PDF herunterladen
CC BY 4.0 · TH Open 2022; 06(04): e335-e346
DOI: 10.1055/s-0042-1757635
Original Article

Analysis of von Willebrand Disease in the “Heart of Europe”

Inge Vangenechten
1   Haemostasis Unit, Antwerp University Hospital, Edegem, Belgium
2   Medicine and Health Sciences, Haemostasis Research Unit, Antwerp University, Antwerp, Belgium
3   Antwerp University, Antwerp, Belgium
,
Petr Smejkal
4   Department of Clinical Haematology, University Hospital Brno, Brno, Czech Republic
5   Department of Laboratory Methods, Faculty of Medicine, Masaryk University, Brno, Czech Republic
,
Jiri Zavrelova
4   Department of Clinical Haematology, University Hospital Brno, Brno, Czech Republic
5   Department of Laboratory Methods, Faculty of Medicine, Masaryk University, Brno, Czech Republic
,
Ondrej Zapletal
6   Department of Pediatric Haematology, University Hospital Brno, Brno, Czech Republic
,
Alexander Wild
7   Department of Haematology, University F. D. Roosevelt Hospital, Banská Bystrica, Slovakia
,
Jan Jacques Michiels
8   Blood Coagulation and Vascular Medicine Center, Goodheart Institute & Foundation in Nature Medicine, Rotterdam, The Netherlands
,
Zwi Berneman
3   Antwerp University, Antwerp, Belgium
9   Department of Haematology, Antwerp University Hospital, Edegem, Belgium
,
Jan Blatny
6   Department of Pediatric Haematology, University Hospital Brno, Brno, Czech Republic
,
Angelika Batorova
10   National Hemophilia Center, Department of Haematology and Blood Transfusion of the Medical School of the Comenius University, Bratislava, Slovakia
,
Tatiana Prigancova
10   National Hemophilia Center, Department of Haematology and Blood Transfusion of the Medical School of the Comenius University, Bratislava, Slovakia
,
Miroslav Penka
4   Department of Clinical Haematology, University Hospital Brno, Brno, Czech Republic
5   Department of Laboratory Methods, Faculty of Medicine, Masaryk University, Brno, Czech Republic
,
Alain Gadisseur
1   Haemostasis Unit, Antwerp University Hospital, Edegem, Belgium
2   Medicine and Health Sciences, Haemostasis Research Unit, Antwerp University, Antwerp, Belgium
3   Antwerp University, Antwerp, Belgium
9   Department of Haematology, Antwerp University Hospital, Edegem, Belgium
› Institutsangaben Funding This study was supported and financed by an unrestricted grant from Bayer Health Care, Belgium and CSL Behring, Belgium.
› Weitere Informationen
Auch verfügbar auf
   Lizenzen und Reprints

Abstract

Background von Willebrand disease (VWD) is a genetic bleeding disorder caused by defects of von Willebrand factor (VWF), quantitative (type 1 and 3) or qualitative (type 2). The laboratory phenotyping is heterogenic making diagnosis difficult.

Objectives Complete laboratory analysis of VWD as an expansion of the previously reported cross-sectional family-based VWD study in the Czech Republic (BRNO-VWD) and Slovakia (BRA-VWD) under the name “Heart of Europe,” in order to improve the understanding of laboratory phenotype/genotype correlation.

Patients and Methods In total, 227 suspected VWD patients were identified from historical records. Complete laboratory analysis was established using all available assays, including VWF multimers and genetic analysis.

Results A total of 191 patients (from 119 families) were confirmed as having VWD. The majority was characterized as a type 1 VWD, followed by type 2. Multimeric patterns concordant with laboratory phenotypes were found in approximately 83% of all cases. A phenotype/genotype correlation was present in 84% (77% type 1, 99% type 2, and 61% type 3) of all patients. Another 45 candidate mutations (23 novel variations), not found in the initial study, could be identified (missense 75% and truncating 24%). An exon 1–3 gene deletion was identified in 14 patients where no mutation was found by direct DNA sequencing, increasing the linkage up to 92%, overall.

Conclusion This study provides a cross-sectional overview of the VWD population in a part of Central Europe. It is an addition to the previously published BRNO-VWD study, and provides important data to the International Society of Thrombosis and Haemostasis/European Association for Haemophilia and Allied Disorders VWD mutation database with identification of novel causal mutations.

Keywords

classification - genotype - phenotype - von Willebrand disease - von Willebrand factor

Addendum

A.G., J.J.M, P.S., and A.B. were responsible for the study initiation. O.Z., P.S., A.B., T.P., and A.W. were responsible for the sample collection. I.V. was involved in study design, data collection, and performing laboratory analysis. I.V. and A.G. were responsible for analysis and interpretation of results and performed statistical analysis. I.V. was the lead author of the initial manuscript. A.G., J.B., J.Z., M.P., O.Z., P.S., and A.B were responsible for revisions of the draft manuscripts. A.G. was responsible for review and approval of the final manuscript for submission.


Disclosure of Conflict of Interest

The authors declare that there are no conflicts of interest.


Supplementary Material



Publikationsverlauf

Eingereicht: 09. Juni 2022

Angenommen: 16. August 2022

Artikel online veröffentlicht:
19. Oktober 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69 (02) 454-459
    CrossrefPubMedSuche in Google Scholar
  • 2 Zhou YF, Eng ET, Zhu J, Lu C, Walz T, Springer TA. Sequence and structure relationships within von Willebrand factor. Blood 2012; 120 (02) 449-458
    CrossrefPubMedSuche in Google Scholar
  • 3 Nyman D. Interaction of collagen with the factor VIII antigen-activity - von Willebrand factor complex. Thromb Res 1977; 11 (03) 433-438
    CrossrefPubMedSuche in Google Scholar
  • 4 Goto S, Salomon DR, Ikeda Y, Ruggeri ZM. Characterization of the unique mechanism mediating the shear-dependent binding of soluble von Willebrand factor to platelets. J Biol Chem 1995; 270 (40) 23352-23361
    CrossrefPubMedSuche in Google Scholar
  • 5 Timmons S, Kloczewiak M, Hawiger J. ADP-dependent common receptor mechanism for binding of von Willebrand factor and fibrinogen to human platelets. Proc Natl Acad Sci U S A 1984; 81 (15) 4935-4939
    CrossrefPubMedSuche in Google Scholar
  • 6 Sadler JE, Budde U, Eikenboom JC. et al; Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4 (10) 2103-2114
    CrossrefPubMedSuche in Google Scholar
  • 7 Tosetto A, Castaman G. How I treat type 2 variant forms of von Willebrand disease. Blood 2015; 125 (06) 907-914
    CrossrefPubMedSuche in Google Scholar
  • 8 Schneppenheim R, Budde U. von Willebrand factor: the complex molecular genetics of a multidomain and multifunctional protein. J Thromb Haemost 2011; 9 (Suppl 1): 209-215
    CrossrefPubMedSuche in Google Scholar
  • 9 Lillicrap D. Von Willebrand disease - phenotype versus genotype: deficiency versus disease. Thromb Res 2007; 120 (Suppl 1): S11-S16
    CrossrefPubMedSuche in Google Scholar
  • 10 Jacobi PM, Gill JC, Flood VH, Jakab DA, Friedman KD, Haberichter SL. Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage. Blood 2012; 119 (19) 4543-4553
    CrossrefPubMedSuche in Google Scholar
  • 11 Federici AB. Classification of inherited von Willebrand disease and implications in clinical practice. Thromb Res 2009; 124 (Suppl 1): S2-S6
    CrossrefPubMedSuche in Google Scholar
  • 12 Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev 2010; 24 (03) 123-134
    CrossrefPubMedSuche in Google Scholar
  • 13 Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease. Blood 2015; 125 (13) 2029-2037
    CrossrefPubMedSuche in Google Scholar
  • 14 Vangenechten I, Mayger K, Smejkal P. et al. A comparative analysis of different automated von Willebrand factor glycoprotein Ib-binding activity assays in well typed von Willebrand disease patients. J Thromb Haemost 2018; 16 (07) 1268-1277
    CrossrefPubMedSuche in Google Scholar
  • 15 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 (01) 112-121
    CrossrefPubMedSuche in Google Scholar
  • 16 Veyradier A, Boisseau P, Fressinaud E. et al; French Reference Center for von Willebrand disease. A laboratory phenotype/genotype correlation of 1167 French patients from 670 families with von willebrand disease: a new epidemiologic picture. Medicine (Baltimore) 2016; 95 (11) e3038
    CrossrefPubMedSuche in Google Scholar
  • 17 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 (01) 145-154
    CrossrefPubMedSuche in Google Scholar
  • 18 Vangenechten I, Smejkal P, Zapletal O. et al. Analysis of von Willebrand disease in the South Moravian population (Czech Republic): results from the BRNO-VWD study. Thromb Haemost 2019; 119 (04) 594-605
    Thieme ConnectPubMedSuche in Google Scholar
  • 19 Favaloro EJ, Oliver S. Evaluation of a new commercial von Willebrand factor multimer assay. Haemophilia 2017; 23 (04) e373-e377
    CrossrefPubMedSuche in Google Scholar
  • 20 Oliver S, Lau KKE, Chapman K, Favaloro EJ. Laboratory testing for Von Willebrand factor multimers. Methods Mol Biol 2017; 1646: 495-511
    CrossrefPubMedSuche in Google Scholar
  • 21 Bowyer AE, Goodfellow KJ, Seidel H. et al. Evaluation of a semi-automated von Willebrand factor multimer assay, the Hydragel 5 von Willebrand multimer, by two European centers. Res Pract Thromb Haemost 2018; 2 (04) 790-799
    CrossrefPubMedSuche in Google Scholar
  • 22 Crist RA, Heikal NM, Rodgers GM, Grenache DG, Smock KJ. Evaluation of a new commercial method for von Willebrand factor multimeric analysis. Int J Lab Hematol 2018; 40 (05) 586-591
    CrossrefPubMedSuche in Google Scholar
  • 23 Pikta M, Zemtsovskaja G, Bautista H. et al. Preclinical evaluation of a semi-automated and rapid commercial electrophoresis assay for von Willebrand factor multimers. J Clin Lab Anal 2018; 32 (06) e22416
    CrossrefPubMedSuche in Google Scholar
  • 24 Oliver S, Vanniasinkam T, Mohammed S, Vong R, Favaloro EJ. Semi-automated von Willebrand factor multimer assay for von Willebrand disease: further validation, benefits and limitations. Int J Lab Hematol 2019; 41 (06) 762-771
    CrossrefPubMedSuche in Google Scholar
  • 25 Vangenechten I, Gadisseur A. Improving diagnosis of von Willebrand disease: reference ranges for von Willebrand factor multimer distribution. Res Pract Thromb Haemost 2020; 4 (06) 1024-1034
    CrossrefPubMedSuche in Google Scholar
  • 26 Raimondi D, Tanyalcin I, Ferté J. et al. DEOGEN2: prediction and interactive visualization of single amino acid variant deleteriousness in human proteins. Nucleic Acids Res 2017; 45 (W1): W201-W206
    CrossrefPubMedSuche in Google Scholar
  • 27 Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002; 30 (17) 3894-3900
    CrossrefPubMedSuche in Google Scholar
  • 28 Adzhubei IA, Schmidt S, Peshkin L. et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7 (04) 248-249
    Suche in Google Scholar
  • 29 Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013; Chapter 7: 20
    PubMedSuche in Google Scholar
  • 30 Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11 (04) 361-362
    Suche in Google Scholar
  • 31 James PD, Connell NT, Ameer B. et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021; 5 (01) 280-300
    Suche in Google Scholar
  • 32 Schneppenheim R, Michiels JJ, Obser T. et al. A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE. Blood 2010; 115 (23) 4894-4901
    CrossrefPubMedSuche in Google Scholar
  • 33 Schneppenheim R, Budde U, Ruggeri ZM. A molecular approach to the classification of von Willebrand disease. Best Pract Res Clin Haematol 2001; 14 (02) 281-298
    CrossrefPubMedSuche in Google Scholar
  • 34 Schneppenheim R, Budde U. Phenotypic and genotypic diagnosis of von Willebrand disease: a 2004 update. Semin Hematol 2005; 42 (01) 15-28
    CrossrefPubMedSuche in Google Scholar
  • 35 Michiels JJ, Berneman Z, Gadisseur A. et al. Classification and characterization of hereditary types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (unclassifiable) von Willebrand disease. Clin Appl Thromb Hemost 2006; 12 (04) 397-420
    CrossrefPubMedSuche in Google Scholar
  • 36 Casonato A, Daidone V, Galletta E, Bertomoro A. Type 2B von Willebrand disease with or without large multimers: a distinction of the two sides of the disorder is long overdue. PLoS One 2017; 12 (06) e0179566
    CrossrefPubMedSuche in Google Scholar
  • 37 Weiss HJ, Sussman II. A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers. Blood 1986; 68 (01) 149-156
    CrossrefPubMedSuche in Google Scholar
  • 38 Holmberg L, Dent JA, Schneppenheim R, Budde U, Ware J, Ruggeri ZM. von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. J Clin Invest 1993; 91 (05) 2169-2177
    CrossrefPubMedSuche in Google Scholar
  • 39 Meyer D, Fressinaud E, Hilbert L, Ribba AS, Lavergne JM, Mazurier C. Type 2 von Willebrand disease causing defective von Willebrand factor-dependent platelet function. Best Pract Res Clin Haematol 2001; 14 (02) 349-364
    CrossrefPubMedSuche in Google Scholar
  • 40 Rabinowitz I, Tuley EA, Mancuso DJ. et al. von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib. Proc Natl Acad Sci U S A 1992; 89 (20) 9846-9849
    CrossrefPubMedSuche in Google Scholar
  • 41 Ribba AS, Loisel I, Lavergne JM. et al. Ser968Thr mutation within the A3 domain of von Willebrand factor (VWF) in two related patients leads to a defective binding of VWF to collagen. Thromb Haemost 2001; 86 (03) 848-854
    PubMedSuche in Google Scholar
  • 42 Flood VH, Lederman CA, Wren JS. et al. Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD. J Thromb Haemost 2010; 8 (06) 1431-1433
    CrossrefPubMedSuche in Google Scholar
  • 43 Castaman G, Federici AB, Tosetto A. et al. Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients. J Thromb Haemost 2012; 10 (04) 632-638
    CrossrefPubMedSuche in Google Scholar
  • 44 Favaloro EJ, Pasalic L, Curnow J. Type 2M and Type 2A von Willebrand disease: similar but different. Semin Thromb Hemost 2016; 42 (05) 483-497
    Thieme ConnectPubMedSuche in Google Scholar
  • 45 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 Hemost 2011; 37 (05) 511-521
    Thieme ConnectPubMedSuche in Google Scholar
  • 46 Mohl A, Marschalek R, Masszi T. et al. An Alu-mediated novel large deletion is the most frequent cause of type 3 von Willebrand disease in Hungary. J Thromb Haemost 2008; 6 (10) 1729-1735
    CrossrefPubMedSuche in Google Scholar
  • 47 Eikenboom J, Van Marion V, Putter H. et al. Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD. J Thromb Haemost 2006; 4 (04) 774-782
    CrossrefPubMedSuche in Google Scholar
  • 48 Flood VH, Christopherson PA, Gill JC. et al. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood 2016; 127 (20) 2481-2488
    CrossrefPubMedSuche in Google Scholar
  • 49 Cumming A, Grundy P, Keeney S. et al; UK Haemophilia Centre Doctors' Organisation. An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb Haemost 2006; 96 (05) 630-641
    PubMedSuche in Google Scholar
  • 50 Yadegari H, Driesen J, Pavlova A, Biswas A, Hertfelder HJ, Oldenburg J. Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients. Thromb Haemost 2012; 108 (04) 662-671
    Thieme ConnectPubMedSuche in Google Scholar
  • 51 Smith NL, Chen MH, Dehghan A. et al; Wellcome Trust Case Control Consortium. 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 (12) 1382-1392
    CrossrefPubMedSuche in Google Scholar
  • 52 van Loon J, Dehghan A, Weihong T. et al. Genome-wide association studies identify genetic loci for low von Willebrand factor levels. Eur J Hum Genet 2016; 24 (07) 1096
    CrossrefPubMedSuche in Google Scholar