Skip to main content
SpringerLink
Log in

Laboratory diagnosis of von Willebrand disease

  • Review
  • Published:
International Journal of Clinical and Laboratory Research

Abstract

Von Willebrand disease is the most-common inherited bleeding disorder, including both quantitative (types 1 and 3) and qualitative (type 2) defects of von Willebrand factor. Among patients with suspected von Willebrand disease, the laboratory diagnosis requires three levels of testing: screening tests, specific assays for von Willebrand factor to establish the diagnosis, and discriminating tests to allow accurate characterization of the numerous types and subtypes of the disease. Because of their poor sensitivity, normal screening tests do not exclude the diagnosis. In most cases, specific measurements of von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity, and factor VIII levels in plasma allow differentiation of quantitative (proportionately decreased levels) and qualitative (discrepant levels) deficiencies of von Willebrand factor. Among the latter, a decreased von Willebrand factor ristocetin cofactor activity/von Willebrand factor antigen ratio is in favor of the three subtypes (2A, 2M, and 2B) defined by an abnormal interaction between von Willebrand factor and platelet glycoprotein Ib, whereas a decreased factor VIII/von Willebrand factor antigen ratio suggests subtype 2N, defined by a defective binding of von Willebrand factor to factor VIII. Several discriminating tests are available to definitively characterize each subtype. Moreover, for all variants, the link between phenotype and genotype is established using DNA analysis. In all cases, the precise characterization of type and subtype of von Willebrand disease remains essential for the choice of optimal therapeutic monitoring of each patient.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Meyer D, Girma JP. von Willebrand factor: structure and function. Thromb Haemost 1993; 70: 99.

    PubMed  CAS  Google Scholar 

  2. Tefferi A, Nichols WL. Acquired von Willebrand disease: concise review of occurrence, diagnosis, pathogenesis and treatment. Am J Med 1997; 103: 536.

    Article  PubMed  CAS  Google Scholar 

  3. Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520.

    PubMed  CAS  Google Scholar 

  4. Nilsson IM, Magnusson S, Borchgrevinck C. The Duke and Ivy methods for determination of the bleeding time. Thromb Diath Haemorrh 1963; 10: 223.

    PubMed  CAS  Google Scholar 

  5. Kundu SK, Heilmann E, Sio R, Garcia C, Davidson RM, Ostgaard RA. Description of an “in vitro” platelet function analyzer-PFA-100™. Semin Thromb Hemost 1995; 21 Suppl 2: 106.

    PubMed  Google Scholar 

  6. Fressinaud E, Veyradier A, Truchaud F, Martin I, Boyer-Neumann C, Trossaert M, Meyer D. Screening for von Willebrand disease with a new analyzer utilizing high shear stress. A study of 60 cases. Blood 1998; 91: 1325.

    PubMed  CAS  Google Scholar 

  7. Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691.

    PubMed  CAS  Google Scholar 

  8. Zimmerman TS, Ratnoff OD, Powell AE. Immunologic differentiation of classic hemophilia (factor VIII deficiency) and von Willebrand disease. J Clin Invest 1971; 50: 244.

    Article  PubMed  CAS  Google Scholar 

  9. Girma JP, Ardaillou N, Meyer D, Lavergne JM, Larrieu MJ. Fluid phase immunoradiometric assay for the detection of qualitative abnormalities of factor VIII/vWF in variants of von Willebrand disease. J Lab Clin Med 1979; 93: 926.

    PubMed  CAS  Google Scholar 

  10. Ingerslev J. A sensitive ELISA for von Willebrand factor (vWF: Ag). Scand J Clin Lab Invest 1987; 47: 143.

    Article  PubMed  CAS  Google Scholar 

  11. Mac Farlane DE, Stibbe K, Kirby EP, Zucker MB, Grant RA, Mc Pherson J. A method for assaying von Willebrand factor (ristocetin cofactor). Thromb Diath Haemorrh 1975; 34: 306.

    CAS  Google Scholar 

  12. Wright RD, Krauss JS. A comparison of two macroscopic platelet agglutination assays for von Willebrand factor. Ann Clin Lab Sci 1990; 20: 73.

    PubMed  CAS  Google Scholar 

  13. Weiss HJ. Abnormalities of factor VIII and platelet aggregation — use of ristocetin in diagnosing the von Willebrand disease syndrome. Blood 1975; 45: 403.

    PubMed  CAS  Google Scholar 

  14. Ruggeri ZM, Zimmerman TS. The complex multimeric composition of factor VIII/von Willebrand factor. Blood 1981; 57: 1140.

    PubMed  CAS  Google Scholar 

  15. Rodeghiero F, Castaman G, Tosetto A, Lattuada A, Mannucci PM. Platelet von Willebrand factor assay: results using two methods for platelet lysis. Thromb Res 1990; 59: 259.

    Article  PubMed  CAS  Google Scholar 

  16. Girma JP, Takahashi Y, Yoshioka A, Diaz J, Meyer D. Ristocetin and botrocetin involve two distinct domains of von Willebrand factor for binding to platelet membrane glycoprotein Ib. Thromb Haemost 1990; 64: 326.

    PubMed  CAS  Google Scholar 

  17. 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.

    PubMed  CAS  Google Scholar 

  18. Favaloro EJ, Grispo L, Dinale A, Berndt M, Koutts J. von Willebrand disease. Laboratory investigation using an improved functional assay for von Willebrand factor. Pathology 1993; 25: 152.

    Article  PubMed  CAS  Google Scholar 

  19. Nishino M, Girma JP, Rothschild C, Fressinaud E, Meyer D. New variant of von Willebrand disease with defective binding to factor VIII. Blood 1989; 74: 1591.

    PubMed  CAS  Google Scholar 

  20. Mc Caroll DR, Ruggeri ZM, Montgomery RR. Correlation between circulating levels of von Willebrand’s antigen II and von Willebrand factor: discrimination between type I and type II von Willebrand disease. J Lab Clin Med 1984; 103: 704.

    Google Scholar 

  21. Mohri H, Motomura S, Kanamori H, Matsuzaki M, Watanabe S, Maruta A, Kodama F, Okubo T. Clinical significance of inhibitors in acquired von Willebrand syndrome. Blood 1998; 91: 3623.

    PubMed  CAS  Google Scholar 

  22. Meyer D, Fressinaud E, Gaucher C, Lavergne JM, Hilbert L, Ribba AS, Jorieux S, Mazurier C and the INSERM Network on Molecular Abnormalities in von Willebrand disease. Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. Thromb Haemost 1997; 78: 451.

    PubMed  CAS  Google Scholar 

  23. Standen GR, Bignell P, Bowen DJ, Peake IR, Bloom AL. Family studies in von Willebrand’s disease by analysis of restriction fragment length polymorphisms and an intragenic variable number tandem repeat (VNTR) sequence. Br J Haematol 1990; 76: 242.

    Article  PubMed  CAS  Google Scholar 

  24. Mancuso DJ, Tuley EA, Castillo R, Bosch N de, Mannucci PM, Sadler JE. Characterization of partial gene deletions in type III von Willebrand disease with alloantibody inhibitors. Thromb Haemost 1994; 72: 180.

    PubMed  CAS  Google Scholar 

  25. Eikenboom JC, Reitsma PH, Peerlinck KM, Briet E. Recessive inheritance of von Willebrand’s disease type I. Lancet 1993; 341: 982.

    Article  PubMed  CAS  Google Scholar 

  26. Eikenboom JC, Matsushita T, Reitsma PH, Tuley EA, Castaman G, Bri’t E, Sadler JE. Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor. Blood 1996; 88: 2433.

    PubMed  CAS  Google Scholar 

  27. Lyons SE, Bruck ME, Bowie EJN, Ginsburg D. Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations. J Biol Chem 1992; 267: 4424.

    PubMed  CAS  Google Scholar 

  28. Gaucher C, Dieval J, Mazurier C. Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease. Blood 1994; 84: 1024.

    PubMed  CAS  Google Scholar 

  29. Schneppenheim R, Brassard J, Krey S, Budde U, Kunicki TJ, Holmberg L, Ware J, Ruggeri ZM. Defective dimerization of von Willebrand factor subunits due to a Cys → Arg mutation in type IID von Willebrand disease. Proc Natl Acad Sci U S A 1996; 93: 3581.

    Article  PubMed  CAS  Google Scholar 

  30. Mannucci PM, Lombardi R, Castaman G, Dent JA, Lattuada A, Rodeghiero F, Zimmerman TS. von Willebrand disease “Vicenza” with larger-than-normal (supranormal) von Willebrand factor multimers. Blood 1988; 71: 65.

    PubMed  CAS  Google Scholar 

  31. Schneppenheim R, Federici AB, Budde U, Castaman G, Drewke E, Krey S, Mannucci PM, Riesen G, Rodeghiero F, Zieger B, Zimmerman R. Candidate mutation for von Willebrand disease type 2M Vicenza in Italian and German patients (abstract). Haemophilia 1998; 4: 282.

    Article  Google Scholar 

  32. 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: 149.

    PubMed  CAS  Google Scholar 

  33. Holmberg L, Berntorp E, Donner M, Nilsson IM. von Willebrand’s disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma. Blood 1986; 68: 668.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. INSERM U 143, Hôpital Bicêtre Le Kremlin Bicêtre and Service d’Hématologie Biologique, Hôpital Antoine Béclère, Clamart, France

    A. Veyradier & D. Meyer

  2. Laboratoire d’Hématologie, CHU Hôtel Dieu, Nantes, France

    E. Fressinaud

Authors
  1. A. Veyradier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Fressinaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veyradier, A., Fressinaud, E. & Meyer, D. Laboratory diagnosis of von Willebrand disease. Int J Clin Lab Res 28, 201–210 (1998). https://doi.org/10.1007/s005990050046

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s005990050046

Key words

Search

Navigation