OC 62.1 - Differential suppression of arterial versus venous thrombosis but preserved hemostasis in mice expressing fibrinogen that cannot support fibrin formation

Tuesday, June 27, 2023

14:45 – 15:00 ET

Room: 710B

Session Available As: On-Demand

Presenting Author(s)

Woosuk Steve Hur, PhD

Postdoctoral Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States

Co-Author(s)

TK

Tomohiro Kawano

Postdoctoral Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Jean Marie Mwiza, PhD (he/him/his)

Postdoctoral Research Associate
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
David S. Paul, PhD

Research Assistant Professor
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
RL

Robert H. H. Lee, PhD

Research Assistant Professor
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
EC

Emily G. Clarke

PhD Student
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
EB

Emma Bouck

PhD Candidate
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Nigel Mackman, PhD

Professor
Univerisity of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Alisa S. Wolberg, PhD

Professor
Univerisity of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Wolfgang Bergmeier, PhD

Professor
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Matthew J. Flick, PhD

Professor
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States

Background: Elevated circulating fibrinogen correlates with increased risk for both cardiovascular and venous thromboembolic diseases. In vitro studies show that formation of a highly dense fibrin matrix is a major determinant of clot structure and stability. However, the precise contribution of fibrin matrix to occlusive arterial and venous thrombus formation in vivo remains largely undefined.

Aims: Determine the contribution of fibrinogen versus fibrin to arterial thrombosis, venous thrombosis, and hemostatic potential in vivo.

Methods: Arterial and venous thrombotic challenges as well as hemostatic tests were performed in wildtype (FgaWT) and FgaEK mice that express normal levels of fibrinogen “locked” in the monomeric form.

Results: In a model arterial thrombosis, a 10% FeCl3 injury to the carotid artery resulted in similar times to occlusion between FgaWT/WT, FgaWT/EK and FgaEK/EK mice, while Fga-/- mice were completely protected. However, when injured with 5% FeCl3, FgaEK/EK mice were partially protected from occlusion but had increased embolic events. These results suggest that fibrinogen can contribute to arterial thrombus formation independent of fibrin formation. Consistently, fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content in FgaWT/WT, FgaWT/EK and FgaEK/EK mice were similar. In an inferior vena cava stasis model of venous thrombosis, FgaEK/EK had near complete protection from thrombus formation. Intriguingly, FgaWT/EK mice also displayed significant reduction in thrombus frequency and mass relative to FgaWT/WT mice. Plasma from FgaWT/EK mice produced prolonged prothrombin and thrombin times with reduced fibrin formation based on turbidity assay. In bleeding models, FgaWT/EK and, FgaEK/EK mice had preserved hemostasis in contrast to Fga-/- mice that presented with significantly impaired hemostasis.

Conclusion(s): These findings show that selective prevention of fibrin polymerization significantly reduces venous thrombosis and suppresses arterial thrombosis based on the severity of injury with minimal disruption to hemostasis. Moreover, the data suggests that administration of non-polymerizable fibrinogen may be a therapeutic strategy against thrombosis.

Learning Objectives:

Upon completion, participants will be able to compare the differential contribution of fibrin formation to the development of arterial and venous thrombosis.
Participants will be able to recognize the respective role of fibrinogen and fibrin to hemostasis
Participants will be able to evaluate the role of fibrin(ogen)-platelet interaction in hemostasis and thrombosis