Tissue Factor's Role in the Pathogenesis of Hypercoagulability in COVID-19

Emerging evidence indicates that the novel SARS-CoV-2 infection is associated with a high incidence of thrombotic complications. Thrombotic complications in COVID-19 patients are found to be life-threatening. Elevated D-dimers and disseminated intravascular coagulation (DIC) are strong predictors of mortality in hospitalized COVID-19 patients. Consistent with the major influence of coagulopathy in the pathogenesis of COVID-19, anticoagulant treatments were shown to improve the survival of critically ill COVID-19 patients. Although the association of coagulation abnormalities with COVID-19 is evident, the underlying mechanism for these abnormalities is unknown. Many diseases, including viral infections, induce tissue factor (TF) expression in monocytes/macrophages and endothelial cells and release TF+ extracellular vesicles (EVs) into circulation. Our recent studies suggest that alterations in sphingomyelin metabolism greatly influence TF activity by controlling TF encryption and decryption, and generation of TF+ EVs. We hypothesize that hypercoagulability associated with SARS-CoV-2 infection stems from increased TF activity and the release of TF+ EVs into the circulation following the infection. We further hypothesize that spike protein-induced activation of acid sphingomyelinase (ASMase) is responsible for increased TF activity via TF decryption and generation of TF+ EVs. We propose that treatment with ASMase functional inhibitors will attenuate coagulopathy associated with SARS-CoV-2 infection. The overall goal of the proposal is to obtain a proof of concept to the above hypothesis. Our aims are: (i) determine the mechanism by which the SARS-CoV-2 spike protein increases TF activity and generates TF+ EVs; (ii) define the role of SARS-CoV-2's spike protein on activation of TF-induced coagulopathy and microvascular thrombosis in hACE2 transgenic mice and determine whether ASMase functional inhibitors attenuate SARS-CoV-2-induced coagulopathy. In the proposed studies, we will use both SARS-CoV-2 spike protein pseudovirus and authentic SARS-CoV-2 infections in cell model systems and a murine model system. Our proposed studies will identify potential mechanisms by which SARS-CoV2 infection induces hypercoagulability and thrombosis. They will also provide clues for the development of novel, targeted, and safe interventions to treat hypercoagulability in COVID-19 patients, which could help to reduce mortality. We have more than thirty years of experience working on TF and have all the tools and resources, and technical expertise to complete the proposed studies successfully.