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

June Li, Dianne E. van der Wal, Guangheng Zhu, Miao Xu, Issaka Yougbare, Li Ma, Brian Vadasz, Naadiya Carrim, Renata Grozovsky, Min Ruan, Lingyan Zhu, Qingshu Zeng, Lili Tao, Zhi-min Zhai, Jun Peng, Ming Hou, Valery Leytin, John Freedman, Karin M. Hoffmeister and Heyu Ni ()
Additional contact information
June Li: University of Toronto
Dianne E. van der Wal: Toronto Platelet Immunobiology Group
Guangheng Zhu: Toronto Platelet Immunobiology Group
Miao Xu: University of Toronto
Issaka Yougbare: Toronto Platelet Immunobiology Group
Li Ma: Toronto Platelet Immunobiology Group
Brian Vadasz: University of Toronto
Naadiya Carrim: Toronto Platelet Immunobiology Group
Renata Grozovsky: Brigham and Women’s Hospital, Harvard Medical School
Min Ruan: Anhui Medical University
Lingyan Zhu: Anhui Medical University
Qingshu Zeng: Anhui Medical University
Lili Tao: Anhui Medical University
Zhi-min Zhai: Anhui Medical University
Jun Peng: Qilu Hospital, Shandong University
Ming Hou: Qilu Hospital, Shandong University
Valery Leytin: University of Toronto
John Freedman: University of Toronto
Karin M. Hoffmeister: Brigham and Women’s Hospital, Harvard Medical School
Heyu Ni: University of Toronto

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8737

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