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Nat Commun. 2015 Jul 17;6:7737. doi: 10.1038/ncomms8737.

Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.

Author information

1
1] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [2] Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada M5B 1W8 [3] Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.
2
1] Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada M5B 1W8 [2] Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8 [3] Canadian Blood Services, Ottawa, Ontario, Canada K1G 4J5.
3
1] Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada M5B 1W8 [2] Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.
4
Translational Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
Department of Hematology, Anhui Medical University, Hefei 230032, China.
6
Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
7
1] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [2] Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada M5B 1W8 [3] Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8 [4] Department of Medicine, University of Toronto, Ontario, Canada M5S 1A8.
8
1] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [2] Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada M5B 1W8 [3] Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8 [4] Canadian Blood Services, Ottawa, Ontario, Canada K1G 4J5 [5] Department of Medicine, University of Toronto, Ontario, Canada M5S 1A8 [6] Department of Physiology, University of Toronto, Ontario, Canada M5S 1A8.

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-FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, 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-FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-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.

PMID:
26185093
PMCID:
PMC4518313
DOI:
10.1038/ncomms8737
[Indexed for MEDLINE]
Free PMC Article

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