# Fibrinogen and Factor XIII in Venous Thromboembolism

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $566,163

## Abstract

RESEARCH AND RELATED Other Project Information
PROJECT SUMMARY/ABSTRACT
Venous thrombosis (VT) and pulmonary embolism (PE), collectively venous thromboembolism (VTE), affect
over 1 million Americans annually. VT is initiated by intravascular activation of coagulation resulting in thrombin
generation and fibrin deposition. Trapping of red blood cells (RBCs) within the developing fibrin network
promotes thrombus growth, culminating in production of an occlusive fibrin- and RBC-rich thrombus. The long-
term goals of our research program are to define cellular and molecular mechanisms that lead to VTE and
develop new approaches for treatment and prevention. During the recent funding period we identified
previously-unrecognized roles for fibrin(ogen), factor XIII (FXIII), and fibrin crosslinking in VT pathogenesis.
Most prominently, we discovered that increased fibrin density and FXIIIa-mediated fibrin crosslinking enhance
RBC retention in thrombi and promote the formation of larger thrombi, that genetic reduction of FXIII reduces
thrombus size in wild-type mice, and that plasma FXIII, but not platelet FXIII, drives RBC retention in thrombi
and thrombus growth. These findings support the scientific premise of this proposal that reducing plasma FXIII
protein or activity and therefore, preventing trapping of RBCs in thrombi, will decrease VTE pathogenesis. The
overall objective of this proposal is to determine mechanisms by which FXIII and fibrin crosslinking affect VT
and PE risk. Our central hypothesis is that fibrin structure, crosslinking, and resistance to lysis are key
determinants of thrombus formation and stability. We will use genetic and pharmacologic methods in human
and mouse experimental systems to determine the impact of FXIII(a) reduction on VT associated with common
hypercoagulable risk factors. We will employ a new murine model developed in our laboratory that
recapitulates VT with subsequent PE to investigate mechanisms coupling FXIII to PE risk. We will also
elucidate cellular and molecular determinants of unique reciprocal, inter-tissue regulation of plasma FXIII
expression. Identifying these mechanisms is significant because it will reveal molecular and cellular events that
promote VTE and characterize FXIII as a new potential therapeutic target for reducing VTE. Since VTE
increases with age, cancer, pregnancy, oral contraceptive use, obesity, and following surgery, our findings will
have broad implications for decreasing morbidity and mortality in numerous diseases.

## Key facts

- **NIH application ID:** 10463593
- **Project number:** 5R01HL126974-07
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Alisa S. Wolberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $566,163
- **Award type:** 5
- **Project period:** 2016-01-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463593

## Citation

> US National Institutes of Health, RePORTER application 10463593, Fibrinogen and Factor XIII in Venous Thromboembolism (5R01HL126974-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10463593. Licensed CC0.

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