Mechanisms Underlying Coagulation Abnormalities in Ebola Hemorrhagic Fever: Overexpression of Tissue Factor in Primate Monocytes/Macrophages Is a Key Event

Abstract

Disseminated intravascular coagulation is a prominent manifestation of Ebola virus (EBOV) infection. Here, we report that tissue factor (TF) plays an important role in triggering the hemorrhagic complications that characterize EBOV infections. Analysis of samples obtained from 25 macaques showed increased levels of TF associated with lymphoid macrophages, whereas analysis of peripheral blood-cell RNA showed increased levels of TF transcripts by day 3. Plasma from macaques contained increased numbers of TF-expressing membrane microparticles. Dysregulation of the fibrinolytic system developed during the course of infection, including a rapid decrease in plasma levels of protein C. Infection of primary human monocytes/macrophages (PHMs) was used to further evaluate the role of TF in EBOV infections. Analysis of PHM RNA at 1-48 h showed increased TF transcripts, whereas levels of TF protein were dramatically increased by day 2. Thus, chemotherapeutic strategies aimed at controlling overexpression of TF may ameliorate the effects of EBOV hemorrhagic fever.

Post-exposure treatments for Ebola and Marburg virus infections

“…Systematic studies in experimentally infected NHPs suggest that monocytes, macrophages and dendritic cells are the early replication sites for EBOV and MARV 41,48,51 . Filovirus infection of mononuclear phagocytes is thought to trigger a series of events that includes the production and release of the procoagulant protein tissue factor 54,55 and an assortment of pro-inflammatory cytokines, chemokines and free radical species in NHPs and humans 48,51,[55][56][57][58][59][60][61][62][63][64][65][66][67][68] . This dysregulated host response likely plays a greater role in the development of the observed pathology than any structural damage caused by viral replication in host cells and/or tissues.…”

“…Results from many studies have shown biochemical and histological evidence of disseminated intravascular coagulation in both experimentally infected NHPs and humans 19,20,22,23,40,[44][45][46][49][50][51]53,54,70,[73][74][75][76][77][78][79] . The mechanisms that cause these coagulation disorders are not fully understood, but the expression or release of tissue factor from filovirus-infected monocytes and macro phages seems to play a role 54,55 . However, the coagulation irregularities noted during filovirus haemorrhagic fever could be caused by other factors, particularly at the end stage of disease.…”

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

“…As noted above, ZEBOV infection induces overexpression of the procoagulant TF in primate monocytes/macrophages (Ref. 63), suggesting that TF-pathway inhibition might ameliorate the effects of EBOV HF. Based on these data, it was postulated that blocking factor VIIa (FVIIa)/TF might be beneficial after EBOV infection (Ref.…”

“…63). This work suggests that protein C might be a critical component to the observed coagulation dysfunction in ZEBOV HF.…”

Virus-Induced Decline in Soluble Vascular Endothelial Growth Receptor 2 Is Associated with Plasma Leakage in Dengue Hemorrhagic Fever

“…It is possible that the effects on endothelial cells in vivo may be an indirect consequence of the interaction between virus and other cell types, as reported in other viral hemorrhagic diseases. In a rhesus model of Ebola virus infection, it has been demonstrated that factors released from infected macrophages enhanced vascular permeability (13,14). Unlike sVEGFR2, exposure to live virus has no effects on the production of sVEGFR1 by endothelial cells.…”