Autoantibody against integrin αvβ3 contributes to thrombocytopenia by blocking the migration and adhesion of megakaryocytes. (20th July 2018)

• Record Type: Journal Article
• Authors: Zeng, D. F.; Chen, F.; Wang, S.; Chen, S. L.; Xu, Y.; Shen, M. Q.; Du, C. H.; Wang, C.; Kong, P. Y.; Cheng, T. M.; Su, Y. P.; Wang, J. P.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 16:Number 9(2018)
• Page Start: 1843
• Page End: 1856
• Publication Date: 2018-07-20
• Subjects: adhesion -- anti‐αvβ3 autoantibody -- immune thrombocytopenic purpura -- megakaryocytes -- migration; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.14214
• Languages: English
• ISSNs: 1538-7933

Abstract

Summary: Essentials The pathogenesis of immune thrombocytopenia (ITP) has not been fully clarified. We analyzed the role of anti‐αvβ3 autoantibody in the pathogenesis of ITP in patients. Anti‐αvβ3 autoantibody impeded megakaryocyte migration and adhesion to the vascular niche. Anti‐αv β3 autoantibody potentially contributes to the pathogenesis of refractory ITP. Summary: Background: The pathogenesis of immune thrombocytopenia (ITP) has not been fully clarified. Anti‐αvβ3 integrin autoantibody is detected in chronic ITP patients, but its contribution to ITP is still unclear. Objectives: To clarify the potential role of anti‐αvβ3 integrin autoantibody in chronic ITP and the related mechanism. Methods: Relationship between levels of anti‐αvβ3 autoantibody and platelets in chronic ITP patients was evaluated. The influence of anti‐αvβ3 antibody on megakaryocyte (MK) survival, differentiation, migration and adhesion was assessed, and the associated signal pathways were investigated. Platelet recovery and MKs' distribution were observed in an ITP mouse model pretreated with different antibodies. Result: In this study, we showed that the anti‐αvβ3 autoantibody usually coexists with anti‐αIIbβ3 autoantibody in chronic ITP patients, and patients with both autoantibodies have lower platelets. In in vitro studies, we showed that the anti‐αvβ3 antibody had no significant effect on the survival and proliferation of MKs, whereas it decreased formations of proplatelet significantly. Anti‐αvβ3 antibody impeded stromal cell derived facor‐1 alpha (SDF‐1α)‐ mediated migration and inhibited the phosphorylation of protein kinase B. Anti‐αvβ3 antibody significantly inhibited MKs' adhesion to endothelial cells and Fibrogen. The phosphorylation of focal adhesion kinase and proto‐oncogene tyrosine‐protein kinase Src induced by adhesion was inhibited when MKs were pretreated with anti‐αvβ3 antibody. In in vivo studies, we showed that injection with anti‐αv antibody delayed platelet recovery in a mouse model of ITP. Conclusions: These findings demonstrate that the autoantibody against integrin αv β3 may aggravate thrombocytopenia in ITP patients by impeding MK migration and adhesion to the vascular niche, which provides new insights into the pathogenesis of ITP.