title: Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia.
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.
authors.affiliation: 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.
authors.forename: June
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Dianne E
authors.initials: DE
authors.lastname: van der Wal
authors.affiliation: 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.
authors.forename: Guangheng
authors.initials: G
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Issaka
authors.initials: I
authors.lastname: Yougbare
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Brian
authors.initials: B
authors.lastname: Vadasz
authors.affiliation: 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.
authors.forename: Naadiya
authors.initials: N
authors.lastname: Carrim
authors.affiliation: Translational Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Grozovsky
authors.affiliation: Department of Hematology, Anhui Medical University, Hefei 230032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ruan
authors.affiliation: Department of Hematology, Anhui Medical University, Hefei 230032, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Anhui Medical University, Hefei 230032, China.
authors.forename: Qingshu
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Hematology, Anhui Medical University, Hefei 230032, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Hematology, Anhui Medical University, Hefei 230032, China.
authors.forename: Zhi-min
authors.initials: ZM
authors.lastname: Zhai
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Hou
authors.affiliation: 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.
authors.forename: Valery
authors.initials: V
authors.lastname: Leytin
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.affiliation: Translational Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hoffmeister
authors.affiliation: 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.
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology*; D001792:Blood Platelets; D015153:Blotting, Western; D005434:Flow Cytometry; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D039661:Integrin beta3 / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000276:immunology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology*
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D009439:Neuraminidase