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: 10643999
• 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/10643999
• 关键词: Animal Model; Animals; Anticoagulants; Anticoagulation; Antisense Oligonucleotides; Artificial Heart; Automobile Driving; Biological; Blood Proteins; Blood Vessels; Blood coagulation; Bradykinin; Cardiac; Cardiac Surgery procedures; Cardiopulmonary Bypass; Circulation; Clinical Trials; Combined Modality Therapy; Complement; Complement Activation; Complement component C6; Coupling; Critical Illness; DNA; Data; Endothelium; Event; Exposure to; Extracorporeal Membrane Oxygenation; Factor Analysis; Factor IXa; Factor XI; Factor XII; Factor XIIa; Factor XIa; Fiber; Future; Gene Targeting; Generations; Heart; Heart and Lung machine; Hemorrhage; Hemostatic Agents; Heparin; High-Molecular-Weight Kininogen; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Kininogenase; Knowledge; 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; 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; particle; pharmacologic; 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 体外膜氧合（ECMO）和心肺旁路（CPB）与A相关 毁灭性但知之甚少的血栓炎性状态。标准抗凝策略导致 严重的出血风险，但由于威胁生命的血栓形成仍然很常见，但不足。没有 有效的策略来减轻在开始机械循环的几分钟内引发的炎症风暴 支持。来自PIS实验室的数据表明，第XII因子（FXII）促进了血栓形成和炎症 ECMO期间介导的器官损伤。 FXII作为机械循环的目标有很大的兴趣， 但是，与机械循环偶联的机制相关的血栓炎不足 研究。 FXII是一种桥接止血和炎症系统的多功能蛋白酶。 FXII激活 因子XI（FXI），导致凝血酶产生。 FXII介导的FXI激活在设置中的重要性 机械循环从未评估过。来自PIS实验室的数据表明机械循环 组件可以促进凝血酶介导的FXI激活，从而显着限制了FXII在某些方面的相关性 上下文。此外，靶向FXII在CPB期间出现不足，有开放的心脏操作 胸骨切开术和心脏操纵增加了循环的组织因子水平。 FXII还激活prekallikrein （PKK）到活性蛋白酶Kallikrein（KAL）。 KAL与多种炎症途径有关，包括 补体激活和心动激素产生。还提出了KAL来促进血栓形成 独立于FXI。提出了FXII介导的库尔巴克库激活，以驱动炎症事件 ECMO，但没有直接评估库尔克机在相关机械循环中的作用的研究 血栓炎。来自PIS实验室的数据表明，针对PKK显着限制了血栓形成和 ECMO的器官损坏。拟议的研究将使用专门为此开发的新型基因靶向大鼠 提案和尖端的药理学剂来检验以下假设：1）FXII促进ECMO 通过与FXI激活有关的独立机制和CPB相关的血栓炎病理学 和PKK。 2）FXI是机械循环环境中的优质抗血栓靶标 循环TF水平，例如CPB期间存在。 3）FXII介导的PKK激活促进关键炎症 导致ECMO/CPB期间器官损伤的事件以及血栓栓塞并发症。 4）合并 针对FXI和FXII或FXI和PKK的策略可更好地保护血栓形成和炎症 器官损坏比仅针对这些因素之一而不会产生主要出血风险。提议 研究将提供有关FXII与机械循环的机制所需的见解 血栓炎性病理。获得的知识将为未来的临床试验提供批判性的信息 以及针对FXII和FXI的新兴药物。拟议的研究还可能识别出其他新颖 靶（例如，库克）限制了血栓炎性驱动的机械循环发病率。

项目成果

Targeting the contact system in a rabbit model of extracorporeal membrane oxygenation.

• DOI: 10.1182/bloodadvances.2022007586
• 发表时间: 2023-04-25
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Tweddell JS;Kharnaf M;Zafar F;Riggs KW;Reagor JA;Monia BP;Revenko A;Leino DG;Owens AP;Martin JK;Gourley B;Rosenfeldt L;Palumbo JS
• 通讯作者: Palumbo JS