The role of contact pathway factors in mechanical circulation

点击翻译按钮获取中文摘要

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.