Analysis of von Willebrand Disease in the South Moravian Population (Czech Republic): Results from the BRNO-VWD Study

Abstract

Background von Willebrand disease (VWD) is an inherited bleeding disorder caused by a quantitative (type 1 and 3) or qualitative (type 2) defect of von Willebrand factor (VWF). The heterogeneity of laboratory phenotyping makes diagnosing difficult.

Objective A cross-sectional, family-based VWD study in a collaboration between University Hospital Brno (Czech Republic) and Antwerp University Hospital (Belgium) to improve the understanding of laboratory phenotype/genotype correlation.

Patients and Methods A total of 205 patients with suspected VWD were identified from historical records. Complete laboratory analysis was established using all available VWD assays including VWF multimers and genetic analysis.

Results Based on the current International Society of Thrombosis and Haemostasis (ISTH) – Scientific and Standardization Committee VWD classification and type 2A sub-division into 2A/IIA, IID, IIC and IIE, the majority was characterized as a type 1 VWD, followed by type 2. Proposed laboratory phenotypes were confirmed by their multimeric pattern within 98% of this cohort. All type 2, 3 and 75% of type 1 VWD patients were confirmed by underlying causative mutations. Forty-six different causal mutations (117 not previously described in the literature) could be identified. Fifty per cent of all cases was represented by eight individual mutations, mainly p.Pro812ArgfsX31. Thirteen patients had a large heterozygous gene alteration.

Conclusion Although an extensive panel of tests was used, VWD classification and (sub)typing remains difficult and fluid. This study provides a cross-sectional overview of the VWD population in the Czech Republic and provides important data to the ISTH/European Association for Haemophilia and Allied Disorders VWD mutation database in linking causal mutations with unique VWD (sub)types. It also identifies new, as not previously described in the literature, causal mutations.

Keywords

classification - mutations - von Willebrand disease - von Willebrand factor - von Willebrand factor assays

• References

• 1 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69 (02) 454-459
• 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
• 3 Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev 2010; 24 (03) 123-134
• 4 Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease. Blood 2015; 125 (13) 2029-2037
• 5 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
• 6 Baronciani L, Cozzi G, Canciani MT. , et al. Molecular defects in type 3 von Willebrand disease: updated results from 40 multiethnic patients. Blood Cells Mol Dis 2003; 30 (03) 264-270
• 7 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
• 8 Eikenboom JC. Congenital von Willebrand disease type 3: clinical manifestations, pathophysiology and molecular biology. Best Pract Res Clin Haematol 2001; 14 (02) 365-379
• 9 Tosetto A, Rodeghiero F, Castaman G. , et al. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost 2006; 4 (04) 766-773
• 10 Bowman M, Tuttle A, Notley C. , et al; Association of Hemophilia Clinic Directors of Canada. The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles. J Thromb Haemost 2013; 11 (03) 512-520
• 11 Sutherland MS, Cumming AM, Bowman M. , et al. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood 2009; 114 (05) 1091-1098
• 12 Tosetto A, Castaman G. How I treat type 2 variant forms of von Willebrand disease. Blood 2015; 125 (06) 907-914
• 13 Schneppenheim R, Budde U. von Willebrand factor: the complex molecular genetics of a multidomain and multifunctional protein. J Thromb Haemost 2011; 9 (Suppl. 01) 209-215
• 14 Lillicrap D. Von Willebrand disease - phenotype versus genotype: deficiency versus disease. Thromb Res 2007; 120 (Suppl. 01) S11-S16
• 15 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
• 16 Federici AB. Classification of inherited von Willebrand disease and implications in clinical practice. Thromb Res 2009; 124 (Suppl. 01) S2-S6
• 17 Rodeghiero F, Tosetto A, Abshire T. , et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
• 18 Bowman M, Riddel J, Rand ML, Tosetto A, Silva M, James PD. Evaluation of the diagnostic utility for von Willebrand disease of a pediatric bleeding questionnaire. J Thromb Haemost 2009; 7 (08) 1418-1421
• 19 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
• 20 Quiroga T, Goycoolea M, Muñoz B. , et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004; 2 (06) 892-898
• 21 Favaloro EJ, Facey D, Henniker A. Use of a novel platelet function analyzer (PFA-100) with high sensitivity to disturbances in von Willebrand factor to screen for von Willebrand's disease and other disorders. Am J Hematol 1999; 62 (03) 165-174
• 22 Cattaneo M, Federici AB, Lecchi A. , et al. Evaluation of the PFA-100 system in the diagnosis and therapeutic monitoring of patients with von Willebrand disease. Thromb Haemost 1999; 82 (01) 35-39
• 23 Castaman G, Tosetto A, Goodeve A. , et al. The impact of bleeding history, von Willebrand factor and PFA-100(®) on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM-1VWD. Br J Haematol 2010; 151 (03) 245-251
• 24 Cumming AM, Wensley RT. Analysis of von Willebrand factor multimers using a commercially available enhanced chemiluminescence kit. J Clin Pathol 1993; 46 (05) 470-473
• 25 Budde U, Schneppenheim R, Plendl H, Dent J, Ruggeri ZM, Zimmerman TS. Luminographic detection of von Willebrand factor multimers in agarose gels and on nitrocellulose membranes. Thromb Haemost 1990; 63 (02) 312-315
• 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
• 27 Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002; 30 (17) 3894-3900
• 28 Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013. ;Chapter 7: Unit 7.20
• 29 Adzhubei IA, Schmidt S, Peshkin L. , et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7 (04) 248-249
• 30 Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11 (04) 361-362
• 31 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
• 32 Schneppenheim R, Budde U. Phenotypic and genotypic diagnosis of von Willebrand disease: a 2004 update. Semin Hematol 2005; 42 (01) 15-28
• 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
• 34 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
• 35 Brehm MA, Huck V, Aponte-Santamaría C. , et al. von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor. Thromb Haemost 2014; 112 (01) 96-108
• 36 Federici AB. Clinical and laboratory diagnosis of VWD. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 524-530
• 37 Borràs N, Batlle J, Pérez-Rodríguez A. , et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. Haematologica 2017; 102 (12) 2005-2014
• 38 Casaña P, Martínez F, Espinós C, Haya S, Lorenzo JI, Aznar JA. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants. Am J Hematol 1998; 59 (01) 57-63
• 39 Yin J, Ma Z, Su J. , et al. Mutations in the D1 domain of von Willebrand factor impair their propeptide-dependent multimerization, intracellular trafficking and secretion. J Hematol Oncol 2015; 8: 73
• 40 Randi AM, Rabinowitz I, Mancuso DJ, Mannucci PM, Sadler JE. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest 1991; 87 (04) 1220-1226
• 41 Lillicrap D, Murray EW, Benford K. , et al. Recurring mutations at CpG dinucleotides in the region of the von Willebrand factor gene encoding the glycoprotein Ib binding domain, in patients with type IIB von Willebrand's disease. Br J Haematol 1991; 79 (04) 612-617
• 42 Laffan MA, Lester W, O'Donnell JS. , et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (04) 453-465
• 43 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
• 44 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
• 45 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
• 46 Flood VH, Gill JC, Morateck PA. , et al. Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor. Blood 2010; 116 (02) 280-286
• 47 Flood VH, Friedman KD, Gill JC. , et al. Limitations of the ristocetin cofactor assay in measurement of von Willebrand factor function. J Thromb Haemost 2009; 7 (11) 1832-1839
• 48 Haberichter SL, Balistreri M, Christopherson P. , et al. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. Blood 2006; 108 (10) 3344-3351
• 49 Sadler JE, Rodeghiero F. ; ISTH SSC Subcommittee on von Willebrand Factor. Provisional criteria for the diagnosis of VWD type 1. J Thromb Haemost 2005; 3 (04) 775-777
• 50 Batlle J, Pérez-Rodríguez A, Corrales I. , et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): proposal for a new diagnostic paradigm. Thromb Haemost 2016; 115 (01) 40-50
• 51 Corrales I, Catarino S, Ayats J. , et al. High-throughput molecular diagnosis of von Willebrand disease by next generation sequencing methods. Haematologica 2012; 97 (07) 1003-1007
• 52 Fidalgo T, Salvado R, Corrales I. , et al. Genotype-phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS. Thromb Haemost 2016; 116 (01) 17-31
• 53 Schneppenheim R, Krey S, Bergmann F. , et al. Genetic heterogeneity of severe von Willebrand disease type III in the German population. Hum Genet 1994; 94 (06) 640-652
• 54 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
• 55 Gupta PK, Saxena R, Adamtziki E. , et al. Genetic defects in von Willebrand disease type 3 in Indian and Greek patients. Blood Cells Mol Dis 2008; 41 (02) 219-222
• 56 Schneppenheim R, Castaman G, Federici AB. , et al. A common 253-kb deletion involving VWF and TMEM16B in German and Italian patients with severe von Willebrand disease type 3. J Thromb Haemost 2007; 5 (04) 722-728