Tong Dongxia, Gao Yuan, Sun Weihua, Yang Jie, Liu Yang, Li Jihe, Zhang Yan
Departments of Oncology, Qingdao Municipal Hospital, Qingdao University, Shandong Province, China.
Departments of Gynaecology, Qingdao Municipal Hospital, Qingdao University, Shandong Province, China.
Thromb Haemost. 2024 Dec 27. doi: 10.1055/a-2493-2499.
Thromboembolism is the second leading cause of death among patients with non-small cell lung cancer (NSCLC), but the precise mechanisms of thrombogenesis in NSCLC remain largely unknown. Our objectives were to evaluate the definitive role of neutrophil extracellular traps (NETs) in the hypercoagulability in NSCLC and to explore its interactions with platelets and endothelial cells (ECs).
The levels of NET markers in samples from 100 NSCLC patients and 30 healthy controls were measured by ELISA. NET formation was detected using immunofluorescence. Procoagulant activity was assessed based on purified coagulation complex, thrombin, clotting time, and fibrin formation assays.
The plasma levels of NETs were increased in a stage-dependent manner in NSCLC patients and were markedly higher than those in controls. Neutrophils from NSCLC patients were more prone to form NETs, resulting in shortened coagulation time, significantly increased thrombin-antithrombin complexes and fibrin compared to controls. Moreover, NETs generation was mediated by High Mobility Group Box 1 from activated platelets in NSCLC patients. Conversely, NETs from NSCLC patients also induce phosphatidylserine exposure on platelets, leading to markedly enhanced procoagulant activity (PCA). Furthermore, NETs can damage endothelial cells and convert them to a procoagulant phenotype. The administration of NETs inhibitors (DNase I/activated protein C) could markedly diminish the PCA of NETs, activated platelets, and ECs.
Our results suggest that NETs contribute to hypercoagulability and may represent a potential therapeutic target to prevent cancer-associated thrombosis in NSCLC patients.
血栓栓塞是非小细胞肺癌（NSCLC）患者的第二大死亡原因，但NSCLC中血栓形成的确切机制仍不清楚。我们的目的是评估中性粒细胞胞外陷阱（NETs）在NSCLC高凝状态中的决定性作用，并探讨其与血小板和内皮细胞（ECs）的相互作用。
采用ELISA法检测100例NSCLC患者和30例健康对照者样本中NET标志物的水平。采用免疫荧光法检测NET的形成。基于纯化的凝血复合物、凝血酶、凝血时间和纤维蛋白形成试验评估促凝活性。
NSCLC患者血浆NETs水平呈阶段依赖性升高，且明显高于对照组。NSCLC患者的中性粒细胞更容易形成NETs，与对照组相比，导致凝血时间缩短，凝血酶 - 抗凝血酶复合物和纤维蛋白显著增加。此外，NSCLC患者中活化血小板的高迁移率族蛋白B1介导NETs的产生。相反，NSCLC患者的NETs也可诱导血小板上磷脂酰丝氨酸的暴露，导致促凝活性（PCA）显著增强。此外，NETs可损伤内皮细胞并使其转变为促凝表型。给予NETs抑制剂（脱氧核糖核酸酶I /活化蛋白C）可显著降低NETs、活化血小板和ECs的PCA。
我们的结果表明，NETs促成高凝状态，可能是预防NSCLC患者癌症相关血栓形成的潜在治疗靶点。
