The role of contact pathway factors in mechanical circulation

接触途径因素在机械循环中的作用

• 批准号: 10518491
• 负责人: David L Morales
• 金额: $ 56.25万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518491
• 关键词: Animal Model; Animals; Anticoagulants; Anticoagulation; Antisense Oligonucleotides; Artificial Heart; Automobile Driving; Biological; Blood Circulation; Blood Proteins; Blood Vessels; Blood coagulation; Bradykinin; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Clinical Trials; Complement; Complement Activation; Complement component C6; Coupling; Critical Illness; DNA; Data; Endothelium; Event; Exposure to; Extracorporeal Membrane Oxygenation; Factor Analysis; Factor IX; Factor XI; Factor XII; Fiber; Future; Gene Targeting; Generations; Heart; Heart-Lung Machine; Hemorrhage; Hemostatic Agents; Heparin; High-Molecular-Weight Kininogen; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Kininogenase; Knowledge; Lead; Life; Link; Lung; Mechanics; Mediating; Membrane Oxygenators; Modeling; Morbidity - disease rate; Myocardial; Myocardium; Natural Immunity; Operative Surgical Procedures; Organ; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Pharmacology; Play; Polyphosphates; Prekallikrein; Rattus; Risk; Role; Sepsis; Sternotomy; Surgical Hemostasis; System; Testing; Therapeutic; Thrombin; Thromboembolism; Thromboplastin; Thrombosis; Translating; experimental study; genetic approach; insight; interest; macromolecule; mechanical circulatory support; mortality; new therapeutic target; novel; operation; organ injury; respiratory; systemic inflammatory response; targeted agent; targeted treatment; therapeutic target; thromboinflammation; thrombotic; thrombotic complications; tool

SUMMARY Extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB) are associated with a devastating but poorly understood thromboinflammatory state. Standard anticoagulation strategies result in significant bleeding risk, yet are inadequate as life-threatening thromboses remain common. There are no effective strategies to mitigate the inflammatory storm initiated within minutes of starting mechanical circulatory support. Data from the PIs lab suggests that factor XII (FXII) promotes both thrombosis and inflammatory mediated organ damage during ECMO. There is significant interest in FXII as a target in mechanical circulation, but the mechanisms coupling FXII to mechanical circulation associated thromboinflammation are under- studied. FXII is a multifunctional protease that bridges the hemostatic and inflammatory systems. FXII activates factor XI (FXI), leading to thrombin generation. The importance of FXII-mediated FXI activation in the setting of mechanical circulation has never been evaluated. Data from the PIs lab suggests mechanical circulation components can promote thrombin-mediated FXI activation, significantly limiting the relevance of FXII in some contexts. Moreover, targeting FXII appears inadequate during CPB with open heart operations where sternotomy and cardiac manipulation increase circulating tissue factor levels. FXII also activates prekallikrein (PKK) to the active protease kallikrein (Kal). Kal is linked to multiple inflammatory pathways, including complement activation and bradykinin generation. Kal has also been proposed to promote thrombosis independently of FXI. FXII-mediated PKK activation has been proposed to drive inflammatory events during ECMO, but there are no studies directly evaluating the role of PKK in mechanical circulation associated thromboinflammation. Data from the PIs lab suggests that targeting PKK significantly limits thrombosis and organ damage in ECMO. The proposed studies will use novel gene-targeted rats developed specifically for this proposal, and cutting-edge pharmacological agents to test the following hypotheses: 1) FXII promotes ECMO and CPB related thromboinflammatory pathologies by independent mechanisms related to activation of FXI and PKK. 2) FXI is a superior antithrombotic target in mechanical circulation contexts with relatively high circulating TF levels, such as exist during CPB. 3) FXII-mediated PKK activation promotes key inflammatory events that lead to organ damage during ECMO/CPB, as well as thromboembolic complications. 4) Combined strategies targeting FXI and FXII, or FXI and PKK, provide better protection from thrombosis and inflammatory organ damage than targeting one of these factors alone, without incurring a major bleeding risk. The proposed studies will provide needed insights into the mechanisms coupling FXII to mechanical circulation associated thromboinflammatory pathologies. The knowledge gained will critically inform future clinical trials of available and emerging agents targeting FXII and FXI. The proposed studies are also likely to identify additional novel targets (e.g., PKK) to limit thromboinflammatory driven morbidity in mechanical circulation.

概括 体外膜肺氧合（ECMO）和体外循环（CPB）与 毁灭性但知之甚少的血栓炎症状态。标准抗凝策略导致 显着的出血风险，但还不够，因为危及生命的血栓仍然常见。没有 减轻机械循环开始后几分钟内引发的炎症风暴的有效策略 支持。 PI 实验室的数据表明，因子 XII (FXII) 会促进血栓形成和炎症 ECMO期间介导的器官损伤。人们对 FXII 作为机械循环的目标产生了浓厚的兴趣， 但 FXII 与机械循环相关血栓炎症的耦合机制尚不明确 研究过。 FXII 是一种多功能蛋白酶，可连接止血和炎症系统。 FXII 激活 XI 因子 (FXI)，导致凝血酶生成。 FXII 介导的 FXI 激活在环境中的重要性 机械循环的影响从未被评估过。 PIs 实验室的数据表明机械循环 成分可以促进凝血酶介导的 FXI 激活，显着限制 FXII 在某些疾病中的相关性 上下文。此外，在进行心脏直视手术的 CPB 期间，针对 FXII 似乎不够充分。 胸骨切开术和心脏操作会增加循环组织因子水平。 FXII 还激活前激肽释放酶 (PKK) 至活性蛋白酶激肽释放酶 (Kal)。 Kal 与多种炎症途径有关，包括 补体激活和缓激肽生成。 Kal 也被认为可以促进血栓形成 独立于 FXI。 FXII 介导的 PKK 激活被认为可以驱动炎症事件 ECMO，但没有研究直接评估PKK在机械循环相关的作用 血栓炎症。来自 PI 实验室的数据表明，靶向 PKK 可以显着限制血栓形成和 ECMO 中的器官损伤。拟议的研究将使用专门为此开发的新型基因靶向大鼠 提案和尖端药物来测试以下假设：1）FXII促进ECMO 和 CPB 相关的血栓炎症病理通过与 FXI 激活相关的独立机制进行 和库尔德工人党。 2) FXI 在机械循环环境中是一个优越的抗血栓靶点，具有相对较高的 循环 TF 水平，例如 CPB 期间存在的水平。 3）FXII介导的PKK激活促进关键炎症 ECMO/CPB 期间导致器官损伤的事件以及血栓栓塞并发症。 4) 综合 针对 FXI 和 FXII 或 FXI 和 PKK 的策略可提供更好的保护，防止血栓形成和炎症 与单独针对这些因素之一相比，可以减少器官损伤，而不会产生重大出血风险。拟议的 研究将为 FXII 与机械循环相关的耦合机制提供所需的见解 血栓炎症病理。所获得的知识将为未来的临床试验提供重要信息 以及针对 FXII 和 FXI 的新兴药物。拟议的研究也可能会发现其他新颖的 目标（例如，PKK）限制机械循环中血栓炎症驱动的发病率。