties aspect of SIAB’s work is to facilitate timely access Since the Sydney 2000 Olympics, sporting feder- to the drugs and biological samples required by our ations have been criticized in some quarters for analytical chemists, to ensure they have ample their reluctance to instigate blood tests based on opportunity to develop and validate direct detec- this model. However critics may not be fully cog- tion methodologies. nizant of the pragmatic considerations and imple- The efficacy of this deterrent will then be deter- mentation issues faced by federations wishing to mined first by the ability to predict correctly at implement such blood tests. Perhaps the single what stage of the year an immoral athlete is using

haematologica vol. 87(3):march 2002 Editorial, comments & views 229 the EPS, second by the development of a sanc- the blood matrix. It is also the only practical way tionable test that directly identifies whichever EPS to detect athletes who have used acute interven- was used, and finally having knowledge of the tions such as HBOCs or blood transfusion to obtain whereabouts and then access required to the ath- an illegal performance advantage. lete during these periods. Locating a blood testing facility at the competi- From a pragmatic standpoint it can be argued that tion site has many potential benefits. Because a sophisticated athlete, faced with the possibility of blood samples can typically be assayed and report- a sanctionable test for r-HuEPO (or any EPS), will ed within minutes, samples could be analyzed on seek to evade antidoping officials during the weeks the morning of a race, or immediately post-race they are injecting the drug. However to take phys- from podium finishers, and results conveyed to iologic advantage of their doping they must even- officials. Athletes who failed a test could be ruled tually arrive at the competition site and be prone to ineligible to compete or receive a medal, avoiding whatever testing procedures the authorities wish to the scandal associated with stripping an award implement. It is at this juncture that antidoping already bestowed on an athlete. If each interna- authorities have access not only to the athlete but tional sporting federation had a dedicated mobile also to whatever sample collection and analysis blood testing facility, this would greatly simplify strategies they elect to use. This seems a logical quality control issues since all samples from ath- point on which to focus antidoping efforts. letes in that sport would be analyzed using a sin- Mobile blood testing laboratory and gle instrument. It would also facilitate the vital post-race blood collection element of unannounced testing, as federations Although the existing paradigm is to use blood would be under no obligation to publicize when and urine tests concurrently to identify r-HuEPO and where they would locate the mobile laborato- abuse – albeit using blood as a screen in some sit- ry to conduct testing. uations – this is not necessarily optimal. This not Although clearly capable of following a compe- only limits its application in out-of-competition tition season to a variety of destinations, the lab- situations, but also dictates that the test can only oratory could maximize the return on investment be conducted at events that have ready access to by collecting out-of-competition samples from sophisticated hematology analyzers. athletes who elect to train in remote locations, and However one tenable solution that addresses may be an attractive option for individual sporting these concerns is to create a mobile testing facil- federations seeking to implement comprehensive ity equipped with a hematology analyzer able to blood testing programs. process the blood sample without delay, as well as Indirect evidence of blood doping freezing capacity to store the urine sample for lat- But there are persuasive arguments – financial er analysis. Rather than equipping a multitude of and physiologic – for deterrent strategies related to laboratories with expensive hematology analyzers blood doping to increase their reliance on indirect that may sit dormant except for occasions when an evidence. Financially, the expense associated with event is in close proximity to the laboratory, pur- having a validated test for every pharmaceutical chasing a single analyzer and mounting it within a product capable of stimulating red cell production mobile testing facility seems to be a cost-effective is substantial and demands a heavy allocation of alternative. The mobile laboratory could relocate resources. Physiologically, as the sophistication of to a remote competition site – in a similar manner medical technology expands its horizons and to the way media utilize mobile television broad- strives to mimic natural biological processes more casting stations to cover sporting events. closely, it is to be expected that pharmacologic Provision of a mobile blood testing facility would intervention will become more and more difficult also allow authorities to instigate a critical aspect – and expensive – to detect. of our proposed strategy to deter the gamut of Demanding that pharmaceutical companies label blood doping practices – making place-getters sub- their difficult-to-detect products with a biological ject to blood testing immediately after competi- tag is unrealistic, since such an approach requires tion. As has been demonstrated at major events companies to regress back to the initial stages of such as the Sydney 2000 Olympic Games and the clinical trials and waste the intellectual and finan- 2001 IAAF World Championships, blood collection cial input invested in a drug’s development. at the competition site is both feasible and ideal- Instead, seeking corporate approval and intellec- ly suited to the unique biological characteristics of tual input from company scientists to develop and

haematologica vol. 87(3):march 2002 230 Editorial, comments & views validate detection strategies in advance of the A major component of the work undertaken by product being (surreptitiously) available to athletes SIAB is to validate the concept of a Hematologic is both realistic and has been favorably received Passport. It is essential to quantify the expected by pharmaceutical companies approached by SIAB. biological variation of critical hematologic para- Unlike the abuse of stimulants, narcotics or ana- meters. Although some work has been undertaken bolic agents which alter physiologic parameters on healthy subjects, scientific rigor demands that that are difficult to objectively quantify or moni- biological variation is established in the elite ath- tor, the goal of blood doping is to increase a sin- letic population. The extent to which sporting fed- gle, easily measurable, and relatively stable hema- erations, sporting institutions and SIAB can coop- tologic parameter – circulating hemoglobin. This erate to achieve this goal is being explored. sole focus may ultimately prove to be blood dop- The benefits of adopting a Hematologic Passport ing’s Achilles heel. concept are far-reaching. Athletes could use the Rather than seeking to identify the EPS or blood Passport as a tool to demonstrate objectively – via doping method used to increase circulating hemo- their constant and normal longitudinal blood pro- globin, an alternative that can be developed along- file – that they had not used blood doping prac- side direct detection techniques, and ideally lessen tices. A longitudinal record of hematologic profiles the reliance on this approach, is to monitor the is an invaluable tool to assist physicians in diag- blood profile of the athlete over time. A profile that nosis of pathology. This has genuine benefits for deviates substantially from expected may lead to all competitors who provide regular blood samples follow-up testing or medical examination. This for analysis. Protection of the athletes’ health and would deter cheats from using any illegal practice well-being is a principal reason for antidoping that disturbs their hematologic profile – whether strategies, and aligning the emphasis of antidop- the administration of novel r-HuEPO variants or ing strategies towards providing a genuine health any one of the myriad of hormones involved in the service has substantial merit. hematopoietic cascade. The International Cycling Union (UCI) has already Exclusion based on medical evidence instigated a similar concept – its athletes are It is perhaps fortuitous then that an emphasis on required to undergo regular medical examination health monitoring also provides an opportunity to and provide a blood sample and are ineligible to harness a powerful deterrent to existing (as well as compete and subject to medical examination if conceivable but not yet realised) blood doping prac- their hematologic profile does not fall within nor- tices. Iron overload and depressed erythropoiesis mal ranges. However the sensitivity of their stance have been shown to accompany cessation of r-HuE- is limited because the reference ranges they use are PO and blood transfusion, and both are medically derived from population statistics. This inevitably justifiable reasons for the athlete to be excluded provides a large margin of tolerance, and allows from competition until the underlying cause has unscrupulous athletes an opportunity to elevate been identified. Further, it is logical to expect that critical parameters – such as circulating hemoglo- a side-effect from any doping practice that bin – to remain just below threshold levels. enhances circulating hemoglobin levels (HBOCs, transfusion, r-HuEPO or any hormone within the Hematologic passport erythropoietic cascade) would be a transitory peri- An alternative may be to compare an athlete’s od of depressed erythropoiesis whilst the body current values with their historical levels obtained regained its previous homeostatic set point. Expand- from previous blood collections. The Italian Cycling ing exclusion criteria to include both of these patho- Federation decided from November 2000 that all logic situations – which can be readily identified first-year juniors had to undergo an hematocrit through simple hematologic analyses – would serve test to provide a benchmark to help show up as a strong deterrent to experiment with novel abnormalities in the future. Because hematologic drugs, since exclusion from competition would parameters are quite stable over time in healthy negate any advantage obtained from prior drug adults, unusually large disparities between an ath- abuse. lete’s historic values contained in their Hemato- This concept is supported by scientific data logic Passport and values obtained from a recent already collected for the EPO2000 project.4 Research blood test may alert officials to potential cases of demonstrated that the so-called OFF-model (OFF r- blood doping or a medical condition requiring clos- HuEPO administration) is capable of delineating er examination. athletes who ceased r-HuEPO from placebo subjects haematologica vol. 87(3):march 2002 Editorial, comments & views 231 for several weeks after injections stopped. Blood of possible methods to boost circulating hemoglo- profiling data collected from in excess of 1000 ath- bin, it would seem that a cost-effective utilization letes around the world failed to find any subject of scarce resources is to focus on deterring blood with a natural hematologic profile similar to the doping by detecting the hematologic signature of depressed erythropoietic state encountered in sub- abuse rather than the product itself. jects who had ceased r-HuEPO injections (unpub- lished observations). Summary Once this abnormal hematologic profile has been To level the playing field significantly, it has been detected by antidoping authorities, it becomes a suggested that a deterrent should produce no or matter of policy and sports law as to what conse- very few false negatives, no false positives, address quences the athlete faces. all accessible alternative ways of doping, and have minimal risks to the Fair Competitor.1 Such an How would this work in practice? approach to deter blood doping is feasible, and Were each of the separate facets of this propos- entails the following: al implemented, it would place dishonest athletes • creation of a Hematologic Passport that con- in an impossible quandary, regardless of which tains historical blood profiles in order to obtain blood doping strategy they had used to surrepti- a license to compete; tiously obtain a podium finish. • implementation of mobile blood testing facili- If they had elected to run the gauntlet and con- ties; tinued to use an EPS up until the time of compe- • collection of blood and urine samples post-race tition or had infused a HBOC immediately before from medal winners; competition, they would risk sanction if the drug • sanctioning if banned products are directly was detected directly (either in urine for an EPS or identified in the blood or urine (either out-of- in a blood sample for HBOC). competition or at the time of competition); If instead they sought to evade detection by • exclusion based on health grounds for those stopping EPS administration several days prior to competitors whose blood profile at the time of competition, or had infused hemoglobin via a competition demonstrates depressed erythro- transfusion, they would risk exclusion from com- poiesis, iron overload and/or hematologic para- petition if the increase in circulating hemoglobin meters that deviate substantially from histori- was beyond the margins of accepted biological cal values. variation compared with their Hematologic Pass- port values, or if the mandatory iron administration Challenges associated with reaching this goal associated with r-HuEPO abuse had elevated their can be clearly defined, but are substantial. Success ferritin values beyond safe limits. will require the concerted effort of all stakehold- But perhaps the most potent weapon to deter ers. International federations and antidoping blood doping is recognition that an inevitable con- authorities must be cognizant of novel deterrents sequence of an athlete boosting circulating hemo- and seek to draft legislation to complement these globin levels is the unmistakable depression of red approaches. However, we must remain mindful that cell production that follows when the stimulant is in our zealous desire to rid sport of doping, we do removed. Our understanding of the hematopoietic not forsake the interests of those for whom we process suggests that, regardless of which stimu- undertake these efforts – the athletes. It is vital lant was used, when usage ceased there would be that athletes are consulted during, and provide an extended period of elevated Hb/Hct in combi- informed consent to, the implementation of anti- nation with depressed erythropoiesis until the set doping measures. Although comprehensive testing point was regained. Excluding athletes from com- is required in order to enjoy a more level playing petition until the underlying cause for this patho- field, a successful antidoping strategy must ulti- logic situation had been identified would make it mately protect the athletes’ health and also respect extremely difficult for an athlete to successfully their privacy. compete whilst retaining any physiologic advan- tage from prior drug abuse. Michael Ashenden, PhD, This OFF-model profile has been demonstrated PO BOX 250, Gumeracha, SA 5233 Australia. to accompany blood transfusion,6 and has been Phone: international +61.409797226. shown to persist for several weeks after r-HuEPO Fax: international +61.409797557. injections cease.4 Faced with the formidable array E-mail: [email protected]

haematologica vol. 87(3):march 2002 232 Editorial, comments & views

receiving chemotherapy, so that this adverse event References should be borne in mind by clinicians but should not prevent the vast majority of patients from ben- 1. Browne A, Lachance V, Pipe A. The ethics of blood test- efiting from a treatment that can improve quality of ing as an element of doping control in sport. Med Sci life and prolong survival. Sports Exerc 1999; 31:497-501. 2. Macdougall IC. Novel erythropoiesis stimulating protein. Doping with erythropoietin is a totally different Semin Nephrol 2000; 20:375-81. issue. Athletes are healthy individuals who do not 3. Chang MSC. Blood substitutes. Switzerland: Karger AG. need any treatment. They abuse rHuEpo or related 1997. drugs to win games unfairly and earn money illicit- 4. Parisotto R, Gore CJ, Emslie KR, Ashenden MJ, Brugnara ly. Any medical risk related to drug abuse is unac- C, Howe C, et al. A novel method utilising markers of altered erythropoiesis for the detection of recombinant ceptable by definition: to realize this, simply con- human erythropoietin abuse in athletes. Haematologica sider to the drama of a (theoretical) young vigorous 2000; 85:564-72. man who abuses rHuEpo to increase his red cell 5. Parisotto R, Wu M, Ashenden MJ, et al. Detection of mass and athletic performance, develops PRCA and recombinant human erythropoietin abuse in athletes uti- becomes transfusion-dependent for the rest of his lizing markers of altered erythropoiesis. Haematologica 2001; 86:128-37. life. According to current rumors, endurance ath- 6. Lasne F, de Ceaurriz J. Recombinant erythropoietin in letes have started abusing darbepoetin alpha urine. Nature 2000; 405:635. (Aranesp): since this molecule differs markedly from 7. Berglund B, Hemmingsson P, Birgegard G. Detection of endogenous erythropoietin, the risk of developing autologous blood transfusions in cross-country skiers. cross-reacting antibodies on long-term abuse can- Int J Sports Med 1987; 8:66-70. not be excluded a priori.6 Finally, we totally agree with the conclusion of Casadevall et al.4 that the severity of rHuEpo- Further concerns about the medical induced PRCA argues also against the use of this risks of blood doping drug for unlicensed indications.

This journal and its editor strongly oppose the Mario Cazzola, M.D. spreading phenomenon of blood doping in sport.1-3 Department of Hematology, Some time ago we wrote: «As hematologists, over University of Pavia Medical School, the next years we could face problems related to 27100 Pavia, Italy blood doping with increasing frequency: atypical cases of iron overload, erythrocytosis of unknown origin, unexplained anemias, atypical thomboem- References bolic complications, and so on».1 1. Cazzola M. A global strategy for prevention and detec- Recent observations emphasize the medical risks tion of blood doping with erythropoietin and related of blood doping, in particular those related to the drugs. Haematologica 2000; 85:561-3. abuse of recombinant human erythropoietin (rHuE- 2. Parisotto R, Gore CJ, Emslie KR, Ashenden MJ, Brugnara po). Casadevall et al.4 have recently identified 22 C, Howe C, et al. A novel method utilizing markers of cases of pure red-cell aplasia in patients with chron- altered erythropoiesis for the detection of recombinant human erythropoietin abuse in athletes. Haematologica ic renal failure who were receiving rHuEpo. These 2000; 85:564-72. individuals develop anti-erythropoietin antibodies 3. Parisotto R, Wu M, Ashenden MJ, Emslie KR, Gore CJ, that neutralize both rHuEpo and endogenous ery- Howe C, et al. Detection of recombinant human ery- thropoietin, thus producing severe PRCA. These thropoietin abuse in athletes utilizing markers of altered patients become totally transfusion-dependent and erythropoiesis. Haematologica 2001; 86:128-37. 4. Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian J-J, Mar- apparently do not respond to erythropoietin mole- tin-Dupont P, et al. Pure red-cell aplasia and antiery- cules other than that used before development of thropoietin antibodies in patients treated with recombi- PRCA.4 Additional cases have been independently nant erythropoietin. N Engl J Med 2002; 346:469-75. reported.5 5. Important safety message: Eprex (epoetin alpha): reports It must be clearly said that this risk is very low in of pure red cell aplasia (PRCA). Bucks, United Kingdom: Janssen Cilag, 2001 (memorandum). renal patients (less than 1:10,000), and probably 6. Bunn HF. Drug-induced autoimmune red-cell aplasia. N even lower in patients with anemia of malignancy Engl J Med 2002; 346:522-3.

haematologica vol. 87(3):march 2002