Lipid-Mediated Relation between Tissue Factor Pathway Inhibitor Activity and Cardiovascular Risk Factors and Diseases in a Large Population Sample

Background: Tissue factor pathway inhibitor (TFPI), a Kunitz-type serine protease, is a potent anticoagulant protein in the extrinsic coagulation pathway and acts by inhibiting both the FXa and the Tissue Factor-FVIIa complex. In contrast to total and free TFPI antigen levels, the reference values and clinical determinants of total TFPI activity have not yet been studied in detail in the general population. In the present study, we aim to identify the cardiovascular determinants for total TFPI activity and investigate its association with cardiovascular disease (CVD) and total mortality, in a population at large.

Methods: For this study, the first 4779 subjects of the population-based Gutenberg Health Study were examined in a highly standardized setting. Total TFPI activity was assessed in platelet poor plasma by the Actichrome TFPI activity assay (American Diagnostica, Stamford, CT, USA). Sex-specific nomograms were developed to demonstrate the relation of total TFPI activity with age. Multivariable regression analysis was performed to assess the determinants of total TFPI activity and to evaluate the association with CVD. Cox-regression models, adjusted for age, sex, cardiovascular risk factors (CVRFs) and CVD, were calculated to investigate the association between total TFPI activity and total mortality.

Results: The multivariable linear regression analysis identified smoking (β, 0.0952 [0.0541 to 0.136],) as a positive determinant for total TFPI activity, while diabetes (β, -0.0716 [-0.134 to -0.00905],), obesity (β, -0.0627 [-0.101 to -0.024],) and history of coronary artery disease (CAD) were negatively associated with TFPI activity, independent of age, sex and the remaining CVRFs. After adjustment for high-density lipoprotein levels (HDL), low-density lipoproteins (LDL) and triglycerides, the association between TFPI activity levels and obesity and CAD was lost. The analysis additionally reveals a strong positive association between TFPI activity levels and LDL (β, 0.221 [0.204 to 0.237],). The Cox regression models revealed that a higher TFPI activity, above 97.5^th percentile of the reference group, was associated with an increased mortality risk (HR = 2.58, [95% CI: 1.49/4.47], p=0.00074) independent of age, sex, CVRFs, CVD, oral contraceptives and hormonal replacement therapy. After additional adjustment for LDL levels, this relation became stronger.

Conclusion: To the best of our knowledge, this is the first large, epidemiological study of the general population, revealing an increased mortality risk in individuals with higher TFPI activity, independent of CVRFs and CVD and emphasized by LDL-levels. Additionally, it demonstrates the negative association between total TFPI activity levels and CVD, particularly CAD. Furthermore, an association between TFPI activity and obesity, mediated through lipoprotein particles is explored. Lastly, it describes the age- and sex-related reference range of total TFPI activity levels in a large population-based data set.