Immunisation against alpha llb beta 3 and alpha v beta 3 in a type 1 variant of Glanzmann's thrombasthenia caused by a missense mutation GIy(540)Asp on beta 3

摘要

Treatment of bleeding in patients with Glanzmann's thrombasthenia (GT) can be hampered by iso-antibodies against the alpha llb beta 3 integrin, which cause rapid clearance of transfused donor platelets. Type 1 GT patients with a total absence of alpha llb beta 3 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 (Gly(540)Asn) located in the EGF3 domain of the beta 3 integrin subunit. Cotransfection analysis in CHO cells demonstrates total absence of alpha llb beta 3 from the surface, based on inappropriate alpha llb maturation. The patient's serum was reactive with alpha llb beta 3 and alpha v beta 3 integrins in a capture assay, when platelets and endothelial cells were used. Two specificities could be isolated from the patient's serum, anti-alpha llb beta 3 and anti-alpha v beta 3 isoantibodies. Both specificities did not interfere with platelet aggregation. In contrast, isoantibodies against alpha v beta 3, but not against alpha llb beta 3, 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 fetaleonatal 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 alpha v beta 3 is required, predominantly in GT patients of childbearing age.