Platelet glycoprotein V spatio-temporally controls fibrin formation.

The activation of platelets and coagulation at vascular injury sites is crucial for haemostasis but can promote thrombosis and inflammation in vascular pathologies. Here, we delineate an unexpected spatio-temporal control mechanism of thrombin activity that is platelet orchestrated and locally limits excessive fibrin formation after initial haemostatic platelet deposition. During platelet activation, the abundant platelet glycoprotein (GP) V is cleaved by thrombin. We demonstrate with genetic and pharmacological approaches that thrombin-mediated shedding of GPV does not primarily regulate platelet activation in thrombus formation, but rather has a distinct function after platelet deposition and specifically limits thrombin-dependent generation of fibrin, a crucial mediator of vascular thrombo-inflammation. Genetic or pharmacologic defects in haemostatic platelet function are unexpectedly attenuated by specific blockade of GPV shedding, indicating that the spatio-temporal control of thrombin-dependent fibrin generation also represents a potential therapeutic target to improve haemostasis.

Déclaration de conflit d'intérêts

Competing interests: SB, DS and BN hold a patent on recombinant GPV for treating thrombotic diseases reporting soluble GPV (lacking a functional transmembrane domain) for use in the treatment or prevention of thrombotic diseases. Data on rhGPV preventing thrombus formation in vivo and reducing infarct volume in a tMCAO model in this manuscript are partly covered by the patent (patent applicant: Julius-Maximilians Universität Würzburg, Inventors: BN, DS, SB, patent published, title: soluble glycoprotein V for treating thrombotic diseases; WO 2017/109212; US Patent No. US 11,028,144 B2). The other authors declare that they have no competing of interest. Extended Information is available for this paper.