Published online before print October 26, 2006, doi: 10.1161/01.RES.0000250834.29108.1a
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Submitted on November 24, 2005
Revised on October 4, 2006
Accepted on October 12, 2006
Effects on Coagulation and Fibrinolysis Induced by Influenza in Mice With a Reduced Capacity to Generate Activated Protein C and a Deficiency in Plasminogen Activator Inhibitor Type 1
Tymen T. Keller *;
From the Departments of Vascular Medicine (T.T.K., V.E.A.G., J.C.M.M., H.R.B., M.L.), Experimental Internal Medicine (K.F.v.d.S., T.v.d.P.), and Pathology (S.F.), Academic Medical Center; and Department of Internal Medicine (M.D.d.K., E.C.M.v.G., D.P.M.B.), Slotervaart Hospital, Amsterdam, The Netherlands.
* To whom correspondence should be addressed. E-mail: t.t.keller{at}amc.uva.nl.
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 TMpro/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.
Key words: thrombotic disease • atherothrombotic disease • infection • inflammation • thrombomodulin • endothelial dysfunction • coagulation • influenza
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