Data from recent prospective studies of hemostasis and thrombosis indicate that the plasma concentration of endogenous tissue-type plasminogen activator (tPA) is often elevated years in advance of a first arterial occlusion. Specifically, among healthy subjects with no prior cardiovascular disease, the risk of future myocardial infarction and stroke appears to be three to four times higher among subjects with high baseline levels of tPA antigen as compared to subjects with lower levels. Whether this relationship represents activation of the endogenous fibrinolytic system in response to the presence of preclinical atherosclerosis or is a reflection of elevated concentrations of local plasminogen activator inhibitors is currently unresolved. However, cross-sectional data indicate that the plasma concentration of tPA antigen is related to several traditional atherosclerotic risk factors, including HDL cholesterol, findings that further support a direct relationship between endogenous tPA and vascular risk. In concert with data concerning the primary inhibitors of plasminogen activation, it has been hypothesized that the endogenous fibrinolytic system varies within the general population such that certain individuals are prone to thrombosis, whereas others may be prone to hemorrhage. Thus, observations regarding fibrinolytic activation and inhibition raise the possibility that assessment of the intrinsic fibrinolytic system may prove useful in identifying individuals at increased risk for vascular thrombosis. In addition, available findings suggest that therapeutic agents capable of favorably shifting the net fibrinolytic balance may provide a new strategy for cardiovascular disease prevention.
This is a preview of subscription content, log in to check access.
We’re sorry, something doesn't seem to be working properly.
Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.
Sprengers ED, Kluft C. Plasminogen activator inhibitors.Blood 1987;69:381–387.
Lucore CL. Regulation of fibrinolysis by vascular endothelium.Coron Art Dis 1991;2:157–166.
Hamsten A, Wiman B, de Fai, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.N Engl J Med 1985;313:1557–1563.
Hamsten A, Walldius G, Szamosi A, Blombäck M, deFaire U, Dahlén G, Wiman B. Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction.Lancet 1987;2:3–9.
Oseroff A, Krishnamurati C, Hassett A, Tang D, Alving B. Plasminogen activator and plasminogen activator inhibitor activities in men with coronary artery disease.J Lab Clin Med 1989;113:88–93.
Azner J, Estelles A, Tormo G, Sapena P, Tomor V, Blanch S, Espana F. Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease.Br Heart J 1988;59:535–541.
Paramo JA, Colucci M,Collen D. Plasminogen activator inhibitor in the blood of patients with coronary artery disease.Br Med J 1985;291:573–574.
Schleef RR, Higgins DL, Pillemer E, Levitt LJ. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor.J Clin Invest 1989;83:1747–1752.
Erickson LA, Fici GJ, Lund JE, Boyle TP, Polites HG, Marotti KR. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene.Nature 1990;346:74–76.
Olofsson BO, Dahlen G, Nilsson TK. Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographically verified coronary artery disease.Eur Heart J 1989;10:77–82.
Huber K, Resch I, Stefenelli T, Lang I, Probst P, Kaindl F, Binder BR. Plasminogen activator inhibitor-1 levels in patients with chronic angina pectoris with or without angiographie evidence of coronary sclerosis.Thromb Haemost 1990;63:336–339.
Salomaa VV, Wu KK, Stinson VL, Kark JD, Folsom AR, Liao D, Paron CC. The association of fibrinolytic activity with asymptomatic carotid atherosclerosis: The ARIC study (abstract).Circulation 1993;87:22.
Vanderkerckhove Y, Baele G, dePuydt H, Weyne A, Clement D. Plasma tissue plasminogen activator levels in patients with coronary heart disease.Thromb Res 1988;50:449–453.
Steering Committee of the Physicians' Health Study Research Group. Final report of the aspirin component of the ongoing Physicians' Health Study.N Engl J Med 1989;321:129–135.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction.Lancet 1993;341:1165–1168.
Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke.Lancet 1994;343:940–943.
Fowkes FGR, Lowe GDO, Housley E, Rattray A, Rumley A, Elton RA, MacGregor IR, Dawes J. Cross-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease.Lancet 1993;342:84–86.
Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long term mortality in patients with coronary artery disease: A seven year follow-up.Circulation 1993;88:2030–2034.
Haverkate F, van de Loo JCW, Thompson SG, on behalf of the ECAT Angina Pectoris Study Group. Hemostasis risk markers, inflammatory and endothelial reactions in angina pectoris. Results of the ECAT Angina Pectoris Study.Thromb Haemost 1993;69:1537.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Shen C, Goldhaber SZ, Hennekens CH. Baseline fibrinolytic state and the risk of venous thrombosis. A Prospective study of endogenous tissue-type plasminogen activator and plasminogen activator inhibitor.Circulation 1992;85:1822–1827.
Ranby M, Bergsdorf N, Nilsson T, Mellbring G, Bucht G, Winblad B. Age dependence of tissue plasminogen activator concentrations in plasma, as studies by an improved enzyme-linked immunosorbent assay.Clin Chem 1986;32:2160–2165.
Rijken DC, Sprengers ED, Van der Hoeven RJ, Kluft C, Engesser L. Plasminogen activator inhibitor 1 (PAI-1) antigen levels in human plasma samples.Fibrinolysis 1988;2:79–84.
Sundell IB, Nilsson TK, Hallmans G, Hellsten G, Dahlen GH. Interrelationships between plasma levels of plasminogen activator inhibitor, tissue plasminogen activator, lipoprotein(a), and established cardiovascular risk factors in a North Swedish population.Atherosclerosis 1989;80:9–16.
Urano T, Sakakibara K, Rydzewski A, Urano S, Takada Y, Takada A. Relationships between euglobulin clot lysis time and the plasma level of tissue plasminogen activator and plasminogen activator inhibitor 1.Thromb Haemost 1990;63:82–86.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. A prospective study of plasminogen activator inhibitor and the risk of future myocardial infarction (abstract).Circulation 1992;86:I325.
ECAT Angina Pectoris Study Group. ECAT angina pectoris study: Baseline associations of haemostatic factors with extent of coronary atherosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography.Eur Heart J 1993;14:8–17.
Hashimoto Y, Kobayashi A, Yamazaki N, Takada Y, Takada A. Relationship between smoking and fibrinolytic system with special reference to tPA and PA inhibitor.Thromb Res 1988;51:303–311.
Laug WE. Ethyl alcohol enhances plasminogen activator secretion by endothelial cells.JAMA 1983;250:772–776.
Smokovitis A, Kokolis N, Ploumis T. Enhancement of plasminogen activator activity in the gastric wall after chronic ethanol consumption.Alcohol 1991;8:17–20.
Sumi H, Hamada H, Tsushima H, Mihara H. Urokinase-like plasminogen activator increased in plasma after alcohol drinking.Alcohol Alcohol 1988;23:33–43.
Veenstra J, Kluft C, Ochuizen T, v.d. Pol H, Wedel M, Schaafsma G. Effects of moderate alcohol consumption on the platelet function, tissue-type plasminogen activator and plasminogen activator inhibitor.Thromb Haemost 1990;63:345–348.
Iso H, Folsom AR, Koike KA, Sato S, Wu KK, Shimamoto T, Iida M, Komachi Y. Antigens of tissue plasminogen activator and plasminogen activator inhibitor 1: Correlates in nonsmoking Japanese and caucasian men and women.Thromb Haemost 1993;70:475–480.
Scarabin PY, Plu-Bureau G, Bara L, Bonithon-Kopp C, Guize L, Samama MM. Haemostatic variables and menopausal status: Influence of hormone replacement therapy.Thromb Haemost 1993;70:584–587.
Kluft C, Potter van Loon BJ, De Maat MPM. Insulin resistance and changes in haemostatic variables.Fibrinolysis 1992;6:11–18.
Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type 1 by insulin and insulin-like growth factor type I: Implications for vascular disease in hyperinsulinemic states.Proc Natl Acad Sci USA 1991;88:9959–9963.
Ridker PM, Vaughan DE, Stampfer MJ, Sacks FM, Hennekens CH. A cross-sectional study of endogenous tissue plasminogen activator, total cholesterol, HDL cholesterol, and apolipoproteins A-I, A-II, and B-100.Arteriosclero Thrombo 1993;13:l-6.
Muller JE, Stone PH, Turi ZG, et al. and the MILIS Study Group: Circadian variation in the frequency of onset of acute myocardial infarction.N Engl J Med 1985;313:1315–1322.
Andreotti F, Kluft C. Circadian variation of fibrinolytic activity in blood.Chronobiol Int 1991;8:336–351.
Angleton P, Chandler WL, Schmer G. Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1).Circulation 1989;79:101–106.
Ridker PM, Manson JE, Buring JE, Muller JE, Hennekens CH. Circadian variation of acute myocardial infarction and the effect of aspirin in a randomized trial of physicians.Circulation 1990;82:897–902.
Eliasson M, Evrin PE, Lundblad D, Asplund K, Ranby M. Influence of gender, age, and sampling time on plasma fibrinolytic variables and fibrinogen.Fibrinolysis 1993;7:316–323.
Bridges AB, McLaren M, Scott NA, Pringle TH, McNeill GP, Belch JJF. Circadian variation of tissue plasminogen activator and its inhibitor, von Willebrand factor antigen, and prostacyclin stimulating factor in men with ischaemic heart disease.Br Heart J 1993;69:121–124.
Underwood MJ, DeBono DP. Increased fibrinolytic activity in the intima of atheromatous coronary arteries: Protection at a price.Cardiovasc Res 1993;27:882–885.
Smokovitis A, Kokolis N, Alexaki-Tzivanidou E. Fatty streaks and fibrous plaques in human aorta show increased plasminogen activator activity.Haemostasis 1988;18:146–153.
Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Diley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in athero-sclerotic human arteries.Proc Natl Acad Sci USA 1992;89:6998.
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;342:1076–1079.
Meade TW, Mellows S, Brozovic M, et al. Haemostatic function and ischaemic heart disease. Principle results of the Northwick Park Heart Study.Lancet 1986;2:533–537.
Stone MC, Thorpe JM. Plasma fibrinogen-A major coronary risk factor.J R Coll Gen Pract 1985;35:565–569.
Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction.N Engl J Med 1984;311:501–505.
Kannel WB, Wolf PA, Castelli WP, D'Angostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study.JAMA 1987;258:1183–1186.
Trip MD, Manger Cats V, van Capelle FJL, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction.N Engl J Med 1990;322:1549–1554.
Martin JF, Bath PMW, Burr ML. Influence of plateletsize on outcome after myocardial infarction.Lancet 1991;338:1409–1411.
Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohen PF. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men.Circulation 1991;84:613–617.
Ridker PM, Hennekens CH. Hemostatic risk factors for coronary heart disease.Circulation 1991;83:1098–1100.
Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. 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;87:1969–1973.
Fugii S, Sobel BE. Direct effects of gemfibrozil on the fibrinolytic system: Diminution of synthesis of plasminogen activator inhibitor type 1.Circulation 1992;85:1888–1893.
About this article
Cite this article
Ridker, P.M. Plasma concentration of endogenous tissue plasminogen activator and the occurrence of future cardiovascular events. J Thromb Thrombol 1, 35–40 (1994). https://doi.org/10.1007/BF01061993
- tissue plasminogen activator
- myocardial infarction