Targeting the contact system in a rabbit model of extracorporeal membrane oxygenation.
Targeting the contact system in a rabbit model of extracorporeal membrane oxygenation.
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DOI：
10.1182/bloodadvances.2022007586
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发表时间：
2023-04-25
期刊：
影响因子：
7.5
通讯作者：
Palumbo JS
中科院分区：
文献类型：
--
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
因子XII和XI驱动ECMO血栓形成。FXII似乎在ECMO中促进器官损伤，而不依赖凝血酶的产生。当组织因子水平高时，凝血酶介导的FXI激活可能掩盖了FXII在ECMO中的作用。以往的研究表明，接触途径因子驱动机械循环血栓形成。我们使用兔静脉-动脉体外循环（VA-ECMO）模型来评估因子XI和XII在ecmo相关血栓形成和器官损伤中的作用。因子XI和XII （FXI， FXII）在放置于血源性VA-ECMO回路之前使用已建立的反义寡核苷酸去除。将FXII或FXI降低至基线活性的5%可显着延长ECMO回路寿命，限制凝血病变的发展，并防止纤维蛋白原消耗。组织学分析表明，FXII耗竭可减轻间质性肺水肿和出血，而肝素和FXI耗竭则无此作用。FXI和FXII耗竭均与其他器官的显著出血无关。体外分析表明，膜氧合纤维（mof）单独能够以FXII和fxi依赖的方式驱动凝血酶的产生。mof也增加凝血酶的产生由低（1 pM）或高（5 pM）组织因子浓度触发。然而，只有FXI的消除完全阻止了由mof驱动的凝血酶生成的增加，这表明mof增强了凝血酶介导的FXI激活。总之，这些结果表明，针对FXII或FXI的治疗限制了与ECMO相关的血栓栓塞并发症。需要进一步的研究来确定在何种情况下，单独或联合靶向FXI和FXII在ECMO中最有益。此外，还需要研究确定FXII与ECMO终末器官损伤耦合的潜在机制。
Factors XII and XI drive thrombosis in ECMO. FXII appears to promote organ damage in ECMO independent of thrombin generation. Thrombin-mediated activation of FXI may overshadow the role of FXII in ECMO when tissue factor levels are high. Previous studies suggested that contact pathway factors drive thrombosis in mechanical circulation. We used a rabbit model of veno-arterial extracorporeal circulation (VA-ECMO) to evaluate the role of factors XI and XII in ECMO-associated thrombosis and organ damage. Factors XI and XII (FXI, FXII) were depleted using established antisense oligonucleotides before placement on a blood-primed VA-ECMO circuit. Decreasing FXII or FXI to < 5% of baseline activity significantly prolonged ECMO circuit lifespan, limited the development of coagulopathy, and prevented fibrinogen consumption. Histological analysis suggested that FXII depletion mitigated interstitial pulmonary edema and hemorrhage whereas heparin and FXI depletion did not. Neither FXI nor FXII depletion was associated with significant hemorrhage in other organs. In vitro analysis showed that membrane oxygenator fibers (MOFs) alone are capable of driving significant thrombin generation in a FXII- and FXI-dependent manner. MOFs also augment thrombin generation triggered by low (1 pM) or high (5 pM) tissue factor concentrations. However, only FXI elimination completely prevented the increase in thrombin generation driven by MOFs, suggesting MOFs augment thrombin-mediated FXI activation. Together, these results suggest that therapies targeting FXII or FXI limit thromboembolic complications associated with ECMO. Further studies are needed to determine the contexts wherein targeting FXI and FXII, either alone or in combination, would be most beneficial in ECMO. Moreover, studies are also needed to determine the potential mechanisms coupling FXII to end-organ damage in ECMO.
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DOI：
10.1097/pcc.0000000000000317
发表时间：
2015-02
期刊：
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
影响因子：
--
作者：
Dalton HJ;Garcia-Filion P;Holubkov R;Moler FW;Shanley T;Heidemann S;Meert K;Berg RA;Berger J;Carcillo J;Newth C;Harrison R;Doctor A;Rycus P;Dean JM;Jenkins T;Nicholson C;Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network
通讯作者：
Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network
DOI：
10.1084/jem.20052458
发表时间：
2006-03-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kleinschnitz C;Stoll G;Bendszus M;Schuh K;Pauer HU;Burfeind P;Renné C;Gailani D;Nieswandt B;Renné T
通讯作者：
Renné T
DOI：
10.1056/nejmoa1405760
发表时间：
2015-01-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
Büller HR;Bethune C;Bhanot S;Gailani D;Monia BP;Raskob GE;Segers A;Verhamme P;Weitz JI;FXI-ASO TKA Investigators
通讯作者：
FXI-ASO TKA Investigators
影响因子：
8.9
作者：
Kalbhenn, Johannes;Schlagenhauf, Axel;Zieger, Barbara
通讯作者：
Zieger, Barbara
DOI：
10.1073/pnas.2014810118
发表时间：
2021-01-19
影响因子：
11.1
作者：
Kearney KJ;Butler J;Posada OM;Wilson C;Heal S;Ali M;Hardy L;Ahnström J;Gailani D;Foster R;Hethershaw E;Longstaff C;Philippou H
通讯作者：
Philippou H