Presence of platelet‐associated anti‐glycoprotein (GP)VI autoantibodies and restoration of GPVI expression in patients with GPVI deficiency

Background: Glycoprotein (GP)VI deficiency is a rare platelet disorder with a mild bleeding tendency. However, its pathophysiology remains unclear. Objectives: We characterized a novel GPVI‐deficient patient with immune thrombocytopenic purpura and searched for the presence of anti‐GPVI autoantibodies in this and another patient with GPVI deficiency. Methods and results: A 12‐year‐old Japanese girl (case 1) with moderate thrombocytopenia and mild bleeding showed selectively impaired collagen‐induced platelet aggregation. Flow cytometric analysis indicated that the patient had a defect in the expression of GPVI–FcRγ. An eluate of her platelet‐associated IgG contained anti‐αIIbβ3 autoantibodies. Moreover, using GPVI–FcRγ‐transfected cells, we unexpectedly identified anti‐GPVI antibodies against the soluble ectodomain of GPVI in the eluate, despite the patient’s GPVI deficiency. In contrast, anti‐GPVI antibodies were not detectable in her plasma. In another case of GPVI deficiency (case 2) without detectable plasma anti‐GPVI antibodies, we again detected platelet‐associated anti‐GPVI antibodies. In a 2‐year follow‐up of case 1, the platelet count increased to within the normal range and the bleeding tendency improved. Interestingly, GPVI was again expressed on her platelets, in association with a decrease in the relative amount of anti‐GPVI antibodies. Conclusions: This is the first demonstration of platelet‐associated anti‐GPVI antibodies in GPVI‐deficient subjects, in one case with spontaneous restoration of GPVI expression. These results strongly suggest an autoimmune mechanism in GPVI deficiency.