Fibrinogen and Factor XIII in Venous Thromboembolism

研究和相关的其他项目信息 项目总结/摘要 静脉血栓形成（VT）和肺栓塞（PE），统称为静脉血栓栓塞（VTE），影响 每年有超过100万美国人。VT由血管内凝血激活引发，导致凝血酶 生成和纤维蛋白沉积。在发育中的纤维蛋白网络内捕获红细胞（RBC） 促进血栓生长，最终产生闭塞性富含纤维蛋白和RBC的血栓。很长的- 我们研究计划的长期目标是确定导致静脉血栓栓塞的细胞和分子机制， 开发新的治疗和预防方法。在最近的资助期间，我们发现 纤维蛋白（原）、因子XIII（FXIII）和纤维蛋白交联在VT发病机制中的作用以前未被认识。 最重要的是，我们发现增加的纤维蛋白密度和FXIIIa介导的纤维蛋白交联增强了纤维蛋白的表达。 红细胞滞留在血栓中并促进较大血栓的形成，即FXIII基因减少减少 野生型小鼠血栓大小，血浆FXIII而不是血小板FXIII驱动血栓中的RBC滞留 和血栓生长。这些发现支持了这一提议的科学前提，即减少血浆FXIII 蛋白质或活性，并因此防止红细胞在血栓中的捕获，将减少VTE发病机制。的 本提案的总体目标是确定FXIII和纤维蛋白交联影响VT的机制 PE风险我们的中心假设是，纤维蛋白的结构，交联和抗溶解是关键 血栓形成和稳定性的决定因素。我们将使用遗传学和药理学方法在人类 和小鼠实验系统，以确定FXIII（a）减少对与常见的 高凝危险因素。我们将采用我们实验室开发的一种新的小鼠模型， 概括VT与随后的PE，以研究FXIII与PE风险的耦合机制。我们还将 阐明血浆FXIII独特的相互、组织间调节的细胞和分子决定因素 表情确定这些机制是重要的，因为它将揭示分子和细胞事件， 促进VTE，并将FXIII表征为降低VTE的新的潜在治疗靶点。自VTE以来 随着年龄的增长，癌症，怀孕，口服避孕药的使用，肥胖和手术后，我们的研究结果将 对降低许多疾病的发病率和死亡率具有广泛意义。

RESEARCH AND RELATED Other Project Information PROJECT SUMMARY/ABSTRACT Venous thrombosis (VT) and pulmonary embolism (PE), collectively venous thromboembolism (VTE), affect over 1 million Americans annually. VT is initiated by intravascular activation of coagulation resulting in thrombin generation and fibrin deposition. Trapping of red blood cells (RBCs) within the developing fibrin network promotes thrombus growth, culminating in production of an occlusive fibrin- and RBC-rich thrombus. The long- term goals of our research program are to define cellular and molecular mechanisms that lead to VTE and develop new approaches for treatment and prevention. During the recent funding period we identified previously-unrecognized roles for fibrin(ogen), factor XIII (FXIII), and fibrin crosslinking in VT pathogenesis. Most prominently, we discovered that increased fibrin density and FXIIIa-mediated fibrin crosslinking enhance RBC retention in thrombi and promote the formation of larger thrombi, that genetic reduction of FXIII reduces thrombus size in wild-type mice, and that plasma FXIII, but not platelet FXIII, drives RBC retention in thrombi and thrombus growth. These findings support the scientific premise of this proposal that reducing plasma FXIII protein or activity and therefore, preventing trapping of RBCs in thrombi, will decrease VTE pathogenesis. The overall objective of this proposal is to determine mechanisms by which FXIII and fibrin crosslinking affect VT and PE risk. Our central hypothesis is that fibrin structure, crosslinking, and resistance to lysis are key determinants of thrombus formation and stability. We will use genetic and pharmacologic methods in human and mouse experimental systems to determine the impact of FXIII(a) reduction on VT associated with common hypercoagulable risk factors. We will employ a new murine model developed in our laboratory that recapitulates VT with subsequent PE to investigate mechanisms coupling FXIII to PE risk. We will also elucidate cellular and molecular determinants of unique reciprocal, inter-tissue regulation of plasma FXIII expression. Identifying these mechanisms is significant because it will reveal molecular and cellular events that promote VTE and characterize FXIII as a new potential therapeutic target for reducing VTE. Since VTE increases with age, cancer, pregnancy, oral contraceptive use, obesity, and following surgery, our findings will have broad implications for decreasing morbidity and mortality in numerous diseases.