blood doping and its detection

8/12/2019 Blood doping and its detection

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doi:10.1182/blood-2011-02-303271Prepublished online June 7, 2011;

Wolfgang Jelkmann and Carsten LundbyBlood doping and its detection

(488 articles)Review Articles(498 articles)Red Cells, Iron,and Erythropoiesis

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Abstract

Hemoglobin mass (Hbmass) is a key factor for maximal exercise capacity. Some athlet

prohibited techniques and substances with intent to increase Hbmassand physical perfo

and this is often difficult to prove directly. Autologous red blood cell (RBC) transfus

cannot be traced, and also recombinant erythropoietic proteins are detectable only wi

certain timeframe. Novel erythropoietic substances, such as mimetics of erythropoiet

and activators of theEpogene may soon enter the sports scene. In addition,Epogene

maneuvers are imaginable. Effective since December 2009, the World Anti-Doping A

(WADA) has therefore implemented Athlete Biological Passport Operating Guidelin

which are based on the monitoring of several parameters for mature RBC and reticulo

Blood doping may be assumed, when these parameters change in a non-physiological

Hematologists should be familiar with blood doping practices as they may play an im

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Introduction

The World Anti-Doping Agency (WADA) defines blood doping as the misuse of ce

techniques and/or substances to increase one's red blood cell mass, which allows the b

transport more O2 to muscles and therefore increase stamina and performance.1Proh

procedures include the use of synthetic O2carriers, the transfusion of red blood cells

the infusion of hemoglobin (Hb), and the artificial stimulation of erythropoiesis. Thiswill focus on erythropoietic substances and RBC parameters that are affected by bloo

and provided the basis for WADA s Athlete Biological Passport Operating Guidelin

Synthetic O2 carriers, such as Hb-based O2carriers or perfluorocarbons are not consid

here. The topic is timely. Experts having knowledge in the fields of clinical hematolo

laboratory medicine/hematology and physiology/hematology may become involved i

evaluation of athletes blood profiles. The experts must be able to analyze and certify



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remains elevated for at least three wks. Effects of rhEpo in normal humans have been

reviewed recently.15

Although Epo is reported to activate several non-hematologic fa

in addition to stimulating erythropoiesis), which are usually also associated with

improvements in aerobic performance, the primary mechanism by which Epo increas

exercise performance in humans is through augmented erythropoiesis.16-18

ESAs are

particularly effective in combination with iron supplementation.19

The administration

results in increased ferritin levels in athletes.20

Ferritin levels >1,000 g L-1have been

observed.

21

There are as yet no reports on physical performance in healthy humans with increased

circulating Epo and Hbmassdue to the administration of compounds stimulating the ex

of the endogenousEpogene or followingEpo gene transfer.

Direct detection of blood doping

Blood and urine samples can be taken in competition and out of competition With re



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detecting non-physiological increases in Hbmassis still investigational,24,25

and beside

practical difficulties related to this method, its potential inclusion in the blood passpo

be problematic,26since the margin of variation when assessing Hbmass(biological and

measurement errors) would still allow athletes to manipulate with blood volumes that

increase exercise performance considerably.27

Finally, it should also be considered th

an athletes point of view it may not be desirable to breathe CO shortly before a comp

as this may limit exercise performance.

Peptidic ESAs

Currently available rhEpo preparations (epoetins) are produced inEpocDNA transfe

Chinese hamster ovary (CHO) or baby hamster kidney (BHK) cell cultures. The only

therapeutic rhEpo engineered in human cells (epoetin delta) is off market since the be

of 2009 (Table 1). Since the patents of the originator epoetins have expired, biosimila

products have been approved in many parts of the world.28Furthermore, various copi



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dependent hydroxylation of an asparagine residue. The HIF-hydroxylases contain F

are inactivated by Fe2+

removal.55

However, iron chelators are not suited for stimulati

erythropoiesis in the long-term, because iron is required for heme synthesis. HIF-dep

Epoexpression is augmented by divalent transition metals such as cobalt or nickel. It

known for long that cobalt increases erythropoiesis in experimental animals.56

Cobalt

HIF-thereby preventing the docking of pVHL.57Cobalt is a very potent inducer of

transcription. In fact, the international Epo unit (IU) was originally defined as the dos

eliciting the same erythropoiesis stimulating response in rats as five micromoles of cochloride.

58The treatment of anemic CKD patients with cobalt (commonly administer

enteric-coated tablets, 30-150 mg daily)59,60

is no longer performed because of its tox

However, cobalt may be misused by athletes as a legitimate means to enhance Epo le

Hbmass.62

Cobalt is very potent, inexpensive and not comprehended in the WADAs P

List. Furthermore, the HIF-hydroxylases require -ketoglutarate for their catalytic

-Ketoglutarate competitors ("HIF stabilizers") are orally active compounds that stim

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Epo glycosylation forms on allogeneicEpotransfer into skeletal muscle of cynomolg

macaquesviaadeno-associated virus (AAV).72

In the initial studies of AAV-mediate

allogeneicEpocDNA transfer to macaques severe anemia developed in many animal

few months, which was likely due to an immune reaction.73,74

However, in using a rap

dimerizer-regulated gene expression system, Rivera et al.75

achieved controlled, long

production (up to 6 years) of Epo in rhesus monkeys, with no apparent immune respo

Regarding the possibility ofEpogene doping in humans, strategies are under develop

specifically amplify intron-less DNA sequences and PCR protocols allowing the dete

small amounts of transgenic DNA in blood.76-78

The tests take into consideration that

transgenes are usually derived from the complementary DNA (cDNA) for the gene to

transferred and cDNA does not contain introns.

An autologous ex vivoapproach was chosen in the first humanEpogene therapy trial

patients with CKD.79

An individual dermal core sample was transfected withEpocD

inserted into a vector containing the CMV promoter and the simian virus 40 polyA si



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Anabolic-androgenic steroids also increase both the production of Epo and the prolife

erythrocytic progenitors in the bone marrow, as reviewed elsewhere.83

WADAs Biological Passport

Traditional anti-doping analyses are based on the detection of a substance in biologic

(Adverse analytical finding). This approach has major limitations regards blood do

outlined above, autologous blood cannot be detected, there is a plethora of ESAs, the

detection window is limited and there is urine manipulation. Some sports federations

introduced upper [Hb] and Hct limits to escape from this dilemma. Athletes tested ab

limits were declared unfit for competition (No-start rule). However, [Hb] and Hct a

influenced by external factors such as body posture, exercise, or residence at altitude

clean athletes can have naturally high [Hb] and Hct values. A large retrospective st

male blood donors in Denmark revealed that 3.9% of non-athletes and 10.4% of elite

had Hct values >0.51, i.e. above the recommended limits for athletic competition.84In



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doping rule violations in accordance with Article 2.2. of the World Anti-Doping (WA

(Use or Attempted Use by an Athlete of a Prohibited Substance or a Prohibited Meth

The guidelines include mandatory requirements for collection, transportation, analysi

blood samples, and results management. The following markersare considered in the

Biological Passport hematologic module: Hct, Hb, RBC count, Ret% (Ret percentage

(Ret number), MCV, MCH, MCHC, and OFF-hr score (Index of stimulation derived

formula ([Hb] (g L-1

) - (60 x (Ret%); normal range: 85-95). In addition, parameters

interest can be the mean Ret cell volume (MCVr), Ret Hb concentration (MCHCr) an

Hb content (MCHr), as measured by flow cytometry like in clinical routine.97

The res

reported to the WADA are processed by an Adaptive Model that identifies abnorm

parameter changes related to the athletes individual profile. In particular, [Hb] or OF

score abnormalities with a 99.9% probability or more shall be reviewed by experts.2

RBC parameters associated with autologous re-transfusion


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incorporating hematologic measures ([Hb], Ret%, OFF-score) allows for detection of

autologous blood transfusion.101

In a comparative study of three blood passport appro

and four blood markers Mrkeberg et al.102re-transfused 29 subjects with either 1 or

of autologous blood. Hbmr (derived from the formula [4.51 x ln (Hbmass) - Ret%]; c

not part of anti-doping testing) demonstrated superior sensitivity in detecting blood

transfusion.102

The same authors have reported that the determination of the ratio betw

mass of Hb in the mature erythrocyte population and in the reticulocyte fraction (RBC

RetHbratio) is the best indicator of autologous blood doping.103

RBC parameters associated with ESA doping

There are no major differences in basal [Hb], RBC count, Hct and MCHC values in e

athletes in comparison to healthy non-athletes.104

When blood samples obtained from

female and 739 male elite athletes from 12 countries were screened for hematologic


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Thus, the treatment with rhEpo appears to increase Ret values twofold: by increased R

release from the bone marrow and by prolonged maturation time of circulating Ret.

Audran et al.12

studied the time-course of Ret# following repeated s.c. injections of rh

U kg-1

b.w. every day) in athletes. Ret# were increased from day 10 to 24 and remain

elevated for 7 days after cessation of rhEpo therapy. Ret# were significantly lower th

baseline values 14 and 25 days after the last rhEpo injection. During treatment up to 1

after the last rhEpo injection sTfR and the sTfR/serum protein ratio were elevated abo

baseline.12Russell et al.113administered first high (50 U kg-1b.w. TIW for 3 wks) and

low doses of rhEpo (20 U kg-1

TIW for 5 wks), with oral or parenteral iron suppleme

Ret% approximately doubled by day 8 of the high-dose rhEpo treatment, but during t

dose phase was not different from baseline values or from those of the placebo group

irrespective of the route of iron administration. During the washout phase Ret% fell t

half of the baseline values in the rhEpo treated subjects. In a similar study, following

weekly injections for 14 days and a concomitant doubling in Ret% Ret% returned to


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accompanied by twice weekly administration of parenteral iron (62 mg i.v.) and oral

The rhEpo treated subjects had higher values for RBC concentrations, [Hb], Hct, MC

Ret%, macrocyte (volume >120 fL) and hypochromic macrocyte counts (MCH


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comply with the minimum recommendations of at least 400 hours of altitude/hypoxia

exposure needed to increase performance. Hence, if the passport approach was to be t

combination with an altitude setting actually leading to performance gains, it seems v

likely that also many of the parameters included in the blood passport will change

substantially, which needs to be accounted for during the evaluation process.

Comments

The WAD Code states that a positive analytical result, i.e. proof of the presence of a

prohibited substance, will always establish liability for a doping offence.119

If a medic

athlete is required to take to treat an illness or condition falls under the Prohibited L

Therapeutic Use Exemption (TUE) may give the athlete the authorization to take th

medicine.1


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The statistical approach for evaluating the passport data is focused on the biological v

of hematologic values. Critical experts in the analysis of laboratory data have claimed

anti-doping tests are based on fraud statistics.121Sottas et al.122have stated that anti-d

a forensic science, not a medical one. In forensics the traditional assumptions of abs

certainty and discernible uniqueness are abandoned in favor of an empirical and

probabilistic approach.

Current anti-doping actions in competitive sports are advocated for reasons of fair-pla

concern for the athlete's health. Most of the efforts concern elite athletes with much le

impact on amateur sports and the general public.123

Indeed, anti-doping rules adopted

pursuant to the WAD Code normally apply only to international- and national-calibre

The monitoring of RBC parameters according to the biological passport is not perform

recreational-level or masters competitors who are not current or potential national-cal

competitors. Thus, the procedure is of little use in leisure sports.



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( , ,

) , ( ,

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)

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( - , - , - )

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Legends of the Figures

Figure 1.Parameters determining the aerobic capacity.The aerobic capacity, as m

as the maximal O2uptake, depends primarily on the individuals total hemoglobin ma

maximal cardiac output and the maximal O2extraction in the heart and the skeletal m

The total hemoglobin mass results from the blood hemoglobin concentration and the

volume.

Figure 2.Hematocrit (%) and total hemoglobin mass (g.kg-1

) in moderately trained y

males (Danish) (commuting to work/school on bicycle and engaged in easy aerobic tr

3 times per week, in trained runners (French, all finishers of the Ultra Trail du Mont

166 km of mountain trail running with 9,500 meter of altitude gain), in national level

(Danish, US, Canada), and in national team cross country skiers (German, Swedish a

French) including several Olympic and World Championship medalists The figure il


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blood doping and its detection

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