# Tissue factor-dependent coagulation in thrombosis and immune responses

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $914,340

## Abstract

Tissue factor (TF) is a transmembrane protein that functions as a high-affinity receptor for factor (F)VII and
FVIIa. The TF-FVIIa complex is the primary initiator of coagulation and plays an essential role in hemostasis.
However, aberrant TF expression underlies most forms of thrombosis. TF expression is also induced in response
to bacterial and viral infections as part of the innate immune response. This expression can be either protective
by limiting the spread of the pathogen or pathologic by triggering disseminated intravascular coagulation (DIC).
TF-dependent generation of coagulation proteases also leads to activation of protease-activated receptors
(PARs). My lab has made major contributions to understanding the roles of TF, coagulation proteases and PARs
in hemostasis, thrombosis, endotoxemia, ischemia-reperfusion injury, atherosclerosis, and viral infections. This
R35 OIA application is an extension of two NHLBI funded R01 grants: Mechanism of venous thrombosis in
pancreatic cancer; Role of the thrombin PAR1 pathway in viral infection. We have shown that levels of circulating
tumor-derived, TF+ extracellular vesicles (EVs) are associated with increased venous thromboembolism in
pancreatic cancer patients. In addition, we found that TF+ EVs enhance venous thrombosis in mice bearing
human pancreatic tumors. We have also shown that TF-dependent activation of coagulation and PAR1 signaling
is protective in response to Coxsackievirus B3 by boosting the antiviral IFNβ pathway in the heart. In contrast,
PAR1 suppresses the pathologic NF-κB response in the lung in response to influenza A H1N1 infection. The OIA
funding mechanism would provide stable funding and increased time for our group to pursue higher risk-higher
reward projects, such as performing proteomic analysis of plasma and EVs, establish new technologies, such
as the ExoView system, and following up on exciting discoveries. Our long-term goals are to further
understand the protective and pathologic roles of TF, coagulation proteases and PARs in cancer and
infections. There are two hypotheses for this proposal: 1/ TF enhances venous thrombosis and tumor growth
in pancreatic cancer, and 2/ TF-dependent activation of coagulation is both protective and pathologic in response
to viral infection. We will continue our studies on the identification of plasma biomarkers of thrombotic risk in
cancer patients using clinical samples. We will identify prothrombotic pathways that contribute to cancer-
associated thrombosis using mouse models. In addition, we will determine the roles of tumor and host derived
TF in the growth of pancreatic tumors in mice. We will identify the cellular sources of pathologic TF in mouse
models of viral infection that may lead to new treatments to prevent DIC. We will elucidate how PAR1 is protective
by both enhancing the IFNβ antiviral pathway in the heart and suppressing the pathologic NF-κB pathway in the
lung in response to viral infection. This knowledge may le...

## Key facts

- **NIH application ID:** 10778570
- **Project number:** 5R35HL155657-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Nigel Mackman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $914,340
- **Award type:** 5
- **Project period:** 2021-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10778570

## Citation

> US National Institutes of Health, RePORTER application 10778570, Tissue factor-dependent coagulation in thrombosis and immune responses (5R35HL155657-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10778570. Licensed CC0.

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