Pathogenesis of Ebola Viral Haemorrhagic Fever: TTP-like Syndrome Associated with Hepatic Coagulopathy based on "Two Activation Theory of the Endothelium"

Abstract

Ebola viral haemorrhagic fever is a serious haemorrhagic disorder associated with Ebola viral sepsis. The demise of the patient occurs due to severe inflammation, multi-organ dysfunction syndrome and haemorrhage associated with a poorly defined coagulopathy. Ebola virus causes endothelial injury that orchestrates inflammation and multi-organ dysfunction, especially in the liver. To address clinical and hematological features, a novel pathogenesis based on the "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 Ebola viral sepsis, activation of inflammatory pathway causes inflammation, but activation of microthrombotic pathway manifests as disseminated intravascular microthrombosis (DIT). The pathogenesis of Ebola viral haemorrhagic fever is hepatic coagulopathy triggered by acute hepatic necrosis as a result of endotheliopathy-associated DIT, which could manifest as TTP-like syndrome.

Selenium and RNA Virus Interactions: Potential Implications for SARS-CoV-2 Infection (COVID-19)

“…It is a single-stranded RNA virus whose complex metabolism remains comparable to RNA viruses such as Influenza virus, some hemorrhagic fever viruses (such as Ebola virus or Hantavirus), Human Immunodeficiency Virus (HIV) and Coxsackievirus ( 2 , 3 ). COVID-19 is a systemic disease and in addition to the more obvious respiratory symptoms, secondary symptoms that are now known to contribute to COVID-19 associated morbidity and mortality include heart problems like myocarditis (a primary feature of Coxsackievirus infection) ( 4 ) and systemic microthrombosis (a feature of hemorrhagic fever viruses) ( 5 ). Although few data are available thus far about the interaction between Se, an essential natural trace element, and SARS-CoV-2, RNA virus and Se interactions are well-documented ( 6 – 9 ).…”

Novel Classification of Thrombotic Disorders Based on Molecular Hemostasis and Thrombogenesis Producing Primary and Secondary Phenotypes of Thrombosis

“…Arterial endotheliopathy often produces the triad of TTP-like syndrome characterized by consumptive thrombocytopenia, MAHA and MODS [ 23 ], but venous endotheliopathy typically causes immune thrombocytopenic purpura (ITP)-like syndrome with “silent clinical feature” [ 10 ]. Surprisingly, this disparity expressed in microthrombotic syndromes in COVID-19 pandemic has provided me a clue that COVID-19 is predominantly the disease of vEA-VMTD (e.g., ARDS and ITP-like syndrome) [ 13 ] while Ebola viral hemorrhagic disease is commonly associated with aEA-VMTD causing hepatocellular necrosis (e.g., hepatic coagulopathy and TTP-like syndrome) [ 24 ], which had been thought to be acute “DIC”.…”

“…The most common thrombosis encountering among many human diseases is microthrombosis (i.e., VMTD), which can be induced by sepsis (e.g., bacterial, viral, fungal, rickettsial and parasitic), polytrauma, envenomation, side effects of drugs, diabetes, autoimmune disease, and complications of surgery, pregnancy and transplant. EA-VMTD is usually disseminated in the microvasculature [ 14 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. It is well established to be due to complement activated endotheliopathy leading to ECs dysfunction [ 28 , 29 ].…”

“…Also, tropism is known to play a significant role producing in clinical phenotypes of microthrombotic disorder such as Waterhouse-Friderichsen syndrome by meningococcus’s propensity attracting to the adrenal glands [ 38 ], ARDS by SARS-CoV-2′s predilection for the lungs [ 32 , 33 ], cerebral malaria by plasmodium falciparum’s attraction to the brain [ 39 ]. Perhaps, the endothelial heterogeneity of host may play a serious role producing posttransplant veno-occlusive disease to the liver [ 37 , 40 ], and Ebola viral hemorrhagic disease leading to hepatic coagulopathy [ 24 ]. In addition to environmental factors such as aging, life style, high altitude travel and smoking, macrothrombosis may be upregulated by genetic factors, especially thrombophilia affecting TF pathway (e.g., gene mutation of protein C and protein S, and factor V Leiden) [ 41 ], and microthrombosis can be upregulated by thrombophilia affecting ULVWF pathway (e.g., ADAMTS13 polymorphism) [ 23 ].…”

Selenium and RNA virus interactions: Potential implications for SARS-CoV-2 infection (COVID-19)

“…It is a single-stranded RNA virus whose complex metabolism remains comparable to RNA viruses such as Influenza virus, some hemorrhagic fever viruses (such as Ebola virus or Hantavirus), Human Immunodeficiency Virus (HIV) and Coxsackievirus (2,3). COVID-19 is a systemic disease and in addition to the more obvious respiratory symptoms, secondary symptoms that are now known to contribute to COVID-19 associated morbidity and mortality include heart problems like myocarditis (a primary feature of Coxsackievirus infection) (4) and systemic microthrombosis (a feature of hemorrhagic fever viruses) (5). Although few data are available thus far about the interaction between Se, an essential natural trace element, and SARS-CoV-2, RNA virus and Se interactions are well-documented (6)(7)(8)(9).…”