A rat monoclonal antibody, INU1, that is specific for mouse CLEC-2 induces activation of SFK and Syk, resulting in platelet activation and internalization of INU1/CLEC-2 complexes (A). In wild-type mice, INU1-bound platelets, which have internalized their INU1/CLEC-2 complexes, are cleared in a manner that depends upon platelet activation (B). In wild-type mice treated with the SFK inhibitor, dasatinib, platelets can neither be activated nor can they internalize CLEC-2/INU1 complexes; consequently, they are cleared in a manner that depends on binding of FcγRs, presumably on phagocytes, to the Fc region of the INU1 IgG heavy chain (C). Interestingly, in Syk-deficient mice, platelets do not become activated but do internalize CLEC-2/INU1 complexes; consequently, they cannot be cleared by either the activation-dependent or FcγR-dependent pathway and therefore continue to circulate (D). These findings show that antibody-mediated CLEC-2 downregulation can be uncoupled from antibody-induced thrombocytopenia, which is a prerequisite for CLEC-2 targeting strategies to be useful as antithrombotic therapies.