Factor Xl in Vascular Thrombosis

血管血栓形成中的 XI 因子

• 批准号: 7393736
• 负责人: David Gailani
• 金额: $ 30.7万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-06 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393736
• 关键词: Anticoagulants; Anticoagulation; Arterial Injury; Binding; Blood; Blood Circulation; Blood Clot; Blood Platelets; Blood Vessels; Blood coagulation; Carboxypeptidase U; Carotid Artery Injuries; Carotid Artery Thrombosis; Coagulation Process; Complex; Condition; Disadvantaged; Disease; Endopeptidases; Factor IX; Factor IXa; Factor XI; Factor XII; Factor XII Deficiency; Fibrin; Fibrinolysis; Generations; Goals; Hemorrhage; Hemostatic Agents; Hemostatic function; Human; In Vitro; Intravenous; Left; Modeling; Mus; Neuraxis; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Plasma; Platelet Activation; Process; Production; Proteins; Pulmonary Embolism; Recombinants; Relative (related person); Reperfusion Injury; Resistance; Risk; Role; System; Testing; Thrombin; Thromboembolism; Thrombosis; Thrombus; Variant; Venous; Venous Thrombosis; Work; artery occlusion; blood vessel occlusion; in vivo; mouse model; novel; prevent; reconstitution

DESCRIPTION (provided by applicant): The protease factor Xla (fXIa) contributes to hemostasis by sustaining thrombin generation after initiation of blood coagulation. In addition to contributing to fibrin formation, fXIa promotes clot resistance to fibrinolysis in a process involving the proteinase TAFI. Several lines of evidence indicate fXIa contributes to pathologic coagulation. Elevated plasma levels of the fXIa precursor fXI are associated with increased risks for arterial and venous thrombosis in humans. We observed that fXI deficient mice are resistant to vascular occlusion in arterial injury models, indicating fXIa contributes to platelet rich thrombus formation. FXI binds to platelets in vitro, and is converted to fXIa by thrombin or factor XI la (fXlla). The importance of these interactions in vivo or in complex in vitro systems is not known, and the relative importance of thrombin and fXlla to fXI activation is not clear. FXI I deficiency does not cause a bleeding abnormality, indicating fXI is activated in vivo by other proteases. However, fXII deficient mice are resistant to arterial occlusion, raising the possibility that formation of a pathologic occlusive thrombus involves processes distinct from those involved in normal hemostasis. In Aim 1 of this proposal, we will use mice with deficiencies of fXI, fXII, and TAFI to investigate the importance of these proteins in models of pathologic coagulation. Using a panel of novel recombinant fXI variants to reconstitute fXI deficient mice, we will determine the importance of fXI interactions with platelets, thrombin and fXlla to these models, and look for alternative functions for fXI and fXII unrelated to classical coagulation pathways. In Aim 2, a murine fXI-dependent bleeding model will be used to determine if fXI interactions with platelets, thrombin and fXlla are required for hemostasis. In Aim 3 we will use human and murine platelet rich plasma systems to examine the importance of fXI and fXII to thrombin generation and platelet activation in vitro, with the primary goal of determining if there are differences between the two species. These studies will allow us to compare the importance of fXI, fXII and TAFI to normal hemostasis and to pathologic coagulation, and will provide valuable information regarding the mechanism(s) for fXI activation in complex systems. Ultimately, the work may demonstrate that fXI and/or fXII contribute in a substantive way to blood vessel occlusion, and are therefore, legitimate targets for novel investigative therapies to treat or prevent vascular thromboembolism in humans. Relevance: Anticoagulant drugs have been very beneficial for treating abnormal blood clots in a variety of diseases, but have the disadvantage of leaving the patient prone to serious bleeding. We are looking for new targets in blood for anticoagulation therapy that will not be associated with high bleeding risk.

描述（由申请人提供）：蛋白酶因子Xla（fXIa）通过在血液凝固开始后维持凝血酶的产生而有助于止血。除了促进纤维蛋白形成外，fXIa 还在涉及蛋白酶 TAFI 的过程中促进血栓对纤维蛋白溶解的抵抗。多项证据表明 fXIa 有助于病理性凝血。 fXIa 前体 fXI 血浆水平升高与人类动脉和静脉血栓形成的风险增加相关。我们观察到 fXI 缺陷小鼠在动脉损伤模型中对血管闭塞有抵抗力，表明 fXIa 有助于富含血小板的血栓形成。 FXI 在体外与血小板结合，并通过凝血酶或因子 XIla (fXIIa) 转化为 fXIa。这些相互作用在体内或复杂的体外系统中的重要性尚不清楚，并且凝血酶和fXIIa对于fXI激活的相对重要性尚不清楚。 FXI I 缺乏不会引起出血异常，表明 fXI 在体内被其他蛋白酶激活。然而，fXII 缺陷小鼠对动脉闭塞具有抵抗力，这增加了病理性闭塞血栓的形成涉及与正常止血不同的过程的可能性。在本提案的目标 1 中，我们将使用 fXI、fXII 和 TAFI 缺陷的小鼠来研究这些蛋白质在病理性凝血模型中的重要性。使用一组新型重组 fXI 变体来重建 fXI 缺陷小鼠，我们将确定 fXI 与血小板、凝血酶和 fXIIa 相互作用对这些模型的重要性，并寻找与经典凝血途径无关的 fXI 和 fXII 的替代功能。在目标 2 中，将使用小鼠 fXI 依赖性出血模型来确定止血是否需要 fXI 与血小板、凝血酶和 fXIIa 的相互作用。在目标 3 中，我们将使用人和鼠富含血小板的血浆系统来检查 fXI 和 fXII 对体外凝血酶生成和血小板激活的重要性，主要目标是确定这两个物种之间是否存在差异。这些研究将使我们能够比较 fXI、fXII 和 TAFI 对正常止血和病理凝血的重要性，并将提供有关复杂系统中 fXI 激活机制的有价值的信息。最终，这项工作可能证明 fXI 和/或 fXII 对血管闭塞有实质性贡献，因此是治疗或预防人类血管血栓栓塞的新型研究疗法的合法目标。相关性：抗凝药物对于治疗多种疾病中的异常血栓非常有益，但缺点是使患者容易发生严重出血。我们正在寻找血液中抗凝治疗的新靶点，这些靶点不会与高出血风险相关。