Immunisation against αIIbβ3 and αvβ3 in a type 1 variant of Glanzmann’s thrombasthenia caused by a missense mutation Gly540Asp on β3

Hevi Wihadmadyatami; Lida Röder; Heike Berghöfer; Gregor Bein; Kathrin Heidinger; Ulrich J. Sachs; Sentot Santoso

doi:10.1160/TH15-12-0982

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 116(02): 262-271
DOI: 10.1160/TH15-12-0982

Cellular Haemostasis and Platelets

Schattauer GmbH

Immunisation against αIIbβ3 and αvβ3 in a type 1 variant of Glanzmann’s thrombasthenia caused by a missense mutation Gly₅₄₀Asp on β3

Hevi Wihadmadyatami

¹Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University Giessen, Germany

²Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia

,

Lida Röder

¹Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University Giessen, Germany

,

Heike Berghöfer

¹Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University Giessen, Germany

,

Gregor Bein

¹Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University Giessen, Germany

,

Kathrin Heidinger

³Haemostasis Center, University Hospital Giessen and Marburg, Giessen, Germany

,

Ulrich J. Sachs

¹Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University Giessen, Germany

³Haemostasis Center, University Hospital Giessen and Marburg, Giessen, Germany

,

Sentot Santoso

¹Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University Giessen, Germany

› Institutsangaben

Abstract

Summary

Treatment of bleeding in patients with Glanzmann’s thrombasthenia (GT) can be hampered by iso-antibodies against the αIIbβ3 integrin, which cause rapid clearance of transfused donor platelets. Type 1 GT patients with a total absence of αIIbβ3 from the platelet surface are known to be susceptible to form such isoantibodies. In this study, we describe a type 1 GT patient with a missense mutation (Gly₅₄₀Asn) located in the EGF3 domain of the β3 integrin subunit. Cotransfection analysis in CHO cells demonstrates total absence of αIIbβ3 from the surface, based on inappropriate αIIb maturation. The patient’s serum was reactive with αIIbβ3 and αvβ3 integrins in a capture assay, when platelets and endothelial cells were used. Two specificities could be isolated from the patient’s serum, anti-αIIbβ3 and anti-αvβ3 isoantibodies. Both specificities did not interfere with platelet aggregation. In contrast, isoantibodies against αvβ3, but not against αIIbβ3, were able to disturb endothelial cell adhesion onto vitronectin, triggered endothelial cell apoptosis and interfered with endothelial tube formation. This intriguing finding may explain more recently observed features of fetal/neonatal iso-immune thrombocytopenia in children from type 1 GT mothers with intracranial haemorrhage, which could be related to anti-endothelial activity of the maternal antibodies. In conclusion, we give evidence that two isoantibody entities exist in type 1 GT patients, which are unequivocally different, both in an immunological and functional sense. Further research on the clinical consequences of immunisation against αvβ3 is required, predominantly in GT patients of childbearing age.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Glanzmann’s thrombasthenia - platelet function defect - isoimmunisation - αvβ3

Volltext

Referenzen

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