Abstract
Plasminogen activator inhibitor type-1 (PAI-1) is a rapid inhibitor of tissue plasminogen activator (tPA) in circulation. Evidence suggests that the PAI-1 concentration is responsible for the regulation of the endogenous fibrinolytic system through its tPA/PAI-1 interactions. Accordingly, increased levels of PAI-1 have emerged as a masker for an increased thrombolic risk. This article represents a status report of mechansism of action, regulation of plasma levels, as well as the role of PAI-1 in arterial and venous thromboembolic disease.
Similar content being viewed by others
References
Van Meijer M, Pannekoek H. Structure of plasminogen activator inhibitor 1 (PAI-1) and its function in fibrinolysis: an update. Fibrinolysis 1995;9:263–276.
Alessi MC, Chomiki N, Berthier R, Schweitzer A, Fossat C, Juhan-Vague I. Detection of plasminogen activator-inhibitor-1 (PAI-1) mRNA in human megakaryocytes by in situ hybridization. Thromb Haemost 1994;72:933–936.
Fay WP, Eitzman DT, Shapiro AD, Madison EL, Ginsburg D. Platelets inhibit fibrinolysis in vitro by both plasminogen activator-dependent and-independent mechanisms. Blood 1994;83:351–356.
Stringer HA, van Swieten P, Heijnen HF, Sixma JJ, Pannekoek H. Plasminogen activator inhibitor-1 released from activated platelets plays a key role in the thrombolysis resistance: studies with thrombi generated in the Chandler loop. Arterioscler 1994;4:1452–1458.
Booth NA, Simpson AH, Croll A, Bennett B, MacGregor IR. Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol 1998;70:327–333.
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;57:453–462.
Lang IM, Schleef RR. Calcium-dependent stabilization of type-1 plasminogen activator inhibitor within platelet alpha-granules. J Biol Chem 1996;271:2754–2761.
Cigolini M, Targher G, Bergamo Andreis IA, Tonoli M, Agostino G, De Sandre G. Visceral fat accumulation and its relation to plasma haemostatic factors in healthy men. Arterioscler Thromb Vasc Biol 1996;16:368–374.
Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor-1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997;46:860–867.
Loskutoff DJ, Samad F. The adipocyte and hemostatic balance in obesity. Studies of PAI-1. Arterioscler Thromb Vasc Biol 1998;18:1–6.
Kooistra T, Sprengers ED, van Hinsbergh VWH. Rapid inactivation of the plasminogen-activator inhibitor upon secretion from cultured human endothelial cells. Biochem J 1986;239:497–503.
Uchiyama T, Kurabayashi M, Ohyama Y, et al. Hypoxia induces transcription of the plasminogen activator inhibitor-1 gene through genistein-sensitive tyrosine kinase pathways in vascular endothelial cells. Arterioscler Thromb Vasc Biol 2000;20:1155–1161.
Vaughan DE. Fibrinolytic balance, the renin-angiotensin system and atherosclerotic disease. Eur Heart J 1998;19:G9–G12.
Saksela O, Rifkin DB. Cell-associated plasminogen activation: regulation and physiologic function. Am Rev Cell Biol 1998;4:93–126.
Booth NA, Bennett B, Wijngaards G, Grieve JH. A new life-long hemorrhagic disorder due to excess plasminogen activator. Blood 1983;61:267–275.
Aznar J, Estelles A, Vila V, Reganon E, Espana F, et al. Inherited fibrinolytic disorder due to an enhanced plasminogen activator level. Thromb Haemost 1984;52:196–200.
Dieval J, Nguyen G, Gross S, Delobel J, Kruithof EK. A lifelong bleeding disorder associated with a defi-ciency of plasminogen activator inhibitor type 1. Blood 1991;77:528–532.
Fay WP, Shapiro AD, Shih JL, Schleef RR, Ginsburg D. Brief report: complete deficiency of plasminogen activator inhibitor type 1 due to a frame shift mutation. N Engl J Med 1992;327:1729–1733.
Dawson S, Henney A. The status of PAI-1 as a risk factor for arterial and thrombotic disease. Atherosclerosis 1992;95:105–117.
Wiman B. Plasminogen activator inhibitor 1 (PAI-1) in plasma: its role in thrombotic disease. Thromb Haemost 1995;74:71–76.
Rallidis LS, Megalou AA, Papageorgakis NH, Trikas AG, Chatzidimitriou GI, Tsitouris GK. Plasminogen activator inhibitor 1 is elevated in the children of men with premature myocardial infarction. Thromb Haemost 1996;76:417–421.
Klinger KW, Winquist R, Riccio A, et al. Plasminogen activator inhibitor type 1 gene is located at region q21.3–q22 of chromosome 7 and genetically linked with cystic fibrosis. Proc Natl Acad Sci USA 1987;84:8548–8552.
Dawson S, Hamsten A, Wiman B, Henney A, Humphries S. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1991;11:183–190.
Dawson SJ, Wiman B, Hamsten A, Grenn F, Humphries S, Henney AM. 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;268:10739–10745.
Ye S, Green FR, Scarabin PY, et al. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 1995;74:837–841.
Falk G, Almquist A, Nordenhem A, Svensson H, Wiman B. Allele specific PCR for detection of a sequence polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene. Fibrinolysis 1995;9:170–174.
Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries SE, Yudkin JS. Determinants of plasminogen activator inhibitor 1 activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor 1 gene. Diabetes 1995;44:37–42.
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;74:842–847.
Margaglione M, Capucci 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;18:562–567.
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;79:354–358.
Benza RL, Grenett H, Li X-N, et al. Gene polymorphisms for PAI-1 are associated with the angiographic extent of coronary artery disease. J Thromb Thrombolysis 1998;5:143–150.
Eriksson P, Kallin B, van't Hooft FM, Bavenholm P, Hamsten A. Allele specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995;92:1851–1855.
Ossei-Gerning N, Mansfield MW, Stickland MH, Wilson IJ, Grant PJ. 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;17:33–37.
Margaglione M, Capucci G, Colaizzo D, et al. The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol 1998;18:152–156.
Benza RL, Grenett HE, Bourge R, et al. Gene polymorphisms for plasminogen activator inhibitor-1/tissue plasminogen activator and development of allograft coronary artery disease. Circulation 1998;98:2248–2254.
Stegnar M, Uhrin P, Peternel P, et al. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: Relationship to plasma PAI-1 level in venous thromboembolism. Thromb Haemost 1998;79:975–979.
Zöller B, Garcia de Frutos P, Dahlbäck B. A common 4G allele in the promotor of the plasminogen activator inhibitor-1 (PAI-1) gene as a risk factor for pulmonary embolism and arterial thrombosis in hereditary protein S deficiency. Thromb Haemost 1998;79:802–807.
Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Miletich JP. 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.
Henry M, Tregouet DA, Alessi MC, et al. Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen plasma concentration: A family study with part of the Stanislas Cohort. Arterioscler Thromb Vasc Biol 1998;18:84–91.
Pyörä lä K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev 1987;3:463–524.
Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374–381.
Laakso M. Insulin resistance and coronary heart disease. Curr Opin Lipidol 1996;7:217–226.
Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334: 952–957.
Juhan-Vague I, Vague P. Hypofibrinolysis and insulin resistance. Diabet Metabol 1991;17:96–100.
Andersen P, Arnesen H, Hjermann I. Hyperlipoproteinemia and reduced fibrinolytic activity in healthy coronary high risk men. Acta Med Scand 1981;209:199–202.
Vague P, Juhan-Vague I, Alessi MC, Badier C, Valadier J. Metformin decreases the high plasminogen activator inhibitor capacity plasma insulin and triglyceride levels in non diabetic obese subjects. Thromb Haemostas 1987;57:326–328.
Landin K, Tengborn L, Smith U. Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med 1990;227:273–278.
Andersen P. Hypercoagulability and reduced fibrinolysis in hyperlipidemia: relationship to the metabolic cardiovascular syndrome. J Cardiovasc Pharmacol 1992;20:S29–S31.
Mussoni L, Mannucci L, Sitori M, et al. Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb 1992;12:19–27.
Potter van Loon BJ, Kluft C, Radder JK, Blankenstein MA, Meinders AE. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism 1993;42:945–949.
Asplund-Carlsson A, Hamsten A, Wiman B, Carlsson LA. Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, insulin levels and insulin sensitivity: studies in randomly selected normoand hypertriglyceridemic men. Diabetologia 1993; 36:817–825.
Juhan-Vague I, Thompson SG, Jespersen J. On behalf of the ECAT Angina Pectoris Study Group. Involvement of the hemostatic system in the insulin resistance syndrome: a study of 1500 patients with angina pectoris. Arterioscler Thromb 1993;13:1865–1873.
Cigolini M, Targher G, Seidell JC, et al. Relationships of plasminogen activator inhibitor-1 to anthropometry, serum insulin, triglycerides and adipose tissue fatty acids in healthy men. Atherosclerosis 1994;106:139–147.
Mykkänen L, Rönnemaa T, Marniemi J, Haffner SM, Bergman R, Laakso M. Insulin sensitivity is not an independent determinant of plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1994;14:1264–1271.
Eliasson M, Asplund K, Evrin P-E, Lindahl B, Lundblad D. Hyperinsulinemia predicts low tissue plasminogen activator activity in a healthy population: the Northern Sweden MONICA study. Metabolism 1994;43:1579–1586.
Gray RP, Mohamed-Ali V, Patterson DLH, Yudkins JS. Determinants of plasminogen activator inhibitor-1 activity in survivors of myocardial infarction. Thromb Haemost 1995;73:261–267.
Toft I, Bonaa K, Ingebretsen O, Nordoy A, Birkeland K, Jenssen T. Gender differences in the relationships between plasma plasminogen activator inhibitor-1 activity and factors linked to the insulin resistance syndrome in essential hypertension. Arterioscler Thromb Vasc Biol 1997;17:553–559.
Gray RP, Panahloo A, Mohamed-Ali V, Patterson DL, Yudkin JS. Proinsulin-like molecules and plasminogen activator inhibitor type 1 (PAI-1) activity in diabetic and non-diabetic subjects with and without myocardial infarction. Atherosclerosis 1997;130:171–178.
Alessi MC, Juhan-Vague I, Kooistra T, Declerck PJ, Collen D. Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line HepG2. Thromb Haemost 1988;60: 491–494.
Kooistra T, Bosma PJ, Töns HAM, van den Berg AP, Meyer P, Princen HMG. Plasminogen activator inhibitor 1: biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemost 1989;62:723–728.
Stiko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis 1990;10:1067–1073.
Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor1 by insulin and insulin-like growth factor type 1: implications for vascular disease in hyperinsulinemic states. Proc Natl Acad Sci USA 1991;88:9959–9963.
Fattal PG, Schneider DJ, Sobel BE, Billadello JJ. Post-transcriptional regulation of expression of plasminogen activator inhibitor type 1 mRNA by insulin and insulin-like growth factor. J Biol Chem 1992;267:12412–12415.
Schneider DJ, Nordt TK, Sobel BE. Stimulation by proinsulin of expression of plasminogen activator inhibitor type-1 in endothelial cells. Diabetes 1992;41:890–895.
Nordt TK, Klassen KJ, Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator Plasminogen Activator Inhibitor Type 1-Part One 189 inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis. Arterioscler Thromb 1993;13:1822–1828.
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: 321–330.
Alessi MC, Anfosso F, Henry M, Peiretti F, Nalbone G, Juhan-Vague I. Upregulation of PAI-1 synthesis by insulin and proinsulin in HepG2 cells but not in endothelial cells. Fibrinolysis 1995;9: 237–242.
Sakata K, Miho N, Shirotani M, Yoshida H, Takada A. Remnant-like particle cholesterol in coronary artery disease: correlation with plasminogen activator inhibitor-1 activity. Fibrinol Proteol 1998;12:123–127.
McCormack L, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 antigen concentration during insulin and oral glucose tolerance tests in obese men. Fibrinolysis 1993;7:225–228.
Seljeflot I, Eritsland J, Torjesen P, Arnesen H. Insulin and PAI-1 levels during oral glucose tolerance test in patients with coronary heart disease. Scand J Clin Lab Invest 1994;54:241–246.
Nordt TK, Sawa H, Fujii S, Sobel BS. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation 1995;91:764–770.
Festa A, D'Agostino R, Mykkänen 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. Arterioscler Thromb Biol 1999;19:562–568.
Abbasi F, McLaughlin T, Lamendola C, Lipinska I, Tofler G, Reaven GM. Arterioscler Thromb Vasc Biol 1999;19:2818–2821.
Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients. A potential factor predisposing to thrombosis and its persistance. Circulation 1998;97:2213–2221.
Jain SK, Nagi DK, Slavin BM, Lumb PJ, Yudkin JS. Insulin therapy in type 2 diabetic subjects suppresses plasminogen activator inhibitor (PAI-1) activity and proinsulin-like molecules independently of glycaemic control. Diabet Med 1993;10:27–32.
Grant PJ, Stickland MH, Booth NA, Prentice CRM. Metformin causes a reduction in basal and postvenous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. Diabet Med 1991;8:361–365.
Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. Journal of Internal Medicine 1991;229:181–187.
Jansson JH, Johansson B, Boman K, Nilsson TK. Effects of doxazosin and atenolol on the fibrinolytic system in patients with hypertension and elevated serum cholesterol. European Journal of Clinical Pharmacology 1991;40:321–326.
Lehtonen A and the Finnish Multicenter Study Group Turku, Finland. Doxazosin effects on insulin and glucose in hypertensive patients. American Heart Journal 1991;121:1307–1311.
Shieh SM, Sheu WHH, Shen DC, Fuh MMT, Chen YDI, Reaven GM. Glucose, insulin, and lipid metabolism in doxazosin treated patients with hypertension. Am J Hypertens 1992;5:827–831.
Giorda C, Appendino M. Effects of doxazosin, a selective alpha-1-inhibitor, on plasma insulin and blood glucose response to a glucose tolerance test in essential hypertension. Metabolism 1993;42:1440–1442.
Kageyama S, Yamamoto J, Mimura A, et al. Doxazosin improves insulin sensitivity in hypertensive patients. Clin Ther 1993;15:829–837.
Zehetgruber M, Christ G, Gabriel H, et al. Effect of antihypertensive treatment with doxazosin on insulin sensitivity and fibrinolytic parameters. Thromb Haemost 1998;79:378–382.
Andersen P, Smith P, Seljeflot I, Brataker S, Arnesen H. Effects of gemfibrozil on lipids and haemostasis after myocardial infarction. Thromb Haemost 1990;63:174–177.
Fujii S, Sobel BE. Direct effects of gemfibrozil on the fibrinolytic system. Circulation 1992;85:1888–1893.
Hamsten A, Syvänne M, Silveira A, et al. Fibrinolytic proteins and progression of coronary artery disease in relation to gemfibrozil therapy. Thromb Haemost 2000;83:397–403.
Brown SL, Sobel BE, Fujii S. Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin. A potential link between lipid lowering and fibrinolysis. Circulation 1995;92:767–772.
Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol. 2000;20:556–562.
Wiesbauer F, Kaun C, Bodlaj G, Maurer G, Huber K, Wojta J. HMG-CoA reductase inhibitors affect the fibrinolytic system of human smooth muscle cells in vitro. J Am Coll Cardiol 2000;35:886–j
Mussoni L, Banfi C, Sironi L, Arpaia M, Tremoli E. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells. Thromb Haemost 2000;84:59–64.
Gebara OCE, Mittleman MA, Sutherland P, et al. Association between increased estrogen status and increased fibrinolytic potential in the Framingham offspring study. Circulation 1995;91:1952–1958.
Grancha S, Estelleés 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. Thromb Haemost 1999;81:516–521.
Teede HJ, McGrath BP, Smolich JJ, et al. Arterioscler Thromb Vasc Biol 2000;20:1404–1409.
Kilbourne EJ, Scicchitano MS. The activation of plasminogen activator inhibitor-1 expression by IL-1β is attenuated by estrogen in hepatoblastoma hepG2 cells expressing estrogen receptors. Thromb Haemost 1999;81:423–427.
Legnani C, Maccaferri M, Tonini P, Cassio A, Cacciari E, Coccheri S. Reduced fibrinolytic response in obese children: association with high baseline activity of the fast acting plasminogen activator inhibitor (PAI-1). Fibrinolysis 1988;2:211–214.
Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo: induction by tumor necrosis factor-alpha and lipopolysaccharide. J Clin Invest 1996;97:37–46.
Lundgren CH, Brown SL, Nordt TK, Sobel BE, Fujii S. Elaboration of type-1 plasminogen activator inhibitor from adipocytes: a potential pathogenetic link between obesity and cardiovascular disease. Circulation 1996;93:106–110.
Shimomura I, Funahashi T, Takahashi M, et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996;2:800–803.
Morange PE, Alessi MC, Verdier M, Casanova D, Magalon G, Juhan-Vague I. PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level. Thromb Vasc Biol 1999;19:1361–1365.
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;83:545–548.
Van Harmelen V, Wahrenberg H, Eriksson P, Arner P. Role of gender and genetic variance in plasminogen activator inhibitor-1 secretion from human adipose tissue. Thromb Haemost 2000;83:304–308.
Folsom AR, Quamhieh HT, Wing RR, et al. Impact of weight lost on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults. Arterioscler Thromb 1993;13:162–169.
Calles-Escandon J, Ballor D, Harvey-Berino J, Ades P, Tracy R, Sobel B. Amelioration of the inhibition of fibrinolysis in the elderly, obese subjects by moderate energy intake restriction. Am J Clin Nutr 1996;64:7–11.
Juhan-Vague I, Alessi MC. PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost 1997;78:656–660.
Kockx M, Leenen R, Seidell J, Princen HMG, Kooistra T. Relationship between visceral fat and PAI-1 in overweight men and women before and after weight loss. Thromb Haemost 1999;82:1490–1496.
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.
Van Leeuven RTJ, Kol A, Andreotti F, Kluft C, Maseri A, Sperti G. Angiotensin II increases plasminogen activator inhibitor type I and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells. Circulation 1994;90: 362–368.
Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor in cultured endothelial cells. J Clin Invest 1995;95:995–1001.
Brown NJ, Nadeau J, Vaughan DE. Stimulation of tissue-type plasminogen activator in vivo by infusion of bradykinin. Thromb Haemost 1997;77:522–525.
Feener EP, Northrup JM, Aiello LP, King GL. Angiotensin II induces plasminogen activator inhibitor-1 and-2 expression in vascular endothelial and smooth muscle cells. J Clin Invest 1995;95:1353–1362.
Nishimura H, Tsuji H, Masuda H, et al. The effects of angiotensin metabolities on the regulation of coagulation and fibrinolysis in cultured rat aortic endothelial cells. Thromb Haemost. 1999;82:1516–1521.
Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest 1995;96:2515–2520.
Chen H, Bouchie JL, Perez AS, et al. Role of the angiotensin AT receptor in rat aortic and cardiac PAI-1 gene expression. Arterioscler Thromb Vasc Biol 2000;20:2297–2302.
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Sourbrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounts for half of the variance of serum enzyme levels. J Clin Invest 1990;86:1343–1346.
Coxterousse O, Allegrini J, Lopez M, Alheno-Gelas F. Angiotensin I-converting enzyme in the human circulating mononuclear cells: genetic polymorphism of expression in T lymphocytes. Biochem J 1993;290:33–40.
Cambien F, Poirier O, Lecerp L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641–644.
Tiret L, Kee F, Poirier O, et al. Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet 1993;341:991–992.
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;17:2082–2087.
Jansson JH, Boman K, Nielsson TK. Enalapril related changes in the fibrinolytic system in survivors of myocardial infarction. Eur J Clin Pharmacol 1993;44:485–488.
Wright RA, Flapan AD, Alberti KGMM, Ludlam CA, Fox KAA. Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction. J Am Coll Cardiol 1994;24: 67–73.
Vaughan DE, Rouleau J, Ridker PM, Arnold JMO, Menapace FJ, Pfeffer MA. On behalf of the HEART Study Investigators: Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation 1997;96: 442–447.
Soejima H, Ogawa H, Yasue H, Suefuji H, Kaikita K, Nishiyama K. Effects of imidapril therapy on endogenous fibrinolysis in patients with recent myocardial infarction. Clin Cardiol 1997;20:441–445.
Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition Plasminogen Activator Inhibitor Type 1-Part One 191 of the renin-angiotensin system on plasma PAI-1. Hypertension 1998;32:965–971.
Goodfield NE, Newby DE, Ludlam CA, Flapan AD. Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 1999;99:2983–2985.
Erdem Y, Usalan C, Haznedaroglu IC, et al. Effects of angiotensin converting enzyme and angiotensin II receptor inhibition on impaired fibrinolysis in systemic hypertension. Am J Hypertens 1999;12: 1071–1076.
Sakata K, Shirotani M, Yoshida H, Urano T, Takada Y, Takada A. Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension. Am Heart J 1999;137:1094–1099.
Zehetgruber M, Beckmann R, Gabriel H, Christ G, Binder BR, Huber K. Comparative cross-over study of the effects of lisinopril and doxazosin on insulin, glucose and lipoprotein metabolism and the endogenous fibrinolytic system. Fibrinolysis 1997;11: 153–158.
Sayer JW, Gutteridge C, Syndercombe-Court D, Wilkinson P, Timmis AD. 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;32:1962–1968.
Hamdan AD, Quist WC, Gagne JB, Feener EP. Angiotensin-converting enzyme inhibition suppress plasminogen activator inhibitor-1 expression in the neointima of balloon-injured rat aorta. Circulation 1996;93:1073–1078.
Hirschl MM, Wagner A, Gwechenberger M, et al. Attenuation of thrombolysis-induced increase of plasminogen activator inhibitor-1 by intravenous enalaprilat. Thromb Haemost 1998;79:140–143.
Eliasson B, Attvall S, Taskinen MR, Smith U. The insulin resistance syndrome in smokers is related to smoking habits. Arterioscler Thromb 1994;14:1946–1950.
Mehrabian M, Peter JB, Barnard RJ, Lusis AJ. Dietary regulation of fibrinolytic factors. Atherosclerosis 1990;84:25–32.
De Geus EJC, Kluft C, de Bart ACW, van Doornen LJP. Effects of exercise training on plasminogen activator inhibitor activity. Med Sci Sports Exercise 1992;24:1210–1219.
El-Sayed MS. Fibrinolytic and hemostatic parameter response after resistance exercise. Med Sci Sports Exercise 1993;25:597–602.
Wiman B, Ljundberg B, Chmielewska J, Urden G, Blombäck M, Johnsson H. The role of the fibrinolytic system in deep venous thrombosis. J Lab Clin Med 1985;105:265–270.
Grimaudo V, Bachmann F, Hauert J, Christe MA, Kruithof EKO. Hypofibrinolysis in patients with a history of idiopathic deep vein thrombosis and/or pulmonary embolism. Thromb Haemost 1992;67:397–410.
Samama M. Hypofibrinolysis and venous thrombosis. In: Neri Serneri GG, Gensini GF, Abbate R, Prisco D, eds. Thrombosis: an update. Florence: Scientific Press, 1992:165–181.
Tabernero MD, Estellés A, Vicente V, Alberca J, Aznar J. Incidence of increased plasminogen activator inhibitor in patients with deep venous thrombosis and/or pulmonary embolism. Thromb Res 1989;56:565–570.
Paramo JA, Alfaro MJ, Roche E. Postoperative changes in the plasmatic level of tissue-type plasminogen activator and its fast-acting inhibitor: relationship to deep vein thrombosis and influence of prophylaxis. Thromb Haemost 1985;54:713–716.
Juhan-Vague I, JV, Alessi MC, et al. Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemost 1987;57: 67–72.
Erickson LA, Fici GJ, Lund JE, Boyle TP, Polites G, Marotti KR. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 1990;346:74–76.
Huber K, Beckmann R, Frank H, Kneussl M, Mlczoch J, Binder BR. Fibrinogen, t-PA, and PAI-1 plasma levels in patients with primary pulmonary hypertension. Am J Crit Care Med 1994;150:929–933.
Moser KM, Auger WR, Fedullo PF, Jamieson SW. Chronic thromboembolic pulmonary hypertension. Eur Resp J 1992;5:334–342.
Olman MA, Marsh JJ, Lang IM, Moser KM, Binder BR, Schleef RR. Endogenous fibrinolytic system in chronic large-vessel thromboembolic pulmonary hypertension. Circulation 1992;86:1241–1248.
Lang IM, Marsh JJ, Olman MA, Moser KM, Loskutoff DJ, Schleef RR. Mechanisms contributing to the stabilization of chronic pulmonary thromboemboli: prevalence of type 1 plasminogen activator inhibitor (PAI-1) expression in the pulmonary vasculature. Circulation 1993:submitted.
Lang IM, Mardh JJ, Olman MA, Moser KM, Loskutoff DJ, Schleef RR. Expression of type 1 plasminogen activator inhibitor in chronic pulmonary thromboemboli. Circulation 1994;89:2715–2721.
Lang IM, Moser KM, Schleef RR. Elevated expression of urokinase-like plasminogen activator and plasminogen activator inhibitor type 1 during the vascular remodeling associated with pulmonary thromboembolism. Arterioscler Thromb Vasc Biol 1998;18:808–815.
Fearns C, Samad F, Loskutoff DJ. Synthesis and localization of PAI-1 in the vessel wall. In: van Hinsbergh VWM, ed. Vascular Control of Hemostasis. Amsterdam: Harwood Academic Publishers, 1995:207–226.
Fujii S, Hopkins WE, Sobel BE. Mechanisms contributing to increased synthesis of plasminogen activator inhibitor type 1 in endothelial cells by constituents of platelets and their implications for thrombosis. Circulation 1991;83:645–651.
Slivka SR, Loskutoff DJ. Platelets stimulate endothelial cells to synthesize type-1 plasminogen activator inhibitor. Blood 1991;77:1013–1019.
Hamsten A, Wiman B, De Faire U, Blombäck M. Increased levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985;313:1557–1563.
Paramo JA, Colucci M, Collen D. Plasminogen activator inhibitor in blood of patients with coronary artery disease. Brit Med J 1985;291:573–574.
Almér LO, Ohlin H. Elevated levels of the rapid inhibitor of plasminogen activator (t-PAI) in acute myocardial infarction. Thromb Res 1987;47:335–339.
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. Euro Heart J 1989;10:77–82.
Huber K, Resch I, Stefenelli T, et al. Plasminogen activator inhibitor-1 levels in patients with chronic angina pectoris with or without angiographic evidence of coronary sclerosis. Thromb Haemost 1990;63:336–339.
Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor-1 and atherothrombosis. Thromb Haemost 1993;70:138–143.
Rocha E, Paramo JA. The relationship between impaired fibrinolysis and coronary heart disease. Fibrinolysis 1994;8:294–303.
Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK. Association of fibrinolytic parameters with early atherosclerosis. The ARIC study. Circulation 1995;91:284–290.
Geppert A, Beckmann R, Graf S, et al. Tissue-type plasminogen activator and type-1 plasminogen activator inhibitor in patients with coronary artery disease: relations to clinical variables and cardiovascular risk factors. Fibrinolysis 1995;9:109–113.
Pedersen OD, Gram J, Jespersen J. Plasminogen activator inhibitor type-1 determines plasmin formation in patients with ischemic heart disease. Thromb Haemost 1995;73:835–840.
Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 1996;94:2057–2063.
Thögersen AM, Jansson J, 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. Circulation 1998;98:2241–2247.
Hamsten A, DeFaire U, Walldius G, et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987;2:3–9.
Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315–1322.
Huber K, Resch I, Rosc D, Schuster E, Glogar D, Binder BR. Circadian variation of plasminogen activator inhibitor and tissue plasminogen activator levels in plasma of patients with unstable coronary artery disease and acute myocardial infarction. Thromb Haemost 1988;60:372–376.
Angleton P, Chandler WL, Schmer G. Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1). Circulation 1989;79:101–106.
Doggen CJM, Bertina RM, Manger Cats V, Reitsma PH, Rosendaal FR. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with myocardial infarction. Thromb Haemost 1999;82:115–120.
Gardemann A, Lohre J, Katz N, Tillmanns H, Hehrlein FW, Haberbosch W. The 4G/4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost 1999;82:1121–1126.
Anvari A, Türel Z, Schuster E, Sarantopoulos O, Gottsauner-Wolf M, Huber K. PAI-1 gene polymorphism in patients with coronary artery disease and malignant ventricular arrhythmias. PACE 1999;22(abstract).
Mikkelsson J, Perola M, Wartiovaara U, et al. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism, coronary thrombosis, and myocardial infarction in middle-aged Finnish men who died suddenly. Thromb Haemost 2000;84:78–82.
Huber K. Plasminogen activator inhibitor type-1 (part two): Role for failure of thrombolytic therapy. PAI-1 resistance as a potential benefit for new fibrinolytic agents. J Thromb Thrombolysis 2001;j.
Huber K, Jörg M, Probst P, et al. A decrease in plasminogen activator inhibitor-1 activity after successful percutaneous transluminal coronary angioplasty is associated with a significantly reduced risk for coronary restenosis. Thromb Haemost 1992;67:209–213.
Sawa H, Lundgren C, Sobel BE, Fujii S. Increased intramural expression of plasminogen activator inhibitor type 1 after balloon injury: a potential progenitor of restenosis. J Am Coll Cardiol 1994;24:1742–1748.
Gottsauner-Wolf M, Sochor H, Jörg M, et al. Predictive value of PAI-1 plasma activity and thallium perfusion imaging for restenosis after percutaneous transluminal angioplasty in clinically asymptomatic patients. Thromb Haemost 1999;81:522–526.
Baumgartner C, Huber K, Holzner F, Zeiler K, Auff E, Binder BR. Untersuchung zur Frage von persistierenden Veränderungen der Fibrinolyseparameter t-PA und PAI bei Patienten nach juvenilem ischä-mischem cerebralem Insult. Klinische Wochenschrift 1988;66:1110–1115.
Lindgren A, Lindoff C, Norrving B, Astedt B, Johansson BB. Tissue plasminogen activator and plasminogen activator inhibitor 1 in stroke patients. Stroke 1996;27:1066–1071.
Margaglione M, DiMinno G, Grandone E, et al. Plasma lipoprotein(a) levels in subjects attending a metabolic ward. Discrimination between individuals with and without a history of ischemic stroke. Arterioscler Thromb Vasc Biol 1996;16:120–128.
Smith FB, Lee AJ, Rumley A, Fowkes FGR, Lowe GDO. Tissue-plasminogen activator, plasminogen activator inhibitor and risk of peripheral arterial disease. Atherosclerosis 1995;115:35–43.
Caputo M, Mantini G, Floriani I, Ciceri M, Noseda A, Bonomo L. Tissue plasminogen activator, tissue plasminogen activator inhibitor and lipoprotein(a) in patients with coronary, epiaortic and peripheral occlusive artery disease. Eur Heart J 1996;17:1329–1336.
Van der Bom JG, Bots ML, Haverkate F, et al. Fibrinolytic activity in peripheral atherosclerosis in the elderly. Thromb Haemost 1999;81:275–280.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Huber, K. Plasminogen Activator Inhibitor Type-1 (Part One): Basic Mechanisms, Regulation, and Role for Thromboembolic Disease. J Thromb Thrombolysis 11, 183–193 (2001). https://doi.org/10.1023/A:1011955018052
Issue Date:
DOI: https://doi.org/10.1023/A:1011955018052