Management of an uncommon form of type 2M VWD: a single centre experience

Sabia Rashid; Patricia Bignell; David Keeling; Nicola Curry

doi:10.17225/jhp00065

Abstract

Abstract

We report a single centre’s experience of the diagnosis and management of an uncommon form of type 2 von Willebrand disease (VWD) in members of two unrelated families. The affected patients presented with mild to moderate bleeding phenotypes and accompanying MCMDM-1 VWD bleeding assessment tool scores of 5 or less. Genetic analysis in both families confirmed a missense mutation in exon 30 of the von Willebrand factor (VWF) gene, a single base substitution T>A at nucleotide 5282 which led to change at codon 1761 from methionine to lysine (M1761K). This mutation lies within the A3 domain of the VWF protein, a region that is important for collagen binding. All affected patients were found to have normal coagulation profiles, normal VWF multimers and normal VWF assays except the VWF collagen-binding (VWF: CB) assay levels, which were significantly reduced. Desmopressin effected a good response in all treated patients, with a 3- to 5-fold rise of VWF:CB levels. However, there was variability in the degree to which VWF:CB levels remained elevated. Surgical procedures, including the delivery of one patient, were able to be managed with either desmopressin and/or tranexamic acid alone, with little need for recourse to VWF factor concentrate therapy.

Article

View Full Article

References

1. Schneppenheim R, Budde U. von Willebrand factor: the complex molecular genetics of a multidomain and multifunctional protein. J Thromb Haemost 2011; 9 Suppl 1: 209-15; doi: 10.1111/j.1538-7836.2011.04324.x.
2. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454-9.
3. Werner EJ, Broxson EH, Tucker EL, et al. Prevalence of von Willebrand disease in children: a multi-ethnic study. J Pediatr 1993; 123: 893-8.
4. 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: 453-65; doi: 10.1111/bjh.13064.
5. University of Sheffield. von Willebrand factor Variant Database (VWFdb). Available from: www.vwf.group.shef.ac.uk/(accessed 21 November 2011).
6. Flood VH, Schlauderaff AC, Haberichter SL, et al. The crucial role for the VWFA1 domain in binding to type IV collagen. Blood 2015; 125: 2297-304; doi: 10.1182/blood-2014-11-610824.
7. Tosetto A, Rodeghiero F, Castaman G, et al. 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: 766-73.
8. Keeling D, Beavis J, Marr R, et al. 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:e33; doi: 10.1111/j.1365-2516.2011.02676.x.
9. Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood 2009; 114: 1158-65; doi: 10.1182/blood-2009-01-153296.
10. 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; doi: 10.1111/j.1365-2516.2007.01610.x.
11. Favaloro EJ. Von Willebrand factor collagen-binding (activity) assay in the diagnosis of von Willebrand disease: A 15-year journey. Semin Thromb Hemost 2002; 28: 191–202.
12. 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: 950-8.
13. Denis C, Baruch D, Kielty CM, et al. Localization of von Willebrand factor binding domains to endothelial extracellular matrix and to type VI collagen. Arterioscler Thromb 1993; 13: 398-406.
14. Bonnefoy A, Romijn RA, Vandervoort PA, et al. von Willebrand factor A1 domain can adequately substitute for A3 domain in recruitment of flowing platelets to collagen. J Thromb Haemost 2006; 4:2151-61.
15. Riddell AF, Gomez K, Millar CM, et al. Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. Blood 2009; 114: 3489-96; doi: 10.1182/blood-2008-10-184317.
16. Sadler JE, Budde U, Eikenboom JC, et al. Working Party own 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: 2103-14.
17. Ribba AS, Loisel I, Lavergne JM, et al. Ser968Thr mutation within the A3 domain of von Willebrand factor (VWF) in two related patients leads to a defective binding of VWF to collagen. Thromb Haemost 2001; 86: 848–54.
18. 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: 1431-3; doi: 10.1111/j.1538-7836.2010.03869.x.

PDF Download

Download PDF

Open in full-page viewer

Authors

Sabia Rashid

Oxford Haemophilia & Thrombosis Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK
Patricia Bignell

Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK
David Keeling

Oxford Haemophilia & Thrombosis Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK
Nicola Curry

nicola.curry@ouh.nhs.uk

Oxford Haemophilia & Thrombosis Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK