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Semin Thromb Hemost 2021; 47(07): 862-874
DOI: 10.1055/s-0041-1726097
Review Article

Type 2A and 2M von Willebrand Disease: Differences in Phenotypic Parameters According to the Affected Domain by Disease-Causing Variants and Assessment of Pathophysiological Mechanisms

Adriana Inés Woods 
1   Laboratorio de Hemostasia y Trombosis, IMEX-CONICET-Academia Nacional de Medicina de Buenos Aires. CABA, Argentina
,
Juvenal Paiva 
2   Departamento de Hemostasia y Trombosis, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina de Buenos Aires. CABA, Argentina
,
Débora Marina Primrose 
3   Química de los Alimentos, Facultad de Agronomía y Ciencias Agroalimentarias, Universidad de Morón. Buenos Aires, Argentina
,
Alicia Noemí Blanco 
2   Departamento de Hemostasia y Trombosis, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina de Buenos Aires. CABA, Argentina
,
Analía Sánchez-Luceros 
1   Laboratorio de Hemostasia y Trombosis, IMEX-CONICET-Academia Nacional de Medicina de Buenos Aires. CABA, Argentina
2   Departamento de Hemostasia y Trombosis, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina de Buenos Aires. CABA, Argentina
› Author Affiliations Funding This work was supported by CONICET, Fundación Rene Barón, and Academia Nacional de Medicina (Buenos Aires), Argentina.
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Abstract

Type 2A and 2M von Willebrand disease (VWD) broadly show similar phenotypic parameters, but involve different pathophysiological mechanisms. This report presents the clinical and laboratory profiles of type 2A and type 2M patients genotypically diagnosed at one large center. Higher bleeding score values and a higher incidence of major bleeding episodes were observed in type 2A compared with type 2M, potentially reflective of the absence of large and intermediate von Willebrand factor (VWF) multimers in 2A. In type 2A, most of disease-causing variants (DCVs) appeared to be responsible for increased VWF clearance and DCV clustered in the VWF-A1 domain resulted in more severe clinical profiles. In type 2M, DCV in the VWF-A1 domain showed different laboratory patterns, related to either reduced synthesis or shortened VWF survival, and DCV in the VWF-A2 domain showed patterns related mainly to shortened survival. VWF-type 1 collagen binding/Ag (C1B/Ag) showed different patterns according to DCV location: in type 2A VWD, C1B/Ag was much lower when DCVs were located in the VWF-A2 domain. In type 2M with DCV in the VWF-A1domain, C1B/Ag was normal, but with DCV in the VWF-A2 domain, C1B/Ag was low. The higher frequency of major bleeding in VWD 2M patients with DCV in the VWF-A2 domain than that with DCV in the VWF-A1 domain could be a summative effect of abnormal C1B/Ag, on top of the reduced VWF-GPIb binding. In silico modeling suggests that DCV impairing the VWF-A2 domain somehow modulates collagen binding to the VWF-A3 domain. Concomitant normal FVIII:C/Ag and VWFpp/Ag, mainly in type 2M VWD, suggest that other nonidentified pathophysiological mechanisms, neither related to synthesis/retention nor survival of VWF, would be responsible for the presenting phenotype.

Keywords

disease-causing variants - phenotype–genotype - von Willebrand disease - von Willebrand factor - collagen binding


Publication History

Article published online:
15 June 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 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
    CrossrefPubMedSearch in Google Scholar
  • 2 Favaloro EJ, Bonar RA, Mohammed S. et al. Type 2M von Willebrand disease - more often misidentified than correctly identified. Haemophilia 2016; 22 (03) e145-e155
    CrossrefPubMedSearch in Google Scholar
  • 3 Woods AI, Kempfer AC, Paiva J, Blanco AN, Sánchez-Luceros A, Lazzari MA. Diagnosis of von Willebrand disease in Argentina: a single institution experience. Ann Blood 2017; 2: 22
    CrossrefPubMedSearch in Google Scholar
  • 4 Swami A, Kaur V. von Willebrand disease: a concise review and update for the practicing physician. Clin Appl Thromb Hemost 2017; 23 (08) 900-910
    CrossrefPubMedSearch in Google Scholar
  • 5 Favaloro EJ, Oliver S, Mohammed S, Vong R. Comparative assessment of von Willebrand factor multimers vs activity for von Willebrand disease using modern contemporary methodologies. Haemophilia 2020; 26 (03) 503-512
    CrossrefPubMedSearch in Google Scholar
  • 6 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
    CrossrefPubMedSearch in Google Scholar
  • 7 Lillicrap D. Von Willebrand disease - phenotype versus genotype: deficiency versus disease. Thromb Res 2007; 120 (Suppl. 01) S11-S16
    CrossrefPubMedSearch in Google Scholar
  • 8 Berntorp E, Ågren A, Aledort L. et al. Fifth Åland Island conference on von Willebrand disease. Haemophilia 2018; 24 (Suppl. 04) 5-19
    CrossrefPubMedSearch in Google Scholar
  • 9 Baronciani L, Goodeve A, Peyvandi F. Molecular diagnosis of von Willebrand disease. Haemophilia 2017; 23 (02) 188-197
    CrossrefPubMedSearch in Google Scholar
  • 10 Zolkova J, Sokol J, Simurda T. et al. Genetic background of von Willebrand disease: history, current state, and future perspectives. Semin Thromb Hemost 2020; 46 (04) 484-500
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 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 ConnectPubMedSearch in Google Scholar
  • 12 Doruelo AL, Haberichter SL, Christopherson PA. et al. Clinical and laboratory phenotype variability in type 2M von Willebrand disease. J Thromb Haemost 2017; 15 (08) 1559-1566
    CrossrefPubMedSearch in Google Scholar
  • 13 Fidalgo T, Oliveira A, Silva Pinto C. et al. VWF collagen (types III and VI)-binding defects in a cohort of type 2M VWD patients - a strategy for improvement of a challenging diagnosis. Haemophilia 2017; 23 (02) e143-e147
    CrossrefPubMedSearch in Google Scholar
  • 14 Tischer A, Campbell JC, Machha VR. et al. Mutational constraints on local unfolding inhibit the rheological adaptation of von Willebrand factor. J Biol Chem 2016; 291 (08) 3848-3859
    CrossrefPubMedSearch in Google Scholar
  • 15 Keeling D, Beavis J, Marr R, Sukhu K, Bignell P. A family with type 2M VWD with normal VWF:RCo but reduced VWF:CB and a M1761K mutation in the A3 domain. Haemophilia 2012; 18 (01) e33
    CrossrefPubMedSearch in Google Scholar
  • 16 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
    CrossrefPubMedSearch in Google Scholar
  • 17 Eikenboom J, Federici AB, Dirven RJ. et al; MCMDM-1VWD Study Group. VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease. Blood 2013; 121 (12) 2336-2339
    CrossrefPubMedSearch in Google Scholar
  • 18 Sanders YV, Groeneveld D, Meijer K. et al; WiN study group. von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease. Blood 2015; 125 (19) 3006-3013
    CrossrefPubMedSearch in Google Scholar
  • 19 Eikenboom JC, Castaman G, Kamphuisen PW, Rosendaal FR, Bertina RM. The factor VIII/von Willebrand factor ratio discriminates between reduced synthesis and increased clearance of von Willebrand factor. Thromb Haemost 2002; 87 (02) 252-257
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Rodeghiero F. Bleeding score and bleeding questionnaire for the diagnosis of type 1 von Willebrand disease. Accessed 2021 at: https://cdn.ymaws.com/www.isth.org/resource/resmgr/ssc/bleeding_type1_vwd.pdf
    PubMed
  • 21 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
    CrossrefPubMedSearch in Google Scholar
  • 22 Janssen CA, Scholten PC, Heintz AP. A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol 1995; 85 (06) 977-982
    CrossrefPubMedSearch in Google Scholar
  • 23 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    CrossrefPubMedSearch in Google Scholar
  • 24 Duncan E, Rodgers S. One-stage factor VIII assays. Methods Mol Biol 2017; 1646: 247-263
    CrossrefPubMedSearch in Google Scholar
  • 25 Favaloro EJ, Mohammed S, Patzke J. Laboratory testing for von Willebrand factor antigen (VWF:Ag). Methods Mol Biol 2017; 1646: 403-416
    CrossrefPubMedSearch in Google Scholar
  • 26 Mohammed S, Favaloro EJ. Laboratory testing for von Willebrand factor ristocetin cofactor (VWF:RCo). Methods Mol Biol 2017; 1646: 435-451
    CrossrefPubMedSearch in Google Scholar
  • 27 Stufano F, Boscarino M, Bucciarelli P. et al. Evaluation of the utility of von Willebrand factor propeptide in the differential diagnosis of von Willebrand disease and acquired von Willebrand syndrome. Semin Thromb Hemost 2019; 45 (01) 36-42
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Farias C, Kempfer AC, Blanco A, Woods A, Lazzari MA. Visualization of the multimeric structure of von Willebrand factor by immunoenzymatic stain using avidin-peroxidase complex instead of avidin-biotin peroxidase complex. Thromb Res 1989; 53 (05) 513-518
    CrossrefPubMedSearch in Google Scholar
  • 29 Woods AI, Sanchez-Luceros A, Kempfer AC. et al. C1272F: a novel type 2A von Willebrand's disease mutation in A1 domain; its clinical significance. Haemophilia 2012; 18 (01) 112-116
    CrossrefPubMedSearch in Google Scholar
  • 30 Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 1997; 18 (15) 2714-2723
    CrossrefPubMedSearch in Google Scholar
  • 31 Kozakov D, Hall DR, Xia B. et al. The ClusPro web server for protein-protein docking. Nat Protoc 2017; 12 (02) 255-278
    CrossrefPubMedSearch in Google Scholar
  • 32 Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ. PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 2005; 33 (Web Server issue): W363-7
    CrossrefPubMedSearch in Google Scholar
  • 33 Laskowski RA, Jabłońska J, Pravda L, Vařeková RS, Thornton JM. PDBsum: structural summaries of PDB entries. Protein Sci 2018; 27 (01) 129-134
    CrossrefPubMedSearch in Google Scholar
  • 34 Pettersen EF, Goddard TD, Huang CC. et al. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004; 25 (13) 1605-1612
    CrossrefPubMedSearch in Google Scholar
  • 35 Agresti A, Coull BA. Approximate is better than ‘exact’ for interval estimation of binomial proportions. Am Stat 1998; 52: 119-126
    PubMedSearch in Google Scholar
  • 36 Ahmad F, Jan R, Kannan M. et al. Characterisation of mutations and molecular studies of type 2 von Willebrand disease. Thromb Haemost 2013; 109 (01) 39-46
    Thieme ConnectPubMedSearch in Google Scholar
  • 37 Ahmad F, Kannan M, Obser T. et al. Characterization of VWF gene conversions causing von Willebrand disease. Br J Haematol 2019; 184 (05) 817-825
    CrossrefPubMedSearch in Google Scholar
  • 38 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 ConnectPubMedSearch in Google Scholar
  • 39 Berber E, Pehlevan F, Akin M, Capan OY, Kavakli K, Çaglayan SH. A common VWF exon 28 haplotype in the Turkish population. Clin Appl Thromb Hemost 2013; 19 (05) 550-556
    CrossrefPubMedSearch in Google Scholar
  • 40 Zhang Q, Zhou YF, Zhang CZ, Zhang X, Lu C, Springer TA. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor. Proc Natl Acad Sci U S A 2009; 106 (23) 9226-9231
    CrossrefPubMedSearch in Google Scholar
  • 41 Xiang Y, de Groot R, Crawley JT, Lane DA. Mechanism of von Willebrand factor scissile bond cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Proc Natl Acad Sci U S A 2011; 108 (28) 11602-11607
    CrossrefPubMedSearch in Google Scholar
  • 42 Gao W, Anderson PJ, Sadler JE. Extensive contacts between ADAMTS13 exosites and von Willebrand factor domain A2 contribute to substrate specificity. Blood 2008; 112 (05) 1713-1719
    CrossrefPubMedSearch in Google Scholar
  • 43 Larsen DM, Haberichter SL, Gill JC, Shapiro AD, Flood VH. Variability in platelet- and collagen-binding defects in type 2M von Willebrand disease. Haemophilia 2013; 19 (04) 590-594
    CrossrefPubMedSearch in Google Scholar
  • 44 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
    CrossrefPubMedSearch in Google Scholar
  • 45 James PD, Notley C, Hegadorn C. et al; Association of Hemophilia Clinic Directors of Canada. Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study. J Thromb Haemost 2007; 5 (09) 1914-1922
    CrossrefPubMedSearch in Google Scholar
  • 46 Hilbert L, Fressinaud E, Ribba AS, Meyer D, Mazurier C. INSERM network on molecular abnormalities in von Willebrand disease. Identification of a new type 2M von Willebrand disease mutation also at position 1324 of von Willebrand factor. Thromb Haemost 2002; 87 (04) 635-640
    Thieme ConnectPubMedSearch in Google Scholar
  • 47 Sanders YV, van der Bom JG, Isaacs A. et al; WiN Study Group. CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease. J Thromb Haemost 2015; 13 (06) 956-966
    CrossrefPubMedSearch in Google Scholar
  • 48 Favaloro EJ. An update on the von Willebrand factor collagen binding assay: 21 years of age and beyond adolescence but not yet a mature adult. Semin Thromb Hemost 2007; 33 (08) 727-744
    Thieme ConnectPubMedSearch in Google Scholar
  • 49 Favaloro EJ, Bonar R, Chapman K, Meiring M, Funk Adcock D. Differential sensitivity of von Willebrand factor (VWF) ‘activity’ assays to large and small VWF molecular weight forms: a cross-laboratory study comparing ristocetin cofactor, collagen-binding and mAb-based assays. J Thromb Haemost 2012; 10 (06) 1043-1054
    CrossrefPubMedSearch in Google Scholar
  • 50 Auton M, Sowa KE, Smith SM, Sedlák E, Vijayan KV, Cruz MA. Destabilization of the A1 domain in von Willebrand factor dissociates the A1A2A3 tri-domain and provokes spontaneous binding to glycoprotein Ibalpha and platelet activation under shear stress. J Biol Chem 2010; 285 (30) 22831-22839
    CrossrefPubMedSearch in Google Scholar
  • 51 Nishio K, Anderson PJ, Zheng XL, Sadler JE. Binding of platelet glycoprotein Ibalpha to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. Proc Natl Acad Sci U S A 2004; 101 (29) 10578-10583
    CrossrefPubMedSearch in Google Scholar
  • 52 Lankhof H, Damas C, Schiphorst ME. et al. von Willebrand factor without the A2 domain is resistant to proteolysis. Thromb Haemost 1997; 77 (05) 1008-1013
    Thieme ConnectPubMedSearch in Google Scholar
  • 53 Martin C, Morales LD, Cruz MA. Purified A2 domain of von Willebrand factor binds to the active conformation of von Willebrand factor and blocks the interaction with platelet glycoprotein Ibalpha. J Thromb Haemost 2007; 5 (07) 1363-1370
    CrossrefPubMedSearch in Google Scholar
  • 54 Butera D, Passam F, Ju L. et al. Autoregulation of von Willebrand factor function by a disulfide bond switch. Sci Adv 2018; 4 (02) eaaq1477
    CrossrefPubMedSearch in Google Scholar
  • 55 van der Plas RM, Gomes L, Marquart JA. et al. Binding of von Willebrand factor to collagen type III: role of specific amino acids in the collagen binding domain of vWF and effects of neighboring domains. Thromb Haemost 2000; 84 (06) 1005-1011
    Thieme ConnectPubMedSearch in Google Scholar
  • 56 Sutherland JJ, O'Brien LA, Lillicrap D, Weaver DF. Molecular modeling of the von Willebrand factor A2 domain and the effects of associated type 2A von Willebrand disease mutations. J Mol Model 2004; 10 (04) 259-270
    CrossrefPubMedSearch in Google Scholar
  • 57 Kashiwagi T, Matsushita T, Ito Y. et al. L1503R is a member of group I mutation and has dominant-negative effect on secretion of full-length VWF multimers: an analysis of two patients with type 2A von Willebrand disease. Haemophilia 2008; 14 (03) 556-563
    CrossrefPubMedSearch in Google Scholar
  • 58 Hassenpflug WA, Budde U, Obser T. et al. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood 2006; 107 (06) 2339-2345
    CrossrefPubMedSearch in Google Scholar
  • 59 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
    CrossrefPubMedSearch in Google Scholar
  • 60 Michiels JJ, van Vliet HH. Dominant von Willebrand disease type 2A groups I and II due to missense mutations in the A2 domain of the von Willebrand factor gene: diagnosis and management. Acta Haematol 2009; 121 (2–3): 154-166
    CrossrefPubMedSearch in Google Scholar
  • 61 Lynch CJ, Cawte AD, Millar CM, Rueda D, Lane DA. A common mechanism by which type 2A von Willebrand disease mutations enhance ADAMTS13 proteolysis revealed with a von Willebrand factor A2 domain FRET construct. PLoS One 2017; 12 (11) e0188405
    CrossrefPubMedSearch in Google Scholar
  • 62 Pagliari MT, Baronciani L, Stufano F. et al. von Willebrand disease type 1 mutation p.Arg1379Cys and the variant p.Ala1377Val synergistically determine a 2M phenotype in four Italian patients. Haemophilia 2016; 22 (06) e502-e511
    CrossrefPubMedSearch in Google Scholar
  • 63 Woods AI, Paiva J, Kempfer AC. et al. Combined effects of two mutations in von Willebrand disease 2M phenotype. Res Pract Thromb Haemost 2017; 2 (01) 162-167
    CrossrefPubMedSearch in Google Scholar
  • 64 Bowman M, Rimmer E, Houston DS, Israels SJ, James P. Discordant von Willebrand factor (VWF) activity in patients with VWF p.Gly1324Ser confirmed in vitro. Haemophilia 2018; 24 (02) e57-e59
    CrossrefPubMedSearch in Google Scholar