Platelet hem-Immunoreceptor Tyrosine–Based Activation Motif Receptors

Platelet interaction with the vessel wall in thrombosis and hemostasis is mediated through a complex interplay of distinct activation and signaling events, involving cell adhesion receptors for matrix proteins (von Willebrand Factor, collagen) and G-protein receptors for soluble agonists (thrombin, ADP, thromboxane A2).1 Adding to this complexity, it has become apparent in recent years that hemostasis and thrombosis as patho(physiological) processes are not identical, raising the hope that new antithrombotic therapeutic targets can be identified that are not associated with increased risk of bleeding.2 Two receptors, with promise, as potential antithrombotic therapeutic targets are members of the (hem)ITAM receptor family on platelets, glycoprotein VI (GPVI)/FcRγ-chain, the primary platelet collagen receptor,1–3 and C-type lectin-like receptor 2 (CLEC-2), which potentially plays a role in platelet aggregate and thrombus formation under arterial flow and is a receptor for the lymphatic endothelial cell protein, podoplanin.4–6 GPVI/FcRγ-chain and CLEC-2 are the only (hem)ITAM receptors present on mouse platelets. Human platelets have a third member of this family, the Fc receptor, FcγRIIa.7 GPVI/FcRγ-chain and CLEC-2 receptors signal through Src-family kinase tyrosine phosphorylation of the receptor cytoplasmic tail and a similar, but not identical, …