Factor XI in Thrombosis

血栓形成中的因子 XI

• 批准号: 8237528
• 负责人: David Gailani
• 金额: $ 40.32万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237528
• 关键词: Address; Affect; Antibodies; Attention; Bacterial Infections; Binding; Biological Assay; Blood; Blood Clot; Blood Platelets; Blood coagulation; Blood flow; Chimera organism; Coagulation Process; Conflict (Psychology); Coronary Arteriosclerosis; Data; Defect; Deposition; Disease; Disseminated Intravascular Coagulation; Enzyme Precursors; Factor IXa; Factor XI; Factor XII; Fibrin; Generations; Goals; Growth; Hemorrhage; Hemostatic function; High-Molecular-Weight Kininogen; Human; In Vitro; Inflammation; Injury; Mediating; Modeling; Molecular; Molecular Conformation; Mus; Oropharyngeal; Oryctolagus cuniculus; Papio; Pathologic; Pathologic Processes; Pathway interactions; Patients; Peptide Hydrolases; Phospholipids; Plasma; Plasma Proteins; Platelet Activation; Platelet aggregation; Play; Population; Prekallikrein; Primates; Process; Proteins; Recombinant Proteins; Resistance; Risk; Role; Sepsis; Structure; Surface; System; Techniques; Testing; Therapeutic; Thrombin; Thromboembolism; Thrombosis; Thrombus; Tissues; Transfection; Trypsin; Urinary tract; Variant; Vascular Graft; Venous; Vitamin K; Whole Blood; Wild Type Mouse; Work; base; cofactor; dimer; epidemiologic data; human data; in vivo; mortality; mouse model; mutant; novel; novel therapeutics; prevent; receptor; stem

DESCRIPTION (provided by applicant): Factor (f) XI, the zymogen of the coagulation protease fXIa, serves a limited role in normal blood clotting (hemostasis), as fXI deficiency is associated with a relatively mild bleeding tendency. Despite this, work in baboons, rabbits, and mice, supported by human population data; strongly indicate that fXI makes important contributions to pathologic coagulation (thromboembolism). In classic coagulation models, fXI is converted to fXIa by activated fXII (fXIIa) in a process called contact activation, which also requires the proteins prekallikrein (PK) and high molecular weight kininogen (HK). The relevance of contact activation to hemostasis has been questioned, justifiably, as patients lacking fXII, PK or HK do not bleed abnormally. Based on this, in newer models of hemostasis fXI is activated through mechanisms distinct from contact activation. However, mice lacking fXII, similar to those lacking fXI, are resistant to thrombosis, suggesting contact activation (or a process similar to it) contributes to pathologic coagulation. While available epidemiologic data are conflicted regarding the importance of contact activation to thrombosis in humans, we noted that fXII contributes to fibrin formation and platelet aggregation in human blood in an ex vivo flow model. We hypothesize that fXII working through contact activation or a related process contributes to pathologic thrombus formation and stability in mice and primates, and that inhibiting this process can produce an anti-thrombotic effect. In Aim 1 of this proposal we will address the hypothesis that fXI must interact with platelets to contribute to thrombus formation by using transfection techniques that allow proteins to be transiently expressed in vivo. We will also investigate the possibility that fXIa can contribute to coagulation by processes distinct from those related to its classic function of activating factor IX. Studies in Aim 2 will investigate the interaction of fXI with fXIIa using chimeric and mutant recombinant proteins, conventional clotting assays, and whole blood flow models. We will also examine the importance of the fXI-HK interaction and the impact of PK deficiency on thrombus formation in mice. Previously we have shown that fXI deficiency confers a survival advantage in mice in models of bacterial infection. In Aim 3 we will compare the effects of fXI deficiency on survival, disseminated intravascular coagulation, and inflammation to those of deficiencies of fXII, HK, and PK in a model of polymicrobial sepsis in mice. We have demonstrated that inhibiting fXI with an antibody has a dramatic effect on the growth of platelet-rich thrombi in a baboon vascular graft thrombosis model. In Aim 4, we will compare the effects of fXI and fXII inhibition in this model to determine if fXII plays an important role in the growth of pathologic thrombi in primates. Results from these studies will give us a stronger understanding of the mechanisms involved in activation of fXI in pathologic coagulation, and may identify novel targets or pathways that could be targeted with novel therapeutic strategies to treat or prevent thromboembolic disease. PUBLIC HEALTH RELEVANCE: Factor XI is a plasma protein that serves a limited role in normal blood coagulation, but appears to make disproportionately greater contributions to thrombosis. We are investigating the mechanisms by which factor XI and related plasma proteins affect thrombotic disease.

描述（由申请人提供）：因子（f）XI，凝血蛋白酶fXIa的酶原，在正常血液凝固（止血）中发挥有限的作用，因为fXI缺乏与相对轻微的出血倾向相关。尽管如此，在人类数据的支持下，对狒狒、兔子和小鼠进行了研究；强烈表明 fXI 对病理性凝血（血栓栓塞）做出了重要贡献。在经典凝血模型中，fXI 通过激活的 fXII (fXIIa) 在称为接触激活的过程中转化为 fXIa，该过程还需要蛋白质前激肽释放酶 (PK) 和高分子量激肽原 (HK)。接触激活与止血的相关性受到质疑，这是合理的，因为缺乏 fXII、PK 或 HK 的患者不会异常出血。基于此，在较新的止血模型中，fXI 通过不同于接触激活的机制被激活。然而，与缺乏 fXI 的小鼠类似，缺乏 fXII 的小鼠对血栓形成具有抵抗力，这表明接触激活（或类似的过程）有助于病理性凝血。虽然现有的流行病学数据对于接触激活对人类血栓形成的重要性存在争议，但我们注意到，在离体流动模型中，fXII 有助于人血液中纤维蛋白的形成和血小板聚集。我们假设 fXII 通过接触激活或相关过程起作用，有助于小鼠和灵长类动物的病理性血栓形成和稳定性，并且抑制该过程可以产生抗血栓作用。在本提案的目标 1 中，我们将通过使用允许蛋白质在体内瞬时表达的转染技术来解决 fXI 必须与血小板相互作用以促进血栓形成的假设。我们还将研究 fXIa 通过与其激活因子 IX 的经典功能相关的过程不同的过程促进凝血的可能性。目标 2 中的研究将使用嵌合和突变重组蛋白、常规凝血测定和全血流模型来研究 fXI 与 fXIIa 的相互作用。我们还将研究 fXI-HK 相互作用的重要性以及 PK 缺陷对小鼠血栓形成的影响。之前我们已经证明，fXI 缺陷在细菌感染模型中赋予小鼠生存优势。在目标 3 中，我们将在多种微生物脓毒症小鼠模型中比较 fXI 缺陷与 fXII、HK 和 PK 缺陷对生存、弥散性血管内凝血和炎症的影响。我们已经证明，在狒狒血管移植血栓形成模型中，用抗体抑制 fXI 对富含血小板的血栓的生长具有显着影响。在目标 4 中，我们将比较该模型中 fXI 和 fXII 抑制的效果，以确定 fXII 是否在灵长类动物病理性血栓的生长中发挥重要作用。这些研究的结果将使我们对病理性凝血中 fXI 激活的机制有更深入的了解，并可能确定新的靶点或途径，以新的治疗策略来治疗或预防血栓栓塞性疾病。 公众健康相关性：XI 因子是一种血浆蛋白，在正常血液凝固中的作用有限，但似乎对血栓形成的贡献更大。我们正在研究因子 XI 和相关血浆蛋白影响血栓性疾病的机制。