Keller Tymen T, van der Sluijs Koen F, de Kruif Martijn D, Gerdes Victor E A, Meijers Joost C M, Florquin Sandrine, van der Poll Tom, van Gorp Eric C M, Brandjes Dees P M, Büller Harry R, Levi Marcel
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Circ Res. 2006 Nov 24;99(11):1261-9. doi: 10.1161/01.RES.0000250834.29108.1a. Epub 2006 Oct 26.
Influenza infections increase the risk of diseases associated with a prothrombotic state, such as venous thrombosis and atherothrombotic diseases. However, it is unclear whether influenza leads to a prothrombotic state in vivo. To determine whether influenza activates coagulation, we measured coagulation and fibrinolysis in influenza-infected C57BL/6 mice. We found that influenza increased thrombin generation, fibrin deposition, and fibrinolysis. In addition, we used various anti- and prothrombotic models to study pathways involved in the influenza-induced prothrombotic state. A reduced capacity to generate activated protein C in TM(pro/pro) mice increased thrombin generation and fibrinolysis, whereas treatment with heparin decreased thrombin generation in influenza-infected C57Bl/6 mice. Thrombin generation was not changed in hyperfibrinolytic mice, deficient in plasminogen activator inhibitor type-1 (PAI-1(-/-)); however, increased fibrin degradation was seen. Treatment with tranexamic acid reduced fibrinolysis, but thrombin generation was unchanged. We conclude that influenza infection generates thrombin, increased by reduced levels of protein C and decreased by heparin. The fibrinolytic system appears not to be important for thrombin generation. These findings suggest that influenza leads to a prothrombotic state by coagulation activation. Heparin treatment reduces the influenza induced prothrombotic state.
流感感染会增加与血栓前状态相关疾病的风险，如静脉血栓形成和动脉粥样硬化血栓形成疾病。然而，目前尚不清楚流感在体内是否会导致血栓前状态。为了确定流感是否会激活凝血，我们检测了流感感染的C57BL/6小鼠的凝血和纤溶情况。我们发现流感会增加凝血酶生成、纤维蛋白沉积和纤溶作用。此外，我们使用了各种抗血栓和促血栓模型来研究流感诱导的血栓前状态所涉及的途径。TM（pro/pro）小鼠中生成活化蛋白C的能力降低，会增加凝血酶生成和纤溶作用，而用肝素治疗可降低流感感染的C57BL/6小鼠的凝血酶生成。在纤溶亢进的小鼠中，凝血酶生成没有变化，这些小鼠缺乏纤溶酶原激活物抑制剂1型（PAI-1（-/-））；然而，观察到纤维蛋白降解增加。用氨甲环酸治疗可减少纤溶作用，但凝血酶生成没有变化。我们得出结论，流感感染会产生凝血酶，蛋白C水平降低会使其增加，而肝素会使其降低。纤溶系统似乎对凝血酶生成并不重要。这些发现表明，流感通过激活凝血导致血栓前状态。肝素治疗可降低流感诱导的血栓前状态。
