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

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.

Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions

“…An aberrant pro-coagulant response has been previously described to contribute to IAV pathogenesis [15,16]. To determine if an IAV infection in epithelial cells was sufficient to induce a pro-coagulant state in the adjacent endothelial cells, we measured the time to thrombin generation by incubating human plasma with either IAV-or mock-infected co-cultures.…”

“…The inflammatory response to IAV may also result in the upregulation of tissue factor, which can be expressed on both endothelial cells and leukocytes. Increased expression of tissue factor on endothelial cells during IAV infection can result in an aberrant pro-coagulant state, leading to the consumption of coagulation factors, microvascular leak and pulmonary haemorrhage [15][16][17]. Furthermore, a pro-coagulant state induces the release of cytokines such as interleukin (IL)-6 and IL-8 [18], which may further enhance the severity of an IAV-induced cytokine storm and any associated barrier damage.…”

Nasal priming with immunobiotic Lactobacillus rhamnosus modulates inflammation–coagulation interactions and reduces influenza virus-associated pulmonary damage

“…Goeijenbier et al [43] associated the pro-coagulant state observed in ferrets infected with influenza with the development of infarction. They also observed hemostatic alterations at both vascular and tissue levels during IFV infections.…”

Aberrant coagulation causes a hyper-inflammatory response in severe influenza pneumonia

“…Animal studies have partly explained the mechanism of activated coagulation by IAV infection. 48 , 49 IAV activates coagulation by increasing thrombin generation, fibrin deposition and fibrinolysis in C57BL/6 mice. 48 D-dimer (a circulating marker for enhanced coagulation and fibrinolysis) concentrations and von Willebrand factor (vWF) activity are both increased in ferrets after infection with seasonal, pandemic or highly pathogenic avian influenza (HPAI)-H5N1 viruses.…”