Page 196 - Haematologica Vol. 107 - September 2022

ARTICLE - Platelet Biology & its Disorders
Antiplatelet antibody predicts platelet desialylation and
apoptosis in immune thrombocytopenia
Shiying Silvia Zheng,1,2 Zohra Ahmadi,1 Halina Hoi Laam Leung,1 Rose Wong,1,2 Feng Yan,1,2 José Sail Perdomo1# and Beng Hock Chong1,2#
1Hematology Research Unit, St. George and Sutherland Clinical School, University of New South Wales, Sydney and 2Department of Hematology, St. George Hospital, Kogarah, New South Wales, Australia
#JSP and BHC contributed equally as co-senior authors.
Abstract
Immune thrombocytopenia (ITP) is a bleeding disorder caused by dysregulated B- and T- cell functions, which lead to platelet destruction. A well-recognized mechanism of ITP pathogenesis involves anti-platelet and anti-megakaryocyte antibodies recognizing membrane glycoprotein (GP) complexes, mainly GPIb/IX and GPIIb/IIIa. In addition to the current view of phagocytosis of the opsonised platelets by splenic and hepatic macrophages via their Fc γ receptors, antibody- induced platelet desialylation and apoptosis have also been reported to contribute to ITP pathogenesis. Nevertheless, the relationship between the specific thrombocytopenic mechanisms and various types of anti-platelet antibodies has not been established. In order to ascertain such association, we used sera from 61 ITP patients and assessed the capacity of anti-platelet antibodies to induce neuraminidase 1 (NEU1) surface expression, RCA-1 lectin binding and loss of mito- chondrial inner membrane potential on donors’ platelets. Sera from ITP patients with detectable antibodies caused sig- nificant platelet desialylation and apoptosis. Anti-GPIIb/IIIa antibodies appeared more capable of causing NEU1 surface translocation while anti-GPIb/IX complex antibodies resulted in a higher degree of platelet apoptosis. In ITP patients with anti-GPIIb/IIIa antibodies, both desialylation and apoptosis were dependent on FcγRIIa signaling rather than platelet ac- tivation. Finally, we confirmed in a murine model of ITP that destruction of human platelets induced by anti-GPIIb/IIIa antibodies can be prevented with the NEU1 inhibitor oseltamivir. A collaborative clinical trial is warranted to investigate the utility of oseltamivir in the treatment of ITP.
Correspondence: S. S. Zheng silvia.zheng@health.nsw.gov.au
Received: Accepted: Prepublished:
August 5, 2021. February 18, 2021. February 24, 2022.
https://doi.org/10.3324/haematol.2021.279751
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
Immune thrombocytopenia (ITP) is an acquired auto- immune disease characterized by enhanced platelet de- struction and impaired platelet production from megakaryocytes.1 ITP patients can present with no predis- posing condition (hence, primary ITP) or with a variety of associated disorders (secondary ITP),2 such as auto- immune diseases (especially systemic lupus erythemato- sus),3 infections (notably Hepatitis C virus and HIV)4 as well as malignancies.5 Primary ITP is estimated to repre- sent approximately 80% of all adult ITP.4 Regarding the incidence of ITP, studies from Europe have estimated that to be 2.9-3.9/100,000 annually in adults,6-9 with an overall incidence slightly higher in females than males. The prevalence is approximately 9.5-23.6/100,000.6,7,10
The pathogenesis of ITP involves antibodies recognizing
membrane glycoprotein (GP) complexes.2,9 The seminal Harrington-Hollingsworth experiment of self-infusion of ITP plasma led to the discovery of a humoral factor ac- countable for platelet destruction in ITP.11,12 Subsequently, Shulman identified that this factor could be adsorbed by platelets and was associated with immunoglobulin G (IgG).13 Currently, the widely-accepted mechanism is that antibody-coated platelets are phagocytosed by splenic and/or hepatic macrophages of the reticuloendothelial system, via their Fc γ receptors (FcγR), resulting in accel- erated platelet clearance.1,9,14 Equally important in the pa- thogenesis of ITP is the dysfunction of T cells.15 Both CD4+ T-regulatory cells reduction16-18 and CD8+ T-cell-mediated cytotoxicity19-21 have been reported in ITP.2,9,15 In addition, CD8+ T-regulatory cells’ immunosuppressive role in ITP has been recognized.22 This further highlights the signifi- cant role of T cells in immune dysregulation and ITP.23
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