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Research Article





Marika Pikta, Kadri Saks , Mirja Varik , Maria Hytti , Kreete Ilves, Mariken Ross 


ABSTRACT: Introduction: Von Willebrand disease (VWD) is considered the most common autosomal inherited bleeding disorder. Laboratory testing for diagnosis or exclusion of VWD is based on a complex of different diagnostic assays. In the diagnostic workup of patients with suspected VWD, the von Willebrand factor (VWF) multimer assay is one of the most important indicators for VWF quality. This study aims to assess the VWF multimers profile in patients with bleeding tendency and increase knowledge and awareness of VWD laboratory diagnosis in Estonia. Methods: This retrospective study investigated the laboratory results of 131 individuals who were selected from the laboratory information system based on the request of VWF tests profile and 31 healthy volunteers for comparison. Results: Control group, non-VWD patients and patients suspected with VWD type 2N or mild haemophilia A demonstrated normal VWF multimer (VWF:MM) pattern. Patients with low VWF and suspected with VWD type 1 also showed normal VWF:MM distribution with reduced intensity. All cases suspected with VWD type 2A or 2M had a decrease of high molecular weight multimers  (HMWM); one of them showed a loss of intermediate molecular weight multimers and HMWM and low-VWF activity to antigen ratio (<0.7). Furthermore, multimers were undetectable in patients suspected with VWD type 3 or severe type 1. Conclusions: This is the first report of VWD laboratory evaluation in Estonia to provide insight into the potential clinical significance of using VWF:MM. The interpretation of VWF multimers should be necessarily complemented by the quantification of fractions of multimers by densitometry additional to visual gel’s examination.


KEY WORDS: von Willebrand disease, von Willebrand factor, von Willebrand factor multimers


  1. Favaloro EJ. Diagnosis and classification of von Willebrand disease: a review of the differential utility of various functional von Willebrand factor assays. Blood Coagul Fibrinolysis 2011;22,7:553-564.

  2. Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008;14,2:171-232.

  3. Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, Meyer D, Fressinaud E, Mazurier C, Goudemand J, Eikenboom J, Schneppenheim R, Budde U, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Lethagen S, Pasi J, Hill F, Peake I. 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;4,4:766-773.

  4. [4] Baronciani L, Peyvandi F. How we make an accurate diagnosis of von Willebrand disease. Thromb Res 2020;196:579-589.

  5. [5] Roberts JC, Flood VH. Laboratory diagnosis of von Willebrand disease. Int J Lab Hematol 2015;37,Suppl 1:11-7.

  6. [6] Miesbach W. Perioperative management for patients with von Willebrand disease: Defining the optimal approach. Eur J Haematol 2020;105:365–377.

  7. [7] Pikta M, Zolotareva V, Tõnne J, Viigimaa M, Banys V. Implementation and Verification of New VWF:Ac Assay System with Components from Different Manufacturers. Laboratorine medicina 2016;72:185–188.

  8. [8] Pikta M, Zemtsovskaja G, Bautista H, Nouadje G, Szanto T, Viigimaa M, Banys V. Preclinical evaluation of a semi-automated and rapid commercial electrophoresis assay for von Willebrand factor multimers. J Clin Lab Anal 2018;32,6:e22416

  9. [9] Pikta M, Szanto T, Viigimaa M, Lejniece S, Balode D, Saks K, Banys V. Evaluation of a new semi-automated hydragel 11 von Willebrand factor multimers assay kit for routine use. J Med Biochem (Epub ahead of print):

  10. [10] Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB; 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;4,10:2103-14.

  11. [11] Favaloro EJ. Rethinking the diagnosis of von Willebrand disease. Thromb Res 2011;127,Suppl:S17‐S21.

  12. [12] Pikta M, Banys V, Vaide I, Varik M, Saks K, Lepik K, Hein M, Joutsi-Korhonen L, Szanto T, Lassila R, Armstrong E, Giangrande P, Laane E. Development of diagnostic algorithm for von Willebrand disease within WFH the Twinning Tallinn-Helsinki program. [Internet] PosterSessionOnline WFH 2018. Available from:

  13. [13] Pikta M, Vasse M, Lejniece S, Smock KJ, Moser KA, Bautista H, Nouadje G, Banys V. Establishing Reference Intervals for von Willebrand Factor Multimers. Res Pract Thromb Haemost 2020;4,Suppl 1.

  14. [14] Favaloro EJ, Mohammed S, Lippi G. Postanalytical considerations that may improve the diagnosis or exclusion of haemophilia and von Willebrand disease. Haemophilia 2018;24,6:849-861. 

  15. [15] Lassila R, Holme P, Landorph A, Petrini P, Onundarson P, Hillarp A. Nordic Haemophilia Council’s practical guidelines on diagnosis and management of von Willebrand Disease. Semin Thromb Hemost 2011;37:495–502.

  16. [16] Michiels JJ, Smejkal P, Penka M, Batorova A, Pricangova T, Budde U, Vangenechten I, Gadisseur A. Diagnostic Differentiation of von Willebrand Disease Types 1 and 2 by von Willebrand Factor Multimer Analysis and DDAVP Challenge Test. Clin Appl Thromb Hemost 2017;23,6:518-531.

  17. [17] Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease. Blood 2015;125,13:2029-2037.

  18. [18] Moenen FCJI, Vries MJA, Nelemans PJ, van Rooy KJM, Vranken JRRA, Verhezen PWM, Wetzels RJH, Ten Cate H, Schouten HC, Beckers EAM, Henskens YMC. Screening for platelet function disorders with Multiplate and platelet function analyzer. Platelets 2019;30,1:81-87.

  19. [19] Schmidt DE, Bruzelius M, Majeed A, Odeberg J, Holmström M, Ågren A. Whole blood ristocetin-activated platelet impedance aggregometry (Multiplate) for the rapid detection of Von Willebrand disease. Thromb Haemost 2017;117,8:1528-1533.

  20. [20] Valarche V, Desconclois C, Boutekedjiret T, Dreyfus M, Proulle V. Multiplate whole blood impedance aggregometry: a new tool for von Willebrand disease. J Thromb Haemost 2011;9:1645–1647.

  21. [21] Gresele P, Bury L, Mezzasoma AM, Falcinelli E. Platelet function assays in diagnosis: an update. Expert Rev Hematol 2019;12,1:29-46.

  22. [22] Nummi V, Lassila R, Joutsi-Korhonen L, Armstrong E, Szanto T. Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function. Int J Lab Hematol 2018;40,3:304-311.

  23.  [23] Favaloro EJ. Diagnosis and classification of von Willebrand disease: a review of the differential utility of various functional von Willebrand factor assays. Blood Coagul Fibrinolysis 2011;22,7:553-64.

  24. [24] Budde U, Schneppenheim R. Interactions of von Willebrand factor and ADAMTS13 in von Willebrand disease and thrombotic thrombocytopenic purpura. Hamostaseologie 2014;34,3:215-25.

  25. [25] Favaloro EJ, Mohammed S, Vong R, Oliver S, Brennan Y, Favaloro JW, Curnow J. How we diagnose 2M von Willebrand disease (VWD): Use of a strategic algorithmic approach to distinguish 2M VWD from other VWD types. Haemophilia 2021;27,1:137-148.

  26. [26] Budde U, Schneppenheim R, Eikenboom J, Goodeve A, Will K, Drewke E, Castaman G, Rodeghiero F, Federici AB, Batlle J, Pérez A, Meyer D, Mazurier C, Goudemand J, Ingerslev J, Habart D, Vorlova Z, Holmberg L, Lethagen S, Pasi J, Hill F, Peake I. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis

  27.     and management of type 1 von Willebrand disease (MCMDM-1VWD). J Thromb Haemost 2008;6,5:762-71.

  28. [27] 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;26,3:503-512.

  29. [28] Fogarty H, Doherty D, O'Donnell JS. New developments in von Willebrand disease. Br J Haematol 2020;191,3:329-339. 

  30. [29] Castaman G, Linari S. Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders. J Clin Med 2017;6,4:45.

  31. [30] Castaman G, Lethagen S. Response to desmopressin is influenced by the genotype and the phenotype in type 1 von Willebrand disease (VWD): Results from the European study MCMDM-1 VWD. Blood 2008;111:3531–3539.

  32. [31] Pikta M, Saks K, Lepik K, Zemtsovskaja G, Willemson K, Bautista H, Nouddje G, Viigimaa M, Banys V. Assessment of biological response to desmopressin using von Willebrand factor multimers analysis. Clin Chem Lab Med 2017; 55,Special Suppl: S727.

  33. [32] Favaloro EJ, Lippi G. Preanalytical issues that may cause misdiagnosis in haemophilia and von Willebrand disease. Haemophilia 2018;24,2:198-210.

  34. [33] Israels SJ. Laboratory testing for platelet function disorders. Int J Lab Hematol 2015;37 Suppl 1:18-24.

  35. [34] Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, Neunert C, Lillicrap D; 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;8,9:2063-2065.

 To cite this article:

Pikta M, Saks  K, Varik M , Hytti  M,Ilves K, Ross  M. Assessment   of the  von  willebrand  factor  multimers profile  in  patients  referred  for  bleeding  tendency evaluation  in  estonia:  a  preliminary  report  of  the von  willebrand  disease  diagnostics  project. Int. J. Med. Lab. Res. 2021; 6,1:17-27.

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