title: Phenotypic Parameters in Genotypically Selected Type 2B von Willebrand Disease Patients: A Large, Single-Center Experience Including a New Novel Mutation.
abstract: von Willebrand disease type 2B (VWD2B) expresses gain-of-function mutations that enhance binding of an individual's von Willebrand factor (VWF) to its platelet ligand, glycoprotein Ib (GPIb), and which are usually identified by increased ristocetin-induced platelet aggregation (RIPA). We describe here the phenotypic profile of 38 genotypically selected VWD2B-affected family members (AFMs) belonging to 19 unrelated families. Major bleeding was observed in 68.4% of AFMs (previous to their diagnosis and registered by lifetime interviews), with a total of 46 episodes (1.21/patient), and was found to be highly related to the individual bleeding score and presence of thrombocytopenia, but otherwise unrelated to other laboratory parameters. Excessive muco-cutaneous bleeding symptoms were often reported, the most frequent of which comprised menorrhagia, epistaxis, easy bruising, and bleeding after teeth extraction/in oral cavity. Eight unaffected family members were also studied. The prevalence of VWD2B within families was 0.826, and the penetrance of mutations was complete, making it mandatory to study entire family sets to complete diagnostic profiles. Seven heterozygous missense mutations were found, the most common being p.V1316M. In the p.R1308C group, 75% of the AFMs showed absence of RIPA at 0.5 mg/mL, 66.6% of whom had VWF:RCo < 10 IU/dL, and 50% of whom had VWF:CB < 10 IU/dL. In the p.S1310F group, none of the AFMs had VWF:RCo/VWF:Ag < 0.6 (RCo/Ag), but 100% had VWF:CB/VWF:Ag < 0.6/(CB/Ag). Patients with p.P1266L and p.R1304V were characterized as atypical VWD2B. Two de novo mutations were found in four AFMs belonging to two families. We also describe a novel mutation: p.Y1258C. Of our patients, 70.5% had O blood group. In conclusion, a normal RCo/Ag and a negative RIPA at 0.5 mg/mL do not necessarily rule out a diagnosis of VWD2B.
authors.affiliation: Laboratorio de Hemostasia y Trombosis, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Adriana Ines
authors.initials: AI
authors.lastname: Woods
authors.affiliation: Laboratorio de Hemostasia y Trombosis, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Ana Catalina
authors.initials: AC
authors.lastname: Kempfer
authors.affiliation: Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Juvenal
authors.initials: J
authors.lastname: Paiva
authors.affiliation: Laboratorio de Hemostasia y Trombosis, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Analia
authors.initials: A
authors.lastname: Sanchez-Luceros
authors.affiliation: Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Emilse
authors.initials: E
authors.lastname: Bermejo
authors.affiliation: Instituto de Investigaciones Epidemiológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chuit
authors.affiliation: Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Maria Fabiana
authors.initials: MF
authors.lastname: Alberto
authors.affiliation: Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Alicia Noemi
authors.initials: AN
authors.lastname: Blanco
authors.affiliation: Laboratorio de Hemostasia y Trombosis, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Lazzari
mesh_terms: D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D056728:von Willebrand Disease, Type 2 / Q000235:genetics*; D014842:von Willebrand Diseases / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D014841:von Willebrand Factor