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

Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TF‐expressing 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.