The Scott syndrome is a rare bleeding disorder associated with a mutation in the gene encoding anoctamin-6 (TMEM16F). After stimulation of Ca2+-mobilizing agonists, syndromatic platelets show a reduced phosphatidylserine exposure and do not form membrane blebs. Given the central role of anoctamin-6 in the platelet procoagulant response, we used quantitative proteomics to understand the underlying molecular mechanisms and the complex phenotypic changes in Scott platelets compared to control platelets. Therefore, we applied an iTRAQ-based multi-pronged strategy to quantify changes in (i) the global proteome, (ii) the phosphoproteome and (iii) proteolytic events between resting and stimulated Scott and control platelets. Our data indicate a limited number of proteins with decreased (70) or increased (64) expression in Scott platelets, among those we observed the absence of anoctamin-6 and the strong up-regulation of aquaporin-1. Furthermore, the quantification of 1,566 phosphopeptides revealed major differences between Scott and control platelets after stimulation with thrombin/convulxin or ionomycin. Finally, we quantified 1,596 N-terminal peptides in activated Scott and control platelets, 180 of which we identified as calpain-regulated, whereas a distinct set of 23 neo-N-termini was caspase-regulated. In Scott platelets, calpain-induced cleavage of cytoskeleton-linked and signaling proteins was down-regulated, in accordance with an increased phosphorylation state. Thus, multi-pronged proteomic profiling of Scott platelets provides detailed insight into their protection against detrimental Ca2+-dependent changes that are normally associated with phosphatidylserine exposure.