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

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2022 · $183,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10448667
- **Project number:** 1R21AI163608-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH CTR AT TYLER
- **Principal Investigator:** Vijaya Mohan Rao Lella
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $183,750
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448667

## Citation

> US National Institutes of Health, RePORTER application 10448667, Tissue Factor's Role in the Pathogenesis of Hypercoagulability in COVID-19 (1R21AI163608-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10448667. Licensed CC0.

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