Liu Ming, Zhao Weiqing, Ma Chaoyu, Awais Muhammad, Chen Xue, Feng Yiting, Wang Tianyu, Zhou Shaoyun, Bai Yan, Jiang Shuai, Zhang Dachuan, Zhu Guangheng, Xu Xiaohong Ruby, Xu Miao, Ni Heyu, Shen Chuanbin
School of Medicine and Pharmacy, Ocean University of China, and the Laboratory of Marine Drugs, Chinese Ministry of Education, Qingdao, Shandong 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, Shandong 266237, China.
School of Medicine and Pharmacy, Ocean University of China, and the Laboratory of Marine Drugs, Chinese Ministry of Education, Qingdao, Shandong 266003, China.
J Hazard Mater. 2025 Aug 15;494:138506. doi: 10.1016/j.jhazmat.2025.138506. Epub 2025 May 5.
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are highly stable man-made chemicals. They have recently garnered significant attention due to their ubiquitous presence in the environment and deleterious effects on human health including cardiovascular diseases (CVDs). Thrombosis due to platelet activation is a major aspect in CVDs. However, the direct effect and underlying mechanism of PFAS on the platelets remains elusive. Here, we observed that PFAS engagement with the extracellular domain of platelet GPIbα, transduced GPIbα-driven inward signals, resulting in intracellular calcium mobilization, activation of Akt and αⅡbβ3 integrin, culminating in platelet aggregation and procoagulant platelet formation. PFAS pretreatment enhanced GPIb-mediated platelet spreading and thrombus formation under high shear conditions. PFAS-induced platelet activation was markedly decreased in Gpibα-deficient mice. PFAS-primed platelets drove neutrophil extracellular traps formation through GPIbα-dependent pathway. Further, PFAS-exposed mice showed heightened risk of thrombus growth and ischemic stroke. Our findings provide experimental evidence for the causal links between PFAS exposure and thrombotic CVDs. Blockade of GPIbα and the downstream pathways could be an instrumental strategy against PFAS-induced platelet activation and thrombosis.
全氟烷基和多氟烷基物质（PFAS）是高度稳定的人造化学品。由于它们在环境中普遍存在且对人类健康有有害影响，包括心血管疾病（CVD），它们最近受到了广泛关注。血小板活化导致的血栓形成是心血管疾病的一个主要方面。然而，PFAS对血小板的直接作用及其潜在机制仍不清楚。在此，我们观察到PFAS与血小板糖蛋白Ibα（GPIbα）的细胞外结构域结合，转导由GPIbα驱动的内向信号，导致细胞内钙动员、Akt和αⅡbβ3整合素激活，最终导致血小板聚集和促凝血小板形成。PFAS预处理增强了高剪切条件下GPIb介导的血小板铺展和血栓形成。在Gpibα基因敲除小鼠中，PFAS诱导的血小板活化明显降低。PFAS预处理的血小板通过GPIbα依赖性途径驱动中性粒细胞胞外陷阱形成。此外，暴露于PFAS的小鼠血栓生长和缺血性中风风险增加。我们的研究结果为PFAS暴露与血栓性心血管疾病之间的因果关系提供了实验证据。阻断GPIbα及其下游途径可能是对抗PFAS诱导的血小板活化和血栓形成的有效策略。
