Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus

Abstract

Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TFexpressing cells also release TF-positive extracellular vesicles (EVs) into the circulation that can be measured using an EVTF activity assay. This review summarizes studies that analyze TF expression, TF-positive EVs, activation of coagulation, and thrombosis after infection with influenza A virus (IAV) and coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome CoV (MERS-CoV). The current pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with SARS-CoV-2. Infection of mice with IAV increased TF expression in lung epithelial cells as well as increased EVTF activity and activation of coagulation in the bronchoalveolar lavage fluid (BALF). Infection of mice with MERS-CoV, SARS-CoV, and SARS-CoV-2 also increased lung TF expression. Single-cell RNA sequencing analysis on the BALF from severe COVID-19 patients revealed increased TF mRNA expression in epithelial cells. TF expression was observed in peripheral blood mononuclear cells infected with SARS-CoV. TF was also expressed by peripheral blood mononuclear cells, monocytes in platelet-monocyte aggregates, and neutrophils isolated from COVID-19 patients. Elevated circulating EVTF activity was observed in severe IAV and COVID-19 patients. Importantly, EVTF activity was associated with mortality in severe IAV patients and with plasma D-dimer, severity, thrombosis, and mortality in COVID-19 patients. These studies strongly suggest that increased TF expression in patients infected with IAV and pathogenic CoVs contributes to thrombosis.

Platelet-Released Factors: Their Role in Viral Disease and Applications for Extracellular Vesicle (EV) Therapy

“…PMV release is stimulated in platelets by the formation of thrombin and by the binding of H1N1 to FcγRIIA [92]. Similar to some reports of DENV, influenza-related mortality correlates with elevated plasma levels of TF-expressing PMVs (Figure 3) [93]. Additionally, thrombocytopenia is associated with increases in influenza virus pathogenicity and is dependent upon the subtype of influenza virus [94].…”

“…Similar to IAV, SARS-CoV-2-associated mortality is correlated with elevated plasma levels of TF-expressing PMVs; however, PMVs are not alone in TF expression as peripheral blood mononuclear cells (PMBCs) also express elevated levels of TF [93,95]. Elevated plasma levels of TF-expressing PMVs is also associated with COVID-19 disease severity and thrombosis [93]. Similar to HIV, IAV, and some DENV cases, SARS-CoV-2 has been found to be associated with increased levels of circulating PMVs and EVs (Figure 3) [96][97][98][99][100].…”

Evaluation of a new bead‐based assay to measure levels of human tissue factor antigen in extracellular vesicles in plasma

“…1 Increased levels of TF+ EVs in the circulation are associated with activation of coagulation and thrombosis in different diseases, such as cancer, sepsis, and coronavirus disease 2019 (COVID‐19). 2 , 3 , 4 , 5 , 6 , 7 Levels of TF+ EVs can be measured using either activity‐based or antigen‐based assays. 8 Activity‐based assays are more sensitive than antigen‐based assays.…”

Extracellular Vesicles and Thrombosis: Update on the Clinical and Experimental Evidence

“…Future studies in this direction will shed more light on the specific contribution of EVs to the coagulopathy in COVID-19 or other viral infections associated with an increased risk of thrombosis [224] and also clarify their role as mediators of thromboinflammation, biomarkers of disease severity or therapeutic vehicles. Please also see the review article by Adriana Georgescu and Maya Simionescu for more details [225].…”