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Thromb Haemost 2020; 120(03): 437-448
DOI: 10.1055/s-0040-1702227
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Unraveling the Influence of Common von Willebrand factor variants on von Willebrand Disease Phenotype: An Exploratory Study on the Molecular and Clinical Profile of von Willebrand Disease in Spain Cohort

Nina Borràs‡
1   Congenital Coagulopathies, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Iris Garcia-Martínez‡
1   Congenital Coagulopathies, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Javier Batlle
3   Department of Hematology, Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
,
Almudena Pérez-Rodríguez
3   Department of Hematology, Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
,
Rafael Parra
1   Congenital Coagulopathies, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Carme Altisent
2   Transfusional Medicine, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
María Fernanda López-Fernández
3   Department of Hematology, Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
,
Joana Costa Pinto
3   Department of Hematology, Complexo Hospitalario Universitario A Coruña, INIBIC, A Coruña, Spain
,
Fernando Batlle-López
4   Department of Research, Lapisoft SA, A Coruña, Spain
,
Ana Rosa Cid
5   Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
,
Santiago Bonanad
5   Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
,
Noelia Cabrera
5   Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
,
Andrés Moret
5   Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
,
María Eva Mingot-Castellano
6   Department of Hematology, Hospital Regional Universitario de Málaga, Málaga, Spain
7   Hospital Universitario Virgen del Rocio, Sevilla, Spain
,
Nira Navarro
8   Department of Hematology, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
,
Rocío Pérez-Montes
9   Department of Hematology, Hospital Universitario Marqués de Valdecilla, Santander, Spain
,
Shally Marcellini
10   Department of Hematology, Salud Castilla y León, Segovia, Spain
,
Ana Moreto
11   Department of Hematology, Hospital Universitario Cruces, Barakaldo, Spain
,
Sonia Herrero
12   Department of Hematology, Hospital Universitario de Guadalajara, Guadalajara, Spain
,
Inmaculada Soto
13   Department of Hematology, Hospital Universitario Central de Asturias, Oviedo, Spain
,
Núria Fernández-Mosteirín
14   Department of Hematology, Hospital Universitario Miguel Servet, Zaragoza, Spain
,
Víctor Jiménez-Yuste
15   Department of Hematology, Hospital Universitario La Paz, Madrid, Spain
,
Nieves Alonso
16   Department of Hematology, Hospital Infanta Cristina, Badajoz, Spain
,
Aurora de Andrés-Jacob
17   Department of Hematology, Complexo Hospitalario Universitario Santiago de Compostela, Spain
,
Emilia Fontanes
18   Department of Hematology, Hospital Universitario Lucus Augusti, Lugo, Spain
,
Rosa Campos
19   Department of Hematology, Hospital Jerez de la Frontera, Cádiz, Spain
,
María José Paloma
20   Department of Hematology, Hospital Virgen del Camino, Pamplona, Spain
,
Nuria Bermejo
21   Department of Hematology, Hospital San Pedro de Alcántara, Cáceres, Spain
,
Rubén Berrueco
22   Department of Hematology, Hospital Sant Joan de Deu, Barcelona, Spain
,
José Mateo
23   Department of Hematology, Hospital Sta Creu i St Pau, Barcelona, Spain
,
Karmele Arribalzaga
24   Department of Hematology, Hospital Universitario Fundación Alcorcón, Madrid, Spain
,
Pascual Marco
25   Department of Hematology, Hospital General de Alicante, Alicante, Spain
,
Ángeles Palomo
6   Department of Hematology, Hospital Regional Universitario de Málaga, Málaga, Spain
,
Nerea Castro Quismondo
26   Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain
,
Belén Iñigo
27   Department of Hematology, Hospital Clínico San Carlos, Madrid, Spain
,
María del Mar Nieto
28   Department of Hematology, Complejo Hospitalario de Jaén, Jaén, Spain
,
Rosa Vidal
29   Department of Hematology, Fundación Jiménez Díaz, Madrid, Spain
,
María Paz Martínez
30   Department of Hematology, Hospital Nuestra Sra. de Sonsoles, Ávila, Spain
,
Reyes Aguinaco
31   Department of Hematology, Hospital Joan XXIII, Tarragona, Spain
,
Maria Tenorio
32   Department of Hematology, Hospital Ramón y Cajal, Madrid, Spain
,
María Ferreiro
33   Department of Hematology, Hospital Montecelo, Pontevedra, Spain
,
Javier García-Frade
34   Department of Hematology, Hospital Río Hortega, Valladolid, Spain
,
Ana María Rodríguez-Huerta
35   Department of Hematology, Hospital Gregorio Marañón, Madrid, Spain
,
Jorge Cuesta
36   Department of Hematology, Hospital Virgen de la Salud, Toledo, Spain
,
Ramón Rodríguez-González
37   Department of Hematology, Hospital Severo Ochoa, Madrid, Spain
,
Faustino García-Candel
38   Department of Hematology, Hospital Universitario Virgen Arrixaca, Murcia, Spain
,
Manuela Dobón
39   Department of Hematology, Hospital Lozano Blesa, Zaragoza, Spain
,
Carlos Aguilar
40   Department of Hematology, Hospital Santa Bárbara, Soria, Spain
,
Irene Corrales
1   Congenital Coagulopathies, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Francisco Vidal
1   Congenital Coagulopathies, Banc de Sang i Teixits, Barcelona, Spain
2   Transfusional Medicine, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
41   CIBER de Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain
› Author Affiliations Funding We are indebted to Baxalta US Inc., now a part of Shire, for support of the PCM-EVW-ES (Grant H13–000845). This study was also supported by the Spanish Ministry of the Economy and Competitiveness (MINECO, Ministerio de Economía y Competitividad), Instituto de Salud Carlos III (ISCIII) (PI15/01643). We are grateful for the kind collaboration of the participating patients and their families. We thank A.P. for providing statistical support and revising the final version of the manuscript. CIBERCV is an initiative of ISCIII, co-financed by the European Regional Development Fund (ERDF), “A way to build Europe.”
Further Information

Publication History

06 November 2019

11 January 2020

Publication Date:
05 March 2020 (online)

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Abstract

The clinical diagnosis of von Willebrand disease (VWD), particularly type 1, can be complex because several genetic and environmental factors affect von Willebrand factor (VWF) plasma levels. An estimated 60% of the phenotypic variation is attributable to hereditary factors, with the ABO blood group locus being the most influential. However, recent studies provide strong evidence that nonsynonymous single nucleotide variants (SNVs) contribute to VWF and factor VIII phenotypic variability in healthy individuals. This study aims to investigate the role of common VWF SNVs on VWD phenotype by analyzing data from 219 unrelated patients included in the “Molecular and Clinical Profile of von Willebrand Disease in Spain project.” To that end, generalized linear mixed-effects regression models were fitted, and additive and epistatic analyses, and haplotype studies were performed, considering five VWD-related measures (bleeding score, VWF:Ag, VWF:RCo, factor VIII:C, and VWF:CB). According to these analyses, homozygotes: for p.Thr789Ala(C) would be expected to show 39% higher VWF:Ag levels; p.Thr1381Ala(C), 27% lower VWF:Ag levels; and p.Gln852Arg(C), 52% lower VWF:RCo levels. Homozygotes for both p.Thr789Ala(C) and p.Gln852Arg(T) were predicted to show 185% higher VWF:CB activity, and carriers of two copies of the p.Thr1381Ala(T)/p.Gln852Arg(T) haplotype would present a 100% increase in VWF:RCo activity. These results indicate a substantial effect of common VWF variation on VWD phenotype. Although additional studies are needed to determine the true magnitude of the effects of SNVs on VWF, these findings provide new evidence regarding the contribution of common variants to VWD, which should be taken into account to enhance the accuracy of the diagnosis and classification of this condition. ClinicalTrials.gov identifier: NCT02869074.

Keywords

von willebrand disease - von willebrand factor - single nucleotide variants - association study

* Nina Borràs and Iris Garcia-Martínez contributed equally to this work.


Supplementary Material

 

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