Abstract

Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc–FcgR interactions. However, we and others have demonstrated that anti-GPIba (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcgR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIba and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIba, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell–Morell receptors, which is fundamentally different from the classical Fc–FcgR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti GPIba-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP.