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.

研究和其他相关的项目信息

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

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

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
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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