title: 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.
abstract: 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.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. t.t.keller@amc.uva.nl
authors.forename: Tymen T
authors.initials: TT
authors.lastname: Keller
authors.forename: Koen F
authors.initials: KF
authors.lastname: van der Sluijs
authors.forename: Martijn D
authors.initials: MD
authors.lastname: de Kruif
authors.forename: Victor E A
authors.initials: VE
authors.lastname: Gerdes
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Eric C M
authors.initials: EC
authors.lastname: van Gorp
authors.forename: Dees P M
authors.initials: DP
authors.lastname: Brandjes
authors.forename: Harry R
authors.initials: HR
authors.lastname: Büller
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D005260:Female; D005342:Fibrinolysis; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009975:Orthomyxoviridae; D009976:Orthomyxoviridae Infections / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency*; D011392:Proline; D011486:Protein C / Q000096:biosynthesis* / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics; D013927:Thrombosis / Q000235:genetics / Q000821:virology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C; D018180:Thrombomodulin; D011392:Proline