Who's shedding now? The mechanism by which ectodomain shedding of GPVI occurs depends on how the platelets are treated. Addition of calmodulin inhibitors like W7 result in activation of ADAM10, while agents like CCCP that influence mitochondrial metabolism and the generation of reactive oxygen species initiate ADAM17-mediated cleavage of the GPVI extracellular domain. Surprisingly, antibody binding–mediated shedding of GPVI, a contemplated therapeutic approach, appears to take place via an entirely different mechanism that involves a still-to-be-defined protease. (Professional illustration by Paulette Dennis).