Role of GPVI/Fibrinogen interplay in platelet activation, thrombus formation and stability

GPVI belongs to the immunoglobulin superfamily. It is specifically expressed on platelets and megakaryocytes. Since GPVI-deficient patients suffer from a very mild bleeding diathesis and GPVI-deficient mice do not present a prolonged tail-bleeding time, GPVI is not absolutely required for hemostasis. Conversely, absence or blockade of GPVI inhibits thrombus formation in vitro and in several experimental thrombosis models. For these reasons, GPVI is considered as a potentially safe anti-thrombotic target. The aim of my PhD work was to characterize the role of the GPVI/fibrinogen interplay in thrombus formation. The main results I obtained are: i) pharmacological blockade of GPVI promotes efficient disaggregation of human thrombi pre-formed on collagen or on human atherosclerotic plaque material in vitro, identifying an unrecognized role of GPVI in thrombus stability, ii) identified a species difference between the human and mouse system related to the contribution of GPVI interplay with fibrinogen in thrombus progression and stability and iii) Finally, provided evidence that GPVI is more important than FcγRIIA in regulating platelet activation events post integrin αIIbβ3-mediated adhesion to fibrinogen, and thereby plays a prominent role in thrombus growth and stability.