Inge M Rietveld1, Mark Schreuder1, Pieter H Reitsma1, Mettine H A Bos2. 1. Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands. 2. Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: M.H.A.Bos@lumc.nl.
Abstract
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.
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.