Download PDF
Thromb Haemost 2000; 84(06): 998-1004
DOI: 10.1055/s-0037-1614162
Review Article
Schattauer GmbH

Identification of Type 2 von Willebrand Disease in Previously Diagnosed Type 1 Patients: a Reappraisal Using Phenotypes, Genotypes and Molecular Modelling

Ioana C. Nitu-Whalley
3   From the Katharine Dormandy Haemophilia Centre and Haemostasis Unit, Department of Haematology, Royal Free and University College Medical School, Rowland Hill Street, London, UK
,
Anne Riddell
3   From the Katharine Dormandy Haemophilia Centre and Haemostasis Unit, Department of Haematology, Royal Free and University College Medical School, Rowland Hill Street, London, UK
,
Christine A. Lee
3   From the Katharine Dormandy Haemophilia Centre and Haemostasis Unit, Department of Haematology, Royal Free and University College Medical School, Rowland Hill Street, London, UK
,
K. John Pasi
3   From the Katharine Dormandy Haemophilia Centre and Haemostasis Unit, Department of Haematology, Royal Free and University College Medical School, Rowland Hill Street, London, UK
,
Dale Owens
3   From the Katharine Dormandy Haemophilia Centre and Haemostasis Unit, Department of Haematology, Royal Free and University College Medical School, Rowland Hill Street, London, UK
,
M. Said Enayat
1   Molecular Haemostasis Laboratory, The Birmingham Children’s Hospital NHS Trust, Birmingham, UK
,
Stephen J. Perkins
2   Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, London, UK
,
P. Vincent Jenkins
3   From the Katharine Dormandy Haemophilia Centre and Haemostasis Unit, Department of Haematology, Royal Free and University College Medical School, Rowland Hill Street, London, UK
› Author AffiliationsDr I. Nitu-Whalley is supported by the EU grant number BMH4CT97-2256. This study was funded by the Katharine Dormandy Trust for Haemophilia and Allied Disorders, Reg. No. 262434. Professor K. J. Pasi is currently at the Division of Haematology, University of Leicester, Leicester, UK. We are grateful to Ms A. Griffioen for statistical analysis, Mr A. McCraw for performing some of the VWF:RiCo assays, Dr J. Hinshelwood for assistance with Fig. 2, and Dr S. Brown for helpful comments on the manuscript.
Further Information

Publication History

Received 12 May 2000

Accepted after revision 17 July 2000

Publication Date:
13 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

In order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.

Keywords

von Willebrand disease - VWF:RiCo/VWF:Ag ratio - VWF plasma multimers - genotype - molecular modelling
 

  • References

  • 1 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454-59.
    PubMedGoogle Scholar
  • 2 Sadler JE, Matsushita T, Dong Z. Molecular mechanism and classification of von Willebrand disease. Throm Haemost 1995; 74: 161-66.
    PubMedGoogle Scholar
  • 3 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-25.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Fujimura Y, Titani K, Holland LZ, Russell SR, Roberts JR, Elder JH, Ruggeri ZM, Zimmerman TS. Von Willebrand factor. A reduced and alkylated 52/48-kDa fragment beginning at amino acid residue 449 contains the domain interacting with platelet glycoprotein Ib. J Biol Chem 1986; 261: 381-5.
    PubMedGoogle Scholar
  • 5 Mohri H, Fujimura Y, Shima M, Yoshioka A, Houghten RA, Ruggeri ZM, Zimmerman TS. Structure of the von Willebrand factor domain interacting with glycoprotein Ib Molecular mechanism and classification of von Willebrand disease. J Biol Chem 1988; 263: 17901-4.
    PubMedGoogle Scholar
  • 6 Mancuso DJ, Kroner PA, Christopherson PA, Vokac EA, Gill JC, Montgomery RR. Type 2M:Milwaukee-1 von Willebrand disease: an in-frame deletion in the Cys509-Cys695 loop of the von Willebrand factor A1 domain causes deficient binding of von Willebrand factor to platelets. Blood 1996; 88: 2559-68.
    PubMedGoogle Scholar
  • 7 Rabinowitz I, Tuley EA, Mancuso DJ, Randi AM, Firkin BG, Howard MA, Sadler JE. Von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib. Proc Natl Acad Sci USA 1992; 89: 9846-49.
    CrossrefPubMedGoogle Scholar
  • 8 Ginsburg D, Sadler JE. von Willebrand disease: a database of point mutations, insertions, and deletions. Thromb Haemost 1993; 69: 177-84.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Hillery CA, Mancuso DJ, Sadler JE, Ponder JW, Jozwiak MA, Christopherson PA, Gill JC, Scott JP, Montgomery RR. Type 2M von Willebrand disease: F606I and I662F mutations in the glycoprotein Ib binding domain selectively impair ristocetin-but not botrocetin-mediated binding of von Willebrand factor to platelets. Blood 1998; 91: 1572-81.
    PubMedGoogle Scholar
  • 10 http://mmg2.im.med.umich.edu
    PubMed
  • 11 Federici AB. Diagnosis of von Willebrand disease. Haemophilia 1998; 04: 654-60.
    CrossrefPubMedGoogle Scholar
  • 12 Murdoch PJ, Woodhams BJ, Matthews KB, Pasi KJ, Goodall AH. Von Willebrand factor activity detected in a monoclonal antibody-based ELISA: an alternative to the ristocetin cofactor platelet agglutination assay for diagnostic use. Thromb Haemost 1997; 78: 1272-77.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Chand S, McCraw A, Hutton R, Tuddenham EG, Goodall AH. A two-site, monoclonal antibody-based immunoassay for von Willebrand factor: demonstration that vWF function resides in a conformational epitope. Characterization of the unique mechanism mediating the shear-dependent binding of soluble von Willebrand factor to platelets. Thromb Haemost 1986; 55: 318-24.
    PubMedGoogle Scholar
  • 14 Hilbert L, Jenkins PV, Gaucher C, Meriane E, Collins PW, Pasi KJ, Mazurier C. Type 2M VWD resulting from a lysine deletion within a four lysine residue repeat in the A1 loop of von Willebrand Factor. Thromb Haemost 2000; 84: 188-94.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Nitu-Whalley IC, Lee CA, Griffioen A, Jenkins PV, Pasi KJ. Type 1 von Willebrand disease – a clinical retrospective study of the diagnosis, the influence of the ABO blood group and the role of the bleeding history. Br J Haematol 2000; 108: 259-64.
    CrossrefPubMedGoogle Scholar
  • 16 Macfarlane DE, Stibbe J, Kirby EP, Zucker MB, Grant RA, McPherson J. A method for assaying von Willebrand factor (ristocetin cofactor). Thromb Diath Haemorrh 1975; 34: 306-8.
    PubMedGoogle Scholar
  • 17 Enayat MS. Multimeric analysis of von Willebrand factor. In Haemostasis and Thrombosis Protocols. Perry DJ, Pasi KJ. Eds. Totowa, NJ: Humana Press; 1999: 187-200.
    Google Scholar
  • 18 Inbal A, Englender T, Kornbrot N, Randi AM, Castaman G, Mannucci PM, Sadler JE. Identification of three novel candidate mutations causing type IIA von Willebrand disease using a rapid non-radioactive allele specific hybridization method. Blood 1993; 82: 830-6.
    PubMedGoogle Scholar
  • 19 Celikel R, Varughese KIMadhusudan, Yoshioka A, Ware J, Ruggeri ZM. Crystal structure of the von Willebrand factor A1 domain in complex with the function blocking NMC-4 Fab. Nat Struct Biol 1998; 05: 189-94.
    CrossrefPubMedGoogle Scholar
  • 20 Emsley JM, Cruz M, Handin R, Liddington R. Crystal structure of the von Willebrand factor A1 domain and implications for the binding of platelet glycoprotein Ib. J Biol Chem 1998; 273: 10396-401.
    CrossrefPubMedGoogle Scholar
  • 21 Jenkins PV, Pasi KJ, Perkins S. Molecular modeling of ligand and mutation sites of the type A domains of human von Willebrand factor and their relevance to von Willebrand’s disease. Blood 1998; 91: 2032-44.
    PubMedGoogle Scholar
  • 22 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 307-10.
    PubMedGoogle Scholar
  • 23 Perkins SJ, Hinshelwood J, Edwards YJK, Jenkins PV. Structural and functional modelling of vWF-A domains in complement and coagulation. Biochem Soc Transact 1999; 27: 815-21.
    CrossrefPubMedGoogle Scholar
  • 24 Cruz MA, Diacovo TG, Emsley J, Liddington R, Handin RI. Mapping the glycoprotein Ib-binding site in the von Willebrand factor A1 domain. J Biol Chem 2000; 275: 19098-105.
    CrossrefPubMedGoogle Scholar
  • 25 Vasudevan S, Roberts JR, McClintock RA, Dent JA, Celikel R, Ware J, Varughese KI, Ruggeri ZM. Modeling and functional analysis of the interaction between von Willebrand factor A1 domain and Glycoprotein Iba. J Biol Chem 2000; 275: 12763-8.
    CrossrefPubMedGoogle Scholar
  • 26 Cooney KA, Nichols WC, Bruck ME, Bahou WF, Shapiro AD, Bowie EJ, Gralnick HR, Ginsburg D. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. J Clin Invest 1991; 87: 1227-33.
    CrossrefPubMedGoogle Scholar
  • 27 Matsushita T, Meyer D, Sadler JE. Localization of von Willebrand factorbinding sites for platelet glycoprotein Ib and botrocetin by charged-to alanine scanning mutagenesis. J Biol Chem 2000; 275: 11044-9.
    CrossrefPubMedGoogle Scholar
  • 28 Hilbert L, Gaucher C, Mazurier C. Identification of two mutations (Arg611Cys and Arg611His) in the A1 loop of von Willebrand factor (vWF) responsible for type 2 von Willebrand disease with decreased platelet-dependent function of vWF. Blood 1995; 86: 1010-18.
    PubMedGoogle Scholar
  • 29 Meyer D, Fressinaud E, Gaucher C, Lavergne JM, Hilbert L, Ribba AS, Horieux S, Mazurier C. Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. Thromb Haemost 1997; 78: 451-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Zhang Z, Lindstedt M, Blomback NI, Anvret M. Effects of the mutant von Willebrand factor gene in von Willebrand disease. Hum Genet 1995; 96: 388-94.
    PubMedGoogle Scholar
  • 31 Hoyer LW, Rizza CR, Tuddenham EGD, Carta CA, Armitage H, Rotblat F. Von Willebrand factor multimer patterns in von Willebrand disease. Br J Haematol 1983; 55: 493-507.
    CrossrefPubMedGoogle Scholar
  • 32 Mannucci PM, Lombardi R, Castaman G, Dent JA, Lattuada A, Rodegheiro F, Zimmerman TS. Von Willebrand Disease “Vicenza” with larger-thannormal (supranormal) von Willebrand factor multimers. Thromb Haemost 1988; 71: 65-70.
    PubMedGoogle Scholar
  • 33 Preston FE. Assays for von Willebrand factor functional activity: a UK NEQAS survey. National External Quality Assessment. Thromb Haemost 1998; 80: 863.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Matsushita T, Sadler JE. Identification of amino acid residues essential for von Willebrand factor binding to platelet glycoprotein Ib. Charged-toalanine scanning mutagenesis of the A1 domain of human von Willebrand factor. J Biol Chem 1995; 270: 13406-14.
    CrossrefPubMedGoogle Scholar
  • 35 Favaloro EJ, Koutts J. Laboratory assays for von Willebrand factor: relative contribution to the diagnosis of von Willebrand’s disease. Pathology 1997; 29: 385-91.
    CrossrefPubMedGoogle Scholar
  • 36 Favaloro EJ, Grispo L, Exner T, Koutts J. Development of a simple collagen based ELISA assay aids in the diagnosis of and permits sensitive discrimination between type I and type II von Willebrand’s disease. Blood Coag Fibrin 1991; 02: 285-91.
    CrossrefPubMedGoogle Scholar
  • 37 Schneppenheim R, Federici AB, Budde U, Castaman G, Drewke E, Krey S, Mannucci PM, Riesen G, Rodegheiro F, Zieger B, Zimmermann R. Von Willebrand disease Type 2M “Vicenza” in Italian and German patients: Identification of the first candidate mutation (G3864A; R1205H) in 8 families. Thromb Haemost 2000; 82: 136-40.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Castaman G, Eikenboom CJ, Rodeghiero F, Briet E, Reitsma PH. A novel candidate mutation (Arg611His) in type I ‘platelet discordant’ von Willebrand’s disease with desmopressin-induced thrombocytopaenia. Br J Haematol 1995; 89: 656-8.
    CrossrefPubMedGoogle Scholar
  • 39 Federici AB, Mannucci PM. Diagnosis and management of von Willebrand disease. Haemophlia 1999; 05 (02) 28-37.
    PubMedGoogle Scholar
  • 40 Vanhoorelbeke K, Cauwenberghs N, Vauterin S, Schlammadinger A, Mazurier C, Deckmyn H. A reliable and reproducible ELISA method to measure ristocetin cofactor activity of von Willebrand factor. Thromb Haemost 2000; 83: 107-13.
    Article in Thieme ConnectPubMedGoogle Scholar