Elevated coagulation factor levels affect the tissue factor-threshold in thrombin generation.

INTRODUCTION: Altered levels of factor (F)VIII, prothrombin, or antithrombin have been associated with an increased risk for venous thromboembolism (VTE). However, the exact molecular mechanism by which these altered factor levels modulate the risk is incompletely understood. Here we hypothesize that elevated factor levels affect the pro- and anticoagulant balance in coagulation such that even minute amounts of tissue factor (TF) will initiate thrombin formation, thereby contributing to the VTE risk. MATERIALS AND METHODS: To test this so-called TF-threshold hypothesis, we monitored thrombin generation initiated by very low TF concentrations in FXII-deficient plasma, to avoid any contact pathway-mediated thrombin formation. Furthermore, similar experiments were performed in the presence of increasing concentrations of pro- and anticoagulant proteins. RESULTS: A TF-threshold was established in the FXII-deficient plasma, which is subject to inter-individual variation. Elevated plasma levels of procoagulant factors, such as FVIII or prothrombin, enhanced thrombin generation and reduced the amount of TF required for the initiation of thrombin formation. Conversely, elevated levels of the coagulation inhibitor antithrombin increased the TF-threshold. CONCLUSIONS: Our findings support a mediating role for the TF-threshold in the association between high procoagulant factor levels and the risk for VTE. Furthermore, elevated levels of anticoagulants may have a protective effect on the development of VTE.

Factor V levels and risk of venous thrombosis: The MEGA case-control study.

BACKGROUND: Blood coagulation levels are associated with risk of venous thrombosis (VT). The role of factor (F)V is ambiguous since it plays a dual role in coagulation: it has a procoagulant role when it serves as a cofactor for the activation of thrombin and it has an anticoagulant role by enhancing the inactivation of activated FVIII. OBJECTIVES: To elucidate the association of FV levels with risk of VT. PATIENTS/METHODS: We analyzed FV antigen levels in 2377 patients with VT and 2943 controls from the MEGA study. FV levels were categorized according using the 1st, 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of FV levels in controls as cut-off points. Odds ratios (ORs) were estimated using logistic regression models and adjusted for age and sex, liver disease, FVIII levels, FV Leiden, and TFPI. RESULTS: The risk estimates were U-shaped with increased ORs for the lowest (<0.57 U/dL) levels (OR 1.46; 95% CI 0.87-2.43) as well as the highest (>1.22 U/dL) (OR 1.86; 95% CI 1.46-2.37) levels as compared with the reference group (25th-50th percentile). FVIII adjustment led to attenuation of the OR for high FV levels (OR 1.14; 95% CI 0.88-1.48), with little change for low FV levels (OR 1.68; 95% CI 0.97-2.91). Other adjustments had limited effects. CONCLUSIONS: We found high FV levels to be associated with increased risk for VT, which was explained by concurrently raised FVIII levels. For low levels of factor V, the increased risk for VT could not be explained by the mechanisms we explored.

Global histone H3 lysine 27 triple methylation levels are reduced in vessels with advanced atherosclerotic plaques.

AIMS: Alterations in epigenetic processes are frequently noted in human disease. These epigenetic processes involve methylation of DNA and post-translational modifications of histones. It is well established that in particular histone methylation plays a key role in gene transcription. In this study, we have investigated the relationship between triple methylation of lysine 27 in histone H3 (H3K27Me3) modifications and atherosclerotic plaque stage. MATERIALS AND METHODS: 28 peri-renal aortic tissue patches covering the entire spectrum of atherosclerotic plaque development were evaluated by immunohistochemistry for the levels of H3K27Me3, EZH2, JMJD3 and BMI1. KEY FINDINGS: The results of our studies are in support of a reduction in global levels of the H3K27Me3 modification in vessels with advanced atherosclerotic plaques. This reduction in H3K27Me3 levels is not accompanied by alterations in global levels of the corresponding histone methyltransferase EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2). Likewise no alterations in global levels of BMI1, a component of the PRC1 complex, which binds to H3K27Me3-modified histones or the global expression levels of the histone demethylase JMJD3, which removes the methyl marks on H3K27, were observed. SIGNIFICANCE: Together, our data show that in atherosclerosis development alterations in global levels of H3K27Me3 occur. The reduction in the number of nuclei in the tunica media that display the repressive H3K27Me3 mark in vessels with advanced atherosclerosis plaques therefore could be a reflection of the dynamic pattern of smooth muscle cell differentiation and proliferation associated with atherosclerotic disease.