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DOI: 10.1160/TH15-04-0282
Molecular and clinical profile of von Willebrand disease in Spain (PCM–EVW–ES): Proposal for a new diagnostic paradigm
Financial support: This study was supported by Baxter Healthcare Corporation for the PCM–EVW–ES support and Baxter BioScience Grant (H13–000845) for the genetic analysis. The Spanish Ministerio de Economía y Competitividad (MINECO)-Instituto de Salud Carlos III (ISCIII) (PI1201494 and RD12/0042/0053).Publication History
Received:
06 April 2015
Accepted after major revision:
26 June 2015
Publication Date:
22 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201601/lookinside/thumbnails/10-1160-th15-04-0282-1.jpg)
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.
† Jesús M. César died on August 25th, 2014.
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References
- 1 Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Blood 2013; 122: 3735-3740.
- 2 Sadler JE, Budde U, Eikenboom JC. et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 04: 2103-2114.
- 3 Batlle J, Perez-Rodriguez A, Pinto JC. et al. Diagnosis and management of von Willebrand disease in Spain. Semin Thromb Haemost 2011; 37: 503-510.
- 4 Costa-Pinto J, Pérez-Rodríguez A, del C Goméz-del-Castillo M. et al. Diagnosis of inherited von Willebrand disease: comparison of two methodologies and analysis of the discrepancies. Haemophilia 2014; 20: 559-567.
- 5 Castaman G, Goodeve A, Eikenboom J. et al. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica 2013; 98: 667-674.
- 6 Favaloro EJ, Bodó I, Israels SJ. et al. von Willebrand disease and platelet disorders. Haemophilia 2014; 20 (Suppl. 04) 59-64.
- 7 Federici A. Therapeutic Progress in von Willebrand Disease. Hematology Am Soc Hematol Educ Program 2014: 524-530.
- 8 Flood VH. Perils, problems, and progress in laboratory diagnosis of von Wille-brand disease. Semin Thromb Haemost 2014; 40: 41-48.
- 9 Tosetto A, Castaman G, Rodeghiero F. Evidence-based diagnosis of type 1 von Willebrand disease: a Bayes theorem approach. Blood 2008; 111: 3998-4003.
- 10 Flood VH, Gill JC, Friedman KD. et al. Von Willebrand disease in the United States: a perspective from Wisconsin. Semin Thromb Haemost 2011; 37: 528-534.
- 11 Batlle J, Pérez-Rodríguez A, Franqueira MD. et al. Type 2M von Willebrand disease: a variant of type 2A?. J Thromb Haemost 2008; 06: 388-390.
- 12 Penas N, Pérez-Rodríguez A, Torea JH. et al. von Willebrand disease R1374C: type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia). Am J Hematol 2005; 80: 188-196.
- 13 Hamilton A, Ozelo M, Leggo J. et al. Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. Thromb Haemost 2011; 105: 501-508.
- 14 Ahmad S, Ptashkin B, DiGiovanni C. et al. False normal von Willebrand factor activity by monoclonal antibody-based ELISA in a patient with type 2A(IID) von Willebrand disease. Thromb Haemost 2011; 106: 1224-1225.
- 15 Gill JC, Haberichter SL, Bellissimo DB. et al. Binding Of VWF To Type IV Collagen: An Additional Collagen Binding Mechanism Beyond Types I, III, and VI Collagen?. Blood 2013; 122: 333.
- 16 Flood VH, Gill JC, Christopherson PA. et al. Critical von Willebrand factor A1 domain residues influence type VI collagen binding. J Thromb Haemost 2012; 10: 1417-1424.
- 17 Flood VH. New Insights into Genotype and Phenotype of von Willebrand Disease. 2014 pp. 531-535.
- 18 Corrales I, Catarino S, Ayats J. et al. High-throughput molecular diagnosis of von Willebrand disease by next generation sequencing methods. Haematologica 2012; 97: 1003-1007.
- 19 Tosetto A, Rodeghiero F, Castaman G. et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicentre European study (MCMDM-1 VWD). J Thromb Haemost 2006; 04: 766-773.
- 20 Casonato A, Pontara E, Zerbinati P. et al. The evaluation of factor VIII binding activity of von Willebrand factor by means of an ELISA method: significance and practical implications. Am J Clin Pathol 1998; 109: 347-352.
- 21 Batlle J, López Fernández MF. Laboratory Assays for von Willebrand Factor. In Coagulation and Bleeding Disorders: The role of Factor VIII and von Wille-brand Factor. Ed Marcel Dekker Inc; New York: 1989. pp. 325-342.
- 22 European Association for Haemophilia and Allied Disorders (EAHAD).. Coagulation Factor Variant Databases. Available at: https://www.grenada.lumc.nl/LOVD2/VWF/home.php?select_db=VWF. Accessed November 25, 2014.
- 23 International Society on Thrombosis and Haemostasis-Scientific and Standard-isation Committee of von Willebrand Factor (ISTH-SSC). VWF Online Database (VWFdb). Available at: http://www.vwf.group.shef.ac.uk/vwd.html. Accessed November 14, 2014.
- 24 Corrales I, Ramírez L, Altisent C. et al. Rapid molecular diagnosis of von Wille-brand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene. Thromb Haemost 2009; 101: 570-576.
- 25 Othman M, Notley C, Lavender FL. et al. Identification and functional characterisation of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease. Blood 2005; 105: 4330-4336.
- 26 Fokkema IF, Taschner PE, Schaafsma GC. et al. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat 2011; 32: 557-563.
- 27 Bellissimo DB, Christopherson PA, Flood VH. et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood 2012; 119: 2135-2140.
- 28 Goodeve A, Eikenboom J, Castaman G. et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood 2007; 109: 112-121.
- 29 James PD, Notley C, Hegadorn C. et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood 2007; 109: 145-154.
- 30 Cumming A, Grundy P, Keeney S. et al. An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb Haemost 2006; 96: 630-641.
- 31 Yadegari H, Driesen J, Pavlova A. et al. Mutation distribution in the von Wille-brand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients. Thromb Haemost 2012; 108: 662-671.
- 32 Federici AB, Bucciarelli P, Castaman G. et al. Management of inherited von Willebrand disease in Italy: results from the retrospective study on 1234 patients. Semin Thromb Haemost 2011; 37: 511-521.
- 33 Casari C, Lenting P, Wohner N. et al. Clearance of von Willebrand factor. J Thromb Haemost 2013; 11 (Suppl. 01) 202-11.
- 34 Smith NL, Chen MH, Dehghan A. et al. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121: 1382-1392.
- 35 Federici AB. Acquired von Willebrand syndrome associated with hypothyroidism: a mild bleeding disorder to be further investigated. Semin Thromb Haemost 2011; 37: 35-40.
- 36 Federici AB, Budde U, Castaman G. et al. Current diagnostic and therapeutic approaches to patients with acquired von Willebrand syndrome: a 2013 update. Semin Thromb Haemost 2013; 39: 191-201.
- 37 Sanders YV, Giezenaar MA, Laros-van Gorkom BA. et al. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost 2014; 12: 1066-1075.
- 38 Montgomery RR. When it comes to von Willebrand disease, does 1 + 1 = 3?. J Thromb Haemost 2006; 04: 2162-2163.
- 39 Casaña P, Martínez F, Haya S. et al. Q1311X: a novel nonsense mutation of putative ancient origin in the von Willebrand factor gene. Br J Haematol 2000; 111: 552-555.
- 40 Jorieux S, Gaucher C, Goudemand J. et al. A novel mutation in the D3 domain of von Willebrand factor markedly decreases its ability to bind factor VIII and affects its multimerisation. Blood 1998; 92: 4663-4670.
- 41 Johnsen JM, Auer PL, Morrison AC. et al. Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project. Blood 2013; 122: 590-597.
- 42 Haberichter SL, Balistreri M, Christopherson P. et al. Assay of the von Wille-brand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. Blood 2006; 108: 3344-3351.
- 43 ten Bosch JR, Grody WW. Keeping up with the next generation: massively parallel sequencing in clinical diagnostics. J Mol Diagn 2008; 10: 484-492.
- 44 Hampshire DJ, Goodeve AC. The international society on thrombosis and haematosis von Willebrand disease database: an update. Semin Thromb Haemost 2011; 37: 470-479.
- 45 Haberichter SL, Hille M, Morateck P. et al. Alanine Scanning Mutagenesis of the VWF-A1 Flanking Regions of VWF and the Impact on Ristocetin-induced VWF Interaction with Platelets. Blood 2013; 122: 1103.
- 46 Goodeve AC. VWF sequence variants: a data goldmine. Blood 2013; 122: 471-473.
- 47 Flood VH, Friedman KD, Gill JC. et al. No increase in bleeding identified in type 1 VWD subjects with D1472H sequence variation. Blood 2013; 121: 3742-3744.
- 48 Souto JC, Almasy L, Soria JM. et al. Genome-wide linkage analysis of von Wille-brand factor plasma levels: results from the GAIT project. Thromb Haemost 2003; 89: 468-474.
- 49 Johnsen JM, Teschke M, Pavlidis P. et al. Selection on cis-regulatory variation at B4galnt2 and its influence on von Willebrand factor in house mice. Mol Biol Evol 2009; 26: 567-578.
- 50 Shavit JA, Manichaikul A, Lemmerhirt HL. et al. Modifiers of von Willebrand factor identified by natural variation in inbred strains of mice. Blood 2009; 114: 5368-5374.
- 51 Gill JC, Endres-Brooks J, Bauer PJ. et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695.
- 52 Rydz N, Swystun LL, Notley C. et al. The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels. Blood 2013; 121: 5228-5237.