Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients

Abstract

SummaryVelocardiofacial syndrome (VCFS) is a common, phenotypically heterogeneous developmental disorder caused by an interstitial microdeletion within human chromosome 22q11. The deleted chromosomal region in >90% of VCFS patients includes the GPIbβ gene, encoding for one subunit of the platelet GPIb-V-IX receptor, which is critical for platelet adhesion under shear, and important in aggregation and thrombin-mediated activation. Complete loss of GPIb-V-IX due to autosomal recessive inheritance of two GPIbα,Ibβ or GP9 gene mutations,results in a severe bleeding disorder,Bernard-Soulier syndrome (BSS). In this study, twenty-one confirmedVCFS patients were analyzed for platelet morphological and functional alterations, resulting from the heterozygous loss of one GPIbβ gene allele. Compared to unaffected family members,VCFS patients showed a significant decrease in platelet count; VCFS platelet size and mean platelet volume were increased, but not as markedly as in BSS. As expected from obligatory heterozygotes for GPIbβ deficiency, VCFS patients showed reduced platelet GPIb-V-IX surface expression and total GPIb content, but with considerable variation between cases. Platelet function tested using the PFA-100™ analyzer was impaired in 70% of patients. Platelet aggregation was reduced in response to a GPIb-dependent agonist, ristocetin, in 50% ofVCFS patients, with 35% showing a reduced response to thrombin receptor activating peptide. Genomic screening was performed to exclude mutations of the subunit genes, indicating that these platelet abnormalities were due to GPIbβ heterozygosity and not spontaneous BSS. In conclusion, many VCFS patients have in-vitro defects in platelet function that may increase their risk of bleeding during surgery.