| First Author | Duval C | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 27 | PubMed ID | 34183396 |
| Mgi Jnum | J:307658 | Mgi Id | MGI:6723714 |
| Doi | 10.1073/pnas.2103226118 | Citation | Duval C, et al. (2021) Elimination of fibrin gamma-chain cross-linking by FXIIIa increases pulmonary embolism arising from murine inferior vena cava thrombi. Proc Natl Acad Sci U S A 118(27):e2103226118 |
| abstractText | 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 gamma-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 gamma-chain cross-linking. Elimination of fibrin gamma-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 gamma-chain cross-linking resulted in increased embolization without affecting clot size or lysis. Our findings point to a central previously unrecognized role for fibrin gamma-chain cross-linking in clot stability. They also indirectly indicate mechanistic targets for the prevention of thrombosis through selective modulation of fibrin alpha-chain but not gamma-chain cross-linking by activated Factor XIII to reduce thrombus size and burden, while maintaining clot stability and preventing embolism. |
