Activated protein C ameliorates coagulopathy but does not influence outcome in lethal H1N1 influenza: a controlled laboratory study

Crit Care. 2010;14(2):R65. doi: 10.1186/cc8964. Epub 2010 Apr 14.

Abstract

Introduction: Influenza accounts for 5 to 10% of community-acquired pneumonias and is a major cause of mortality. Sterile and bacterial lung injuries are associated with procoagulant and inflammatory derangements in the lungs. Activated protein C (APC) is an anticoagulant with anti-inflammatory properties that exert beneficial effects in models of lung injury. We determined the impact of lethal influenza A (H1N1) infection on systemic and pulmonary coagulation and inflammation, and the effect of recombinant mouse (rm-) APC here on.

Methods: Male C57BL/6 mice were intranasally infected with a lethal dose of a mouse adapted influenza A (H1N1) strain. Treatment with rm-APC (125 microg intraperitoneally every eight hours for a maximum of three days) or vehicle was initiated 24 hours after infection. Mice were euthanized 48 or 96 hours after infection, or observed for up to nine days.

Results: Lethal H1N1 influenza resulted in systemic and pulmonary activation of coagulation, as reflected by elevated plasma and lung levels of thrombin-antithrombin complexes and fibrin degradation products. These procoagulant changes were accompanied by inhibition of the fibrinolytic response due to enhanced release of plasminogen activator inhibitor type-1. Rm-APC strongly inhibited coagulation activation in both plasma and lungs, and partially reversed the inhibition of fibrinolysis. Rm-APC temporarily reduced pulmonary viral loads, but did not impact on lung inflammation or survival.

Conclusions: Lethal influenza induces procoagulant and antifibrinolytic changes in the lung which can be partially prevented by rm-APC treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / antagonists & inhibitors*
  • Anticoagulants / metabolism
  • Anticoagulants / therapeutic use*
  • Blood Coagulation / drug effects*
  • Down-Regulation / genetics
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / pathogenicity*
  • Lung / drug effects
  • Lung / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Orthomyxoviridae Infections / blood*
  • Orthomyxoviridae Infections / physiopathology
  • Protein C / antagonists & inhibitors*
  • Protein C / genetics
  • Protein C / metabolism
  • Protein C / therapeutic use*
  • Recombinant Proteins
  • Viral Load

Substances

  • Anticoagulants
  • Protein C
  • Recombinant Proteins