Vascular hemostasis results from a regulated interaction of a coagulation and fibrinolytic systems, which are in dynamic equilibrium in a normal situation. Any imbalance between these systems leads to a tendency to bleeding or to an increased thrombogenesis. Obesity is an independent risk factor for the development of atherosclerotic cardiovascular disease, and it is associated with hypertriglyceridemia, hyperinsulinemia, and non-insulin-dependent diabetes (NIDDM). These states increase blood coagulability, a complicated set of interactions among several clotting and fibrinolytic factors. In this paper, the emphasis will be on the impact of physical activity on platelet aggregation, fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in the obese. While exercise-induced acute effects on hemostatic factors have been reviewed recently (4), the present article focuses on the impact of exercise training on blood coagulation and fibrinolysis in controlled clinical trials.
In general, physical exercise increases acutely 1) platelet number and activity, 2) activation of coagulation leading to a slight but significant thrombin generation, and 3) simultaneous activation of fibrinolysis. While the hemostatic balance is maintained during exercise, fibrinolysis diminishes rapidly during the recovery phase; this might constitute a key mechanism for the exercise-induced cardiovascular complications. Currently, hemostatic changes resulting from regular exercise training are limited to few data on platelets, blood coagulation, and to some indications of increased fibrinolysis. Although obesity associates with several unfavorable derangements in the hemostatic system, data on the interactions of regular physical activity with the hemostasis and coagulation in overweight or obese subjects are scarce. Several factors make it difficult to evaluate and combine the results from the exercise studies; a large variation in study populations and in exercise intensities and durations, as well as in measurements of physical activity, are probably the main reasons for the contradictory results. Moreover, the duration of the intervention may have been too short and the number of subjects too small to reveal the true exercise-induced effects on hemostatic factors.
Platelets react to many foreign surfaces, especially to the damaged endothelium of vessel walls, by changing their shape to irregular spheres and putting out pseudopods. These activated platelets adhere to the vessel wall and to each other to form aggregates. The secondary aggregation, which leads to irreversible platelet aggregation and development of firm hemostatic plug, associates with prostaglandin formation (13). Strenuous exercise activates platelets acutely, while moderate exercise has a suppressing effect on platelet aggregation in young healthy men (45). Regular physical activity reduces platelet aggregability in overweight middle-aged men (27)and in young men (43), as well as in young women (44) (Table 1).
Physical activity can induce at least two different mechanisms that affect platelet function. Regular physical activity increases serum high density lipoprotein (HDL), which can stimulate prostacyclin production (26) and thereby decrease platelet aggregation. In addition, physical activity increases release of nitric oxide, a potent mediator of antiplatelet effects, for instance, by elevating cGMP contents in platelets, which in turn suppress platelet reactivity (43). However, the resting and exercise-induced reductions in platelet aggregation reverse back to the pretraining level after deconditioning (43,44), indicating the importance of engaging in physical activity in a regular manner.
Regular physical training inhibits platelet aggregability in overweight men. (Evidence Category B)
Fibrinogen plays a central role in the final phase of the blood coagulation cascade, and the binding of fibrinogen to platelet glycoprotein IIb/IIIa receptors is the principal mechanism for platelet aggregation (15). Fibrinogen is elevated in inflammatory states, smokers, obesity, diabetes, and hyperlipidemia, and epidemiological studies show that increased fibrinogen level is an independent risk factor for cardiovascular disease and mortality (6,7). Although an inverse relationship between fibrinogen and physical activity and/or cardiorespiratory fitness has been found in several cross-sectional studies (40), the fibrinogen lowering effect of regular physical activity has been reported only in few exercise intervention studies: in an uncontrolled study in old men (36), in sedentary subjects with newly diagnosed NIDDM (39), and after 10 wk of strenuous and intensive training in young men (21). On the contrary, an intensive exercise program increased plasma fibrinogen in elderly subjects (35) (Table 1). Thus far, only one study has been concentrated on overweight subjects, and they reported that combined diet and physical activity program could not decrease fibrinogen level (37). Fibrinogen is an acute phase protein, and it has a relatively high intraindividual variability (29). Therefore, repeated measurements are preferable to show the real exercise-induced effect on fibrinogen level (42).
Recently two studies have examined whether genetic polymorphisms in the fibrinogen genes can modulate the association between physical activity and plasma fibrinogen. We found an interaction between habitual physical activity and an α-fibrinogen polymorphism on fibrinogen level in postmenopausal women. The physically most active women, who were homozygous for the more frequent Rsa I allele, displayed a decreased plasma fibrinogen, while the association was not seen in other genotypes (28). An acute phase response in fibrinogen level was reported in young men after an exhausting 2-d military exercise period. The subjects carrying the A allele of the G-453-A polymorphism in the β-fibrinogen gene had higher increase in plasma fibrinogen than in men with the GG genotype (21). Controlled exercise intervention studies are needed to evaluate further the effect of genetic variation at the fibrinogen gene loci on the relationship between physical activity and fibrinogen level in both genders as well as in obese subjects.
Despite cross-sectional findings and nonrandomized trials suggesting that physical activity decreases plasma fibrinogen, this hypothesis has not yet been confirmed in the few randomized controlled trials in either obese or nonobese subjects. (Evidence Category C)
PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1)
Most data on thrombogenic profile in the obese relate to PAI-1, the primary physiological inhibitor of the fibrinolytic system. Elevated PAI-1 activity decreases fibrinolytic activity and increases the risk of coronary artery disease, venous thromboembolism, and acute myocardial infarction (10,12,30). Obese and NIDDM subjects have significantly higher plasma PAI-1 than control subjects (19), and waist/hip-ratio correlates strongly positively with coagulation factors and negatively with fibrinolytic factors in premenopausal women with abdominal obesity (1). Older women receiving postmenopausal hormone therapy have more favorable PAI-1 and fibrinogen levels than nonusers (20).
The active role of adipose tissue as an important contributor to thrombogenesis has been understood only very recently (31). Elevated plasma PAI-1 activity may result in PAI-1 release from an increased visceral adipose tissue (16). In addition to insulin (32), two cytokines, tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β), induce PAI-1 gene expression in the adipose tissue, the excess of which in obese subjects serves as an additional source for PAI-1 production (32,33). Strenuous physical activity in young athletes increases acutely serum TNF-α (46). However, it is not known how regular exercise training may modulate these two cytokines chronically or acutely in a response to a single bout of physical exercise.
Fibrinolytic response to acute physical activity is modified by exercise intensity (25), and increased plasma epinephrine during exercise is the primary stimulus for t-PA, thereby leading to reduction in PAI-1 activity (2). However, this exercise-induced increase in fibrinolytic activity is short lived (25). There is also suggestive evidence that regular exercise training decreases PAI-1 level at least in sedentary young men (9,38) and in elderly men (3,36) (Table 1). Currently, no corresponding data are available on fibrinolytic activity in obese subjects. Several preanalytical factors such as diurnal variation and difficulties in blood collection and handling have significant effects on fibrinolytic activity (11,14), and these confounding factors make it essential to include a reference group in a study design. The 4G allele of the 4G/5G polymorphism in the PAI-1 promoter gene associates with an increased PAI-1 level and higher risk of cardiovascular diseases (5,18,23). Moreover, at least in diabetic patients (17,23) and subjects who have suffered myocardial infarction (22), homozygotes for the 4G allele are particularly sensitive for the increasing effect of hypertriglyceridemia on PAI-1 level. These observations raise the question of whether the response to physical activity in fibrinolysis varies between different 4G/5G genotypes. We observed in a 3-yr controlled randomized exercise intervention in a population based sample of middle-aged men that the 4G4G subjects tend to have higher PAI-1 activity than other genotypes, but the 4G4G men were also more sensitive to a PAI-1 lowering effect of physical activity (41). A change in waist circumference, although not identical to measurement of visceral fat, did not explain this finding.
Regular physical training increases fibrinolysis, which may be modified by the genetic variability; however, data pertaining specifically to the obese are currently not available. (Evidence Category B)
To avoid false negative conclusions in clinical intervention trials on the effects of physical activity on thrombogenic profile, not only in obese subjects but also in other populations, it is necessary to make careful power calculations with a large enough sample size, preferably as a representative sample of the study population. Another central issue is a requirement for controlled randomized studies. In the future, studies on physical activity and thrombogenic factors should neither be funded nor published if they do not fulfill these basic criteria.
We suggest the following research topics for future clinical trials:
1. Effects of regular low-to-moderate intensity physical activity on thrombogenesis involved in atherosclerosis with special reference to body composition.
2. Effects of regular low-to-moderate intensity physical activity on thrombogenic profile in postmenopausal women with special reference to body composition.
3. Effects of regular physical activity of different intensities on hemostatic factors with special references to genetic variations in thrombogenic factors.
4. Exercise-induced antithrombotic mechanisms and their modification by regular physical activity in obese and nonobese subjects.
1. Avellone, G., V. Di Garbo, R. Cordova, G. Raneli, R. De Simone, and G. Bompiani. Coagulation, fibrinolysis, and haemorheology in premenopausal obese women with different body fat distribution. Thromb. Res. 75: 223–231, 1994.
2. Chandler, W. L., W. C. Levy, and J. R. Stratton. The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine. Circulation 92: 2984–2994, 1995.
3. Chandler, W. L., R. S. Schwartz, J. R. Stratton, and M. V. Vitiello. Effects of endurance training on the circadian rhythm of fibrinolysis in men and women. Med. Sci. Sports Exerc. 28: 647–655, 1996.
4. El-Sayed, M. S. Effects of exercise on blood coagulation, fibrinolysis, and platelet aggregation. Sports. Med. 22: 282–298, 1996.
5. Eriksson, P., B. Kallin, F. M. van’t Hooft, P. Båvenholm, and A. Hamsten. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc. Natl. Acad. Sci. USA 92: 1851–1855, 1995.
6. Ernst, E. Fibrinogen as a cardiovascular risk factor: interrelationship with infections and inflammation. Eur. Heart J. 14(Suppl. K): 82–87, 1993.
7. Ernst, E. The role of fibrinogen as a cardiovascular risk factor. Atherosclerosis 100: 1–12, 1993.
8. de Geus, E. J. C., C. Kluft, A. C. W. de Bart, and L. J. P. van Doornen. Effects of exercise training on plasminogen activator inhibitor activity. Med. Sci. Sports Exerc. 24: 1210–1219, 1992.
9. Gris, J. C., J. F. Schved, O. Feugeas, et al. Impact of smoking, physical training, and weight reduction on FVII, PAI-1, and hemostatic markers in sedentary men. Thromb. Haemost. 64: 516–520, 1990.
10. Hamsten, A., U. De Faire, G. Walldius, et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 2: 3–9, 1987.
11. Juhan-Vague, I., M. C. Alessi, D. Raccah, et al. Daytime fluctuations of plasminogen activator inhibitor 1 (PAI-1) in populations with high PAI-1 levels. Thromb. Haemost. 67: 76–82, 1992.
12. Juhan-Vague, I., S. D. Pyke, M. C. Alessi, J. Jespersen, F. Haverkate, and S. G. Thompson. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris: ECAT Study Group. Eur. Concerted Action on Thrombosis and Disabilities. Circulation 94: 2057–2063, 1996.
13. Kazal, L. A. Coagulation chemistry. In:Clinical Biochemistry: Contemporary Theories and Techniques.
Vol. 2. H. E. Spiegel (Ed.). New York: Academic Press, 1982, pp. 73–143.
14. Kluft, C. and J. H. Verheijen. Leiden fibrinolysis working party: blood collection and handling procedures for assessment of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Fibrinolysis 4(Suppl. 2): 155–161, 1990.
15. Lefkovits, J., E. F. Plow, and E. J. Topol. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N. Engl. J. Med. 332: 1553–1559, 1995.
16. Lundgren, C. H., S. L. Brown, T. K. Nordt, B. E. Sobel, and S. Fujii. Elaboration of type-1 plasminogen activator inhibitor from adipocytes: a potential pathogenic link between obesity and cardiovascular disease. Circulation 93: 106–110, 1996.
17. Mansfield, M. W., M. H. Stickland, and P. J. Grant. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb. Haemost. 74: 842–847, 1995.
18. Margaglione, M., G. Cappucci, D. Colaizzo, et al. The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 18: 152–156, 1998.
19. McGill, J. B., D. J. Schneider, C. L. Arfken, C. L. Lucore, and B. E. Sobel. Factors responsible for impaired fibrinolysis on obese subjects and NIDDM patients. Diabetes 43: 104–109, 1994.
20. Meilahn, E. N., J. A. Cauley, R. P. Tracy, E. O. Macy, J. P. Gutai, and L. H. Kuller. Association of sex hormones and adiposity with plasma levels of fibrinogen and PAI-1 in postmenopausal women. Am. J. Epidemiol. 143: 159–166, 1996.
21. Montgomery, H. E., P. Clarkson, O. M. Nwose, et al. The acute rise in plasma fibrinogen concentration with exercise is influenced by the G-453
-A polymorphism of the β-fibrinogen gene. Arterioscler. Thromb. Vasc. Biol. 16: 386–391, 1996.
22. Ossei-Gerning, N., M. W. Mansfield, M. H. Stickland, I. J. Wilson, and P. J. Grant. Plasminogen activator inhibitor-1 promoter 4G/5G genotype and plasma levels in relation to a history of myocardial infarction in patients characterized by coronary angiography. Arterioscler. Thromb. Vasc. Biol. 17: 33–37, 1997.
23. Panahloo, A., V. Mohamed-Ali, A. Lane, F. Green, S. E. Humphries, and J. S. Yudkin. Determinants of plasminogen activator inhibitor 1 activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor 1 gene. Diabetes 44: 37–42, 1995.
24. Rankinen, T., R. Rauramaa, S. Väisänen, P. Halonen, and I. M. Penttilä. Blood coagulation and fibrinolytic factors are unchanged by aerobic exercise or fat modified diet: randomized clinical trial in middle-aged men. Fibrinolysis 8: 48–53, 1994.
25. Rankinen, T., S. Väisänen, I. Penttilä, and R. Rauramaa. Acute dynamic exercise increases fibrinolytic activity. Thromb. Haemost. 73: 281–286, 1995.
26. Rauramaa, R., J. T. Salonen, K. Kukkonen-Harjula, et al. Effects of mild physical exercise on serum lipoproteins and metabolites of arachidonic acid: a controlled randomised trial in middle aged men. Br. Med. J. 288: 603–606, 1984.
27. Rauramaa, R., J. T. Salonen, K. Seppänen, et al. Inhibition of platelet aggregability by moderate-intensity physical exercise: a randomized clinical trial in overweight men. Circulation 74: 939–944, 1986.
28. Rauramaa, R., S. Väisänen, A. Nissinen, et al. Physical activity, fibrinogen plasma level, and gene polymorphisms in postmenopausal women. Thromb. Haemost. 78: 840–844, 1997.
29. Rosenson, R. S., C. C. Tangney, and J. M. Hafner. Intraindividual variability of fibrinogen levels and cardiovascular risk profile. Arterioscler. Thromb. 14: 1928–1932, 1994.
30. Salomaa, V., V. Stinson, J. D. Kark, A. R. Folsom, C. E. Davis, and K. K. Wu. Association of fibrinolytic parameters with early atherosclerosis: The Atherosclerosis Risk in Communities Study. Circulation 91: 284–290, 1995.
31. Samad, F. and D. J. Loskutoff. The fat mouse: a powerful genetic model to study elevated plasminogen activator inhibitor 1 in obesity/NIDDM. Thromb. Haemost. 78: 652–655, 1997.
32. Samad, F. and D. J. Loskutoff. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol. Med. 2: 568–582, 1996.
33. Samad, F., K. Yamamoto, M. Pandey, and D. J. Loskutoff. Elevated expression of transforming growth factor-β in adipose tissue from obese mice. Mol. Med. 3: 37–48, 1997.
34. Schneider, S. H., H. C. Kim, A. K. Khachadurian, and N. B. Ruderman. Impaired fibrinolytic response to exercise in type II diabetes: effects of exercise and physical training. Metabolism 37: 924–929, 1988.
35. Schuit, A. J., E. G. Schouten, C. Kluft, M. de Maat, P. P. Menheere, and F. J. Kok. Effect of strenuous exercise on fibrinogen and fibrinolysis in healthy elderly men and women. Thromb. Haemost. 78: 845–851, 1997.
36. Stratton, J. R., W. L. Chandler, R. S. Schwartz, et al. Effects of physical conditioning on fibrinolytic variables and fibrinogen in young and old healthy adults. Circulation 83: 1692–1697, 1991.
37. Svendsen, O. L., C. Hassager, C. Christiansen, J. D. Nielsen, and K. Winther. Plasminogen activator inhibitor-1, tissue-type plasminogen activator, and fibrinogen: effect of dieting with or without exercise in overweight postmenopausal women. Arterioscler. Thromb. Vasc. Biol. 16: 381–385, 1996.
38. van den Burg, P. J., J. E. Hospers, M. van Vliet, W. L. Mosterd, B. N. Bouma, and I. A. Huisveld. Effect of endurance training and seasonal fluctuation on coagulation and fibrinolysis in young sedentary men. J. Appl. Physiol. 82: 613–620, 1997.
39. Vanninen, E., J. Laitinen, and M. Uusitupa. Physical activity and fibrinogen concentration in newly diagnosed NIDDM. Diabetes Care 17: 1031–1038, 1994.
40. Väisänen, S. Associations of Physical Activity, Fibrinogen Genotypes, and Blood Lipoproteins with Thrombogenic Factors in Humans
. Doctoral Dissertation. Kuopio University Publ. D. Med. Sci. 131:ISBN951–781-651–0. Kuopio, Finland, 1997.
41. Väisänen, S. B., S. E. Humphries, L. A. Luong, I. M. Penttilä, C. Bouchard, and R. Rauramaa. Regular exercise, plasminogen activator inhibitor-1 (PAI-1) activity, and the 4G/5G promoter polymorphism in the PAI-1 gene. Thromb. Haemost. 82: 1117–1120, 1999.
42. Väisänen, S., R. Rauramaa, I. Penttilä, et al. Variation in plasma fibrinogen over one year: relationships with genetic polymorphisms and non-genetic factors. Thromb. Haemost. 77: 884–889, 1997.
43. Wang, J. S., C. J. Jen, and H. I. Chen. Effects of exercise training and deconditioning on platelet function in men. Arterioscler. Thromb. Vasc. Biol. 15: 1668–1674, 1995.
44. Wang, J. S., C. J. Jen, and H. I. Chen. Effects of chronic exercise and deconditioning on platelet function in women. J. Appl. Physiol. 83: 2080–2085, 1997.
45. Wang, J. S., C. J. Jen, H. C. Kung, L. J. Lin, T. R. Hsiue, and H. I. Chen. Different effects of strenuous exercise and moderate exercise on platelet function in men. Circulation 90: 2877–2885, 1994.
46. Weinstock, C., D. Könif, R. Harnischmacher, J. Keul, A. Berg, and H. Northoff. Effect of exhaustive exercise stress on the cytokine response. Med. Sci. Sports Exerc. 29: 345–354, 1997.