ADAM10-mediated shedding of human platelet GPVI. (A) GPVI on the platelet surface is a 62-kDa transmembrane glycoprotein with 2 extracellular immunoglobulin domains, a short mucin-like domain, a transmembrane domain, and a cytoplasmic tail. Following activation of the metalloproteinase ADAM10 by exposure to elevated shear stress, coagulation, or GPVI ligands, an ∼55-kDa ectodomain of sGPVI is irreversibly shed, leaving a remnant membrane-associated fragment. Membrane properties/tetraspanin expression may also regulate ADAM10 activity toward GPVI. Platelet surface density of GPVI is crucial for signaling/adhesive function to collagen and thrombus stability via GPVI/fibrin. (B-C) Although surface density of GPVI may depend on multiple causes including genotype and/or bone marrow defects, and expression levels may in turn influence plasma levels of sGPVI, higher surface density may be related to increased thrombotic risk, whereas abnormally low levels of GPVI due to deficiency or disease, enhanced ADAM10-mediated shedding together with elevated plasma sGPVI may be associated with an increased risk of bleeding.