Anti-GPIbα mediated platelet desialylation and activation: a novel Fc-independent platelet clearance mechanism and potential therapeutic and diagnostic target in ITP

Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests antibody-mediated platelet destruction occurs in the spleen via Fcγ receptors (FcγR). However, it has been demonstrated that anti...

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Bibliographic Details
Main Author Li, June
Format Dissertation
LanguageEnglish
Published ProQuest Dissertations & Theses 01.01.2014
Subjects
Immunology
Pathology
Physiology
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Summary:Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests antibody-mediated platelet destruction occurs in the spleen via Fcγ receptors (FcγR). However, it has been demonstrated that anti-GPIbα-mediated ITP is often refractory to therapies targeting FcγR pathways. Utilizing a panel of murine monoclonal antibodies (mAbs) against murine and human GPIIbIIIa and GPIbα, it was found that anti-GPIbα induces not only platelet activation to a much greater extent than anti-GPIIbIIIa antibodies, but also significant surface expression of neuraminidase 1 and platelet desialylation. Utilizing inhibitors of platelet activation and desialylation, it was found that these two processes are not mutually exclusive, but rather exist in a positive feedback loop, leading to FcγR-independent platelet clearance in the liver likely via Ashwell-Morell receptors. Furthermore, in a murine model of ITP, sialidase inhibitor treatment rescued platelet counts in predominantly anti-GPIbαα-mediated thrombocytopenia.
ISBN:9781321394245
1321394241