A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease

Agnès Veyradier (1, 2) , Pierre Boisseau (3) , Edith Fressinaud (4, 5) , Claudine Caron (6) , Catherine Ternisien (7) , Mathilde Giraud (3) , Christophe Zawadzki (6) , Marc Trossaërt (7) , Nathalie Itzhar-Baikian (1, 2) , Marie Dreyfus (4) , Roseline d'Oiron (4) , Annie Borel-Derlon (8) , Sophie Susen (6) , Stéphane Bézieau (3) , Cecile Denis (4, 5) , Jenny Goudemand (6) , French Reference Center For von Willebrand Disease , Jean-Christophe Gris (9, 10)

1 Service d'hématologie biologique
2 UPD7 - Université Paris Diderot - Paris 7
3 Service de génétique médicale - Unité de génétique clinique [Nantes]
4 Hôpital Bicêtre
5 HITH - U1176 Inserm - CHU Bicêtre - Hémostase, Inflammation, Thrombose
6 Hôpital cardiologique
7 CHU Nantes - Centre Hospitalier Universitaire de Nantes
8 Laboratoire d'Hématologie Biologique [CHU Caen]
9 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
10 EA 2992 - Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires

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.

Domaines: Médecine humaine et pathologie

Agnès Veyradier, Pierre Boisseau, Edith Fressinaud, Claudine Caron, Catherine Ternisien, et al.. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease. Medicine, 2016, 95 (11), pp.e3038. ⟨10.1097/MD.0000000000003038⟩. ⟨hal-01872774⟩