Viral hemorrhagic fevers due to endotheliopathy-associated disseminated intravascular microthrombosis and hepatic coagulopathy: pathogenesis based on “two activation theory of the endothelium”

Viral hemorrhagic fevers are rare but the life-threatening hemorrhagic disorder associated with viral sepsis. The demise of the patient occurs due to severe inflammation, multi-organ dysfunction syndrome and hemorrhage associated with poorly-defined coagulopathy. Sepsis of several families of RNA viruses causes endothelial injury that orchestrates inflammation and multi-organ dysfunction including the liver. To address additional clinical and hematological features, a novel pathogenesis based on "two-activation theory of the endothelium" is proposed. Endothelial injury activates endothelial cells that promote various clinical syndromes such as consumptive thrombocytopenia, multi-organ dysfunction and thrombotic microangiopathy. Endotheliopathy initiates two independent molecular events at endothelial cells: 1) release of inflammatory cytokines and 2) activation of the platelet and exocytosis of unusually large von Willebrand factor multimers. The former triggers activation of inflammatory pathway and the latter mediates activation of microthrombotic pathway. In viral sepsis, the activation of inflammatory pathway causes inflammation, but the activation of microthrombotic pathway manifests as disseminated intravascular microthrombosis (DIT). The pathogenesis of viral hemorrhagic fevers is hepatic coagulopathy triggered by acute hepatic necrosis as a result of endotheliopathy-associated DIT, which also could manifest as TTP-like syndrome.