Molecular and clinical profile of von Willebrand disease in Spain (PCM–EVW–ES): Proposal for a new diagnostic paradigm

Javier Batlle; Almudena Pérez-Rodríguez; Irene Corrales; María Fernanda López-Fernández; Ángela Rodríguez-Trillo; Esther Lourés; Ana Rosa Cid; Santiago Bonanad; Noelia Cabrera; Andrés Moret; Rafael Parra; María Eva Mingot-Castellano; Ignacia Balda; Carmen Altisent; Rocío Pérez-Montes; Rosa María Fisac; Gemma Iruín; Sonia Herrero; Inmaculada Soto; Beatriz de Rueda; Víctor Jiménez-Yuste; Nieves Alonso; Dolores Vilariño; Olga Arija; Rosa Campos; María José Paloma; Nuria Bermejo; Teresa Toll; José Mateo; Karmele Arribalzaga; Pascual Marco; Ángeles Palomo; Lizheidy Sarmiento; Belén Iñigo; María del Mar Nieto; Rosa Vidal; María Paz Martínez; Reyes Aguinaco; Jesús María César; María Ferreiro; Javier García-Frade; Ana María Rodríguez-Huerta; Jorge Cuesta; Ramón Rodríguez-González; Faustino García-Candel; Rosa Cornudella; Carlos Aguilar; Nina Borràs; Francisco Vidal

doi:10.1160/TH15-04-0282

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 115(01): 40-50
DOI: 10.1160/TH15-04-0282

Coagulation and Fibrinolysis

Schattauer GmbH Schattauer

Molecular and clinical profile of von Willebrand disease in Spain (PCM–EVW–ES): Proposal for a new diagnostic paradigm

Authors

Javier Batlle

¹Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
Almudena Pérez-Rodríguez

¹Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
Irene Corrales

²Banc de Sang i Teixits, Barcelona, Spain
María Fernanda López-Fernández

¹Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
Ángela Rodríguez-Trillo

¹Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
Esther Lourés

¹Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
Ana Rosa Cid

³Hospital Universitario y Politécnico La Fe, Valencia, Spain
Santiago Bonanad

³Hospital Universitario y Politécnico La Fe, Valencia, Spain
Noelia Cabrera

³Hospital Universitario y Politécnico La Fe, Valencia, Spain
Andrés Moret

³Hospital Universitario y Politécnico La Fe, Valencia, Spain
Rafael Parra

²Banc de Sang i Teixits, Barcelona, Spain

⁴Hospital Universitari Vall d’Hebron, Barcelona, Spain
María Eva Mingot-Castellano

⁵Hospital Regional Universitario de Málaga, Málaga, Spain
Ignacia Balda

⁶Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
Carmen Altisent

⁴Hospital Universitari Vall d’Hebron, Barcelona, Spain
Rocío Pérez-Montes

⁷Hospital Universitario Marqués de Valdecilla, Santander, Spain
Rosa María Fisac

⁸Salud Castilla y León, Segovia, Spain
Gemma Iruín

⁹Hospital Universitario Cruces, Barakaldo, Spain
Sonia Herrero

¹⁰Hospital Universitario de Guadalajara, Guadalajara, Spain
Inmaculada Soto

¹¹Hospital Universitario Central de Asturias, Oviedo, Spain
Beatriz de Rueda

¹²Hospital Universitario Miguel Servet, Zaragoza, Spain
Víctor Jiménez-Yuste

¹³Hospital Universitario La Paz, Madrid, Spain
Nieves Alonso

¹⁴Hospital Infanta Cristina, Badajoz, Spain
Dolores Vilariño

¹⁵Complexo Hospitalario Universitario Santiago de Compostela, Spain
Olga Arija

¹⁶Hospital Universitario Lucus Augusti, Lugo, Spain
Rosa Campos

¹⁷Hospital Jerez de la Frontera, Cádiz, Spain
María José Paloma

¹⁸Hospital Virgen del Camino, Pamplona, Spain
Nuria Bermejo

¹⁹Hospital San Pedro de Alcántara, Cáceres, Spain
Teresa Toll

²⁰Hospital Sant Joan de Deu, Barcelona, Spain
José Mateo

²¹Hospital Sta Creu i St Pau, Barcelona, Spain
Karmele Arribalzaga

²²Hospital Universitario Fundación Alcorcón, Madrid, Spain
Pascual Marco

²³Hospital General de Alicante, Alicante, Spain
Ángeles Palomo

⁵Hospital Regional Universitario de Málaga, Málaga, Spain
Lizheidy Sarmiento

²⁴Hospital Universitario 12 de Octubre, Madrid, Spain
Belén Iñigo

²⁵Hospital Clínico San Carlos, Madrid, Spain
María del Mar Nieto

²⁶Complejo Hospitalario de Jaén, Jaén, Spain
Rosa Vidal

²⁷Fundación Jiménez Díaz, Madrid, Spain
María Paz Martínez

²⁸Hospital Nuestra Sra. de Sonsoles, Ávila, Spain
Reyes Aguinaco

²⁹Hospital Joan XXIII, Tarragona, Spain
Jesús María César^†

³⁰Hospital Ramón y Cajal, Madrid, Spain
María Ferreiro

³¹Hospital Montecelo, Pontevedra, Spain
Javier García-Frade

³²Hospital Río Hortega, Valladolid, Spain
Ana María Rodríguez-Huerta

³³Hospital Gregorio Marañón, Madrid, Spain
Jorge Cuesta

³⁴Hospital Virgen de la Salud, Toledo, Spain
Ramón Rodríguez-González

³⁵Hospital Severo Ochoa, Madrid, Spain
Faustino García-Candel

³⁶Hospital Universitario Virgen Arrixaca, Murcia, Spain
Rosa Cornudella

³⁷Hospital Lozano Blesa, Zaragoza, Spain
Carlos Aguilar

³⁸Hospital Santa Bárbara, Soria, Spain
Nina Borràs

²Banc de Sang i Teixits, Barcelona, Spain
Francisco Vidal

²Banc de Sang i Teixits, Barcelona, Spain

Abstract

Summary

The diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/ genotypic association was estimated in 96.5 % of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

VWD - VWF - NGS - phenotype - genotype

Volltext

Referenzen

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