Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses

Viral hemorrhagic fever (VHF) describes different diseases caused by several viruses from 6 virus families: Filoviridae, Nairoviridae, Phenuiviridae, Hepadnaviridae, Arenaviridae, and Flaviviridae. VHF was once considered a geographically localized problem, but due to expanding vector ranges and increased human contact with animal reservoirs and hosts, the number of VHF cases is increasing. As the name indicates, VHF is associated with bleeding. Both direct effects from viral infection of host cells and indirect effects caused by the host response to the virus contribute to dysregulation of the hemostatic system. Many studies have measured different parameters and various biomarkers in samples from infected humans and nonhuman primate models. For example, Ebola virus infection in a nonhuman primate model leads to increased TF (tissue factor) expression in peripheral blood mononuclear cells and extracellular vesicles. In dengue virus infection, thrombocytopenia and platelet dysfunction occur. There are likely both common and distinct mechanisms underlying bleeding in different VHFs, as sites of bleeding differ between the viruses. Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability. While a significant body of work exists examining different aspects of the various viral infections that may lead to bleeding, there are still many open questions and areas for investigation. Therefore, more studies are needed to better understand the mechanisms underlying bleeding in VHF caused by different viruses.