Perfluoroalkyl and polyfluoroalkyl substances interact with platelet glycoprotein Ibα and exacerbate thrombosis

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.