Rapid hemodilution induced by desmopressin after erythropoietin administration in humans

Fabian Sanchis-Gomar, Vladimir Martinez-Bello, Frederic Derbré, Ernesto García-López, Rebeca García-Valles, Thomas Brioche, Beatriz Ferrando, Sandra Ibañez-Sania, Elios Pareja-Galeano, Mari Carmen Gomez-Cabrera, José Viña

Abstract

We have shown that treatment with desmopressin has a very effective hemodilution effect in healthy humans. These results led us to suggest the possible role of desmopressin to mask blood doping in sports. Based on our results, the World Anti-Doping Agency included the desmopressin in the 2011 List of Prohibited Substances and Methods. On this occasion, the aim of our study was to test the desmopressin-induced hemodilution after rHuEpo administration in humans. This was an intra-subject, crossover study in which five physically active males acted as their own controls. A basal blood sample was taken on their first visit to the laboratory. The next day, the subjects began the treatment. They received a subcutaneous rHuEpo injection three times/week for a two-week period. On the second visit to the laboratory, seventeen days later, a blood sample was taken. Thereafter, the subjects received an oral dose of 4.3 μg/kg of desmopressin and were instructed to ingest 1.5 liters of mineral water during the following fifteen minutes. Three hours after the water ingestion a second blood sample was obtained. The samples were analyzed for hematocrit (HCT), hemoglobin (Hb), reticulocytes (Ret%) and OFF Hr-Score. We found significantly higher HCT, Hb and Ret% levels after rHuEpo administration. Administration of desmopressin significantly decreased the HCT and Hb values but we did not find significant changes in Ret%. The values of the OFF Hr-Score also decreased after treatment with desmopressin. Desmopressin has a very effective hemodilution effect after rHuEpo administration and significantly modifies the hematological values measured by the anti-doping authorities to detect blood doping. We consider that these results reinforce the conclusions reported in our first study and confirm that desmopressin is a very effective masking agent for blood doping.


Keywords

Haemoglobin; Haematocrit; Reticulocytes; Stimulation index and plasma volume expanders

References

Ashenden, M., Gough, C.E., Garnham, A., Gore, C.J., Sharpe, K. Current markers of the Athlete Blood Passport do not flag microdose EPO doping. Eur J Appl Physiol. 2011. https://doi.org/10.1007/s00421-011-1867-6

Audran, M., Gareau, R., Matecki, S., Durand, F., Chenard, C., Sicart, M.T., Marion, B., Bressolle, F. Effects of erythropoietin administration in training athletes and possible indirect detection in doping control. Med Sci Sports Exerc. 1999; 31:639-645. https://doi.org/10.1097/00005768-199905000-00003

Berger, N.J., Campbell, I.T., Wilkerson, D.P., Jones, A.M. Influence of acute plasma volume expansion on VO2 kinetics, VO2 peak, and performance during high-intensity cycle exercise. J Appl Physiol. 2006; 101:707-714. https://doi.org/10.1152/japplphysiol.00154.2006

Brien, A.J., Simon, T.L. The effects of red blood cell infusion on 10-km race time. Jama. 1987; 257:2761-2765. https://doi.org/10.1001/jama.1987.03390200101022

Cooper, C.E., Beneke, R. Drugs and Ergogenic Aids to Improve Sport Performance. London: Portland Press; 2008.

Damsgaard, R., Munch, T., Morkeberg, J., Mortensen, S.P., Gonzalez-Alonso, J. Effects of blood withdrawal and reinfusion on biomarkers of erythropoiesis in humans: Implications for anti-doping strategies. Haematologica. 2006; 91:1006-1008.

Dimson, S.B. Desmopressin as a treatment for enuresis. Lancet. 1977; 1:1260. https://doi.org/10.1016/S0140-6736(77)92467-9

Ekblom, B., Wilson, G., Astrand, P.O. Central circulation during exercise after venesection and reinfusion of red blood cells. J Appl Physiol. 1976; 40:379-383.

Gilbert, S. The biological passport. Hastings Cent Rep. 2010; 40:18-19. https://doi.org/10.1353/hcr.0.0235

Gore, C.J., Parisotto, R., Ashenden, M.J., Stray-Gundersen, J., Sharpe, K., Hopkins, W., Emslie, K.R., Howe, C., Trout, G.J., Kazlauskas, R., Hahn, A.G. Second-generation blood tests to detect erythropoietin abuse by athletes. Haematologica. 2003; 88:333-344.

Guddat, S., Thevis, M., Schanzer, W. Identification and quantification of the plasma volume expander dextran in human urine by liquid chromatography-tandem mass spectrometry of enzymatically derived isomaltose. Biomed Chromatogr. 2005; 19:743-750. https://doi.org/10.1002/bmc.509

Guddat, S., Thevis, M., Thomas, A., Schanzer, W. Rapid screening of polysaccharide-based plasma volume expanders dextran and hydroxyethyl starch in human urine by liquid chromatography-tandem mass spectrometry. Biomed Chromatogr. 2008; 22:695-701. https://doi.org/10.1002/bmc.986

Kim, R.J., Malattia, C., Allen, M., Moshang, T., Jr., Maghnie, M. Vasopressin and desmopressin in central diabetes insipidus: adverse effects and clinical considerations. Pediatr Endocrinol Rev. 2004; 2(1):115-123.

Lasne, F. Double-blotting: a solution to the problem of non-specific binding of secondary antibodies in immunoblotting procedures. J Immunol Methods. 2001; 253:125-131. https://doi.org/10.1016/S0022-1759(01)00355-6

Levy, J.H. Pharmacologic methods to reduce perioperative bleeding. Transfusion. 2008; 48:31S-38S. https://doi.org/10.1111/j.1537-2995.2007.01574.x

Morkeberg, J., Belhage, B., Ashenden, M., Borno, A., Sharpe, K., Dziegiel, M.H., Damsgaard, R. Screening for autologous blood transfusions. Int J Sports Med. 2009a; 30:285-292. https://doi.org/10.1055/s-0028-1105938

Morkeberg, J., Sharpe, K., Belhage, B., Damsgaard, R., Schmidt, W., Prommer, N., Gore, C.J., Ashenden, M.J. Detecting autologous blood transfusions: a comparison of three passport approaches and four blood markers. Scand J Med Sci Sports. 2009b. https://doi.org/10.1111/j.1600-0838.2009.01033.x

Parisotto, R., Ashenden, M.J., Gore, C.J., Sharpe, K., Hopkins, W., Hahn, A.G. The effect of common hematologic abnormalities on the ability of blood models to detect erythropoietin abuse by athletes. Haematologica. 2003; 88:931-940.

Parisotto, R., Wu, M., Ashenden, M.J., Emslie, K.R., Gore, C.J., Howe, C., Kazlauskas, R., Sharpe, K., Trout, G.J., Xie, M. Detection of recombinant human erythropoietin abuse in athletes utilizing markers of altered erythropoiesis. Haematologica. 2001; 86:128-137.

Robinson, A.G. DDAVP in the treatment of central diabetes insipidus. N Engl J Med. 1976; 294:507-511. https://doi.org/10.1056/NEJM197603042941001

Sanchis-Gomar, F., Martinez-Bello, V.E., Gomez-Cabrera, M.C., Vina, J. The hybrid algorithm (Hbmr) to fight against blood doping in sports. Scand J Med Sci Sports. 2010a; 20:789-79. https://doi.org/10.1111/j.1600-0838.2010.01224.x

Sanchis-Gomar, F., Martinez-Bello, V.E., Nascimento, A.L., Perez-Quilis, C., Garcia-Gimenez, J.L., Vina, J., Gomez-Cabrera, M.C. Desmopressin and hemodilution: implications in doping. Int J Sports Med. 2010b; 31:5-9. https://doi.org/10.1055/s-0029-1239500

Sharpe, K., Ashenden, M.J., Schumacher, Y.O. A third generation approach to detect erythropoietin abuse in athletes. Haematologica. 2006; 91:356-363.

Thevis, M., Opfermann, G., Schanzer, W. Detection of the plasma volume expander hydroxyethyl starch in human urine. J Chromatogr B Biomed Sci Appl. 2000; 744:345-350. https://doi.org/10.1016/S0378-4347(00)00251-6

Ventura, R., Segura, J. Masking and manipulation. Handb Exp Pharmacol. 2010; 327-354. https://doi.org/10.1007/978-3-540-79088-4_15

WADA. The 2011 prohibited list of Substances international standard. www.wada-ama.org. 2011; 1-11.

Zorzoli, M., Rossi, F. Implementation of the biological passport: the experience of the International Cycling Union. Drug Test Anal. 2010; 2:542-547. https://doi.org/10.1002/dta.173




DOI: https://doi.org/10.4100/jhse.2011.62.12