Mechanisms of anti-GPIbα antibody-induced thrombocytopenia in mice
Yosuke Morodomi, Sachiko Kanaji, Eric Won, Zaverio M Ruggeri, Taisuke Kanaji, Yosuke Morodomi, Sachiko Kanaji, Eric Won, Zaverio M Ruggeri, Taisuke Kanaji
Abstract
Immune thrombocytopenia (ITP) is an acquired bleeding disorder characterized by antibody-mediated platelet destruction. Different mechanisms have been suggested to explain accelerated platelet clearance and impaired thrombopoiesis, but the pathophysiology of ITP has yet to be fully delineated. In this study, we tested 2 mouse models of immune-mediated thrombocytopenia using the rat anti-mouse GPIbα monoclonal antibody 5A7, generated in our laboratory. After a single IV administration of high-dose (2 mg/kg) 5A7, opsonized platelets were rapidly cleared from the circulation into the spleen and liver; this was associated with rapid upregulation of thrombopoietin (TPO) messenger RNA. In contrast, subcutaneous administration of low-dose 5A7 (0.08-0.16 mg/kg) every 3 days gradually lowered the platelet count; in this case, opsonized platelets were observed only in the spleen, and TPO levels remained unaltered. Interestingly, in both models, the 5A7 antibody was found on the surface of, as well as internalized to, bone marrow megakaryocytes. Consequently, platelets generated in the chronic phase of repeated subcutaneous 5A7 administration model showed reduced GPIbα membrane expression on their surface. Our findings indicate that evaluation of platelet surface GPIbα relative to platelet size may be a useful marker to support the diagnosis of anti-GPIbα antibody-induced ITP.
Conflict of interest statement
Conflict-of-interest disclosure: Z.M.R. is founder, president, and CEO of MERU-VasImmune Inc, which may develop commercial products based on methodologies presented in this article. S.K. and T.K. have equity interest in MERU-VasImmune Inc. The remaining authors declare no competing financial interests.
© 2020 by The American Society of Hematology.
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Source: PubMed