Department of Pathology and Laboratory Medicine and McAllister Heart Institute, University of North Carolina, Chapel Hill, NC; and.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH.
Blood Adv. 2018 Jan 3;2(1):25-35. doi: 10.1182/bloodadvances.2017011890. eCollection 2018 Jan 9.
The transglutaminase factor XIII (FXIII) stabilizes clots against mechanical and biochemical disruption and is essential for hemostasis. In vitro and in vivo models of venous thrombosis demonstrate that FXIII mediates clot size by promoting red blood cell (RBC) retention. However, the key source of FXIII and whether FXIII activity can be reduced to suppress thrombosis without imposing deleterious hemostatic consequences are 2 critical unresolved questions. FXIII is present in multiple compartments, including plasma (FXIII) as a heterotetramer of A and B subunits and platelets (FXIII) as an A homodimer. We determined the role of the FXIII compartment and level in clot contraction, composition, and size in vitro and using in vivo models of hemostasis and venous thrombosis. Reducing overall FXIII levels decreased whole blood clot weight but did not alter thrombin generation or contraction of platelet-rich plasma clots. In reconstituted platelet-rich plasma and whole blood clot contraction assays, FXIII, but not FXIII, produced high-molecular-weight fibrin crosslinks, promoted RBC retention, and increased clot weights. Genetically imposed reduction of FXIII delayed FXIII activation and fibrin crosslinking, suggesting FXIII levels mediate the kinetics of FXIII activation and activity and that the timing of these processes is a critical determinant of RBC retention during clot formation and contraction. A 50% reduction in FXIII produced significantly smaller venous thrombi but did not increase bleeding in tail transection or saphenous vein puncture models in vivo. Collectively, these findings suggest that partial FXIII reduction may be a therapeutic strategy for reducing venous thrombosis.
转谷氨酰胺酶因子 XIII（FXIII）稳定血栓，防止其受到机械和生化破坏，是止血所必需的。静脉血栓形成的体外和体内模型表明，FXIII 通过促进红细胞（RBC）保留来调节血栓大小。然而，FXIII 的关键来源以及 FXIII 活性是否可以降低以抑制血栓形成而不产生有害的止血后果，这是两个关键的未解决的问题。FXIII 存在于多个隔室中，包括血浆（FXIII）中的 A 和 B 亚基的异四聚体和血小板（FXIII）中的 A 同源二聚体。我们确定了 FXIII 隔室和水平在体外和止血及静脉血栓形成的体内模型中血栓收缩、组成和大小中的作用。降低整体 FXIII 水平会降低全血血栓的重量，但不会改变凝血酶生成或富含血小板的血浆血栓的收缩。在重建的富含血小板的血浆和全血血栓收缩测定中，FXIII 而不是 FXIII 产生高分子量纤维蛋白交联，促进 RBC 保留，并增加血栓重量。遗传上降低 FXIII 会延迟 FXIII 的激活和纤维蛋白交联，表明 FXIII 水平介导 FXIII 激活和活性的动力学，并且这些过程的时间是 RBC 在血栓形成和收缩过程中保留的关键决定因素。FXIII 减少 50%会显著减小静脉血栓形成，但不会增加体内尾部横断或隐静脉穿刺模型中的出血。总之，这些发现表明部分 FXIII 减少可能是减少静脉血栓形成的治疗策略。
