What causes von Willebrand disease (vWD) type 3?

Updated: Dec 30, 2019
  • Author: Eleanor S Pollak, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
  • Print

Patients with vWD type III, a severe, quantitative deficiency associated with very little or no detectable plasma or platelet vWF, have a profound bleeding disorder. vWD type III appears to result from the inheritance of a mutant vWF gene from both parents. In the most straightforward model, vWD type I would simply represent the heterozygous form of vWD type III; however, inheritance patterns indicate greater complexity.

vWD type III is much rarer than the predicted frequency of 1 case per 40,000 persons based on this model, instead having a frequency closer to 1 case per 1 million persons. Although few mutations have been identified in families with pure vWD type I, some vWD type I cases have been suggested to be due to a mutant vWF subunit that interferes in a dominant, negative way with the normal allele, accounting for the autosomal dominant inheritance.

The discovery of a deletion of vWF (c.221-977_532 + 7059del [p.Asp75_Gly178del]) in 7 of 12 white patients with vWD type III from 6 unrelated families, and its absence in 9 Asian patients, led Sutherland et al to develop a genomic deoxyribonucleic acid (DNA) ̶ based assay for the deletion of vWF exons 4 and 5. [5] This deletion was also found in 12 of 34 vWD type I families and was associated with a specific vWF haplotype, which the investigators noted may indicate a possible founder origin. Additional studies demonstrated the presence of the mutation in other patients with type I vWD and in a family that expressed both type I and type III vWD. [5]

Sutherland et al reported the c.221-977_532 + 7059del mutation as a novel cause of type I and type III vWD and suggested that screening for this mutation in other type I and type III vWD patient populations may clarify its contribution to vWD that arises from quantitative vWF deficiencies. [5]

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!