Fibrin at the interface of platelet activation and thrombus stabilisation (360G-Wellcome-204951_B_16_Z)

We have recently shown that fibrin, but not its precursor fibrinogen, activates platelets through a receptor complex, GPVI-FcRg-chain, which was identified by one of us (SPW) in the 1990s, and is recognised as the primary signalling receptor for collagen. The paradigm-changing observation that GPVI is a receptor for fibrin establishes a role for GPVI not only in initiation (via collagen) but also in propagation (via fibrin) of thrombus growth and may explain the increase in embolisation in thrombosis models in GPVI-deficient mice. We propose that the interaction of fibrin with GPVI represents a target for a new class of antiplatelet agent that may have benefits over current antiplatelet drugs. To investigate this we will map the site of interaction of fibrin with GPVI and develop agents (inhibitors and mouse models) that block this interaction but preserve the activation of GPVI by collagen. We will use these to determine the importance of GPVI-fibrin in haemostasis and thrombosis, and in other vascular pathways where GPVI is known to play a role including maintenance of vascular integrity.