Scheme showing ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors. Binding of ligands to either FcγRIIa (14A2 or VM58) or GPVI/FcRγ (collagen, CRP, or convulxin) activates both (a) extracellular metalloproteinase-mediated ectodomain shedding of GPVI,¹²  and (b) intracellular calpain-mediated cleavage of FcγRIIa, resulting in deletion of the ITAM domain. Both pathways are also induced by the calmodulin inhibitor, W7, which dissociates calmodulin from the cytoplasmic domain of GPVI and FcγRIIa.