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: Agnès Veyradier, Pierre Boisseau, Edith Fressinaud, Claudine Caron, Catherine Ternisien, Mathilde Giraud, Christophe Zawadzki, Marc Trossaert, Nathalie Itzhar-Baïkian, Marie Dreyfus, Roseline d'Oiron, Annie Borel-Derlon, Sophie Susen, Stéphane Bezieau, Cécile V Denis, Jenny Goudemand, French Reference Center for von Willebrand disease
• Journal: Medicine (Medicine (Baltimore)) Vol. 95 Issue 11 Pg. e3038 (Mar 2016) ISSN: 1536-5964 [Electronic] United States
• PMID: 26986123 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Child
• Child, Preschool
• Female
• France (epidemiology)
• Genotype
• Humans
• Infant
• Male
• Middle Aged
• Mutation
• Phenotype
• Young Adult
• von Willebrand Diseases (epidemiology, genetics)