Cited by 602Blood Coagulation and Thrombosis MechanismsAcute Myocardial Infarction ResearchBlood properties and coagulation

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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

Thögersen, Anna M., Jansson, Jan-Håkan, Boman, Kurt, Nilsson, Torbjörn K., Weinehall, Lars, Huhtasaari, Fritz, Hallmans, Göran·1998·Circulation

DOI 10.1161/01.cir.98.21.2241

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Abstract

Background —In patients with established ischemic heart disease, prospective cohort studies have indicated that plasminogen activator inhibitor (PAI-1), the inhibitor of the fibrinolytic system, may predict cardiovascular events. So far, there have been no primary prospective studies of PAI-1. Methods and Results —The aim of the present study was to test whether plasma levels of PAI-1, tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), and thrombomodulin (TM) could predict the occurrence of a first acute myocardial infarction (AMI) in a population with high prevalence of coronary heart disease by use of a prospective nested case-control design. Mass concentrations of PAI-1 and tPA were significantly higher for the 78 subjects who developed a first AMI compared with the 156 references matched for age, sex, and sampling time; for tPA, this increase was independent of smoking habits, body mass index, hypertension, diabetes, cholesterol, and apolipoprotein A-I. The ratio of quartile 4 to 1 for tPA was 5.9 for a patient to develop a first AMI. The association between tPA and AMI was seen in both men and women. Increased levels of vWF were associated with AMI in a univariate analysis. High levels of TM were associated with AMI in women but not in men. Conclusions —The plasma levels of PAI-1, tPA, and vWF are associated with subsequent development of a first AMI; for PAI-1 and tPA, this relation was found in both men and women. For tPA but not for PAI-1 and vWF, this association is independent of established risk factors.

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Background
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Yeh, E. T. H., & Khan, B. V. (2006) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2006.02202.x · Cited by 27
Cardiovascular effects of the thiazolidinediones
Qayyum, R., & Schulman, P. M. (2005) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.596 · Cited by 27
“Elevated levels of markers of inflammation and cytokines, such as C-reactive protein (CRP), CD40, and its ligand CD40L, interleukin-6 (IL-6), and TNF-α are present in patients with CAD as well as in patients with insulin resistance [29,30].”
BackgroundInfluential
HIGH CYSTEINE LEVELS IN RENAL TRANSPLANT RECIPIENTS
Marcucci, R., Fedi, S., Brunelli, T., Pepe, G., Prisco, D., Rosati, A., Zanazzi, M., Bertoni, E., Abbate, R., & Salvadori, M. (2001) · Transplantation · doi:10.1097/00007890-200103270-00010 · Cited by 27
Dietary lipids and vascular function: UK Food Standards Agency workshop report
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“1998) and tissue plasminogen activator (Thogersen et al. 1998) have been shown to predict future cardiovascular events.”
Background
Primary and Secondary Hemostasis in Patients With Subclinical Hypothyroidism: Effect of Levothyroxine Treatment
Lupoli, R., Di Minno, M. N. D., Tortora, A., Scaravilli, A., Cacciapuoti, M., Barba, L., Di Minno, A., Ambrosino, P., Lupoli, G. A., & Lupoli, G. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1726 · Cited by 26
Von Willebrand factor in diagnostics and treatment of cardiovascular disease: Recent advances and prospects
Kozlov, S. G., Денисович, О. С., Avtaeva, Y., Сергеевич, М. И., Matroze, E., & Ахнафович, Г. З. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.1038030 · Cited by 26
Relationships of PAI-1 levels to central obesity and liver steatosis in a sample of adult male population in southern Italy
Barbato, A., Iacone, R., Tarantino, G., Russo, O., Sorrentino, P., Avallone, S., Galletti, F., Farinaro, E., Valle, E. D., & Strazzullo, P. (2009) · Internal and Emergency Medicine · doi:10.1007/s11739-009-0240-9 · Cited by 26
Glucose-independent persistence of PAI-1 gene expression and H3K4 tri-methylation in type 1 diabetic mouse endothelium: Implication in metabolic memory
Takizawa, F., Mizutani, S., Ogawa, Y., & Sawada, N. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.02.064 · Cited by 26
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“Finally, the endothelium has the capacity to produce cytokines and adhesion molecules that regulate the inflammatory process.(3,4) The most important endothelium product is NO and generally loss of NO bioavailability indicates a broadly dysfunctional phenotype.”
Background
Plasminogen-activator-inhibitor-1 promoter polymorphism as a risk factor for adult periodontitis in non-smokers
Hollá, L. I., Bučková, D., Fassmann, A., Beneš, P., & Znojil, V. (2002) · Genes and Immunity · doi:10.1038/sj.gene.6363874 · Cited by 24
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“High plasma PAI-1 concentrations are linked with increased risk of various thrombotic disorders, including myocardial infarction (Thögersen et al., 1998), stroke (Margaglione et al.”
Background
Endothelial Damage and Activation of the Hemostatic System During Radiofrequency Catheter Isolation of Pulmonary Veins
Bulava, A., Slavík, L., Fiala, M., Heinc, P., Škvařilová, M., LUKL, J., Krčová, V., & Indrák, K. (2004) · Journal of Interventional Cardiac Electrophysiology · doi:10.1023/b:jice.0000026924.96281.be · Cited by 23
“Secondly, patients undergoing electrophysiological study are usually older and have more cardiovascular diseases that can be associated with higher vWf, t-PA and PAI-1 concentrations [18,30,34, 35 ] compared to the generally healthy population undergoing RFA for atrial fibrillation.”
Background
Contribution of Genetic and Metabolic Syndrome to Omental Adipose Tissue PAI-1 Gene mRNA and Plasma Levels in Obesity
Bouchard, L., Vohl, M., Lebel, S., Hould, F., Marceau, P., Bergeron, J., Përusse, L., & Mauriège, P. (2010) · Obesity Surgery · doi:10.1007/s11695-010-0079-1 · Cited by 23
Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease
Mills, J. D., Mansfield, M. W., & Grant, P. J. (2002) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/hq0402.105902 · Cited by 23
Is plasminogen activator inhibitor‐1 a physiological bottleneck bridging major depressive disorder and cardiovascular disease?
Savoy, C. D., Lieshout, R. J. V., & Steiner, M. S. (2016) · Acta Physiologica · doi:10.1111/apha.12726 · Cited by 24
“A 1998 study by Thogersen et al. found elevated serum concentrations for both PAI-1 and tPA to be associated with first acute myocardial infarction (AMI) in both men and women (Thogersen et al. 1998).”
Positive impact of hormone replacement therapy on the fibrinolytic system: a long-term randomized controlled study in healthy postmenopausal women
Madsen, J. S., Kristensen, S. R., Gram, J., Bladbjerg, E., Henriksen, F. L., Gram, J., Christensen, K., & Jespersen, J. (2003) · Journal of Thrombosis and Haemostasis · doi:10.1046/j.1538-7836.2003.00362.x · Cited by 23
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Dandona, P., Ghanim, H., Chaudhuri, A., & Mohanty, P. (2008) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2006.10.009 · Cited by 23
Neointima formation and thrombosis after vascular injury in transgenic mice overexpressing plasminogen activator inhibitor‐1 (PAI‐1)
LIJNEN, H. R., HOEF, B. V., Umans, K., & Collen, D. (2004) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2003.00533.x · Cited by 23
Fibrinolysis and lipoprotein(a) in women with coronary artery disease. Influence of hormone replacement therapy.
Falcó, C., Tormo, G., Estellés, A., España, F., Tormo, E., Gilabert, J., Velasco, J. A., & Aznar, J. (2001) · PubMed · Cited by 23
Carbon Monoxide-Induced Early Thrombolysis Contributes to Heme Oxygenase-1-Mediated Inhibition of Neointimal Growth after Vascular Injury in Hypercholesterolemic Mice
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“Concordant with the present observation, previous studies have shown that increased circulating level of PAI-1 is a risk factor for myocardial infarction and restenosis in human patients [21–23].”
Result
Variations of cardiovascular disease associated genes exhibit sex-dependent influence on human longevity
Tan, Q., Yashin, A. I., Bladbjerg, E., de Maat, M. P. M., Andersen‐Ranberg, K., Jeune, B., Christensen, K., & Vaupel, J. W. (2001) · Experimental Gerontology · doi:10.1016/s0531-5565(01)00102-4 · Cited by 23
Effect of levothyroxine replacement therapy on coagulation and fibrinolysis in severe hypothyroidism
Chadarevian, R., Jublanc, C., Bruckert, E., Giral, P., Ankri, A., Leenhardt, L., Chapman, J., & Turpin, G. (2005) · Journal of Endocrinological Investigation · doi:10.1007/bf03347217 · Cited by 22
Atherosclerosis is associated with plasminogen activator inhibitor type‐1 in chronic haemodialysis patients
Peng, Y., Liu, H., Liu, F., Ouyang, L., Cheng, M., Gao, L., Fulin, P., Liu, Y., CHEN, X., & Li, J. (2008) · Nephrology · doi:10.1111/j.1440-1797.2008.00987.x · Cited by 22
A Randomized Controlled Clinical Trial to Evaluate the Efficacy, Safety, Cost-Effectiveness and Effect on PAI-1 Levels of the Three Low-Molecular-Weight Heparins – Enoxaparin, Nadroparin and Dalteparin
Shafiq, N., Malhotra, S., Pandhi, P., Sharma, N., Bhalla, A. K., & Grover, A. (2006) · Pharmacology · doi:10.1159/000096484 · Cited by 22
Association of PAI‐1 gene polymorphism with survival and chemotherapy‐related vascular toxicity in testicular cancer
de Haas, E. C., Zwart, N., Meijer, C., Suurmeijer, A. J. H., Meijer, K., Guchelaar, H., Hoekstra, H. J., van Leeuwen, F. E., Sleijfer, D. T., Boezen, H. M., et al. (2010) · Cancer · doi:10.1002/cncr.25300 · Cited by 22
“Level, median [range] 89 [1-540,000] 34 [1-70,600] 22 [1-19,570] .”
PAI-1 Levels are Related to Insulin Resistance and Carotid Atherosclerosis in Subjects with Familial Combined Hyperlipidemia
Carratalá, A., Martínez‐Hervás, S., Borja, E. R., Benito, E., Real, J. T., Sáez, G. T., Carmena, R., & Ascaso, J. F. (2017) · Journal of Investigative Medicine · doi:10.1136/jim-2017-000468 · Cited by 22
S35225 is a direct inhibitor of Plasminogen Activator Inhibitor type-1 activity in the blood
Rupin, A., Gaertner, R., Mennecier, P., Richard, I., Benoist, A., Nanteuil, G. D., & Verbeuren, T. J. (2008) · Thrombosis Research · doi:10.1016/j.thromres.2007.11.006 · Cited by 22
Influence of prolonged dalteparin treatment on coagulation, fibrinolysis and inflammation in unstable coronary artery disease
Oldgren, J., FELLENIUS, C., Boman, K., Jansson, J., Nilsson, T., Wallentin, L. C., & Siegbahn, A. G. (2005) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2005.01562.x · Cited by 22
Self-citation
Fibrinolytic status in acute coronary syndromes: Evidence of differences in relation to clinical features and pathophysiological pathways
Shantsila, E., Montoro‐García, S., Tapp, L. D., Apostolakis, S. Z., Wrigley, B., & Lip, G. Y. H. (2012) · Thrombosis and Haemostasis · doi:10.1160/th12-01-0011 · Cited by 22
Plasminogen Activator Inhibitor-1 Is Associated with Impaired Endothelial Function in Women with Systemic Lupus Erythematosus
Somers, E. C., Marder, W., Kaplan, M. J., Brook, R. D., & McCune, W. J. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1361.068 · Cited by 22
Insulin Resistance and Elevated Levels of Tissue Plasminogen Activator in First-Degree Relatives of South Asian Patients With Ischemic Cerebrovascular Disease
Kain, K., Catto, A. J., Young, J., Bamford, J., Bavington, J., & Grant, P. J. (2001) · Stroke · doi:10.1161/01.str.32.5.1069 · Cited by 22
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Itakura, H., Sobel, B. E., Boothroyd, D. B., Leung, L. L. K., Iribarren, C., Go, A. S., Fortmann, S. P., Quertermous, T., & Hlatky, M. A. (2007) · American Heart Journal · doi:10.1016/j.ahj.2007.09.015 · Cited by 22
Biomarkers of Vulnerable Atheromatous Plaques
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Krychtiuk, K. A., Speidl, W. S., Giannitsis, E., Gigante, B., Gorog, D. A., Jaffe, A. S., Mair, J. M., Möckel, M., Mueller, C. E., Storey, R. F., et al. (2020) · European Heart Journal Acute Cardiovascular Care · doi:10.1093/ehjacc/zuaa025 · Cited by 21
Adipocytokines as features of the metabolic syndrome determined using confirmatory factor analysis
Smits, M. M., Woudstra, P., Utzschneider, K. M., Tong, J., Gerchman, F., Faulenbach, M. V., Carr, D. B., Aston‐Mourney, K., Chait, A., Knopp, R. H., et al. (2013) · Annals of Epidemiology · doi:10.1016/j.annepidem.2013.03.001 · Cited by 21
Exploring biomarkers associated with deteriorating vascular health using a targeted proteomics chip
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Elevated Plasma Plasminogen Activator Inhibitor Type-1 is an Independent Predictor of Coronary Microvascular Dysfunction in Hypertension
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Admission Levels of C-Reactive Protein and Plasminogen Activator Inhibitor-1 in Patients With Acute Myocardial Infarction With and Without Cardiogenic Shock or Heart Failure on Admission
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Maximal PAI-1 inhibition in vivo requires neutralizing antibodies that recognize and inhibit glycosylated PAI-1
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“recent case–control study identified a strong association between elevated PAI-1 levels and an increased risk for development of a first myocardial infarction in both men and women [13].”
Background

Authors: Thögersen, A. M., Jansson, J.-H., Boman, K., Nilsson, T. K., Weinehall, L., Huhtasaari, F., & Hallmans, G.
Affiliations: From the Department of Medicine (A.M.T.), Department of Clinical Chemistry (T.K.N.), and Departments of Nutritional Research and Pathology (G.H.), Umeå University Hospital; Department of Medicine-Geriatric, Skellefteå County Hospital (J.-H.J., K.B.) and Department of Epidemiology and Public Health (L.W.), University of Umeå; and Department of Medicine, Luleå Hospital (F.H.), Sweden.
University Hospital of Umeå (SE)
ORCID: Boman, Kurt
Weinehall, Lars
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 1998-11-24
Volume: 98
Issue: 21
Pages: 2241-2247
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/01.cir.98.21.2241
OpenAlex: W1976057876
Cited by: 602
References: 30
Citations by year: 2026: 3 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 19 · 2021: 10 · 2020: 10 · 2019: 6 · 2018: 14 · 2017: 7 · 2016: 17 · 2015: 12 · 2014: 27 · 2013: 20 · 2012: 19
FWCI: 10.91
Type: journal article
Language: en
Open access: closed
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
Funders: Umeå Universitet
Topics: Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
Health Sciences › Medicine › Hematology › Blood properties and coagulation
Keywords: plasminogen activator inhibitor-1, tissue plasminogen activator, acute myocardial infarction, von Willebrand factor, thrombomodulin, fibrinolysis, coronary artery disease, cardiovascular risk prediction, sex differences, plasma biomarkers
MeSH terms: Adult, Age Factors, Female, Fibrinolysis, Humans, Middle Aged, Myocardial Infarction, Tissue Plasminogen Activator, Predictive Value of Tests, Prospective Studies, Risk Factors, Sex Factors, Sweden, Biomarkers, Plasminogen Inactivators, Incidence, Case-Control Studies, Dehydroepiandrosterone Sulfate

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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

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