Dimerization of glycoprotein Ib is not sufficient to induce platelet clearance

• Type of Material: Article
• Authors: Xin Liang, Emory University; Anum K. Syed, Emory University; Susan R Russell, University of Arkansas Medical Sciences; Jerry Ware, University of Arkansas Medical Sciences; Renhao Li, Emory University
• Language: English
• Date: 2016-02-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 International Society on Thrombosis and Haemostasis.
• Final Published Version (URL): http://dx.doi.org/10.1111/jth.13221
• Title of Journal or Parent Work: Journal of Thrombosis and Haemostasis
• ISSN: 1538-7933
• Volume: 14
• Issue: 2
• Start Page: 381
• End Page: 386
• Grant/Funding Information: This work was supported in part by National Institutes of Health grants HL082808 and HL123984.
• Keywords: glycoprotein receptor GPIb-IX; ALPHA; IMMUNE THROMBOCYTOPENIA; Hematology; INTRAVENOUS IMMUNOGLOBULIN-G; COMPLEX; platelet activation; Science & Technology; blood platelets; LIPID RAFTS; MONOCLONAL-ANTIBODIES; NONHUMAN-PRIMATES; Life Sciences & Biomedicine; antibody-binding sites; IX; VON-WILLEBRAND-FACTOR; Peripheral Vascular Disease; MICE; thrombocytopenia; Cardiovascular System & Cardiology
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background: The mechanism of platelet clearance is not clear. Many antibodies binding the membrane-distal ligand-binding domain of glycoprotein (GP)Ibα induce rapid clearance of platelets and acute thrombocytopenia, which requires the bifurcated antibody structure. It was thought that binding of these antibodies induced lateral dimerization or clustering of GPIbα in the plasma membrane, which leads to downstream signaling and platelet clearance. However, many antibodies targeting GPIbβ and GPIX, which are associated with GPIbα in the GPIb-IX complex, do not induce platelet clearance, which is in contradiction to the clustering model. Objectives: To test whether dimerization or clustering of GPIbα is sufficient to transmit the signal that leads to platelet clearance. Methods: We have recently raised several mAbs targeting the mechanosensitive domain (MSD) of GPIbα. Binding of these anti-MSD antibodies was characterized with biochemical methods. Their ability to stimulate platelets and induce platelet clearance in mice was assessed. Results and conclusion: Infusion of anti-MSD antibodies does not cause thrombocytopenia in mice. These antibodies show no detectable effects on platelet activation and aggregation in vitro. Further biochemical investigation showed that the anti-MSD antibody 3D1 binds two copies of GPIbα on the platelet surface. Therefore, lateral dimerization of GPIbα induced by antibody binding is not sufficient to initiate GPIb-IX signaling and induce platelet clearance. Our results suggest that a factor other than or in addition to clustering of GPIbα is required to induce platelet clearance.