Strenuous exercise induces a hyperreactive rebalanced haemostatic state that is more pronounced in men

Summary

Physical exercise is recommended for a healthy lifestyle. Strenuous exercise, however, may trigger the haemostatic system, increasing the risk of vascular thrombotic events and the incidence of primary cardiac arrest. Our goal was to study the effects of strenuous exercise on risk factors of cardiovascular disease. Blood was collected from 92 healthy volunteers who participated in the amateur version of the protour Amstel Gold cycling race, before and directly after the race. Thrombin generation showed a shortening of the lag time and time to peak and an increase of the velocity index. Interestingly, the endogenous thrombin potential measured in plasma decreased due to reduced prothrombin conversion. Platelet reactivity increased and this effect was stronger in men than in women. Lower fibrinogen and higher D-dimer levels after exercise indicated higher fibrin formation. On the other hand, fibrinolysis was also elevated as indicated by a shortening of the clot lysis time. Exercise activated the endothelium (von Willebrand factor (VWF) and active VWF levels were elevated) and the immune system (concentrations IL-6, IL-8, MCP-1, RANTES and PDGF increased). Additionally, an increased cardiac troponin T level was measured post-exercise. Strenuous exercise induces a temporary hyperreactive state in the body with enhanced proand anticoagulant responses. As strenuous exercise has a more pronounced effect on platelet function in male subjects, this gives a possible explanation for the higher incidence of sudden cardiac death during exercise compared to women. This trial is registered at www.clinicaltrials.gov as NCT02048462.

Keywords

Exercise - coagulation - platelets - thrombin - fibrinolysis

^* These authors contributed equally to this work.

• References

• 1 Albert CM, Mittleman MA, Chae CU. et al. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med 2000; 343: 1355-1361.
• 2 Siscovick DS, Weiss NS, Fletcher RH. et al. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med 1984; 311: 874-877.
• 3 Chen YW, Chen JK, Wang JS. Strenuous exercise promotes shear-induced thrombin generation by increasing the shedding of procoagulant microparticles from platelets. Thromb Haemost 2010; 104: 293-301.
• 4 Lippi G, Maffulli N. Biological influence of physical exercise on hemostasis. Semin Thromb Hemost 2009; 35: 269-276.
• 5 Hilberg T, Prasa D, Sturzebecher J. et al. Thrombin potential and thrombin generation after exhaustive exercise. Int J Sports Med 2002; 23: 500-504.
• 6 Whang W, Manson JE, Hu FB. et al. Physical exertion, exercise, and sudden cardiac death in women. J Am Med Assoc 2006; 295: 1399-1403.
• 7 Posthuma JJ, van der Meijden PE, Ten Cate H. et al. Shortand Long-term exercise induced alterations in haemostasis: a review of the literature. Blood Rev. 2014 Epub ahead of print..
• 8 Posthuma JJ, Loeffen R, van Oerle R. et al. Long-term strenuous exercise induces a hypercoagulable state through contact activation. Thromb Haemost 2014; 111: 1197-1199.
• 9 Smith JE. Effects of strenuous exercise on haemostasis. Br J Sports Med 2003; 37: 433-435.
• 10 Womack CJ, Nagelkirk PR, Coughlin AM. Exercise-induced changes in coagulation and fibrinolysis in healthy populations and patients with cardiovascular disease. Sports Med 2003; 33: 795-807.
• 11 Lin X, El-Sayed MS, Waterhouse J. et al. Activation and disturbance of blood haemostasis following strenuous physical exercise. Int J Sports Med 1999; 20: 149-153.
• 12 Rankinen T, Vaisanen S, Penttila I. et al. Acute dynamic exercise increases fibrinolytic activity. Thromb Haemost 1995; 73: 281-286.
• 13 Li N, Wallen NH, Hjemdahl P. Evidence for prothrombotic effects of exercise and limited protection by aspirin. Circulation 1999; 100: 1374-1379.
• 14 Wang JS, Cheng LJ. Effect of strenuous, acute exercise on alpha2-adrenergic agonist-potentiated platelet activation. Arterioscler Thromb Vasc Biol 1999; 19: 1559-1565.
• 15 Wang JS, Jen CJ, Kung HC. et al. Different effects of strenuous exercise and moderate exercise on platelet function in men. Circulation 1994; 90: 2877-2885.
• 16 Tozzi-Ciancarelli MG, Penco M, Di Massimo C. Influence of acute exercise on human platelet responsiveness: possible involvement of exercise-induced oxidative stress. Eur J Appl Physiol 2002; 86: 266-272.
• 17 Kestin AS, Ellis PA, Barnard MR. et al. Effect of strenuous exercise on platelet activation state and reactivity. Circulation 1993; 88: 1502-1511.
• 18 Wallen NH, Goodall AH, Li N. et al. Activation of haemostasis by exercise, mental stress and adrenaline: effects on platelet sensitivity to thrombin and thrombin generation. Clin Sci 1999; 97: 27-35.
• 19 Ninivaggi M, Apitz-Castro R, Dargaud Y. et al. Whole-blood thrombin generation monitored with a calibrated automated thrombogram-based assay. Clin Chem 2012; 58: 1252-1259.
• 20 Hemker HC, Kremers R. Data management in thrombin generation. Thromb Res 2013; 131: 3-11.
• 21 Kremers RM, Peters TC, Wagenvoord RJ. et al. The balance of proand anticoagulant processes underlying thrombin generation. J Thromb Haemost 2015; 13: 437-447.
• 22 Roest M, van Holten TC, Fleurke GJ. et al. Platelet Activation Test in Unprocessed Blood (Pac-t-UB) to Monitor Platelet Concentrates and Whole Blood of Thrombocytopenic Patients. Transfus Med Hemother 2013; 40: 117-125.
• 23 Rutten B, Maseri A, Cianflone D. et al. Plasma levels of active Von Willebrand factor are increased in patients with first ST-segment elevation myocardial infarction: a multicenter and multiethnic study. Eur Heart J Acute Cardiovasc Care 2015; 04: 64-74.
• 24 Hyseni A, Kemperman H, de Lange DW. et al. Increased mortality in systemic inflammatory response syndrome patients with high levels of coagulation factor VIIa. J Thromb Haemost 2013; 11: 2111-2117.
• 25 Giannitsis E, Kurz K, Hallermayer K. et al. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem 2010; 56: 254-261.
• 26 Lip GY, Blann A. von Willebrand factor: a marker of endothelial dysfunction in vascular disorders?. Cardiovasc Res 1997; 34: 255-265.
• 27 Lamprecht M, Moussalli H, Ledinski G. et al. Effects of a single bout of walking exercise on blood coagulation parameters in obese women. J Appl Physiol 2013; 115: 57-63.
• 28 Huisveld IA, Hospers JE, Bernink MJ. et al. The effect of oral contraceptives and exercise on hemostatic and fibrinolytic mechanisms in trained women. Int J Sports Med 1983; 04: 97-103.
• 29 Kremers RM, Wagenvoord RJ, Hemker HC. The effect of fibrin(ogen) on thrombin generation and decay. Thromb Haemost 2014; 112: 486-494.
• 30 Dielis AW, Castoldi E, Spronk HM. et al. Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost 2008; 06: 125-131.
• 31 Hansen JB, Olsen JO, Osterud B. Physical exercise enhances plasma levels of extrinsic pathway inhibitor (EPI). Thromb Haemost 1990; 64: 124-126.
• 32 Yusof A, Leithauser RM, Roth HJ. et al. Exercise-induced hemolysis is caused by protein modification and most evident during the early phase of an ultraendurance race. J Appl Physiol 2007; 102: 582-586.
• 33 Whelihan MF, Zachary V, Orfeo T. et al. Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation. Blood 2012; 120: 3837-3845.
• 34 Kratz A, Lewandrowski KB, Siegel AJ. et al. Effect of marathon running on hematologic and biochemical laboratory parameters, including cardiac markers. Am J Clin Pathol 2002; 118: 856-863.
• 35 McCarthy DA, Dale MM. The leucocytosis of exercise A review and model. Sports Med 1988; 06: 333-363.
• 36 Bourey RE, Santoro SA. Interactions of exercise, coagulation, platelets, and fibrinolysis--a brief review. Med Sci Sports Exerc 1988; 20: 439-446.
• 37 Johnson M, Ramey E, Ramwell PW. Sex and age differences in human platelet aggregation. Nature 1975; 253: 355-357.
• 38 Yee DL, Sun CW, Bergeron AL. et al. Aggregometry detects platelet hyperreactivity in healthy individuals. Blood 2005; 106: 2723-2729.
• 39 Capodanno D, Angiolillo DJ. Impact of race and gender on antithrombotic therapy. Thromb Haemost 2010; 104: 471-484.
• 40 Bailey AL, Scantlebury DC, Smyth SS. Thrombosis and antithrombotic therapy in women. Arterioscler Thromb Vasc Biol 2009; 29: 284-288.
• 41 Thompson PD. Athletes, athletics, and sudden cardiac death. Med Sci Sports Exerc 1993; 25: 981-984.
• 42 Thompson PD, Franklin BA, Balady GJ. et al. Exercise and acute cardiovascular events placing the risks into perspective: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology. Circulation 2007; 115: 2358-2368.
• 43 Parker B, Augeri A, Capizzi J. et al. Effect of air travel on exercise-induced coagulatory and fibrinolytic activation in marathon runners. Clin J Sport Med 2011; 21: 126-130.
• 44 Sedaghat-Hamedani F, Kayvanpour E, Frankenstein L. et al. Biomarker Changes after Strenuous Exercise Can Mimic Pulmonary Embolism and Cardiac Injury-A Metaanalysis of 45 Studies. Clin Chem. 2015 Epub ahead of print..
• 45 Ribeiro J, Almeida-Dias A, Ascensao A. et al. Hemostatic response to acute physical exercise in healthy adolescents. J Sci Med Sport 2007; 10: 164-169.
• 46 Siegel AJ, Stec JJ, Lipinska I. et al. Effect of marathon running on inflammatory and hemostatic markers. Am J Cardiol 2001; 88: 918-20 1oA9.