Blood Boosting

2006 – Prohibited MethodsM1. Enhancement of Oxygen Transfer

• Blood doping, including the use of autologous, homologous, or heterologous blood or red blood cell products of any origin.

• Artificially enhancing the uptake, transport or delivery of oxygen, perfluorochemicals, efaproxiral (RSR13) and modified Hb products

Blood Boosting

• Oxygen delivery vital for aerobic exercise• Determined by total body Hb• Blood boosting/doping – techniques employed to

augment O2 carrying capacity• Includes:

– Blood transfusion;– Endogenous stimulation of rbcs via legal altitude

training, hypoxic tents, EPOs, EPO gene therapy, or EPO mimetics;

– Blood substitutes eg. Modified Hb solutions and perfluorochemicals

Blood Transfusion

• Blood units removed, RBC harvested, stored, later reinfused

• Notable Finnish and Italian distance runners have admitted use

• US cyclists at 1984 Olympics• Improved performance is

immediate• Buick et al., (1980), reinfusion

elevated Hb, VO2max and run time to exhaustion

• 10km running >1min faster, improvement lasted for at least 2 weeks

Blood Boosting

Blood Boosting

Erythropoiesis

• Skull, bony thorax, vertebrae, iliac crests, upper ends femur and humerus.

• Controlled by circulating levels of EPO

• Stimulus is reduced O2 delivery to kidney ie. Altitude, anaemia

• Net effect is ↑number of rbc’s and rate of release into circulation.

EPO• Recombinant DNA techniques

rHuEPO– rHuEPO-α, rHuEPO-β – rHuEPO-ω (lower doses needed) and

Darbepoietin-α (Aranesp)– Dynepo (EPO produced by human stem

cells)• Recombinant EPO (r-HuEPO) used

tx renal failure• Admin subcutaneously or iv

– Oral forms being developed encapsulated in liposomes

– Subcutaneous encapsulated forms• Same effect as altitude but are able to

maintain training intensity.

EPO• Raises Hct to abnormally high levels and increases Fe

requirement;• ↑bp and viscosity - ↑risk thrombosis and stroke;• Long-term - LV hypertrophy and ultimately heart failure;• Blunted endogenous EPO response severe anaemia;• Development of anti-EPO antibodies• Deaths of 18+ cyclists – rumoured to be EPO abuse;• Does it work?

– Most studies on unhealthy– Audran et al., (1999) 9 athletes, rHuEPO (50IU.kg-1) 26d. Tx

stopped if Hct>50%. • ↑Hct, Hb, VO2max (8.5%), and VO2 at VT.• All ↑ aerobic power

• Marion Jones? Power events?

EPO and Environmental Stress

• Altitude– Brief studies (<1hr) in hypobaric chamber

• Pace et al., (1947) lower hr;

• Robertson et al., (1982) less reduction in VO2max.

– Longer stays at altitude• Young et al., (1996) – no diff in decline VO2max or

performance

– Ergogenic effect may diminish as altitude increases;

– Ergogenic effect may only be apparent with acute hypoxic exposure.

EPO and Environmental Stress

• Heat– Magnitude of ↑Tc related to relative exercise

intensity;– Also blood doping may allow O2 requirements

to be met with lower blood flow – alleviating competition between muscle and skin;

– Studies by Sawka et al., (1987/8/9) support thermoregulatory advantage

– But dehydration will exacerbate ↑ viscosity

EPO Mimetics

• Interest in identifying active peptide domains of EPO;

• Synthesise derivatives• Discover nonpeptide small mimetics with

resistance to proteolytic digestion, good permeability, oral admin.

• Xenobiotics – so easy to detect– But short half life may pose detection problem

Testing - EPO

• 1990 IOC added to banned list;• XC skiers and [Hb]• UCI ’97 – Hct 50% – banned for 15 days for

health• Hard evidence ’98 with Voet/Festina affair• 1st test Sydney – blood and urine• Difficult to test – short plasma ½ life, close

homology between endogenous and recombinant EPO

Blood Substitutes

• Used due to risk of eg. CJD with homologous/heterologous blood;

• Perfluorocarbons (PFC’s) and Hb based oxygen carriers (HBCO’s);

• PFC’s are highly fluorinated inert organic compounds that can dissolve large volumes of oxygen (Lowe, 2001). Unreactive and excreted as a vapour by exhalation;

• Exchange gases more rapidly/completely than rbc’s – but require high %s of inspired oxygen

Blood Substitutes

• HBOC’s are x-linked (↓ O2 affinity & stabilises molecule so reduces renal toxicity) or microencapsulated Hb molecules;

• Right shifted sigmoidal Hb-oxygen dissociation curve;• Hughes et al.,(1995)- performance similar to autologous

blood transfusion• One near fatal suspected case with Swiss cylcist in ’98• 2001 Giro d’Italia – an HBOC (Hemassist) found in hotel

room of Italian cyclist

Allosteric effectors of Hb

• Bind reversibly to Hb, decrease oxygen affinity• Eg. RSR13 (effraproximal sodium) – used in tx

brain tumours, and has potential in conditions with tissue hypoxia (eg. Cardiovascular events)

• Mimics effect of 2,3-BPG – shifts O2-dissociation curve to the R ;

• Effect lasts 3-6 hours after iv infusion – but manufacturer reports sensitive and validated methods of detection in blood/urine.

RSR-13 (Right Shifting Reagent)

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Oxygen partial pressure (mm Hg)

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Acid pH

Acid pH in tissue promotes oxygenrelease

Tricks haemoglobin to deliver more oxygenClinically used to increase tissue pO2 prior to tumour radiation therapy

Plasma Expanders

• Hydroxyethyl starch (HES, HespanTM)

• Expands plasma for 24 hrs, but detected for 17 – 24 weeks

• Masks a raised Hct.

• Side effects – increased coagulation

• Finish XC skier tested +ve 2001.

Refs

• Gaudard et al., (2003) Drugs for increasing oxygen transport and their potential use in doping. Sports Med. 33(3): 187 – 212

• Sawka et al., (1996) ACSM Position Stand: The Use of Blood Doping as an Ergogenic Aid. MSSE 28(10) 127 - 134