Platelet activation and signaling in thrombus formation

In thrombosis and hemostasis, the formation of a platelet-fibrin thrombus or clot is a highly controlled process that varies, depending on the pathological context. Major signaling pathways in platelets are well established. However, studies with genetically modified mice have identified the contribution of hundreds of additional platelet-expressed proteins in arterial thrombus formation and bleeding. Using phenotype information of 540 mouse genes, involved in arterial thrombosis and hemostasis, we review current insights into established and novel platelet signaling mechanisms. We discuss pathways involved in platelet adhesion, shape change, integrin activation, intracellular vesicle trafficking and protein processing, granule secretion, aggregate formation, and procoagulant activity. Specific attention is paid to the signaling routes used by immunoreceptor tyrosine-based activation motif linked, immunoreceptor tyrosine-based inhibitory motif linked, and G protein-coupled receptors, as well as downstream events feeding into GTPase regulation and protein kinase activation. We further summarize known alterations in platelet responses under conditions of venous, inflammatory, and infection-dependent thrombosis, taking into account interactions of platelets with the endothelium, leukocytes, and red blood cells. Understanding the genes and proteins involved in platelet signaling in the context of hemostasis, thrombosis, and inflammation may lead to improved therapies to prevent and treat thrombotic disorders.