Mice expressing nonpolymerizable fibrinogen have reduced arterial and venous thrombosis with preserved hemostasis

Abstract

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. Here, we analyzed the impact of nonpolymerizable fibrinogen on arterial and venous thrombosis as well as hemostasis in vivo using FgaEK mice that express normal levels of a fibrinogen that cannot be cleaved by thrombin. In a model of carotid artery thrombosis, FgaWT/EK and FgaEK/EK mice were protected from occlusion with 4% FeCl3 challenges compared to FgaWT/WT mice, but this protection was lost with injuries driven by higher concentrations of FeCl3. In contrast, fibrinogen-deficient (Fga-/-) mice showed no evidence of occlusion even with high concentration FeCl3 challenge. Fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content were similar in FgaWT/WT, FgaWT/EK and FgaEK/EK mice, consistent with preserved fibrinogen-platelet interactions that support arterial thrombosis with severe challenge. In an inferior vena cava stasis model of venous thrombosis, FgaEK/EK mice had near complete protection from thrombus formation. FgaWT/EK mice also displayed reduced thrombus incidence and a significant reduction in thrombus mass relative to FgaWT/WT mice following IVC stasis, suggesting partial expression of nonpolymerizable fibrinogen was sufficient for conferring protection. Notably, FgaWT/EK and FgaEK/EKmice had preserved hemostasis in multiple models as well as normal wound healing times following skin incision, unlike Fga-/-mice that displayed significant bleeding and delayed healing. These findings indicate that a nonpolymerizable fibrinogen variant can significantly suppress occlusive thrombosis while preserving hemostatic potential in vivo.

Characterization of active peptides derived from three leeches and comparison of their anti-thrombotic mechanisms using the tail vein thrombosis model in mice and metabonomics

“…Thrombus formation in the arteries or veins blocks the flow of blood and alters the blood rheology. The increased WBV decreases blood flow and may lead to cardiovascular diseases ( Hur et al, 2023 ). APTT is an indicator of the endogenous coagulation pathway activity.…”

Comprehensive Analysis of the Role of Fibrinogen and Thrombin in Clot Formation and Structure for Plasma and Purified Fibrinogen

“…For example, there is contradictory evidence on the role of FXIII on clot structure [79,80]; our combination of techniques could aid in the understanding of this role. Furthermore, recent studies have explored the role of mutant fibrinogens [26]; future studies could utilize our multi-technique approach to systematically analyze changes in clot structure due to mutant fibrinogen, genetic polymorphisms [81,82], and post-translational modifications of fibrinogen [83]. It would be expected that alterations in normal fibrinogen would impact the clot structure.…”

“…Diseases such as cancer [20,21], diabetes [14,22], and COVID-19 [23,24] have also been linked to the altered structural properties of in vitro plasma clots, which could potentially impede clot degradation and increase the risk of thrombotic events [25]. The coagulation cascade is a complex process; irregularities at any step can lead to aberrant clot structures [26]. To understand why some diseases are linked with altered fibrin structure, it is first necessary to understand what factors cause structural changes to fibrin networks.…”