Fibrinogen and Factor XIII in Venous Thromboembolism

静脉血栓栓塞中的纤维蛋白原和因子 XIII

• 批准号: 10649632
• 负责人: Alisa S. Wolberg
• 金额: $ 55.38万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649632
• 关键词: Address; Affect; Age; American; Antifibrinolytic Agents; Antigens; Automobile Driving; Biological; Blood Platelets; Circulation; Coagulation Process; Contraceptive Usage; Contracts; Coupling; Cultured Cells; Cytolysis; Data; Deposition; Development; Disease; Edema; Erythrocytes; Event; Factor XIII; Fibrin; Fibrinogen; Foundations; Funding; Generations; Genetic; Goals; Growth; Hemorrhage; Hepatocyte; Human; Knowledge; Laboratories; Leg Ulcer; Malignant Neoplasms; Mediating; Medical; Methods; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Obesity; Operative Surgical Procedures; Oral Contraceptives; Pathogenesis; Pathway interactions; Patients; Plasma; Postphlebitic Syndrome; Pregnancy; Prevention; Production; Proteins; Public Health; Publishing; Pulmonary Embolism; Recurrence; Regulation; Research; Resistance; Risk; Risk Factors; Role; Source; Structure; System; Testing; Thrombin; Thrombophilia; Thrombus; Tissues; United States National Institutes of Health; Venous; Venous Thrombosis; Wild Type Mouse; Work; chronic pain; chronic thromboembolic pulmonary hypertension; crosslink; density; diet-induced obesity; factor V Leiden; human disease; innovation; knowledgebase; mortality; mouse model; novel; novel therapeutic intervention; pharmacologic; posttranscriptional; prevent; programs; therapeutic target; tool; venous thromboembolism

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.

研究和相关的其他项目信息 项目摘要/摘要 静脉血栓形成（VT）和肺栓塞（PE），集体静脉血栓栓塞（VTE），影响 每年超过100万美国人。 VT是通过血管内激活引发的，导致凝血酶 产生和纤维蛋白沉积。发育中的纤维蛋白网络中的红细胞（RBC）捕获 促进血栓生长，最终导致闭塞纤维蛋白和富含RBC的血栓的产生。长期 我们研究计划的术语目标是定义导致VTE和的细胞和分子机制 开发新的治疗和预防方法。在最近的资金期间，我们确定了 在VT发病机理中，先前未认可的纤维蛋白（OGEN），因子XIII（FXIII）和纤维蛋白交联的作用。 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 RBC在血栓中保留并促进了较大的血栓形成，FXIII的遗传还原可减少 野生型小鼠的血栓尺寸，以及血浆FXIII，但不是血小板FXIII，可驱动rbc保留在血栓中 和血栓生长。这些发现支持了该提案的科学前提，该提议减少了血浆FXIII 蛋白质或活性，因此，防止RBC在血栓中捕获会减少VTE发病机理。这 该建议的总体目的是确定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，交联和对裂解的耐药性是关键 血栓形成和稳定性的决定因素。我们将在人类中使用遗传和药理方法 和小鼠实验系统，以确定FXIII（a）减少对与常见相关的VT的影响 高凝风险因素。我们将在我们的实验室中采用一种新的鼠模型， 用随后的PE概括VT，以研究将FXIII耦合到PE风险的机制。我们也会 阐明血浆FXIII的独特互相，组织间调节的细胞和分子决定因素 表达。识别这些机制是重要的，因为它将揭示分子和细胞事件 促进VTE并将FXIII表征为减少VTE的新潜在治疗靶标。自VTE以来 随着年龄的增长，癌症，怀孕，口服避孕药，肥胖和手术后的增加，我们的发现将 对降低许多疾病的发病率和死亡率具有广泛的影响。

项目成果

Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery.

• DOI: 10.1111/jth.15114
• 发表时间: 2021-01
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Miszta A;Ahmadzia HK;Luban NLC;Li S;Guo D;Holle LA;Berger JS;James AH;Gobburu JVS;van den Anker J;de Laat B;Wolberg AS
• 通讯作者: Wolberg AS

Novel venous thromboembolism mouse model to evaluate the role of complete and partial factor XIII deficiency in pulmonary embolism risk.

• DOI: 10.1111/jth.15510
• 发表时间: 2021-12
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Kattula S;Sang Y;de Ridder G;Silver AC;Bouck EG;Cooley BC;Wolberg AS
• 通讯作者: Wolberg AS

Recombinant porcine factor VIII for high-risk surgery in paediatric congenital haemophilia A with high-titre inhibitor.

重组猪因子 VIII 用于具有高滴度抑制剂的儿童先天性血友病 A 的高风险手术。

• DOI: 10.1111/hae.13157
• 发表时间: 2017
• 期刊: Haemophilia : the official journal of the World Federation of Hemophilia
• 作者: Croteau,SE;Abajas,YL;Wolberg,AS;Nielsen,BI;Marx,GR;Baird,CW;Neufeld,EJ;Monahan,PE
• 通讯作者: Monahan,PE

Case Report: Unmasked Inherited Dysfibrinogenemia After Everolimus Therapy.

• DOI: 10.3389/fmed.2020.591546
• 发表时间: 2020
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Merkulova AA;Mitchell SC;Merkulov S;Wolberg AS;Neerman-Arbez M;Schmaier AH
• 通讯作者: Schmaier AH

Plasma-based assays distinguish hyperfibrinolysis and shutdown subgroups in trauma-induced coagulopathy.

• DOI: 10.1097/ta.0000000000003723
• 发表时间: 2022-11-01
• 期刊: The journal of trauma and acute care surgery