Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients Hai Po Helena Liang 1,2 , Marie-Christine Morel-Kopp 1,2 , Julie Curtin 3 , Meredith Wilson 4 , John Hewson 5 , Walter Chen 1,2 , Christopher M. Ward 1,2 1 Northern Blood Research Centre, University of Sydney, Camperdown,Australia; 2 Department of Haematology & Transfusion Medicine, Royal North Shore Hospital, St. Leonards, Australia; 3 Department of Haematology and 4 Department of Clinical Genetics, Children’s Hospital at Westmead, Westmead, Australia; 5 Institute of Clinical Pathology & Medical Research, Westmead Hospital, Westmead, Australia Summary Velocardiofacial 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 inherit- ance 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 het- erozygous loss of one GPIbβ gene allele. Compared to unaf- fected family members,VCFS patients showed a significant de- crease in platelet count; VCFS platelet size and mean platelet Keywords GPIb, platelet function, inherited platelet disorder, velocardiofa- cial syndrome volume were increased, but not as markedly as in BSS.As ex- pected from obligatory heterozygotes for GPIbβ deficiency, VCFS patients showed reduced platelet GPIb-V-IX surface ex- pression and total GPIb content, but with considerable variation between cases.Platelet function tested using the PFA-100 ™ ana- lyzer 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 heterozy- gosity and not spontaneous BSS. In conclusion, many VCFS pa- tients have in-vitro defects in platelet function that may increase their risk of bleeding during surgery. Thromb Haemost 2007; 98: 1298–1308 Platelets and Blood Cells Correspondence to: Christopher M. Ward Northern Blood Research Centre Department of Haematology & Transfusion Medicine Level 4, Block 1, Royal North Shore Hospital St Leonards, NSW 2065, Australia Tel.: +61 2 9926 7118, Fax: +61 2 9906 1635 E-mail: cward@med.usyd.edu.au Footnote: H. Liang is a recipient of the Australian Postgraduate Award from the University of Sydney. Received May 15, 2007 Accepted after revision September 22, 2007 Prepublished online November 9, 2007 doi:10.1160/TH07–05–0350 Introduction The interstitial monoallelic microdeletion of the proximal long arm of chromosome 22 (del22q11.2) is the second most common genomic imbalance disorder after Down syndrome, with an esti- mated prevalence of 1/4000 live births (1). Del22q11.2 is the well-established cause of a number of developmental disorders, notably the DiGeorge anomaly, conotruncal anomaly face syn- drome, and velocardiofacial syndrome (VCFS), which all share a common etiology and have significant phenotypic overlap. VCFS is characterized by a wide spectrum of congenital anomalies including velopharyngeal dysfunction, typical facial appearance, neurobehavioural problems, and congenital conot- runcal cardiac defects that often require surgical correction (2, 3). The severity of the phenotypic abnormalities is highly vari- able and ranges from neonatal death to clinical symptoms so mild that the condition is diagnosed in a parent only after the birth of a more severely affected child (4, 5). Apart from the few VCFS patients who have atypical deletions or translocations, >85% of VCFS patients have a typically deleted chromosomal © 2007 Schattauer GmbH, Stuttgart 1298 For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2014-05-29 | ID: 1001068480 | IP: 129.78.233.212