Wu Wei, Tong Dongxia, Xia Wei, Song Bin, Li Guangwen, Zhou Lihui, Xie Fangyu, Zhang Chunquan, Liu Yvhao, Wang Haiyang, Du Zhaona, Shao Yibing, Li Jihe
Department of Cardiology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, China (W.W.).
Departments of Oncology (D.T.), Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, China.
Arterioscler Thromb Vasc Biol. 2025 Jun;45(6):1006-1019. doi: 10.1161/ATVBAHA.124.322376. Epub 2025 Apr 3.
Patients with severe aortic stenosis, undergoing transcatheter aortic valve replacement (TAVR), are more likely to develop thrombotic complications. However, the definite mechanisms underlying the hypercoagulation state remain unclear to date. Our objectives were to explore whether and how neutrophil extracellular traps (NETs) play a procoagulant role in patients after TAVR alone or TAVR with percutaneous coronary intervention within 1 year and further to evaluate their interactions with platelets and endothelial cells.
The levels of plasma NETs, platelets, and endothelial cell activation markers were analyzed by ELISA. NET formation was observed by immunofluorescence. Procoagulant activity was measured by clotting time, fibrin, and TAT (thrombin-antithrombin) complex generation assays. Phosphatidylserine exposure on cells was assessed by flow cytometry.
Compared with pre-TAVR, controls, or severe aortic stenosis without TAVR patients, the plasma NET levels in patients after TAVR alone, especially TAVR with percutaneous coronary intervention, increased from 7 days, peaking at 3 months, and then gradually decreased until the 12th month. Furthermore, neutrophils and plasma from patients post-TAVR are more prone to promote NET formation; NETs from these patients markedly decreased clotting time and increased fibrin and TAT generation. Additionally, a high concentration of NETs induced platelet aggregation and exerted a strong cytotoxic effect on endothelial cells and transformed them into a procoagulant phenotype.
These results lead us to believe that NETs contribute to the hypercoagulability in patients post-TAVR. Our study may provide a new target for preventing thrombotic complications in patients post-TAVR by blocking NET generation.
接受经导管主动脉瓣置换术（TAVR）的严重主动脉瓣狭窄患者更易发生血栓并发症。然而，迄今为止，高凝状态背后的确切机制仍不清楚。我们的目的是探讨中性粒细胞胞外陷阱（NETs）在单独接受TAVR或在1年内接受TAVR联合经皮冠状动脉介入治疗的患者中是否以及如何发挥促凝作用，并进一步评估它们与血小板和内皮细胞的相互作用。
采用酶联免疫吸附测定法（ELISA）分析血浆NETs、血小板和内皮细胞活化标志物的水平。通过免疫荧光观察NET的形成。采用凝血时间、纤维蛋白和凝血酶 - 抗凝血酶（TAT）复合物生成试验测定促凝活性。通过流式细胞术评估细胞上磷脂酰丝氨酸的暴露情况。
与TAVR术前、对照组或未接受TAVR的严重主动脉瓣狭窄患者相比，单独接受TAVR，尤其是接受TAVR联合经皮冠状动脉介入治疗的患者，血浆NET水平从术后7天开始升高，在3个月时达到峰值，然后逐渐下降直至第12个月。此外，TAVR术后患者的中性粒细胞和血浆更易于促进NET的形成；这些患者的NET显著缩短凝血时间，并增加纤维蛋白和TAT的生成。此外，高浓度的NETs诱导血小板聚集，并对内皮细胞产生强烈的细胞毒性作用，使其转变为促凝表型。
这些结果使我们相信NETs促成了TAVR术后患者的高凝状态。我们的研究可能为通过阻断NET生成来预防TAVR术后患者的血栓并发症提供一个新靶点。
