Plasminogen activator inhibitor-type 1: its plasma determinants and relation with cardiovascular risk

Summary

The habitual level of PAI-1 is influenced by many factors, of which obesity and insulin resistance are the most important. It is possible to reduce plasma PAI-1 by changes in life style, e.g. weight reduction and physical activity. Data on potential interactions between environmental and metabolic variables on one hand, and the 4G/5G-polymorphism on the other hand, are still scarce. It becomes more and more clear that PAI-1 may possibly not be a major (causal) factor in cardiovascular disease, but its role in inflammation deserves further attention. In the presence of the 4G-allele not only the PAI-1 response was more pronounced, but also the response of other acute-phase reactants, which implies that the increases of these reactants are secondary to the increase in PAI-1. A myocardial infarction also provokes an acute phase response. It can thus be hypothesized that the 4G-allele might exacerbate tissue injury during the acute phase after a myocardial infarction, and thereby negatively affect the prognosis.

Keywords

PAI-1 - determinants - review

• References

• 1 Kluft C, Verheijen JH, Jie AF. et al. The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest 1985; 45: 605-10.
• 2 Hekman CM, Loskutoff DJ. Kinetic analysis of the interactions between plasminogen activator inhibitor 1 and both urokinase and tissue plasminogen activator. Arch Biochem Biophys 1988; 262: 199-210.
• 3 Preissner KT, Seiffert D. Role of vitronectin and its receptors in haemostasis and vascular remodeling. Thromb Res 1998; 89: 1-21.
• 4 Sayer JW, Gutteridge C, Syndercombe CD. et al. Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: Effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 1998; 32: 1962-8.
• 5 Angleton P, Chandler WL, Schmer G. Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1). Circulation 1989; 79: 101-6.
• 6 Nordenhem A, Wiman B. Plasminogen activator inhibitor-1 (PAI-1) content in platelets from healthy individuals genotyped for the 4G/5G polymorphism in the PAI-1 gene. Scand J Clin Lab Invest 1997; 57: 453-61.
• 7 Wiman B. Plasminogen activator inhibitor 1 (PAI-1) in plasma: its role in thrombotic disease. Thromb Haemost 1995; 74: 71-6.
• 8 Kooistra T, Sprengers ED, van Hinsbergh VW. Rapid inactivation of the plasminogenactivator inhibitor upon secretion from cultured human endothelial cells. Biochem J 1986; 239: 497-503.
• 9 Alessi MC, Morange P, Juhan VI. Fat cell function and fibrinolysis. Hormone Metab Res 2000; 32: 504-8.
• 10 Irigoyen JP, Munoz CP, Montero L. et al. The plasminogen activator system: biology and regulation. Cell Molec Life Sc 1999; 56: 104-32.
• 11 Owensby DA, Morton PA, Wun TC. et al. Binding of plasminogen activator inhibitor type-1 to extracellular matrix of Hep G2 cells: Evidence that the binding protein is vitronectin. J Biol Chem 1991; 266: 4334-40.
• 12 Hekman CM, Loskutoff DJ. Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants. J Biol Chem 1985; 260: 11581-7.
• 13 Hong YL, Pedersen NL, Egberg N. et al. Moderate genetic influences on plasma levels of plasminogen activator inhibitor-1 and evidence of genetic and environmental influences shared by plasminogen activator inhibitor1, triglycerides, and body mass index. Arterioscler Thromb Vasc Biol 1997; 17: 2776-82.
• 14 Cesari M, Sartori MT, Patrassi GM. et al. Determinants of plasma levels of plasminogen activator inhibitor-1 A study of normotensive twins. Arterioscler Thromb Vasc Biol 1999; 19: 316-20.
• 15 de-Lange M, Snieder H, Ariens RAS. et al. The genetics of haemostasis: a twin study. Lancet 2001; 357: 101-5.
• 16 Freeman MS, Mansfield MW, Barrett JH. et al. Genetic contribution to circulating levels of hemostatic factors in healthy families with effects of known genetic polymorphisms on heritability. Arterioscler Thromb Vasc Biol 2002; 22: 506-10.
• 17 Pankow JS, Folsom AR, Province MA. et al. Segregation analysis of plasminogen activator inhibitor-1 and fibrinogen levels in the NHLBI family heart study. Arterioscler Thromb Vasc Biol 1998; 18: 1559-67.
• 18 Nordt TK, Lohrmann J, Bode C. Regulation of PAI-1 expression by genetic polymorphisms Impact on atherogenesis. Thromb Res 2001; 103 (Suppl. 01) S1-S5.
• 19 Dawson SJ, Wiman B, Hamsten A. et al. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-45.
• 20 Eriksson P, Kallin B, van’t Hooft FM. et al. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
• 21 Henry M, Tregouët DA, Alessi MC. et al. Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen plasma concentrations – A family study with part of the Stanislas Cohort. Arterioscler Thromb Vasc Biol 1998; 18: 84-91.
• 22 Burzotta F, Di Castelnuovo A, Amore C. et al. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in Italians: A model of gene-environment interaction. Thromb Haemost 1998; 79: 354-8.
• 23 Margaglione M, Grandone E, Vecchione G. et al. Plasminogen activator inhibitor-1 (PAI-1) antigen plasma levels in subjects attending a metabolic ward: Relation to polymorphisms of PAI-1 and angiotensin converting enzyme (ACE) genes. Arterioscler Thromb Vasc Biol 1997; 17: 2082-7.
• 24 Henry M, Chomiki N, Scarabin PY. et al. Five frequent polymorphisms of the PAI-1 gene – Lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. Arterioscler Thromb Vasc Biol 1997; 17: 851-8.
• 25 Cigolini M, Tonoli M, Borgato L. et al. Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNFalpha?. Atherosclerosis 1999; 143: 81-90.
• 26 Eriksson P, Nilsson L, Karpe F. et al. Verylow-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol 1998; 18: 20-26.
• 27 Menges T, Hermans PWM, Little SG. et al. Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 2001; 357: 1096-7.
• 28 Grenett HE, Benza RL, Li XN. et al. Expression of plasminogen activator inhibitor type I in genotyped human endothelial cell cultures: Genotype-specific regulation by insulin. Thromb Haemost 1999; 82: 1504-9.
• 29 Li XN, Grenett HE, Benza RL. et al. Genotype-specific transcriptional regulation of PAI-1 expression by hypertriglyceridemic VLDL and Lp(a) in cultured human endothelial cells. Arterioscler Thromb Vasc Biol 1997; 17: 3215-23.
• 30 Grenett HE, Benza RL, Fless GM. et al. Genotype-specific transcriptional regulation of PAI-1 gene by insulin, hypertriglyceridemic VLDL, and Lp(a) in transfected, cultured human endothelial cells. Arterioscler Thromb Vasc Biol 1998; 18: 1803-9.
• 31 Sakkinen PA, Wahl P, Cushman M. et al. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000; 152: 897-907.
• 32 Sartori MT, Vettor R, De-Pergola G. et al. Role of the 4G/5G polymorphism of PAI-1 gene promoter on PAI-1 levels in obese patients – Influence of fat distribution and insulin-resistance. Thromb Haemost 2001; 86: 1161-9.
• 33 Kockx M, Leenen R, Seidell J. et al. Relationship between visceral fat and PAI-1 in overweight men and women before and after weight loss. Thromb Haemost 1999; 82: 1490-6.
• 34 Mavri A, Stegnar M, Krebs M. et al. Impact of adipose tissue on plasma plasminogen activator inhibitor-1 in dieting obese women. Arterioscler Thromb Vasc Biol 1999; 19: 1582-7.
• 35 Mutch NJ, Wilson HM, Booth NA. Plasminogen activator inhibitor-1 and haemostasis in obesity. Proc Nutr Soc 2001; 60: 341-7.
• 36 Samad F, Uysal KT, Wiesbrock SM. et al. Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci USA 1999; 96: 6902-7.
• 37 Morange PE, Alessi MC, Verdier M. et al. PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level. Arterioscler Thromb Vasc Biol 1999; 19: 1361-5.
• 38 Cigolini M, Tonoli M, Borgato L. et al. Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNFalpha?. Atherosclerosis 1999; 143: 81-90.
• 39 Frühbeck G, Gómez-Ambrosi J, Muruzábal FJ. et al. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrin Metab 2001; 280: E827-E847.
• 40 Bastelica D, Morange P, Berthet B. et al. Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat – Evidence of differences between visceral and subcutaneous deposits. Arterioscler Thromb Vasc Biol 2002; 22: 173-8.
• 41 Alessi MC, Bastelica D, Morange P. et al. Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 2000; 49: 1374-80.
• 42 Eriksson P, Van Harmelen V, Hoffstedt J. et al. Regional variation in plasminogen activator inhibitor-1 expression in adipose tissue from obese individuals. Thromb Haemost 2000; 83: 545-8.
• 43 Eriksson P, Reynisdottir S, Lonnqvist F. et al. Adipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals. Diabetologia 1998; 41: 65-71.
• 44 Gottschling ZH, Birgel M, Rohrig K. et al. Effect of tumor necrosis factor alpha and transforming growth factor beta 1 on plasminogen activator inhibitor-1 secretion from subcutaneous and omental human fat cells in suspension culture. Metabolism 2000; 49: 666-71.
• 45 Bastard JP, Vidal H, Jardel C. et al. Subcutaneous adipose tissue expression of plasminogen activator inhibitor-1 gene during very low calorie diet in obese subjects. Int J Obes 2000; 24: 70-4.
• 46 Van-Harmelen V, Wahrenberg H, Eriksson P. et al. Role of gender and genetic variance in plasminogen activator inhibitor-1 secretion from human adipose tissue. Thromb Haemost 2000; 83: 304-8.
• 47 McCormack LJ, Nagi DK, Stickland MH. et al. Promoter (4G/5G) plasminogen activator inhibitor-1 genotype in Pima Indians: relationship to plasminogen activator inhibitor-1 levels and features of the insulin resistance syndrome. Diabetologia 1996; 39: 1512-8.
• 48 Ossei-Gerning N, Mansfield MW, Stickland MH. et al. 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 1997; 17: 33-7.
• 49 Schäfer K, Fujisawa K, Konstantinides S. et al. Disruption of the plasminogen activator inhibitor-1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J 2001; 55: 1447-55.
• 50 Hoffstedt J, Andersson LL, Persson L. et al. The common-675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is strongly associated with obesity. Diabetologia 2002; 45: 584-7.
• 51 Juhan-Vague I, Pyke SM, Alessi MC. et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-63.
• 52 Stiko-Rahm A, Wiman B, Hamsten A. et al. Secretion of plasminogen activator inhibitor1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis JID 8401388 1990; 10: 1067-73.
• 53 Sironi L, Mussoni L, Prati L. et al. Plasminogen activator inhibitor type-1 synthesis and mRNA expression in HepG2 cells are regulated by VLDL. Arterioscler Thromb Vasc Biol 1996; 16: 89-96.
• 54 Tremoli E, Camera M, Maderna P. et al. Increased synthesis of plasminogen activator inhibitor-1 by cultured human endothelial cells exposed to native and modified LDLs An LDL receptor-independent phenomenon. Arterioscler Thromb 1993; 13: 338-46.
• 55 Latron Y, Chautan M, Anfosso F. et al. Stimulating effect of oxidized low density lipoproteins on plasminogen activator inhibitor-1 synthesis by endothelial cells. Arterioscler Thromb 1991; 11: 1821-9.
• 56 Zhang J, Ren S, Sun D. et al. Influence of glycation on LDL-induced generation of fibrinolytic regulators in vascular endothelial cells. Arterioscler Thromb Vasc Biol 1998; 18: 1140-8.
• 57 Silveira A. Postprandial triglycerides and blood coagulation. Exp Clin Endocrinol Diabet 2001; 109: S527-S532.
• 58 Krebs M, Geiger M, Polak K. et al. Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man. Thromb Haemost 2003; 90: 422-8.
• 59 Kemme MJB, Burggraaf J, Schoemaker RC. et al. No influence of acute hypertriglyceridemia on plasma t-PA in healthy male volunteers. Thromb Res 2001; 103: 9-16.
• 60 Mansfield MW, Stickland MH, Grant PJ. 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 1995; 74: 842-7.
• 61 Bastard JP, Pieroni L, Hainque B. Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance. Diabet Metab Res Rev 2000; 16: 192-201.
• 62 Meigs JB, Mittleman MA, Nathan DM. et al. Hyperinsulinemia, hyperglucemia, and impaired hemostasis – The Framingham offspring study. JAMA 2000; 283: 221-8.
• 63 Festa A, D’-Agostino R, Mykkanen L. et al. Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance – The Insulin Resistance Atherosclerosis Study (IRAS). Arterioscler Thromb Vasc Biol 1999; 19: 562-8.
• 64 Nordt TK, Schneider DJ, Sobel BE. Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin A potential risk factor for vascular disease. Circulation 1994; 89: 321-30.
• 65 Schneider DJ, Absher PM, Ricci MA. Dependence of augmentation of arterial endothelial cell expression of plasminogen activator inhibitor type 1 by insulin on soluble factors released from vascular smooth muscle cells. Circulation 1997; 96: 2868-76.
• 66 Vuorinen MH, Puhakainen I, Yki JH. No evidence for short-term regulation of plasminogen activator inhibitor activity by insulin in man. Thromb Haemost 1992; 67: 117-20.
• 67 Landin K, Tengborn L, Chmielewska J. et al. The acute effect of insulin on tissue plasminogen activator and plasminogen activator inhibitor in man. Thromb Haemost 1991; 65: 130-3.
• 68 Aso Y, Matsumoto S, Fujiwara Y. et al. Impaired fibrinolytic compensation for hypercoagulability in obese patients with type 2 diabetes: Association with increased plasminogen activator inhibitor-1. Metab Clin Exp 2002; 51: 471-6.
• 69 Maiello M, Boeri D, Podesta F. et al. Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose. Diabetes 1992; 41: 1009-15.
• 70 Pandolfi A, Iacoviello L, Capani F. et al. Glucose and insulin independently reduce the fibrinolytic potential of human vascular smooth muscle cells in culture. Diabetologia 1996; 39: 1425-31.
• 71 Festa A, D’-Agostino R, Tracy RP. et al. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes – The insulin resistance atherosclerosis study. Diabetes 2002; 51: 1131-7.
• 72 Myrup B, Rossing P, Jensen T. et al. Concentration changes during venous occlusion of proteins with affinity for extracellular matrix in insulin-dependent diabetes mellitus. A sign of vascular damage in patients with diabetic nephropathy? Fibrinolysis Proteolysis 1999; 13: 142-7.
• 73 Ridker PM, Gaboury CL, Conlin PR. et al. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation 1993; 87: 1969-73.
• 74 Skurk T, Lee YM, Hauner H. Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture. Hypertension 2001; 37: 1336-40.
• 75 Mehta JL, Li DY, Yang H. et al. Angiotensin II and IV stimulate expression and release of plasminogen activator inhibitor-1 in cultured human coronary artery endothelial cells. J Cardiovasc Pharmacol 2002; 39: 789-94.
• 76 Vaughan DE. Angiotensin and vascular fibrinolytic balance. Am J Hypertens 2002; 15: 3S-8S.
• 77 Margaglione M, Cappucci G, d’Addedda M. et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis – Relation to environmental and genetic determinants. Arterioscler Thromb Vasc Biol 1998; 18: 562-7.
• 78 Brown NJ, Agirbasli MA, Williams GH. et al. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998; 32: 965-71.
• 79 Brown NJ, Murphey LJ, Srikuma N. et al. Interactive effect of PAI-1 4G/5G genotype and salt intake on PAI-1 antigen. Arterioscler Thromb Vasc Biol 2001; 21: 1071-7.
• 80 Gebara OC, Mittleman MA, Sutherland P. et al. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952-8.
• 81 Shahar E, Folsom AR, Salomaa VV. et al. Relation of hormone-replacement therapy to measures of plasma fibrinolytic activity Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation 1996; 93: 1970-5.
• 82 Cushman M, Meilahn EN, Psaty BM. et al. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999; 19: 893-9.
• 83 Meilahn EN, Cauley JA, Tracy RP. et al. Association of sex hormones and adiposity with plasma levels of fibrinogen and PAI-1 in postmenopausal women. Am J Epidemiol 1996; 143: 159-66.
• 84 Koh KK, Jin DK, Yang SH. et al. Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001; 103: 1961-6.
• 85 van Baal WM, Emeis JJ, van der Mooren MJ. et al. Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomised, placebo-controlled 12week study. Thromb Haemost 2000; 83: 29-34.
• 86 Teede HJ, McGrath BP, Smolich JJ. et al. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arterioscler Thromb Vasc Biol 2000; 20: 1404-9.
• 87 Lobo RA, Bush T, Carr BR. et al. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 2001; 76: 13-24.
• 88 Lowe GDO, Upton MN, Rumley A. et al. Different effects of oral and transdermal hormone replacement therapies on Factor IX, APC resistance, t-PA, PAI and C-reactive protein – A cross-sectional population survey. Thromb Haemost 2001; 86: 550-6.
• 89 Vehkavaara S, Silveira A, Hakala-Ala PT. et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001; 85: 619-25.
• 90 Lansink M, Jong M, Bijsterbosch M. et al. Increased clearance explains lower plasma levels of tissue-type plasminogen activator by estradiol: Evidence for potently enhanced mannose receptor expression in mice. Blood 1999; 94: 1330-6.
• 91 Grancha S, Estelles A, Tormo G. et al. Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease – Influence of hormone replacement therapy. Thromb Haemost 1999; 81: 516-21.
• 92 Brown NJ, Abbas A, Byrne D. et al. Comparative effects of estrogen and angiotensin-converting enzyme inhibition on plasminogen activator inhibitor-1 in healthy postmenopausal women. Circulation 2002; 105: 304-9.
• 93 Madsen JS, Kristensen SR, Gram J. et al. Positive impact of hormone replacement therapy on the fibrinolytic system: a longterm randomized controlled study in healthy postmenopausal women. J Thromb Haemost 2003; 01: 1984-91.
• 94 Scarabin PY, Vissac AM, Kirzin JM. et al. Elevated plasma fibrinogen and increased fibrin turnover among healthy women who both smoke and use low-dose oral contraceptives – A preliminary report. Thromb Haemost 1999; 82: 1112-6.
• 95 Scarabin PY, Plu BG, Zitoun D. et al. Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: absence of dose-dependent effect on PAI-1 activity. Thromb Haemost 1995; 74: 928-32.
• 96 Meijers JCM, Middeldorp S, Tekelenburg W. et al. Increased fibrinolytic activity during use of oral contraceptives is counteracted by an enhanced factor XI-independent down regulation of fibrinolysis – A randomized cross-over study of two low-dose oral contraceptives. Thromb Haemost 2000; 84: 9-14.
• 97 Winkler UH, Schindler AE, Endrikat J. et al. A comparative study of the effects of the hemostatic system of two monophasic gestodene oral contraceptives containing 20 mu G and 30 mu G ethinylestradiol. Contraception 1996; 53: 75-84.
• 98 Winkler UH, Howie H, Buhler K. et al. A randomized controlled double-blind study of the effects on hemostasis of two progestogenonly pills containing 75 mu g desogestrel or 30 mu g levonorgestrel. Contraception 1998; 57: 385-92.
• 99 Bloemenkamp KW, de Maat MP, DersjantRoorda MC. et al. Genetic polymorphisms modify the response of factor VII to oral contraceptive use: an example of gene-environment interaction. Vasc Pharmacol 2002; 39: 131-6.
• 100 Grundt H, Nilsen DWT, Hetland O. et al. Atherothrombogenic risk modulation by n-3 fatty acids was not associated with changes in homocysteine in subjects with combined hyperlipidaemia. Thromb Haemost 1999; 81: 561-5.
• 101 Fumeron F, Brigant L, Ollivier V. et al. n-3 polyunsaturated fatty acids raise low-density lipoproteins, high-density lipoprotein 2, and plasminogen-activator inhibitor in healthy young men. Am J Clin Nutr 1991; 54: 118-22.
• 102 Toft I, Bonaa KH, Ingebretsen OC. et al. Fibrinolytic function after dietary supplementation with omega 3 polyunsaturated fatty acids. Arterioscler Thromb Vasc Biol 1997; 17: 814-9.
• 103 Prisco D, Paniccia R, Filippini M. et al. No changes in PAI-1 levels after four-month n-3 PUFA ethyl ester supplementation in healthy subjects. Thromb Res 1994; 76: 237-44.
• 104 Hansen J, Grimsgaard S, Nordoy A. et al. Dietary supplementation with highly purified eicosapentaenoic acid and docosahexaenoic acid does not influence PAI-1 activity. Thromb Res 2000; 98: 123-32.
• 105 Djoussé L, Pankow JS, Arnett DK. et al. Alcohol consumption and plasminogen activator inhibitor type 1: the National Heart, Lung, and Blood Institute Family Heart Study. Am Heart J 2000; 139: 704-9.
• 106 Yarnell JWG, Sweetnam PM, Rumley A. et al. Lifestyle and hemostatic risk factors for ischemic heart disease – The Caerphilly Study. Arterioscler Thromb Vasc Biol 2000; 20: 271-9.
• 107 Mukamal KJ, Jadhav PP, D’-Agostino RB. et al. Alcohol consumption and hemostatic factors Analysis of the Framingham Offspring cohort. Circulation 2001; 104: 1367-73.
• 108 Hendriks HF, Veenstra J, Velthuis-te WE. et al. Effect of moderate dose of alcohol with evening meal on fibrinolytic factors. BMJ 1994; 308: 1003-6.
• 109 Numminen H, Syrjälä M, Benthin G. et al. The effect of acute ingestion of a large dose of alcohol on the hemostatic system and its circadian variation. Stroke 2000; 31: 1269-73.
• 110 Sierksma A, van der Gaag MS, Schaafsma G. et al. Moderate alcohol consumption and fibrinolytic factors of preand postmenopausal women. Nutr Res 2001; 21: 171-81.
• 111 Kluft C, Veenstra J, Schaafsma G. et al. Regular moderate wine consumption for five weeks increases plasma activity of the plasminogen activator inhibitor-1 (PAI-1) in healthy young volunteers. Fibrinolysis 1990; 04: S69-S70.
• 112 McConnell MV, Vavouranakis I, Wu LL. et al. Effects of a single, daily alcoholic beverage on lipid and hemostatic markers of cardiovascular risk. Am J Cardiol 1997; 80: 1226.
• 113 Dimmitt SB, Rakic V, Puddey IB. et al. The effects of alcohol on coagulation and fibrinolytic factors: a controlled trial. Blood Coagul Fibrinolysis 1998; 09: 39-45.
• 114 Gorinstein S, Zemser M, Lichman I. et al. Moderate beer consumption and the blood coagulation in patients with coronary artery disease. J Intern Med 1997; 241: 47-51.
• 115 Venkov CD, Su M, Shyr Y. et al. Ethanolinduced alterations in the expression of endothelial-derived fibrinolytic components. Fibrinolysis Proteolysis 1997; 11: 115-8.
• 116 Grenett HE, Aikens ML, Tabengwa EM. et al. Ethanol downregulates transcription of the PAI-1 gene in cultured human endothelial cells. Thromb Res 2000; 97: 247-55.
• 117 Woodhouse PR, Meade TW, Khaw KT. Plasminogen activator inhibitor-1, the acute phase response and vitamin C. Atherosclerosis 1997; 133: 71-6.
• 118 Rifici VA, Schneider SH, Chen YJ. et al. Administration of antioxidant vitamins does not alter plasma fibrinolytic activity in subjects with central obesity. Thromb Haemost 1997; 78: 1111-4.
• 119 Devaraj S, Chan AVC, Jialal I. alphaTocopherol supplementation decreases plasminogen activator inhibitor-1 and P-selectin levels in type 2 diabetic patients. Diabetes Care 2002; 25: 524-9.
• 120 Orbe J, Rodriguez JA, Calvo A. et al. Vitamins C and E attenuate plasminogen activator inhibitor-1 (PAI-1) expression in a hypercholesterolemic porcine model of angioplasty. Cardiovasc Res 2001; 49: 484-92.
• 121 Sasaki A, Kurisu A, Ohno M. et al. Overweight/obesity, smoking, and heavy alcohol consumption are important determinants of plasma PAI-1 levels in healthy men. Am J Med Sci 2001; 322: 19-23.
• 122 Simpson AJ, Gray RS, Moore NR. et al. The effects of chronic smoking on the fibrinolytic potential of plasma and platelets. Br J Haematol 1997; 97: 208-13.
• 123 Calori G, D’Angelo A, Della VP. et al. The effect of cigarette-smoking on cardiovascular risk factors: a study of monozygotic twins discordant for smoking. Thromb Haemost 1996; 75: 14-18.
• 124 Eliasson M, Asplund K, Evrin PE. et al. Relationship of cigarette smoking and snuff dipping to plasma fibrinogen, fibrinolytic variables and serum insulin The Northern Sweden MONICA Study. Atherosclerosis 1995; 113: 41-53.
• 125 Pellegrini MP, Newby DE, Maxwell S. et al. Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man. Cardiovasc Res 2001; 52: 321-7.
• 126 DeSouza CA, Jones PP, Seals DR. Physical activity status and adverse age-related differences in coagulation and fibrinolytic factors in women. Arterioscler Thromb Vasc Biol 1998; 18: 362-8.
• 127 Scarabin PY, Aillaud MF, Amouyel P. et al. Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction – The prime study. Thromb Haemost 1998; 80: 749-56.
• 128 Eliasson M, Asplund K, Evrin PE. Regular leisure time physical activity predicts high activity of tissue plasminogen activator: The Northern Sweden MONICA Study. Intern J Epidemiol 1996; 25: 1182-8.
• 129 Eriksson-Berg M, Egberg N, Eksborg S. et al. Retained fibrinolytic response and no coagulation activation after acute physical exercise in middle-aged women with previous myocardial infarction. Thromb Res 2002; 105: 481-6.
• 130 Fernhall B, Szymanski LM, Gorman PA. et al. Fibrinolytic activity is similar in physically active men with and without a history of myocardial infarction. Arterioscler Thromb Vasc Biol 1997; 17: 1106-13.
• 131 Mustonen P, Lepantalo M, Lassila R. Physical exertion induces thrombin formation and fibrin degradation in patients with peripheral atherosclerosis. Arterioscler Thromb Vasc Biol 1998; 18: 244-9.
• 132 Smith DT, Hoetzer GL, Greiner JJ. et al. Effects of ageing and regular aerobic exercise on endothelial fibrinolytic capacity in humans. J Physiol 2003; 546: 289-98.
• 133 Van den Burg PM, Hospers JH, van Vliet M. et al. Effect of endurance training and seasonal fluctuation on coagulation and fibrinolysis in young sedentary men. J Appl Physiol 1997; 82: 613-20.
• 134 Chandler WL, Schwartz RS, Stratton JR. et al. Effects of endurance training on the circadian rhythm of fibrinolysis in men and women. Med Sci Sports Exerc 1996; 28: 647-55.
• 135 Paramo JA, Olavide I, Barba J. et al. Longterm cardiac rehabilitation program favorably influences fibrinolysis and lipid concentrations in acute myocardial infarction. Haematologica 1998; 83: 519-24.
• 136 Ponjee GA, Janssen GM, van Wersch JW. Prolonged endurance exercise and blood coagulation: a 9 month prospective study. Blood Coagul Fibrinolysis 1993; 04: 21-25.
• 137 Stratton JR, Chandler WL, Schwartz RS. et al. Effects of physical conditioning on fibrinolytic variables and fibrinogen in young and old healthy adults. Circulation 1991; 83: 1692-7.
• 138 Schuit AJ, Schouten EG, Kluft C. et al. Effect of strenuous exercise on fibrinogen and fibrinolysis in healthy elderly men and women. Thromb Haemost 1997; 78: 845-51.
• 139 De Geus EJ, Kluft C, de Bart AC. et al. Effects of exercise training on plasminogen activator inhibitor activity. Med Sci Sports Exerc 1992; 24: 1210-9.
• 140 Torjesen PA, Birkeland KI, Anderssen SA. et al. Lifestyle changes may reverse development of the insulin resistance syndrome: The Oslo Diet and Exercise Study: A randomized trial. Diabetes Care 1997; 20: 26-31.
• 141 ElSayed MS. Effects of high and low intensity aerobic conditioning programs on blood fibrinolysis and lipid profile. Blood Coagul Fibrinolysis 1996; 07: 484-90.
• 142 Väisänen SB, Humphries SE, Luong LA. et al. Regular exercise, plasminogen activator inhibitor-1 (PAI-I) activity and the 4G/5G promoter polymorphism in the PAI-1 gene. Thromb Haemost 1999; 82: 1117-20.
• 143 Irokawa M, Nishinaga M, Funayama H. et al. Effect of a change in the sleep/wake cycle on the diurnal variation of fibrinolytic parameters. J Thromb Thrombolysis 1998; 05: 165-8.
• 144 Andreotti F, Prevost R, Lupi A. et al. Circadian patterns of plasma t-PA and PAI-1 antigen levels in patients with severe peripheral atherosclerosis. Fibrinolysis 1996; 10 (Suppl. 02) 159-60.
• 145 Huber K, Rosc D, Resch I. et al. Circadian fluctuations of plasminogen activator levels in plasma of patients with unstable coronary artery disease and acute myocardial infarction. Thromb Haemost 1988; 60: 372-6.
• 146 Van der Bom JG, Bots ML, Haverkate F. et al. The 4G5G polymorphism in the gene for PAI-1 and the circadian oscillation of plasma PAI-1. Blood 2003; 101: 1841-4.
• 147 Hoekstra T, Geleijnse JM, Schouten EG. et al. Diurnal variation in PAI-1 activity predominantly confined to the 4G-allele of the PAI-1 gene. Thromb Haemost 2002; 88: 794-8.
• 148 Maemura K, de La Monte SM, Chin MT. et al. CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression. J Biol Chem 2000; 275: 36847-51.
• 149 Westendorp RGJ, Hottenga JJ, Slagboom PE. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 1999; 354: 561-3.
• 150 Jones K, Powell J, Brown L. et al. The influence of 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene promoter on the incidence, growth and operative risk of abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 2002; 23: 421-5.
• 151 Panahloo A, Mohammad AV, Gray RP. et al. Plasminogen activator inhibitor-1 (PAI-1) activity post myocardial infarction: the role of acute phase reactants, insulin-like molecules and promoter (4G/5G) polymorphism in the PAI-1 gene. Atherosclerosis 2003; 168: 297-304.
• 152 Cushman M, Lemaitre RN, Kuller LH. et al. Fibrinolytic activation markers predict myocardial infarction in the elderly The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 493-8.
• 153 Lowe GO, Yarnell JG, Sweetnam PM. et al. Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998; 79: 129-33.
• 154 Thögersen AM, Jansson JH, Boman K. et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: Evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-7.
• 155 Folsom AR, Wu KK, Rosamond WD. et al. Prospective study of hemostatic factors and incidence of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1997; 96: 1102-8.
• 156 Lindgren A, Lindoff C, Norrving B. et al. Tissue plasminogen activator and plasminogen activator inhibitor-1 in stroke patients. Stroke 1996; 27: 1066-71.
• 157 Kohler HP, Grant PJ. Mechanisms of disease: Plasminogen-activator inhibitor type 1 and coronary artery disease. New Engl J Med 2000; 342: 1792-801.
• 158 Takazoe K, Ogawa H, Yasue H. et al. Increased plasminogen activator inhibitor activity and diabetes predict subsequent coronary events in patients with angina pectoris. Ann Med 2001; 33: 206-12.
• 159 Hamsten A, Wiman B, de-Faire U. et al. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
• 160 Hamsten A, de-Faire U, Walldius G. et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 02: 3-9.
• 161 Boekholdt SM, Bijsterveld NR, Moons AHM. et al. Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction. Circulation 2001; 104: 3063-8.
• 162 Yamada Y, Izawa H, Ichihara S. et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. New Engl J Med 2002; 347: 1916-23.
• 163 Atherosclerosis Thrombosis and Vascular Biology Italian Study Group. No evidence of association between prothrombotic gene Polymorphisms and the development of acute myocardial infarction at a young age. Circulation 2003; 107: 1117-22.
• 164 Iwai N, Shimoike H, Nakamura Y. et al. The 4G/5G polymorphism of the plasminogen activator inhibitor gene is associated with the time course of progression to acute coronary syndromes. Atherosclerosis 1998; 136: 109-14.
• 165 Roest M, van der Schouw YT, Banga JD. et al. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000; 101: 67-70.
• 166 Heijmans BT, Westendorp RGJ, Knook DL. et al. Angiotensin I-converting enzyme and plasminogen activator inhibitor-1 gene variants: Risk of mortality and fatal cardiovascular disease in an elderly population-based cohort. J Am Coll Cardiol 1999; 34: 1176-83.
• 167 Ridker PM, Hennekens CH, Lindpaintner K. et al. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997; 95: 59-62.
• 168 Johansson L, Jansson JH, Boman K. et al. Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke. Stroke 2000; 31: 26-32.
• 169 Catto AJ, Carter AM, Stickland M. et al. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and levels in subjects with cerebrovascular disease. Thromb Haemost 1997; 77: 730-4.
• 170 Margaglione M, Di MG, Grandone E. et al. Abnormally high circulation levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with a history of ischemic stroke. Arterioscler Thromb 1994; 14: 1741-5.
• 171 Hoekstra T, Geleijnse JM, Kluft C. et al. The 4G/4G-genotype of the PAI-1 gene is associated with a reduced risk of stroke in elderly. Stroke 2003; 34: 2822-8.
• 172 Roest M, Banga JD. Editorial comment – genetic make-up for increased PAI-1 expression protects against stroke. Stroke 2003; 34: 2828-9.
• 173 CO Park HK, Ahn MY. et al. 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene and insertion/deletion polymorphism of the tissue-type plasminogen activator gene in atherothrombotic stroke. Cerebrovasc Dis 2001; 11: 294-9.