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

Abstract

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.

Resistance to activated protein C and impaired TFPI activity in women with previous hormone-induced venous thromboembolism

“…This difference was less pronounced, if the protein S function was inhibited by a specific antibody and completely reversed by addition of TFPI antibody or at high tissue factor concentrations. Altogether, this strongly suggests that smoking increases activity of the TFPI system, confirming the data of van Paridon et al, who also demonstrated lower peak height at 1 pM of tissue factor in a part of their population, consisting of smoking women [28] and later confirmed that smokers have increased TFPI activity [29]. Higher TFPI activity in smokers could possibly be a result of endothelial damage or chronical inflammation in the vessel wall with consequently increased synthesis, release or altered binding of TFPI to the endothelium by glucosaminoglycans [30].…”

Role of tissue factor pathway inhibitor in hormone-induced venous thromboembolism

“…Remarkably, smoking status appeared to be a strong factor, increasing activity of the TFPI system and response to APC [37,56]. The clinical relevance of this increase in the TFPI levels induced by smoking remains unclear but it is likely to counteract the prothrombotic changes, like elevated fibrinogen, factor IX and decreased antithrombin, that have been previously described in the context of smokers [57].…”

Proteomic profiling for prediction of recurrent cardiovascular event in patients with acute coronary syndrome and obstructive sleep apnea: A post-hoc analysis from the ISAACC study

“…STK4 is a key component of the Hippo signaling pathway and is thus an essential regulator of cardiac development and regeneration/repair after injury [46,47]. TFPI is implicated in the development of atherosclerosis [48,49] and is associated with fibrinogen levels [50,51]. In addition, a previous study of OSA patients compared to non-OSA patients reported a profile of 65 proteins, highlighting a differentially expressed profile pattern of TFPI in patients with OSA [52].…”