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High Altitude pp 203-216 | Cite as

Blood and Haemostasis

  • Peter Bärtsch
  • Jim S. Milledge
Chapter

Abstract

This chapter deals with oxygen-carrying capacity of blood and haemostasis. It focuses on the effects of intermittent exposure to hypoxia on red blood cell mass, particularly in the various settings used by athletes. Furthermore, mechanisms of neocytolysis occurring on descent from high altitude are discussed, as well as mechanisms accounting for a rapid decline of erythropoietin serum levels during persistent hypoxia, whilst increased erythropoiesis is maintained. Different strategies of adaptation to chronic hypoxia with regard to haemoglobin and oxygenation of the Andean, Ethiopian and Tibetan populations are discussed in the light of recent findings of genetic mutations in these populations. The review on haemostasis includes studies on platelets, blood coagulation and fibrinolysis in acute and chronic exposure to hypoxia and the discussion of potential mechanisms of activation of blood coagulation at altitudes above 4,000 m.

Keywords

Intermittent Hypoxia Hypobaric Hypoxia Fibrin Formation Hepcidin Level Normobaric Hypoxia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Grover RF, Bärtsch P. Blood. In: Hornbein TF, Schoene RB, editors. High altitude—an exploration of human adaptation. New York: Marcel Dekker; 2001. p. 493–523.Google Scholar
  2. 2.
    Chapman RF, Stickford JL, Levine BD. Altitude training considerations for the winter sport athlete. Exp Physiol. 2010;95:411–21.PubMedCrossRefGoogle Scholar
  3. 3.
    Schumacker PT, Suggett AJ, Wagner PD, West JB. Role of hemoglobin P50 in O2 transport during normoxic and hypoxic exercise in the dog. J Appl Physiol. 1985;59:749–57.PubMedGoogle Scholar
  4. 4.
    Wagner PD. A theoretical analysis of factors determining VO2max at sea level and altitude. Respir Physiol. 1996;106:329–43.PubMedCrossRefGoogle Scholar
  5. 5.
    Siebenmann C, Robach P, Jacobs RA, Rasmussen P, Nordsborg N, Diaz V, et al. “Live high-train low” using normobaric hypoxia: a double-blinded, placebo-controlled study. J Appl Physiol. 2012;112:106–17.PubMedCrossRefGoogle Scholar
  6. 6.
    Schmidt W, Prommer N. Effects of various training modalities on blood volume. Scand J Med Sci Sports. 2008;18 Suppl 1:57–69.PubMedCrossRefGoogle Scholar
  7. 7.
    Gore CJ, Rodriguez FA, Truijens MJ, Townsend NE, Stray-Gundersen J, Levine BD. Increased serum erythropoietin but not red cell production after 4 wk of intermittent hypobaric hypoxia (4,000-5,500 m). J Appl Physiol. 2006;101:1386–93.PubMedCrossRefGoogle Scholar
  8. 8.
    Buick FJ, Gledhill N, Froese AB, Spriet L, Meyers EC. Effect of induced erythrocythemia on aerobic work capacity. J Appl Physiol. 1980;48(4):636–42.PubMedGoogle Scholar
  9. 9.
    Young AJ, Sawka MN, Muza SR, Boushel R, Lyons T, Rock PB, et al. Effects of erythrocyte infusion on VO2max at high altitude. J Appl Physiol. 1996;81(1):252–9.PubMedGoogle Scholar
  10. 10.
    Calbet JAL, Radegran G, Boushel R, Sondergaard H, Saltin B, Wagner PD. Effect of blood haemoglobin concentration on VO2, max and cardiovascular function in lowlanders acclimatised to 5260 m. J Physiol. 2002;545(2):715–28.PubMedCrossRefGoogle Scholar
  11. 11.
    Robach P, Calbet JAL, Thomsen JJ, Boushel R, Mollard P, Rasmussen P, et al. The ergogenic effect of recombinant human erythropoietin on VO2max depends on the severity of arterial hypoxemia. PLoS One. 2008;3(8):e2996.PubMedCrossRefGoogle Scholar
  12. 12.
    Milledge JS, Cotes PM. Serum erythropoietin in humans at high altitude and its relation to plasma renin. J Appl Physiol. 1985;59:360–4.PubMedGoogle Scholar
  13. 13.
    Risso A, Turello M, Biffoni F, Antonutto G. Red blood cell senescence and neocytolysis in humans after high altitude acclimatization. Blood Cells Mol Dis. 2007;38(2):83–92.PubMedCrossRefGoogle Scholar
  14. 14.
    Rice L, Ruiz W, Driscoll T, Whitley CE, Tapia R, Hachey DL. Neocytolysis on descent from altitude: a newly recognized mechanism for the control of red cell mass. Ann Intern Med. 2001;134:652–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Alfrey CP, Udden MM, Leach-Huntoon CS, Driscoll T, Pickett MH. Control of red blood cell mass in space flight. J Appl Physiol. 1996;81:98–104.PubMedGoogle Scholar
  16. 16.
    Rice L, Alfrey CP. The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations. Cell Physiol Biochem. 2005;15:245–50.PubMedCrossRefGoogle Scholar
  17. 17.
    Chang CC, Chen Y, Modi K, Awar OG, Alfrey CP, Rice L. Changes of red blood cell surface markers in a blood-doping model of neocytolysis. J Investig Med. 2009;57:650–4.PubMedGoogle Scholar
  18. 18.
    Risso A, Santamaria B, Pistarino E, Cosulich ME, Pompach P, Bezouska K, et al. Fragmentation of human erythrocyte actin following exposure to hypoxia. Acta Haematol. 2010;123:6–13.PubMedCrossRefGoogle Scholar
  19. 19.
    Trial J, Rice L, Alfrey CP. Erythropoietin withdrawal alters the interaction between young red blood cells, splenic endothelial cells and macrophages: an in vitro model of neocytolysis. J Investig Med. 2001;49:335–45.PubMedCrossRefGoogle Scholar
  20. 20.
    Alfrey CP, Rice L, Udden MM, Driscoll T. Neocytolysis: a physiologic down-regulator of red blood cell mass. Lancet. 1997;349:1389–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Pugh CW. Modulation of the hypoxic response. In: Roach RC, Hackett PH, editors. Hypoxia and exercise (in press).Google Scholar
  22. 22.
    Rosenberger C, Mandriota S, Jürgensen JSJ, Wiesener MS. Hörstrup. JH, Frei U, et al. Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol. 2002;13:1721–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Tan CC, Eckardt K-U, Frith Ratcliffe PJ. Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol Renal Physiol. 1992;263:474–81.Google Scholar
  24. 24.
    Silva M, Grillot D, Benito A, Richard C, Nunez G, Fernández-Luna JL. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood. 1996;88:1576–82.PubMedGoogle Scholar
  25. 25.
    Li P, Huang J, Tian HJ, Huang QY, Jiang CH, Gao YQ. Regulation of bone marrow hematopoietic stem cell is involved in high-altitude erythrocytosis. Exp Hematol. 2011;39:37–46.PubMedCrossRefGoogle Scholar
  26. 26.
    Robach P, Recalcati S, Girelli D, Gelfi C, Aachmann-Andersen NJ, Thomsen JJ, et al. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin. Blood. 2009;113:6707–15.PubMedCrossRefGoogle Scholar
  27. 27.
    Piperno A, Galimberti S, Mariani R, Pelucchi S, Ravasi G, Lombardi C, et al. Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project. Blood. 2011;117:2953–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Talbot NP, Lakhatl S, Smith TG, Privat C, Nickol AH, Rivera-Ch M, et al. Regulation of hepcidin expression at high altitude. Blood. 2012;119:857–60.PubMedCrossRefGoogle Scholar
  29. 29.
    Hathorn MKS. The influence of hypoxia on iron absorption in the rat. Gastroenterology. 1971;60:76–81.PubMedGoogle Scholar
  30. 30.
    Raja KB, Pippard MJ, Simpson RJ, Peters TJ. Relationship between erythropoiesis and the enhanced intestinal uptake of ferric iron in hypoxia in the mouse. Br J Haematol. 1986;64:587–93.PubMedCrossRefGoogle Scholar
  31. 31.
    Beall CM, Decker MJ, Brittenham GM, Kushner I, Gebremedhin A, Strohl KP. An Ethiopian pattern of human adaptation to high-altitude hypoxia. Proc Natl Acad Sci USA. 2002;99:17215–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, et al. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci USA. 2010;107:11459–64.PubMedCrossRefGoogle Scholar
  33. 33.
    Simonson TS, Yang Y, Huf CD, Yun H, Qin G, Witherspoon DJ, et al. Genetic evidence for high-altitude adaptation in Tibet. Science. 2010;329:72–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, et al. Sequencing of 50 human exomes reveals adaptation to high altitude. Science. 2010;329:75–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, et al. Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet. 2010;6:e1001116.PubMedCrossRefGoogle Scholar
  36. 36.
    Peng Y, Yang Z, Zhang H, Cui C, Qi X, Luo X, et al. Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol Biol Evol. 2011;28:1075–81.PubMedCrossRefGoogle Scholar
  37. 37.
    Xu S, Li S, Yang Y, Tan J, Lou H, Jin W, et al. A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol Biol Evol. 2011;28:1003–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Lehmann T, Mairbäurl H, Pleisch B, Maggiorini M, Bärtsch P, Reinhart WH. Platelet count and function at high altitude and in high-altitude pulmonary edema. J Appl Physiol. 2006;100:690–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Toff WD, Jones CI, Ford I, Pearse RJ, Watson GG, Wattt SJ, et al. Effect of hypobaric hypoxia, simulating conditions during long-haul air travel, on coagulation, fibrinolysis, platelet function and endothelial activation. JAMA. 2006;295:2251–61.PubMedCrossRefGoogle Scholar
  40. 40.
    Hodkinson PD, Hunt BJ, Parmar K, Ernsting J. Is mild normobaric hypoxia a risk factor for venous thromboembolism? J Thromb Haemost. 2003;1:2131–3.PubMedCrossRefGoogle Scholar
  41. 41.
    Hartmann S, Krafft A, Huch R, Breymann C. Effect of altitude on thrombopoietin and the platelet count in healthy volunteers. Thromb Haemost. 2005;93:115–7.PubMedGoogle Scholar
  42. 42.
    Hudson JG, Bowen AL, Navia P, Rios-Dalenz J, Pollard A, Williams D, et al. The effect of high altitude on platelet counts, thrombopoietin and erythropoietin levels in young Bolivian airmen visitin the Andes. Int J Biometeorol. 1999;43:85–90.PubMedCrossRefGoogle Scholar
  43. 43.
    Vij AG. Effect of prolonged stay at high altitude on platelet aggregation and fibrinogen levels. Platelets. 2009;20:421–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Lapostolle F, Surget V, Borron SW, Desmaizieres M, Sordelet D, Lapandry C, et al. Severe pulmonary embolism associated with air travel. N Engl J Med. 2001;345:779–83.PubMedCrossRefGoogle Scholar
  45. 45.
    Scurr JH, Machin SJ, Bailey-King S, Mackie IJ, McDonald S, Coleridge Smith PD. Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomised trial. Lancet. 2001;357:1485–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Crosby A, Talbot NP, Harrison P, Keeling D, Robbins PA. Relation between acute hypoxia and activation of coagulation in human beings. Lancet. 2003;361:2207–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Bendz B, Rostrup M, Sevre K, Andersen TO, Sandset PM. Association between acute hypobaric hypoxia and activation of coagulation in human beings. Lancet. 2000;356:1657–8.PubMedCrossRefGoogle Scholar
  48. 48.
    van Känel R, Loredo JS, Powell FL, Adler KA, Dimsdale JE. Short-term isocapnic hypoxia and coagulation activation in patients with sleep apnea. Clin Hemorheol Microcirc. 2005;33:369–77.Google Scholar
  49. 49.
    Bärtsch P, Straub PW, Haeberli A. Hypobaric hypoxia. Lancet. 2001;357:955.PubMedCrossRefGoogle Scholar
  50. 50.
    Schreijer AJM, Cannegieter SC, Meijers JCM, Middeldorp S, Buller HR, Rosendaal FR. Activation of coagulation system during air travel: a crossover study. Lancet. 2006;367(9513):832–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Boulos P, Kouroukis C, Blake G. Superior sagittal sinus thrombosis occurring at high altitude associated with protein C deficiency. Acta Haematol. 1999; 102:104–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Basnyat B, Graham L, Lee S-D, Lim Y. A language barrier, abdominal pain, and double vision. Lancet. 2001;357:2022.PubMedCrossRefGoogle Scholar
  53. 53.
    Nair V, Mohapatro AK, Sreedhar M, Indrajeet IK, Tewari AK, Anand AC, et al. A case of hereditary protein S deficiency presenting with cerebral sinus venous thrombosis and deep vein thrombosis at high altitude. Acta Haematol. 2008;119:158–61.PubMedCrossRefGoogle Scholar
  54. 54.
    Weiss C, Seitel G, Bärtsch P. Coagulation and fibrinolysis after moderate and very heavy exercise in healthy male subjects. Med Sci Sports Exerc. 1998;30:246–51.PubMedCrossRefGoogle Scholar
  55. 55.
    Bärtsch P, Siedler K, Kreutzberger R, Menold E, Weiss C. Acute mormobaric hypoxia does not enhance exercise-induced thrombin formation (Abstract). Med Sci Sports Exerc. 2001;33:S99.CrossRefGoogle Scholar
  56. 56.
    DeLoughery TG, Robertson DG, Smith CA, Sauer D. Moderate hypoxia suppresses exercise-induced procoagulant changes. Br J Haematol. 2004;125: 369–72.PubMedCrossRefGoogle Scholar
  57. 57.
    Le Roux G, Larmignat P, Marchal M, Richalet J-P. Haemostasis at high altitude. Int J Sports Med. 1992;13:S49–51.PubMedCrossRefGoogle Scholar
  58. 58.
    Pichler-Hefti J, Risch L, Hefti U, Scharrer I, Risch G, Merz TM, et al. Changes of coagulation parameters during high altitude expedition. Swiss Med Wkly. 2010;140:111–7.PubMedGoogle Scholar
  59. 59.
    Ren Y, Cui F, Lei Y, Fu Z, Wu Z, Cui B. High-altitude pulmonary edema is associated with coagulation and fibrinolytic abnormalities. Am J Med Sci. 2012; 344(3):186–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Bärtsch P, Haeberli A, Franciolli M, Kruithof EKO, Straub PW. Coagulation and fibrinolysis in acute mountain sickness and beginning pulmonary edema. J Appl Physiol. 1989;66:2136–44.PubMedGoogle Scholar
  61. 61.
    Bärtsch P, Waber U, Haeberli A, Maggiorini M, Kriemler S, Oelz O, et al. Enhanced fibrin formation in high-altitude pulmonary edema. J Appl Physiol. 1987;63:752–7.PubMedGoogle Scholar
  62. 62.
    Bärtsch P, Haeberli A, Nanzer A, Lämmle B, Vock P, Oelz O, et al. High altitude pulmonary edema: blood coagulation. In: Sutton JR, Houston CS, Coates G, editors. Hypoxia and molecular medicine. Burlington: Queen City Printers; 1993. p. 252–8.Google Scholar
  63. 63.
    Kotwal J, Apte CV, Kotwal A, Mukherjee B, Jayaram J. High altitude: a hypercoagulable state: results of a prospective cohort study. Thromb Res. 2007;120:391–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Jha SK, Anand AC, Sharma V, Kumar N, Adya CM. Stroke at high altitude: Indian experience. High Alt Med Biol. 2002;3:21–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Anand AC, Saha A, Seth AK, Chopra GS, Nair V, Sharma V. Symptomatic portal system thrombosis in soldiers due to extended stay at extreme altitude. J Gastroenterol Hepatol. 2005;20(5):777–83.PubMedCrossRefGoogle Scholar
  66. 66.
    Rupert JL, Devine DV, Monsalve MV, Hochachka PW. Beta-fibrinogen allele frequencies in Peruvian Quechua, a high-altitude native population. Am J Phys Anthropol. 1999;109:181–6.PubMedCrossRefGoogle Scholar
  67. 67.
    van Veen JJ, Makris M. Altitude and coagulation activation: does going high provoke thrombosis? Acta Haematol. 2008;119:156–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang J-S, Cheng M-L, Yen H-C, Lou B-S, Liu H-C. Vitamin E suppresses enhancement of factor VIII-dependent thrombin generation by systemic hypoxia. Stroke. 2009;40:656–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Schoene RB. Pulmonary edema at high altitude. Review, pathophysiology, and update. Clin Chest Med. 1985;6:491–507.PubMedGoogle Scholar
  70. 70.
    Fink T, Kazlauskas A, Poellinger L, Ebbesen P, Zachar V. Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1. Blood. 2002;99:2077–83.PubMedCrossRefGoogle Scholar
  71. 71.
    Schreijer AJM, Hoylaerts MF, Meijers JCM, Lijnen HR, Middeldorp S, Büller HR, et al. Explanations for coagulation activation after air travel. J Thromb Haemost. 2010;8:971–8.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of Sports Medicine, Department of Internal MedicineMedical University Clinic, University of HeidelbergHeidelbergGermany
  2. 2.Center for Altitude, Space and Extreme Environment Medicine UCLUniversity College LondonLondonUK

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