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

Award Number: R21AI163608
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Allergy and Infectious Diseases Research	000	2	6/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $220,500 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Allergy and Infectious Diseases Research	000	2	2/15/2023	NON-COMPETING CONTINUATION	$220,500
														Subtotal = $220,500

Issue Date FY: 2022 ( Subtotal = $183,750 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Allergy and Infectious Diseases Research	000	1	2/28/2022	NEW	$183,750
														Subtotal = $183,750

Grand Total All Awards = $404,250

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

Award Number: R21AI163608

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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