title: A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture.
abstract: von Willebrand disease (VWD) is a genetic bleeding disease due to a defect of von Willebrand factor (VWF), a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels <50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50 IU/dL). The French reference center for VWD performed a laboratory phenotypic and genotypic analysis in 1167 VWD patients (670 families) selected by their basic biologic phenotype: type 3, type 2, and type 1 with VWF levels <30 IU/dL. In these patients indeed, to achieve an accurate diagnosis of VWD type and subtype is crucial for the management (treatment and genetic counseling). A phenotype/genotype correlation was present in 99.3% of cases; 323 distinct VWF sequence variations (58% of novel) were identified (missense 67% versus truncating 33%). The distribution of VWD types was: 25% of type 1, 8% of type 3, 66% of type 2 (2A: 18%, 2B: 17%, 2M: 19%, 2N: 12%), and 1% of undetermined type. Type 1 VWD was related either to a defective synthesis/secretion or to an accelerated clearance of VWF. In type 3 VWD, bi-allelic mutations of VWF were found in almost all patients. In type 2A, the most frequent mechanism was a hyper-proteolysis of VWF. Type 2B showed 85% of patients with deleterious mutations (distinct from type 2B New York). Type 2M was linked to a defective binding of VWF to platelet glycoprotein Ib or to collagen. Type 2N VWD included almost half type 2N/3. This biologic study emphasizes the complex mechanisms for both quantitative and qualitative VWF defects in VWD. In addition, this study provides a new epidemiologic picture of the most bleeding forms of VWD in which qualitative defects are predominant.
authors.affiliation: From the Service d'Hématologie biologique (AV, NI-B), Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris; Service de Génétique médicale (PB, MG, SB), Hôpital Hôtel-Dieu, CHU de Nantes, Nantes; Inserm UMR_S1176 (EF, CVD), Université Paris-Sud, Le Kremlin Bicêtre; Service d'Hématologie biologique (CC, CZ, SS, JG), Hôpital cardiologique, CHRU de Lille, Lille; Service d'Hématologie biologique (CT, MT), Hôpital Hôtel-Dieu, CHU de Nantes, Nantes; Service d'Hématologie biologique et Centre Régional de Traitement de l'Hémophilie (MD, RD), Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, Le Kremlin-Bicêtre; and Service d'Hématologie biologique (AB-D), Hôpital de la Côte de Nacre, CHU de Caen, Caen, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Veyradier
authors.forename: Pierre
authors.initials: P
authors.lastname: Boisseau
authors.forename: Edith
authors.initials: E
authors.lastname: Fressinaud
authors.forename: Claudine
authors.initials: C
authors.lastname: Caron
authors.forename: Catherine
authors.initials: C
authors.lastname: Ternisien
authors.forename: Mathilde
authors.initials: M
authors.lastname: Giraud
authors.forename: Christophe
authors.initials: C
authors.lastname: Zawadzki
authors.forename: Marc
authors.initials: M
authors.lastname: Trossaert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Itzhar-Baïkian
authors.forename: Marie
authors.initials: M
authors.lastname: Dreyfus
authors.forename: Roseline
authors.initials: R
authors.lastname: d'Oiron
authors.forename: Annie
authors.initials: A
authors.lastname: Borel-Derlon
authors.forename: Sophie
authors.initials: S
authors.lastname: Susen
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bezieau
authors.forename: Cécile V
authors.initials: CV
authors.lastname: Denis
authors.forename: Jenny
authors.initials: J
authors.lastname: Goudemand
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D005602:France / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D055815:Young Adult; D014842:von Willebrand Diseases / Q000453:epidemiology / Q000235:genetics*