Fibrinogen and Factor XIII in Venous Thromboembolism

研究和其他相关项目信息 项目摘要/摘要 静脉血栓形成(VT)和肺栓塞(PE)，统称静脉血栓栓塞症(VTE)，影响 每年有100多万美国人。室性心动过速是由血管内激活凝血酶引起的。 产生和纤维蛋白沉积。红细胞在发育中的纤维蛋白网络中的捕获 促进血栓生长，最终形成闭塞的富含纤维蛋白和红细胞的血栓。长的- 我们研究计划的学期目标是确定导致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)、凝血因子XIII(FXIII)和纤维蛋白交联在室性心动过速发病中的作用以前未知。 最显著的是，我们发现纤维蛋白密度的增加和FXIIIa介导的纤维蛋白交联会增强 RBC在血栓中滞留并促进较大血栓的形成，即FXIII基因减少 野生型小鼠血栓大小和血浆FXIII，而不是血小板FXIII，促使RBC在血栓中滞留 和血栓的增长。这些发现支持了这一提议的科学前提，即降低血浆FXIII 因此，阻止红细胞在血栓中的滞留，将减少VTE的发病。这个 这项提议的总体目标是确定FXIII和纤维蛋白交联影响室性心动过速的机制 和体育风险。我们的中心假设是纤维蛋白结构、交联度和抗裂解能力是关键。 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学和药理学方法 并以小鼠实验系统确定FXIII(A)降低VT的相关共同 高凝危险因素。我们将使用我们实验室开发的一种新的小鼠模型 重述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独特的组织间相互调节的细胞和分子决定因素 表情。确定这些机制具有重要意义，因为它将揭示分子和细胞事件 推广VTE，并将FXIII描述为降低VTE的新的潜在治疗靶点。自VTE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，我们的发现将 对减少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.