Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome

Abstract

We report a novel case of gray platelet syndrome (GPS) where a severe deficiency of the platelet collagen receptor, glycoprotein (GP) VI, accompanies classical symptoms of a low platelet count and platelets lacking ␣-granules. Dense granules were normally present. Platelet aggregation with collagen was severely decreased, as was the response to convulxin (Cvx), a GPVI agonist. Quantitative analysis of GPVI using fluorescein isothiocyanate (FITC)-Cvx in flow cytometry showed its virtual absence on the patient's platelets. The GPVI deficiency was confirmed using monoclonal antibodies in Western blotting and in immunogold labeling on frozen thin sections where internal pools of GPVI were confirmed for normal platelets. The Fc receptor ␥-chain, constitutively associated with GPVI in normal platelets, was present in subnormal amounts, and the phospholipase C␥2-dependent activation pathway appeared to function normally. No autoantibodies to GPVI were found in the patient's serum using monoclonal antibody immobilization of platelet antigen (MAIPA). Sequencing of coding regions of the GPVI gene failed to show abnormalities, and mRNA for GPVI was present in the patient's platelets, pointing to a probable acquired defect in GPVI expression. Our results may provide a molecular explanation for the subgroup of patients with severely deficient collagen-induced platelet aggregation as previously described for GPS in the

Multivariate QTL linkage analysis suggests a QTL for platelet count on chromosome 19q

“…33 It has been demonstrated that polymorphism in this gene is associated with differences in collagen-induced platelet aggregation. 34 Very recently, Nurden et al (2004) reported a patient with symptoms of gray platelet syndrome (ie a low platelet count and absence of a-granules) accompanied by a severe deficiency in glycoprotein VI. 35 These and similar observations have led to speculation that polymorphism in the gene for glycoprotein VI may be a risk factor in the development of arterial thrombosis.…”

“…34 Very recently, Nurden et al (2004) reported a patient with symptoms of gray platelet syndrome (ie a low platelet count and absence of a-granules) accompanied by a severe deficiency in glycoprotein VI. 35 These and similar observations have led to speculation that polymorphism in the gene for glycoprotein VI may be a risk factor in the development of arterial thrombosis. 36 Our results suggest that glycoprotein VI or a gene close by may be responsible for nonpathological variation in platelet count.…”

Inherited thrombocytopenias

“…Collageninduced platelet aggregation is particularly affected in a cohort of GPS patients with an acquired deficiency of the collagen receptor, GPVI. 29 This probably results from an aberrant metalloprotease activity. Electron microscopy has shown that the α-granules in gray platelets and megakaryocytes are small and almost empty rather than absent, many vacuoles are to be seen.…”

Diagnosis and Management of Inherited Platelet Disorders

“…24 substrates is starting to be used. 25 Platelet receptors can be quantified by flow cytometry using panels of antibodies directed against specific epitopes of the receptors.…”