Anticoagulation increases alveolar hemorrhage in mice infected with influenza A

Abstract

Influenza A virus infection is a common respiratory tract infection. Alveolar hemorrhage has been reported in patients with influenza pneumonia and in mice infected with influenza A. In this study, we investigated the effect of two anticoagulants on alveolar hemorrhage after influenza A virus (IAV) infection of wild‐type mice. Wild‐type mice were anticoagulated with either warfarin or the direct thrombin inhibitor dabigatran etexilate and then infected with a mouse‐adapted influenza virus (A/Puerto Rico/8/34 H1N1). Alveolar hemorrhage was assessed by measuring hemoglobin levels in the bronchoalveolar lavage fluid (BALF). We also measured vascular permeability and viral genomes in the lung, as well as white blood cells, inflammatory mediators, and protein in BALF. Survival and body weight were monitored for 14 days after influenza A infection. In infected mice receiving either warfarin or dabigatran etexilate we observed decreased activation of coagulation in the BALF and increased alveolar hemorrhage. Warfarin but not dabigatran etexilate increased vascular permeability and mortality of influenza A‐infected mice. Anticoagulation did not affect levels of influenza A genomes, white blood cells, inflammatory mediators, or protein in the BALF. Our study indicates that systemic anticoagulation increases alveolar hemorrhage in influenza A‐infected mice.

The coagulation system in host defense

“…We found that dabigatran decreased activation of coagulation in the lung measured by TAT levels in the BALF of H1N1 IAV infected mice which was associated with increased pulmonary hemorrhages . However, we could not find any differences in the survival between dabigatran and placebo treated H1N1 IAV infected mice .…”

“…We found that dabigatran decreased activation of coagulation in the lung measured by TAT levels in the BALF of H1N1 IAV infected mice which was associated with increased pulmonary hemorrhages . However, we could not find any differences in the survival between dabigatran and placebo treated H1N1 IAV infected mice . Importantly, we observed that anticoagulation with the vitamin‐K antagonist warfarin increased pulmonary hemorrhages and mortality of H1N1 IAV infected mice .…”

“…Importantly, we could not find any contribution for myeloid, endothelial, or hematopoietic TF on the activation of coagulation nor survival after H1N1 IAV infection . The current studies indicating that H1N1 IAV infection is a hemostatic challenge and epithelial cell TF‐dependent fibrin deposition mediates lung hemostasis . Indeed, reduction of fibrin(ogen) levels with the snake venom ancrod led to an increase of H1N1 IAV infection pathology in mice .…”

“…However, we could not find any differences in the survival between dabigatran and placebo treated H1N1 IAV infected mice . Importantly, we observed that anticoagulation with the vitamin‐K antagonist warfarin increased pulmonary hemorrhages and mortality of H1N1 IAV infected mice . Anticoagulation with warfarin unselective reduces the vitamin K–dependent procoagulant factors prothrombin, FVII, FIX, FX, and the anticoagulant factors protein C and S, whereas dabigatran only inhibits thrombin activity.…”

“…In the past, research was focused on the effect of endotoxemia and bacteremia/sepsis on the coagulation system with regards to DIC, septic shock, and bleeding complications. Newer studies have tried to understand its protective role in viral infections, such as H1N1 influenza A virus (IAV), Ebola virus, and emerging viral pathogens including Dengue and Zika virus …”