Leeds Thrombosis Collective, Discovery & Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9NL, United Kingdom.
School of Physics and Astronomy, University of Leeds, Leeds LS2 3AR, United Kingdom.
Proc Natl Acad Sci U S A. 2021 Jul 6;118(27). doi: 10.1073/pnas.2103226118.
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.
静脉血栓栓塞症（包括肺栓塞）的发病，对全球每年超过 100 万人的健康造成了重大负担。目前的治疗选择基于抗凝，这对于预防进一步的栓塞事件效果并不理想。为了开发治疗血栓栓塞症的更好方法，我们试图了解血栓的结构和力学特性，以及这如何影响体内栓塞。我们建立了一个模型，即通过激活的因子 XIII 消除纤维蛋白 γ 链交联（FGG3X）的小鼠模型，并应用方法研究整体和器官水平的血栓栓塞。我们表明，FGG3X 小鼠具有正常的表型，除了纤维蛋白 γ 链交联的完全抑制外，总体凝血参数、血小板聚集和功能基本不受影响。消除纤维蛋白 γ 链交联导致血栓强度降低，容易碎裂。使用 Xtreme 光学成像和光片显微镜分析体内栓塞表明，消除纤维蛋白 γ 链交联导致栓塞增加，而不影响血栓大小或溶解。我们的发现指出了纤维蛋白 γ 链交联在血栓稳定性中的一个以前未被认识到的核心作用。它们还间接表明，通过激活的因子 XIII 选择性调节纤维蛋白 α 链而非 γ 链交联来减少血栓大小和负担，同时保持血栓稳定性并预防栓塞，可以作为血栓形成的机制靶点。
