open access

Vol 11, No 3 (2018)
REVIEWS
Published online: 2019-01-15
Get Citation

TYPE 2M VON WILLEBRAND DISEASE CLASSIFICATION AND DIAGNOSTIC PROBLEMS

Ksenia Bykowska, Bernadeta Ceglarek
Journal of Transfusion Medicine 2018;11(3):100-111.

open access

Vol 11, No 3 (2018)
REVIEWS
Published online: 2019-01-15

Abstract

Type 2M von Willebrand disease (type 2M VWD) is an autosomaly dominant inherited bleeding disorder characterized by a decrease in the affinity of the Willebrand factor (von Willebrand factor; VWF) for platelets in the absence of any deficiency of high molecular weight (HMW) VWF multimers. Type 2M VWD accounts for 5-10% of the general population of patients with von Willebrand disease and is frequently misdiagnosed with type 1 and type 2A VWD. The underlying cause of this bleeding disorder are missence mutations and deletions in WVD-A1 domain (binding site for glycoprotein Ib and collagen) and much rarely in WVD-A3 domain (binding site for collagen). Laboratory characteristics of type 2M VWD include: lower ristocetin cofactor activity (VWF:RCo), normal/decreased collagen binding, discrepancy between VWF antigen and ristocetin activity (VWF:RCo/VWF:Ag rate < 0,7) and normal multimer distribution. Diagnosis of type 2M VWD is particularily difficult as it should take into account not only defects in VWF binding with platelet receptor GPIbα (VWF:RCo) but also with epithelial collagen (VWF:CB). Furthermore, 2M VWD requires multimer analysis so it is predominantly recognized in high-tech laboratories. Correct recognition of 2M VWD may have impact on the choice of therapy. Literature reports present disparity in the evaluation of 2M VWD treatment. In some 2M VWD patients treatment with desmopressin (DDAVP) is often ineffective due to increased VWF clearance from plasma. However, replacement therapy with concentrates containing FVIII and VWF has proved as effective as in type 1 and 2A VWD.

Abstract

Type 2M von Willebrand disease (type 2M VWD) is an autosomaly dominant inherited bleeding disorder characterized by a decrease in the affinity of the Willebrand factor (von Willebrand factor; VWF) for platelets in the absence of any deficiency of high molecular weight (HMW) VWF multimers. Type 2M VWD accounts for 5-10% of the general population of patients with von Willebrand disease and is frequently misdiagnosed with type 1 and type 2A VWD. The underlying cause of this bleeding disorder are missence mutations and deletions in WVD-A1 domain (binding site for glycoprotein Ib and collagen) and much rarely in WVD-A3 domain (binding site for collagen). Laboratory characteristics of type 2M VWD include: lower ristocetin cofactor activity (VWF:RCo), normal/decreased collagen binding, discrepancy between VWF antigen and ristocetin activity (VWF:RCo/VWF:Ag rate < 0,7) and normal multimer distribution. Diagnosis of type 2M VWD is particularily difficult as it should take into account not only defects in VWF binding with platelet receptor GPIbα (VWF:RCo) but also with epithelial collagen (VWF:CB). Furthermore, 2M VWD requires multimer analysis so it is predominantly recognized in high-tech laboratories. Correct recognition of 2M VWD may have impact on the choice of therapy. Literature reports present disparity in the evaluation of 2M VWD treatment. In some 2M VWD patients treatment with desmopressin (DDAVP) is often ineffective due to increased VWF clearance from plasma. However, replacement therapy with concentrates containing FVIII and VWF has proved as effective as in type 1 and 2A VWD.
Get Citation

Keywords

von Willebrand disease (VWD), classification, von Willebrand disease 2M, phenotypic diagnosis, treatment

About this article
Title

TYPE 2M VON WILLEBRAND DISEASE CLASSIFICATION AND DIAGNOSTIC PROBLEMS

Journal

Journal of Transfusion Medicine

Issue

Vol 11, No 3 (2018)

Pages

100-111

Published online

2019-01-15

Bibliographic record

Journal of Transfusion Medicine 2018;11(3):100-111.

Keywords

von Willebrand disease (VWD)
classification
von Willebrand disease 2M
phenotypic diagnosis
treatment

Authors

Ksenia Bykowska
Bernadeta Ceglarek

References (64)
  1. Castaman G. Epidemiology and diagnosis of von Willebrand disease. Haematologica 2001; 86. ; 10(supl. 2): 1–9.
  2. Ruggeri ZM, Zarpellon A, Roberts JR, et al. Working Party on von Willebrand Disease Classification. Structure and function of von Willebrand factor. Thromb Haemost. 1999; 82(2): 576–584.
  3. de Wee EM, Sanders YV, Mauser-Bunschoten EP, et al. WiN study group. Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease. Thromb Haemost. 2012; 108(4): 683–692.
  4. Leebeek F, Eikenboom J. Von Willebrand’s Disease. New England Journal of Medicine. 2016; 375(21): 2067–2080.
  5. Kadir RA, Edlund M, Von Mackensen S. The impact of menstrual disorders on quality of life in women with inherited bleeding disorders. Haemophilia. 2010; 16(5): 832–839.
  6. Bauduer F, Ducout L. Is the assessment of von Willebrand disease prevalence an achievable challenge? The example of the French Basque Country where blood group O and factor XI deficiency are highly prevalent. J Thromb Haemost. 2004; 2(10): 1724–1726.
  7. Miesbach W, Berntorp E. When von Willebrand disease comes into age - a matter of change? Eur J Haematol. 2011; 86(6): 496–501.
  8. Sanders YV, Giezenaar MA, Laros-van Gorkom BAP, et al. WiN study group. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost. 2014; 12(7): 1066–1075.
  9. Borghi M, Guglielmini G, Mezzasoma AM, et al. Increase of von Willebrand factor with aging in type 1 von Willebrand disease: fact or fiction? Haematologica. 2017; 102(11): e431–e433.
  10. Seaman CD, Ragni MV. The Association of Aging With Von Willebrand Factor Levels and Bleeding Risk in Type 1 Von Willebrand Disease. Clin Appl Thromb Hemost. 2018; 24(3): 434–438.
  11. Nichols WL, Hultin MB, James AH, et al. 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.
  12. Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease. Blood. 2015; 125(13): 2029–2037.
  13. Sadler JE. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematology Am Soc Hematol Educ Program. 2009: 106–112.
  14. Zdziarska J, Chojnowski K, Klukowska A, et al. Postępowanie w chorobie von Willebranda. Zalecenia Polskiego Towarzystwa Hematologów i Transfuzjologów. Med Prakt. 2008; 12: 1–16.
  15. Mancuso DJ, Tuley EA, Westfield LA, et al. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry. 1991; 30(1): 253–269.
  16. Keeney S, Cumming AM. The molecular biology of von Willebrand disease. Clin Lab Haematol. 2001; 23(4): 209–230.
  17. Federici AB. Current and emerging approaches for assessing von Willebrand disease in 2016. Int J Lab Hematol. 2016; 38 Suppl 1: 41–49.
  18. Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev. 2010; 24(3): 123–134.
  19. de Jong A, Eikenboom J. Von Willebrand disease mutation spectrum and associated mutation mechanisms. Thromb Res. 2017; 159: 65–75.
  20. 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(1): 145–154.
  21. 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(1): 112–121.
  22. Castaman G, Lethagen S, Federici AB, et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood. 2008; 111(7): 3531–3539.
  23. Federici AB. The use of desmopressin in von Willebrand disease: the experience of the first 30 years (1977-2007). Haemophilia. 2008; 14 Suppl 1: 5–14.
  24. Sadler JEA. revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standarization Committee of the International Society on osis and asis. Thromb Haemost. 1994; 71: 520–525.
  25. Sadler JE, Budde U, Eikenboom JCJ, 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.
  26. Michiels JJ, Smejkal P, Penka M, et al. 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.
  27. Larsen DM, Haberichter SL, Gill JC, et al. Variability in platelet- and collagen-binding defects in type 2M von Willebrand disease. Haemophilia. 2013; 19(4): 590–594.
  28. Favaloro EJ, Forsyth C, Koutts J. Distinguishing types 1 and 2M von Willebrand disease. Int J Lab Hematol. 2012; 34(1): 102–105.
  29. 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(9): 1914–1922.
  30. 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(4): 632–638.
  31. Hermans C, Batlle J. Autosomal dominant von Willebrand disease type 2M. Acta Haematol. 2009; 121(2-3): 139–144.
  32. Laffan M, Brown SA, Collins PW, et al. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization. Haemophilia. 2004; 10(3): 199–217.
  33. Mancuso DJ, Kroner PA, Christopherson PA, et al. 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(7): 2559–2568.
  34. Mannucci PM, Lombardi R, Castaman G, et al. von Willebrand disease "Vicenza" with larger-than-normal (supranormal) von Willebrand factor multimers. Blood. 1988; 71(1): 65–70.
  35. Zieger B, Budde U, Jessat U, et al. New families with von Willebrand disease type 2M (Vicenza). Thromb Res. 1997; 87(1): 57–64.
  36. Howard MA, Salem HH, Thomas KB, et al. Variant von Willebrand's disease type B--revisited. Blood. 1982; 60(6): 1420–1428.
  37. Rabinowitz I, Tuley EA, Mancuso DJ, et al. von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib. Proc Natl Acad Sci U S A. 1992; 89(20): 9846–9849.
  38. Meyer D, Fressinaud E, Gaucher C, et al. Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. INSERM Network on Molecular Abnormalities in von Willebrand Disease. Thromb Haemost. 1997; 78(1): 451–456.
  39. Ciavarella G, Ciavarella N, Antoncecchi S, et al. High-resolution analysis of von Willebrand factor multimeric composition defines a new variant of type I von Willebrand disease with aberrant structure but presence of all size multimers (type IC). Blood. 1985; 66(6): 1423–1429.
  40. Lopez-Fernandez MF, Gonzalez-Boullosa R, Blanco-Lopez MJ, et al. Abnormal proteolytic degradation of von Willebrand factor after desmopressin infusion in a new subtype of von Willebrand disease (ID). Am J Hematol. 1991; 36(3): 163–170.
  41. Goodeve A. Diagnosing von Willebrand disease: genetic analysis. Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 678–682.
  42. Fujimura Y, Titani K, Holland LZ, et al. 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(1): 381–385.
  43. Pareti FI, Niiya K, McPherson JM, et al. Isolation and characterization of two domains of human von Willebrand factor that interact with fibrillar collagen types I and III. J Biol Chem. 1987; 262(28): 13835–13841.
  44. Posch S, Obser T, König G, et al. Interaction of von Willebrand factor domains with collagen investigated by single molecule force spectroscopy. J Chem Phys. 2018; 148(12): 123310.
  45. Tischer A, Madde P, Moon-Tasson L, et al. Misfolding of vWF to pathologically disordered conformations impacts the severity of von Willebrand disease. Biophys J. 2014; 107(5): 1185–1195.
  46. 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(8): 3848–3859.
  47. Stepanian A, Ribba AS, Lavergne JM, et al. A new mutation, S1285F, within the A1 loop of von Willebrand factor induces a conformational change in A1 loop with abnormal binding to platelet GPIb and botrocetin causing type 2M von Willebrand disease. Br J Haematol. 2003; 120(4): 643–651.
  48. Lankhof H, van Hoeij M, Schiphorst ME, et al. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost. 1996; 75(6): 950–958.
  49. Flood VH, Gill JC, Christopherson PA, et al. Critical von Willebrand factor A1 domain residues influence type VI collagen binding. J Thromb Haemost. 2012; 10(7): 1417–1424.
  50. Flood VH, Schlauderaff AC, Haberichter SL, et al. Zimmerman Program Investigators. Crucial role for the VWF A1 domain in binding to type IV collagen. Blood. 2015; 125(14): 2297–2304.
  51. Favaloro EJ. Laboratory identification of von Willebrand disease: technical and scientific perspectives. Semin Thromb Hemost. 2006; 32(5): 456–471.
  52. Favaloro EJ. Evaluation of commercial von Willebrand factor collagen binding assays to assist the discrimination of types 1 and 2 von Willebrand disease. Thromb Haemost. 2010; 104(5): 1009–1021.
  53. Favaloro EJ, Bonar RA, Mohammed S, et al. Type 2M von Willebrand disease - more often misidentified than correctly identified. Haemophilia. 2016; 22(3): e145–e155.
  54. Favaloro EJ, Pasalic L, Curnow J. Type 2M and Type 2A von Willebrand Disease: Similar but Different. Semin Thromb Hemost. 2016; 42(5): 483–497.
  55. Favaloro EJ, Bonar RA, Mohammed S, et al. Diagnosis of type 1 vs. 2A and 2M von Willebrand disease. Haemophilia. 2012; 18(1): e9–11.
  56. Doruelo AL, Haberichter SL, Christopherson PA, et al. Clinical and laboratory phenotype variability in type 2M von Willebrand disease. J Thromb Haemost. 2017; 15(8): 1559–1566.
  57. Budde U, Drewke E, Mainusch K, et al. Laboratory diagnosis of congenital von Willebrand disease. Semin Thromb Hemost. 2002; 28(2): 173–190.
  58. Budde U, Schneppenheim R, Eikenboom J, et al. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). J Thromb Haemost. 2008; 6(5): 762–771.
  59. Oliver S, Lau KK, Chapman K, et al. Laboratory Testing for Von Willebrand Factor Multimers. Methods Mol Biol. 2017; 1646: 495–511.
  60. Favaloro EJ. Toward a new paradigm for the identification and functional characterization of von Willebrand disease. Semin Thromb Hemost. 2009; 35(1): 60–75.
  61. Flood VH, Gill JC, Friedman KD, et al. Zimmerman Program Investigators. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem. 2013; 59(4): 684–691.
  62. Favaloro EJ, Mohammed S. Evaluation of a von Willebrand factor three test panel and chemiluminescent-based assay system for identification of, and therapy monitoring in, von Willebrand disease. Thromb Res. 2016; 141: 202–211.
  63. Stufano F, Baronciani L, Mane-Padros D, et al. A comparative evaluation of a new fully automated assay for von Willebrand factor collagen binding activity to an established method. Haemophilia. 2018; 24(1): 156–161.
  64. Jousselme E, Jourdy Y, Rugeri L, et al. Comparison of an automated chemiluminescent assay to a manual ELISA assay for determination of von Willebrand Factor collagen binding activity on VWD plasma patients previously diagnosed through molecular analysis of VWF. Int J Lab Hematol. 2018; 40(1): 77–83.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

Czasopismo Journal of Transfusion Medicine dostęne jest również w Ikamed - księgarnia medyczna

Wydawcą serwisu jest Via Medica sp. z o.o. sp. komandytowa, ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail: viamedica@viamedica.pl