G protein-coupled receptor-mediated platelet thrombus formation

Platelet G protein-coupled receptor (GPCR) signaling plays a central role in platelet activation and thrombus formation; however, much of our current understanding of GPCR regulation is derived from isolated platelets and single-receptor knockout mouse models, and it does not fully capture vascular bed-specific regulation in vivo . This review highlights recent advances in GPCR regulatory mechanisms, including GPCR kinases (GRKs) and biased signaling, and discusses the challenges posed by interspecies differences in modeling and interpreting human thrombin/PAR signaling.

Recent work reveals distinct roles of platelets in arterial thrombosis versus venous thromboembolism, platelet heterogeneity within developing thrombi, and the emergence of procoagulant platelets as a functional link between coagulation and thromboinflammation. Together, these findings indicate that platelet GPCR signaling should be reconsidered in the context of vascular bed-specific cues, platelet-immune cell crosstalk, and the spatial organization of growing thrombi, highlighting its dynamic and context-dependent nature.

Spatiotemporal regulation of platelet GPCR signaling provides a conceptual framework to better understand context-dependent platelet function in hemostasis and thrombosis and may inform the development of more selective antithrombotic strategies, including approaches that target specific GPCR downstream effectors or signaling bias while preserving physiological hemostasis.