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Molecular and functional characterization of novel mutations in GPIX and BETA3 integrin giving rise to Bernard-Soulier syndrome and to an atypical glanzmann's thrombasthenia-like syndrome in two patients misdiagnosed with idiopathic thrombocytopenic purpu
Abstract number: PP-WE-764
Antón1 A., Navarro-Núñez1 L., Lozano1 M., González-Manchón2 C., Jayo2 A., Martínez1 C., Roldán1 V., Vicente1 V., Rivera1 J.
11Centro Regional de Hemodonacion, Servicio de Hematología y Oncología médica. H.U. Morales Meseguer, Universidad de Murcia, Murcia 22Departamento de Fisiopatología Celular y Molecular, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
How-to-cite Antón A, Navarro-Núñez L, Lozano M, González-Manchón C, Jayo A, Martínez C, Roldán V, Vicente V, Rivera J. Molecular and functional characterization of novel mutations in GPIX and BETA3 integrin giving rise to Bernard-Soulier syndrome and to an atypical glanzmann's thrombasthenia-like syndrome in two patients misdiagnosed with idiopathic thrombocytopenic purpu. Journal of Thrombosis and Haemostasis 2009; Volume 7, Supplement 2: Abstract PP-WE-764
Congenital platelet disorders are a heterogeneous group of rare diseases. Appropriate diagnosis is crucial for correct management and for preventing morbidity secondary to inappropriate treatment. We investigated two patients with lifelong mucocutaneous hemorrhagic diathesis, both diagnosed and treated for years as idiopathic thrombocytopenic purpura. Case 1: A 17-year-old woman with severe macrothrombocytopenia. Flow cytometry showed absence of glycoprotein (GP) GPIbalpha, normal secretion of CD62 and CD63 and lack of antiplatelet antibodies. DNA sequencing of GPIbalpha, GPIbbeta and GPIX genes confirmed suspicion of Bernard-Soulier Syndrome (BSS) revealing a new GPIX homozygous missense mutation 226T > C giving rise to an aminoacid change Trp71Arg. Case 2: A 40-year-old woman with mild thrombopenia. Flow cytometry analysis showed: normal levels of GPIbalpha and GPIa; a 50% decrease in surface alphaIIb and beta3; deficient fibrinogen binding and absent TRAP-induced CD62 and CD63 granular secretion. This patient showed severely impaired platelet aggregation with ADP, epinephrine, collagen, arachidonic acid and dithiotreitol, but an increased aggregation to ristocetin. VWF antigen and ristocetin cofactor activity were elevated (200%). Molecular analysis of alphaIIb and beta3 genes revealed a novel heterozygous mutation 2231T > C in exon 14 of beta3 gene leading to Leu718Pro change in the intracellular domain of beta3 chain. Identical alleles for alphaIIb bore five polymorphisms (HPA3 in exon 26; 3063C > T in exon 30; and IVS21 + 36delCAGGGCTC, IVS21-7C > G, and IVS21-254A > G in intron 21) that might impair mRNA expression. These two cases strengthen the relevance of an accurate diagnosis in patients with bleeding diathesis from childhood. We identify a new mutation in GPIX giving rise to BSS and a novel heterozygous beta3 integrin mutation associated with atypical Glanzmann thrombasthenia-like syndrome displaying mild thrombocytopenia and deficiencies in aggregation and secretion.
Acknowledgements: Grants: SAF2006-06212; 04515/GERM/06; RECAVA RD06/0014/0004.
Disclosure of interest: none declared.
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2007; Volume 5, Supplement 2: abstract number
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