A new variant of Glanzmann's thrombasthenia with defective activation-dependent fibrinogen binding and altered expression of epitopes for several monoclonal antibodies against GP IIb-IIIa

Abstract

In a family, a moderate bleeding disorder in two patients has been specified as Glanzmann's thrombasthenia because of characteristic defects in platelet function. Analysis of platelet membrane glycoproteins revealed about a 50% decrease in the amount of GP IIb-IIIa complex (α_11bβ₃ integrin), which appeared normal with respect to electrophoretic mobility, apparent M, and isoelectric behaviour of GP IIb and GP IIIa. Content of platelet fibrinogen (Fg) was normal. [¹²⁵I]Fg binding to ADP-stimulated platelets was strongly reduced but K_d values indicated a much higher affinity of the residual receptors for both [¹²⁵I]Fg and RGD peptide. Fg bound to the isolated complex as detected by crossed immunoelectrophoresis and there was substantial expression of endogenous Fg on the surface of washed thrombin-stimulated platelets. RGD-peptide induced increased binding of conformation-specific monoclonal antibodies (Mabs) LIBS 1 and PMI-1. Flow cytometric analysis revealed defective binding of nine Mabs, among them two out of three tested antibodies specific for GP IIIa (C 17, AP 5). Results indicate a genetic variant of GP IIb-IIIa complex with the structural abnormality possibly related to defective conformational change upon activation.