Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Thromb Res. 2018 Dec;172:104-109. doi: 10.1016/j.thromres.2018.10.020. Epub 2018 Oct 25.
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.
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.
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.
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.
因子(F)VIII、凝血酶原或抗凝血酶水平的改变与静脉血栓栓塞症(VTE)的风险增加有关。然而，这些改变的因子水平调节风险的确切分子机制尚不完全清楚。在这里，我们假设升高的因子水平会影响凝血中的促凝和抗凝平衡，使得即使是微量的组织因子(TF)也会引发血栓形成，从而增加 VTE 的风险。
为了验证所谓的 TF 阈值假说，我们在 FXII 缺乏的血浆中监测了由极低浓度 TF 引发的凝血酶生成，以避免任何接触途径介导的凝血酶形成。此外，还在存在浓度逐渐增加的促凝和抗凝蛋白的情况下进行了类似的实验。
在 FXII 缺乏的血浆中建立了 TF 阈值，该阈值存在个体间差异。促凝因子如 FVIII 或凝血酶原的血浆水平升高会增强凝血酶生成，并减少启动凝血酶形成所需的 TF 量。相反，凝血抑制剂抗凝血酶水平的升高会增加 TF 阈值。
我们的发现支持 TF 阈值在高促凝因子水平与 VTE 风险之间的关联中起介导作用。此外，抗凝剂水平的升高可能对 VTE 的发展具有保护作用。
