Fibrinogen and Factor XIII in Venous Thromboembolism

研究及相关其他项目信息 项目概要/摘要 静脉血栓（VT）和肺栓塞（PE），统称为静脉血栓栓塞（VTE），影响 每年超过 100 万美国人。 VT 由血管内凝血激活导致凝血酶引发 生成和纤维蛋白沉积。在发育中的纤维蛋白网络中捕获红细胞 (RBC) 促进血栓生长，最终形成富含纤维蛋白和红细胞的闭塞性血栓。长- 我们研究计划的长期目标是定义导致 VTE 和 开发新的治疗和预防方法。在最近的资助期内，我们确定 纤维蛋白（原）、因子 XIII (FXIII) 和纤维蛋白交联在 VT 发病机制中的作用此前未被认识。 最突出的是，我们发现纤维蛋白密度增加和 FXIIIa 介导的纤维蛋白交联增强 红细胞滞留在血栓中并促进更大血栓的形成，FXIII 的基因减少减少了 野生型小鼠中的血栓大小，血浆 FXIII（而非血小板 FXIII）驱动血栓中红细胞滞留 和血栓生长。这些发现支持了该提案的科学前提，即减少血浆 FXIII 因此，防止红细胞被血栓捕获，将减少 VTE 发病机制。的 该提案的总体目标是确定 FXIII 和纤维蛋白交联影响 VT 的机制 和PE风险。我们的中心假设是纤维蛋白结构、交联和抗裂解性是关键 血栓形成和稳定性的决定因素。我们将在人类身上使用遗传和药理学方法 和小鼠实验系统，以确定 FXIII(a) 减少对常见的 VT 的影响 高凝危险因素。我们将采用我们实验室开发的新小鼠模型 将 VT 与随后的 PE 一起概括，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 表达。识别这些机制具有重要意义，因为它将揭示影响这些机制的分子和细胞事件。 促进 VTE 并将 FXIII 描述为减少 VTE 的新潜在治疗靶点。自静脉血栓栓塞以来 随着年龄、癌症、怀孕、口服避孕药的使用、肥胖和手术后的增加，我们的研究结果将 对降低多种疾病的发病率和死亡率具有广泛的影响。

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.