Determinants of tPA Antigen and Associations with Coronary Artery Disease and Acute Cerebrovascular Disease

Summary

The aim of this study was to determine the association of tPA antigen levels with CAD and ischaemic stroke and whether associations are independent of levels of PAI-1 antigen. In subjects with CAD (n = 247) tPA was associated with the number of coronary arteries with ≥50% stenosis, but this association was lost after adjustment for PAI-1, which was found to be the largest determinant of tPA levels in linear regression models and accounted for as much as 38% of the variation in levels. Levels of tPA were significantly higher in patients with a history of MI compared with those without, even after adjustment for covariates and PAI-1 (MI: 10.0 [9.4-10.6] ng/ml; no MI: 8.9 [8.5-9.4] ng/ml, p = 0.004). In a logistic regression model comparing patients with MI to patients without MI, the odds ratio for tPA levels in the upper quartile compared with the lowest quartile was 2.03 (1.33-3.10). Levels of tPA in subjects with ischaemic stroke (n = 338) were significantly higher than age matched healthy control subjects (n = 366) and again this difference remained after adjustment (patients: 10.4 [9.9-10.9] ng/ml; controls: 9.0 [8.7-9.3] ng/ml, p <0.0001). In a logistic regression model comparing patients with ischaemic stroke to healthy control subjects the odds ratio for tPA in the upper quartile compared with the lowest quartile was 4.23 (3.02-5.92). These data suggest that the associations of tPA with acute thrombosis are independent of levels of PAI-1 but the mechanisms whereby enhanced fibrinolysis may predis-pose to thrombosis remain unclear.

• References

• 1 Fielding JE. Smoking: health effects and control. N Engl J Med 1985; 313: 491-8.
• 2 Schneidau A, Harrison MJG, Hurst C, Wilkes HC, Meade TW. Arterial disease risk factors and angiographic evidence of atheroma of the carotid artery. Stroke 1989; 20: 1466-71.
• 3 Genest J, Cohn JS. Clustering of cardiovascular risk factors: targeting high-risk individuals. Am J Cardiol 1995; 76: 8A-20A.
• 4 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
• 5 Falkenberg M, Tjarnstrom J, Ortenwall P, Olausson M, Risberg B. Localization of fibrinolytic activators and inhibitors in normal and atherosclerotic vessels. Thromb Haemost 1996; 75: 933-8.
• 6 Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940-3.
• 7 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
• 8 van der Bom JG, de Knijff P, Haverkate F, Bots ML, Meijer P, de Jong PTVM, Hofman A, Kluft C, Grobbee DE. Tissue plasminogen activator and risk of myocardial infarction. Circulation 1997; 95: 2623-7.
• 9 Lindgren A, Lindoff C, Norrving B, Astedt B, Johansson BB. Tissue plasminogen activator and plasminogen activator inhibitor-1 in stroke patients. Stroke 1996; 27: 1066-71.
• 10 Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemo-static factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-41.
• 11 Nomenclature and criteria for diagnosis of ischemic heart disease. Report of the Joint International Society and Federation of Cardiology/World Health Organization task force on standardization of clinical nomenclature. Circulation 1979; 59: 607-9.
• 12 Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991; 337: 1521-6.
• 13 Catto AJ, Carter AM, Stickland MH, Bamford JM, Davies JA, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and levels in subjects with cerebrovascular disease. Thromb Haemost 1997; 77: 730-4.
• 14 Ossei-Gerning N, Mansfield MW, Stickland MH, Wilson IJ, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and levels in relation to a history of myocardial infarction in patients characterised by coronary angiography. Arterioscler Thromb Vasc Biol 1997; 17: 33-7.
• 15 Carter AM, Catto AJ, Bamford JM, Grant PJ. Gender specific associations of the fibrinogen Bβ 448 polymorphism, fibrinogen levels and acute cerebrovascular disease. Arterioscler Thromb Vasc Biol 1997; 17: 589-94.
• 16 ECAT Angina Pectoris Study Group.. ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993; 14: 8-17.
• 17 Hamsten A, Walldius G, De Faire U, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
• 18 Margaglione M, Di Minno G, Grandone E, Vecchione G, Celentano E, Cappucci G, Grilli M, Simone P, Panico S, Mancini M. 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.
• 19 Carter AM, Grant PJ. Vascular homeostasis, adhesion molecules, and macrovascular disease in non-insulin-dependent diabetes mellitus. Diabet Med 1997; 14: 423-32.
• 20 Bini A, Kudryk BJ. Fibrinogen in human atherosclerosis. Ann N Y Acad Sci 1995; 748: 461-71.
• 21 Robbie LA, Booth NA, Brown AJ, Bennett B. Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler Thromb Vasc Biol 1996; 16: 539-45.
• 22 Lupu F, Heim DA, Bachmann F, Hurni M, Kakkar VV, Kruithof EK. Plasminogen activator expression in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 1995; 15: 1444-55.
• 23 Padro T, Emeis JJ, Steins M, Schmid KW, Kienast J. Quantification of plasminogen activators and their inhibitors in the aortic vessel wall in relation to the presence and severity of atherosclerotic disease. Arterioscler Thromb Vasc Biol 1995; 15: 893-902.
• 24 Lyons RM, Gentry LE, Purchio AF, Moses HL. Mechanism of activation of latent recombinant transforming growth factor β1 by plasmin. J Cell Biol 1990; 110: 1361-7.
• 25 Sato Y, Rifkin DB. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-β1-like molecule by plasmin during co-culture. J Cell Biol 1989; 109: 309-15.