Activation of coagulation and tissue fibrin deposition in experimental influenza in ferrets.

Kamran Bakhtiari,Judith MA Van den Brand,Marco Goeijenbier,Joost CM Meijers,Koert Stittelaar,Albert DME Osterhaus,Thijs Kuiken,Geert van Amerongen,Eric CM van Gorp,Byron EE Martina,Joris JTH Roelofs

doi:10.1186/1471-2180-14-134

Abstract

BackgroundEpidemiological studies relate influenza infection with vascular diseases like myocardial infarction. The hypothesis that influenza infection has procoagulant effects on humans has been investigated by experimental animal models. However, these studies often made use of animal models only susceptible to adapted influenza viruses (mouse adapted influenza strains) or remained inconclusive. Therefore, we decided to study the influence of infection with human influenza virus isolates on coagulation in the well-established ferret influenza model.ResultsAfter infection with either a seasonal-, pandemic- or highly pathogenic avian influenza (HPAI-H5N1) virus strain infected animals showed alterations in hemostasis compared to the control animals. Specifically on day 4 post infection, a four second rise in both PT and aPTT was observed. D-dimer concentrations increased in all 3 influenza groups with the highest concentrations in the pandemic influenza group. Von Willebrand factor activity levels increased early in infection suggesting endothelial cell activation. Mean thrombin-antithrombin complex levels increased in both pandemic and HPAI-H5N1 virus infected ferrets. At tissue level, fibrin staining showed intracapillary fibrin deposition especially in HPAI-H5N1 virus infected ferrets.ConclusionThis study showed hemostatic alterations both at the circulatory and at the tissue level upon infection with different influenza viruses in an animal model closely mimicking human influenza virus infection. Alterations largely correlated with the severity of the respective influenza virus infections.

Highlights

Epidemiological studies relate influenza infection with vascular diseases like myocardial infarction
Clinical reports range from mild increased coagulation and fibrinolysis markers such as von Willebrand factor (VWF) and D-dimer levels, to disseminated intravascular coagulation observed in severe avian influenza [12,13,14]
All animals infected with H3N2, pH1N1, or mock infection, survived the infections

Summary

Introduction

Epidemiological studies relate influenza infection with vascular diseases like myocardial infarction. The hypothesis that influenza infection has procoagulant effects on humans has been investigated by experimental animal models. These studies often made use of animal models only susceptible to adapted influenza viruses (mouse adapted influenza strains) or remained inconclusive. Current data suggest that influenza virus infection causes an unbalanced coagulation manifested by a procoagulant state (for review see [8,9,10,11]). Indications for this increased clotting tendency have come from clinical, experimental mouse and in vitro data. Experimental animal studies and epidemiological data have largely remained inconclusive and cannot readily be translated into clinically relevant conclusions

Methods

Results

Discussion

Conclusion