Relation between Tissue Factor Pathway Inhibitor Activity and Cardiovascular Risk Factors and Diseases in a Large Population SampleFunding The Gutenberg Health Study is funded through the government of Rhineland-Palatinate (“Stiftung RheinlandPfalz für Innovation,” contract AZ 961–386261/733), the research programs “Wissenschafft Zukunft” and “Center for Translational Vascular Biology (CTVB)” of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including unrestricted grants for the Gutenberg Health Study. This work was supported by the German Federal Ministry of Education and Research (BMBF 01EO1003) and the Center for Translational Vascular Biology (CTVB) of the University Medical Center Mainz (to P.S.W.). H.t.C. was a Fellow of the Gutenberg Research Foundation.
Objective Tissue factor pathway inhibitor (TFPI) is a potent anticoagulant protein in the extrinsic coagulation pathway. In the present study, we aim to identify the cardiovascular determinants for total TFPI activity and its association with cardiovascular disease (CVD) and total mortality.
Methods Total TFPI activity was assessed in a selection of the population-based Gutenberg Health Study (n = 5,000). Statistical analysis was performed to identify the determinants for total TFPI activity as well as the associations with CVD and mortality.
Results Multivariable linear regression analysis identified smoking (β 0.095 [0.054–0.136]) as a positive determinant for total TFPI activity, while diabetes (β –0.072 [–0.134 to –0.009]), obesity (β –0.063 [–0.101 to –0.024]), and history of coronary artery disease (CAD) were negatively associated with total TFPI activity, independent of age, sex, and the remaining cardiovascular risk factors. After adjustment for lipoprotein levels, the association between total TFPI activity levels and obesity and CAD was lost. The analysis additionally revealed a strong positive association between total TFPI activity levels and low-density lipoprotein (β 0.221 [0.204–0.237]). The Cox regression models revealed that a higher total TFPI activity, above 97.5th percentile of the reference group, was associated with an increased mortality risk (hazard ratio = 2.58 [95% confidence interval: 1.49–4.47]), independent of age, sex, and cardiovascular risk profile.
Conclusion In the Gutenberg Health Study population-based cohort, the highest percentage of total TFPI correlated with an increased mortality risk. While elevated TFPI may reflect endothelial cell activation, the associations between total TFPI activity and obesity and CAD, points to additional mechanistic interactions.
* Equal contribution.
Received: 13 May 2020
Accepted: 24 July 2020
02 September 2020 (online)
Georg Thieme Verlag KG
Stuttgart · New York
- 1 Huang ZF, Wun TC, Broze Jr GJ. Kinetics of factor Xa inhibition by tissue factor pathway inhibitor. J Biol Chem 1993; 268 (36) 26950-26955
- 2 Hackeng TM, Seré KM, Tans G, Rosing J. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci U S A 2006; 103 (09) 3106-3111
- 3 Hansen JB, Huseby KR, Huseby NE, Ezban M, Nordøy A. Tissue factor pathway inhibitor in complex with low density lipoprotein isolated from human plasma does not possess anticoagulant function in tissue factor-induced coagulation in vitro. Thromb Res 1997; 85 (05) 413-425
- 4 van Doorn P, Rosing J, Wielders SJ, Hackeng TM, Castoldi E. The C-terminus of tissue factor pathway inhibitor-α inhibits factor V activation by protecting the Arg1545 cleavage site. J Thromb Haemost 2017; 15 (01) 140-149
- 5 Winckers K, Thomassen S, Ten Cate H, Hackeng TM. Platelet full length TFPI-α in healthy volunteers is not affected by sex or hormonal use. PLoS One 2017; 12 (02) e0168273
- 6 Morange PE, Renucci JF, Charles MA. , et al. Plasma levels of free and total TFPI, relationship with cardiovascular risk factors and endothelial cell markers. Thromb Haemost 2001; 85 (06) 999-1003
- 7 Mitchell CT, Kamineni A, Palmas W, Cushman M. Tissue factor pathway inhibitor, vascular risk factors and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 2009; 207 (01) 277-283
- 8 Harris GM, Stendt CL, Vollenhoven BJ, Gan TE, Tipping PG. Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Hematol 1999; 60 (03) 175-180
- 9 Dahm A, Van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101 (11) 4387-4392
- 10 Winckers K, Ten Cate-Hoek AJ, Beekers KC. , et al. Impaired tissue factor pathway inhibitor function is associated with recurrent venous thromboembolism in patients with first unprovoked deep venous thrombosis. J Thromb Haemost 2012; 10 (10) 2208-2211
- 11 Winckers K, Siegerink B, Duckers C. , et al. Increased tissue factor pathway inhibitor activity is associated with myocardial infarction in young women: results from the RATIO study. J Thromb Haemost 2011; 9 (11) 2243-2250
- 12 Crawley J, Lupu F, Westmuckett AD, Severs NJ, Kakkar VV, Lupu C. Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2000; 20 (05) 1362-1373
- 13 Winckers K, ten Cate H, Hackeng TM. The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Rev 2013; 27 (03) 119-132
- 14 Wild PS, Zeller T, Beutel M. , et al. The Gutenberg Health Study [in German]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2012; 55 (6-7): 824-829
- 15 Schnabel RB, Wilde S, Wild PS, Munzel T, Blankenberg S. Atrial fibrillation: its prevalence and risk factor profile in the German general population. Dtsch Arztebl Int 2012; 109 (16) 293-299
- 16 Wild PS, Sinning CR, Roth A. , et al. Distribution and categorization of left ventricular measurements in the general population: results from the population-based Gutenberg Heart Study. Circ Cardiovasc Imaging 2010; 3 (05) 604-613
- 17 Zakai NA, Lutsey PL, Folsom AR, Heckbert SR, Cushman M. Total tissue factor pathway inhibitor and venous thrombosis. The Longitudinal Investigation of Thromboembolism Etiology. Thromb Haemost 2010; 104 (02) 207-212
- 18 Morange PE, Simon C, Alessi MC. , et al. PRIME Study Group. Endothelial cell markers and the risk of coronary heart disease: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. Circulation 2004; 109 (11) 1343-1348
- 19 Novotny WF, Brown SG, Miletich JP, Rader DJ, Broze Jr GJ. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood 1991; 78 (02) 387-393
- 20 Ellery PER, Hilden I, Sejling K. , et al. Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S. Res Pract Thromb Haemost 2018; 2 (01) 93-104
- 21 Høibraaten E, Qvigstad E, Andersen TO, Mowinckel MC, Sandset PM. The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism--results from a randomized, double-blind, clinical trial. Thromb Haemost 2001; 85 (05) 775-781
- 22 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 (15) 1961-1966
- 23 Dahm AEA, Iversen N, Birkenes B, Sandset PM. Production of tissue factor pathway inhibitor in endothelial cell cultures is reduced by estrogens, selective estrogen receptor modifiers, and a selective estrogen receptor downregulator. Blood 2005; 106 (11) 70b-b
- 24 Zawadzki C, Susen S, Richard F. , et al. Dyslipidemia shifts the tissue factor/tissue factor pathway inhibitor balance toward increased thrombogenicity in atherosclerotic plaques: evidence for a corrective effect of statins. Atherosclerosis 2007; 195 (02) e117-e125
- 25 Roldán V, Marín F, Fernández P. , et al. Tissue factor/tissue factor pathway inhibitor system and long-term prognosis after acute myocardial infarction. Int J Cardiol 2001; 78 (02) 115-119
- 26 Sandset PM. Tissue factor pathway inhibitor (TFPI)--an update. Haemostasis 1996; 26 (Suppl. 04) 154-165