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(Circulation Research. 2006;99:1261.)
© 2006 American Heart Association, Inc.

Integrative Physiology

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, Koen F. van der Sluijs, Martijn D. de Kruif, Victor E. A. Gerdes, Joost C. M. Meijers, Sandrine Florquin, Tom van der Poll, Eric C. M. van Gorp, Dees P. M. Brandjes, Harry R. Büller, Marcel Levi

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.

Correspondence to Tymen Keller, MD, Department of Vascular Medicine, Academic Medical Center, Rm F4-121, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 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 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.

Key Words: thrombotic disease • atherothrombotic disease • infection • inflammation • thrombomodulin • endothelial dysfunction • coagulation • influenza

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