Characterization of a patient with glycoprotein (GP) VI deficiency possessing neither anti-GPVI autoantibody nor genetic aberration

Abstract

Background: There have been only seven reported cases of glycoprotein (GP) VI deficiency. However, the pathogenesis of this disorder has not been well-elucidated. Objectives: We characterized a novel patient with GPVI deficiency and used these platelets to investigate the role of GPVI in normal hemostasis. Patient: A 31-year-old female with immune thrombocytopenic purpura who had been suffering from mild bleeding diathesis even after recovery from thrombocytopenia. Results and conclusion: The patient's platelets did not aggregate in response to either convulxin or collagen-related peptide. Immunoblotting revealed complete absence of the GPVI molecule, whereas a significantly reduced but substantial amount of Fc receptor (FcR) γ-chain was expressed. Platelet stimulation with convulxin did not induce tyrosine-phosphorylation of FcR γ-chain, indicating a defect in GPVI-mediated signaling. Concerning the underlying pathogenesis, we found normal level of GPVI-mRNA expression, no aberration of the sequence of the entire coding region of GPVI, and presence of degraded GPVI in her plasma. However, no anti-GPVI autoantibody was detected either by the binding assay to GPVI-Fc2 fusion protein or by immunoblotting/immunoprecipitation using the patient's immunoglobulin. We thus consider that either a short-time exposure to anti-GPVI autoantibody or a continuous exposure to low titers of the autoantibody has resulted in persistent GPVI deficiency. Under high shear flow, the patient's platelets could not form large aggregates, although initial platelet attachment was obviously observed. These results suggest that GPVI deficiency in this patient resulted in defective platelet thrombi development, manifesting as bleeding diathesis. Furthermore, our observations indicate that coordination of GPVI with integrin α2β1 is essential for physiological platelet thrombus formation. © 2006 International Society on Thrombosis and Haemostasis.