Platelet glycoprotein V as modulator of hemostasis, thrombosis and thrombo-inflammation

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The activation of platelets and coagulation at vascular injury sites is crucial for hemostasis but can promote thrombosis and inflammation in vascular pathologies. In our preliminary work we have provided evidence for a platelet orchestrated mechanism that locally limits excessive fibrin formation after initial hemostatic platelet deposition that is centrally regulated by the abundant platelet glycoprotein (GP) V. During platelet activation, GPV is cleaved by thrombin and we propose that the formed GPV/thrombin complex modulates thrombin localization and its fibrin-forming activity. In the proposed project, we will use genetic and pharmacological approaches to investigate the exact mechanisms how GPV-thrombin interactions modulate fibrin formation and thus regulate hemostatic, thrombotic and thrombo-inflammatory pathways. Utilizing novel genetic mouse models, recombinant soluble GPV variants and panels of monoclonal antibodies we will study GPV regulation and its (patho-)physiological activity in various murine disease models and in human blood. These tools will further be combined with advanced microscopy methods to decipher the spatio-temporal modulation of thrombus/fibrin formation by GPV. With these studies, we expect to gain a detailed understanding of platelet-dependent modulation of thrombin activity / coagulation in hemostasis, thrombosis and thrombo-inflammation that could provide a basis for the development of new therapeutic strategies for patients at risk of bleeding, thrombosis or inflammatory tissue damage.