The Molecular Basis of Type 3 von Willebrand Disease

Cumming A M, Sutherland M S, Keeney S.  The Molecular Basis of Type 3 von Willebrand Disease.  Journal of Coagulation Disorders, July 2010; 2(2):  29-35

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Anthony M Cumming, Megan S Sutherland and Stephen Keeney

Affiliations: Molecular Diagnostics Centre, University Department of Haematology, Manchester Royal Infirmary, Manchester, UK


ABSTRACT

Type 3 von Willebrand disease (VWD), the result of a severe quantitative deficiency of von Willebrand factor (VWF), is associated with moderate to severe bleeding symptoms including epistaxis, menorrhagia, arthropathy, and postoperative bleeding. Inheritance of type 3 VWD is autosomal recessive and the disorder is considered to have a prevalence of 0.5-1 per million individuals in the general population. It was originally assumed that type 3 VWD is caused by large deletions of the gene-encoding VWF (VWF). However, of 109 VWF mutations reported on the International Society on Thrombosis and Hemostasis (ISTH) VWF database (http://www.vwf.group.shef.ac.uk/) to cause type 3 VWD, only 11 are large deletions-ranging from the deletion of a single exon up to the deletion of the entire VWF gene. Approximately 80% of VWF mutations in type 3 VWD give rise to a VWF null allele, ie, nonsense mutations, deletions, splice-site mutations, and small insertions. Missense changes in VWF account for only about 20% of the mutations associated with type 3 VWD. This is unlike type 1 VWD, the result of a partial quantitative deficiency of VWF, where approximately two-thirds of reported mutations are missense in nature. This observation reflects the different genetic basis of type 3 and type 1 VWD in most cases.

Keywords: inherited bleeding disorder, von Willebrand disease, type 3 VWD, VWF mutations, type 3 VWD genetics

Correspondence: Dr. Tony Cumming, Molecular Diagnostics Centre, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. Tel: +44 (0)161 276 4880; e-mail: tony.cumming@cmft.nhs.uk