Abstract
The onset of venous thromboembolism, including pulmonary embolism, represents a significant health burden affecting more than 1 million people annually worldwide. Current treatment options are based on anticoagulation, which is suboptimal for preventing further embolic events. In order to develop better treatments for thromboembolism, we sought to understand the structural and mechanical properties of blood clots and how this influences embolism in vivo. We developed a murine model in which fibrin γ-chain cross-linking by activated Factor XIII is eliminated (FGG3X) and applied methods to study thromboembolism at whole-body and organ levels. We show that FGG3X mice have a normal phenotype, with overall coagulation parameters and platelet aggregation and function largely unaffected, except for total inhibition of fibrin γ-chain cross-linking. Elimination of fibrin γ-chain cross-linking resulted in thrombi with reduced strength that were prone to fragmentation. Analysis of embolism in vivo using Xtreme optical imaging and light sheet microscopy demonstrated that the elimination of fibrin γ-chain cross-linking resulted in increased embolization without affecting clot size or lysis. Our findings point to a central previously unrecognized role for fibrin γ-chain cross-linking in clot stability. They also indirectly indicate mechanistic targets for the prevention of thrombosis through selective modulation of fibrin α-chain but not γ-chain cross-linking by activated Factor XIII to reduce thrombus size and burden, while maintaining clot stability and preventing embolism.
Highlights
The onset of venous thromboembolism, including pulmonary embolism, represents a significant health burden affecting more than 1 million people annually worldwide
We developed a thromboembolism protocol supported by state-of-theart in vivo imaging, coupled to a genetically modified murine model of reduced clot strength caused by mutations in the cross-linking sites of fibrin, which provides the mechanical scaffold of the clot
In order to investigate the effects of γ-chain cross-linking by FXIIIa on clot stability and embolism in a pathophysiological setting, we developed two protocols to evaluate the level of thromboembolism to the lungs (PE) from thrombi in the inferior vena cava
Summary
The onset of venous thromboembolism, including pulmonary embolism, represents a significant health burden affecting more than 1 million people annually worldwide. Our findings point to a central previously unrecognized role for fibrin γ-chain crosslinking in clot stability They indirectly indicate mechanistic targets for the prevention of thrombosis through selective modulation of fibrin α-chain but not γ-chain cross-linking by activated Factor XIII to reduce thrombus size and burden, while maintaining clot stability and preventing embolism. Thrombosis is complicated by life-threatening embolic events, caused by parts of an intravascular blood clot breaking off and traveling downstream to block other blood vessels supplying critical organs Thromboembolism occurs in both the venous and arterial circulation and is associated with life-threatening pulmonary embolism (PE) [1] and ischemic stroke [2]. We find that fibrin γ-chain cross-linking is essential for clot stability and reduces embolism These findings introduce an important concept indicating that maintenance of clot stability during thrombosis treatment is essential to prevent thromboembolism
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