Do platelets prematurely age in canine immune thrombocytopenia (ITP)? Development of a novel flow cytometric assay to assess the role of platelet desialylation in ITP pathogenesis

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2023-08
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Barchilon, Michael
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LeVine, Dana N
Viall, Austin K
Jergens, Albert J
Mansell, Thomas
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Veterinary Biomedical Sciences
Abstract
Immune thrombocytopenia (ITP) is an aggressive hemostatic disorder of dogs with significant morbidity and mortality. In this autoimmune disease, anti-platelet antibodies promote platelet destruction. The ensuing thrombocytopenia may cause fatal hemorrhage, leading to mortality approaching 30%. However, immunosuppressive therapies to combat ITP can cause dangerous side-effects; a novel, targeted therapy is sorely needed. Antiplatelet antibodies are traditionally thought to target platelets for clearance by splenic macrophages, however, recent work in mice and humans has revealed some autoantibodies cause desialylation of platelet surface glycoproteins. Desialylated platelets resemble aged platelets and are prematurely cleared by hepatocytes. Human ITP patients with such autoantibodies are resistant to immunosuppression but respond to the sialidase inhibitor oseltamivir (Tamiflu). While platelet desialylation in canine ITP has never been investigated, preventing desialylation could represent a safe, new therapy for ITP dogs. Furthermore, platelet desialylation may contribute to thrombocytopenia in other life-threatening canine diseases like sepsis. There is currently no way to assess canine platelet desialylation. We propose to fill this critical gap by developing a novel flow cytometric assay using lectin binding to detect desialylated dog platelets. This much-needed investigative tool will allow us to explore the pathologic significance of platelet desialylation in canine ITP and other thrombocytopenic diseases, and ultimately set the stage for therapeutic breakthroughs in ITP therapy for dogs as it has in human medicine.
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