体外膜氧合支持启动后中性粒细胞细胞外陷阱增加，并存在于血栓中：使用绵羊作为动物模型的临床前研究。
Neutrophil extracellular traps are increased after extracorporeal membrane oxygenation support initiation and present in thrombus: A preclinical study using sheep as an animal model.
机构信息
Department of Laboratory Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, No.167, Beilishi Road, Xicheng District, Beijing 100037, China.
Department of Laboratory Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, No.167, Beilishi Road, Xicheng District, Beijing 100037, China; Center of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
出版信息
Thromb Res. 2023 Jan;221:173-182. doi: 10.1016/j.thromres.2022.10.019. Epub 2022 Nov 5.
BACKGROUND
The balance between thrombosis and hemostasis is a difficult issue during extracorporeal membrane oxygenation (ECMO) support. The pathogenesis leading to thrombotic complications during ECMO support is not well understood. Neutrophil extracellular traps (NETs) were reported to participate in thrombosis and have a key role in inflammation. This study aimed to explore the role of NETs in thrombosis during ECMO support and investigate NETs as a predictive biomarker for thrombotic complications during ECMO assistance.
METHODS
Ten ovine models of ECMO support were established. Animals were then randomly divided into 2 groups (5 sheep/group): venoarterial (VA) ECMO group and venovenous (VV) ECMO group. The venous blood samples were collected at different time points. Markers of NETs were detected in plasma, neutrophils, and thrombi from the vessels and membrane. Moreover, circulating NETs levels in 8 adults treated in the intensive care unit (ICU) who received VA-ECMO and 8 healthy controls were detected; patient survival was also recorded.
RESULTS
In vivo study showed that neutrophils and NETs markers (dsDNA and citH3) levels were significantly elevated 6 h after ECMO compared to baseline. Isolated neutrophils from fresh blood at 6 h could release more NETs. dsDNA and citH3 levels were significantly higher in the VA mode than in the VV mode. NETs were found in thrombi from the vessel and membrane. Clinical data further revealed that dsDNA, citH3, and nucleosomes were higher in patients who received ECMO than in healthy controls.
CONCLUSIONS
These data suggest NETs might be associated with thrombus during ECMO support, especially in the VA mode. These findings provide new insight into preventing thrombotic complications by targeting NETs. Also, NETs may potentially become an early warning biomarker for thrombosis under ECMO assistance.
背景
体外膜肺氧合（ECMO）支持期间，血栓形成和止血之间的平衡是一个难题。导致 ECMO 支持期间血栓形成并发症的发病机制尚不清楚。中性粒细胞胞外陷阱（NETs）被报道参与血栓形成，并在炎症中起关键作用。本研究旨在探讨 NETs 在 ECMO 支持期间血栓形成中的作用，并研究 NETs 作为 ECMO 辅助治疗期间血栓形成并发症的预测生物标志物。
方法
建立了 10 只绵羊 ECMO 支持模型。然后，动物被随机分为 2 组（每组 5 只羊）：静脉-动脉（VA）ECMO 组和静脉-静脉（VV）ECMO 组。在不同时间点采集静脉血样本。检测血浆、中性粒细胞和血管及膜内血栓中的 NETs 标志物。此外，还检测了在重症监护病房（ICU）接受 VA-ECMO 治疗的 8 例成人和 8 例健康对照者的循环 NETs 水平；并记录患者的生存情况。
结果
体内研究表明，与基线相比，ECMO 后 6 小时中性粒细胞和 NETs 标志物（dsDNA 和 citH3）水平显著升高。在 6 小时从新鲜血液中分离的中性粒细胞可以释放更多的 NETs。VA 模式下的 dsDNA 和 citH3 水平明显高于 VV 模式。在血管和膜中的血栓中发现了 NETs。临床数据进一步表明，接受 ECMO 的患者的 dsDNA、citH3 和核小体水平高于健康对照组。
结论
这些数据表明，NETs 可能与 ECMO 支持期间的血栓形成有关，尤其是在 VA 模式下。这些发现为通过靶向 NETs 预防血栓形成并发症提供了新的见解。此外，NETs 可能成为 ECMO 辅助治疗下血栓形成的早期预警生物标志物。
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