Increased tissue factor pathway inhibitor activity is associated with myocardial infarction in young women: results from the RATIO study

Abstract

Summary. Background: The tissue factor pathway inhibitor (TFPI)/protein S anticoagulant system is a potent inhibitor of blood coagulation. TFPI and protein S are major determinants of thrombin generation (TG) tests determined at low tissue factor (TF) and at high TF concentrations in the presence of activated protein C (APC). Both TFPI and protein S protect against venous thrombosis, but the importance of the TFPI/protein S system in arterial thrombosis remains unclear. Objectives: To investigate the influence of the TFPI/protein S anticoagulant system on the risk of myocardial infarction (MI) in young women. Methods: The RATIO study is a case-control study in women under 50 years of age, including 205 patients and 638 controls. TFPI and protein S were quantified using ELISA. The TFPI/ protein S activity (nTFPIr) and the APC sensitivity ratio (nAPCsr) were determined using TG tests. Odds ratios (ORs) adjusted for putative confounders and corresponding 95% confidence intervals (95% CI) were determined. Results: Women with MI had higher TFPI levels than controls (135.9 ± 40% vs. 124.2 ± 41%), resulting in increased TFPI/protein S activities and increased APC sensitivity. Furthermore, an increased TFPI activity was associated with MI [nTFPIr: adjusted OR Q1 vs. Q4 = 2.1 (95%CI 1.1-4.1)]. Additionally, an increased APC sensitivity was associated with MI [nAPCsr: adjusted OR Q1 vs. Q4 = 1.7 (95% CI 0.9-3.2)] Conclusion: Women with MI had increased TFPI levels compared with controls. Consequently, the TFPI/protein S activity and APC sensitivity are increased in women with MI. Whether this increase in TFPI activity acts as a compensating mechanism for an increased procoagulant state or is a marker of endothelial damage remains to be investigated.

Thrombin Generation in the Glasgow Myocardial Infarction Study

“…The prolonged lag time in cases of the present study is in accordance with the observation in the MARK study, where lagtime was prolonged in the acute phase but also at later timepoints [3]. This prolongation may be due to release of TFPI from perturbed endothelium such as demonstrated in a recent case control study in young women with manifestations of arterial thrombosis (AMI or stroke) [10]. However, also other changes in the balance between pro- and anticoagulant proteins may be involved in the alterations in thrombin generation profile.…”

Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Coronary Heart Disease Due To Combined Estrogen Plus Progestin Therapy

“…Our findings that decreased APC sensitivity is associated with CHD risk stand in contrast to another large study which found increased (rather than decreased) sensitivity to APC in young women with myocardial infarction. 19 However, since this was a retrospective case-control study the measurement of APC sensitivity was performed in prevalent cases and therefore it is uncertain whether the findings reflect a compensating mechanism for an increased procoagulant state associated with underlying arterial disease. The prospective design of the current study is better suited towards identification of risk factors preceding incident disease.…”

“…In a retrospective case-control study of myocardial infarction in young women cases compared to controls showed a decrease (rather than the expected increase) in APC resistance using the thrombin generation-based APC resistance test. 19 On the other hand a positive association of APC resistance with severity of arterial disease was found using the classical APC resistance test. 20 EPT induces an acquired resistance to APC in women without genotypic FVL, increases resistance in those with FVL, and increases risk of VT in women with and without FVL.…”

“…21 Paradoxically, however, higher TFPI levels have been noted in patients with subclinical or symptomatic atherosclerosis compared to controls. 19, 24–26 Reductions in TFPI and of protein S are thought to be key determinants underlying the activation of coagulation and the development of acquired APC resistance associated with OCs. 4,10,11 Protein S binds to TFPI and as a co-factor has a biological interaction, increasing TFPI activity in laboratory studies, but an interaction on venous thrombosis was not found in an epidemiologic study.…”

“…27 Though free TFPI is considered to be the most biologically active form, epidemiologic studies have variably measured total TFPI, free TFPI, or TFPI activity; where more than one form was measured the results were generally concordant. 9,19,26 In the current study we investigated all 3 forms of TFPI as well as acquired APC resistance, but not protein S or antithrombin levels.…”