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Controlled Clinical Trial
. 2008 May;99(5):916-24.
doi: 10.1160/TH07-09-0565.

Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: influence of glycosylation, proteolysis and gene mutations

Carolyn M Millar  1 , Anne F Riddell, Simon A Brown, Richard Starke, Ian Mackie, Derrick J Bowen, P Vincent Jenkins, Jan A van Mourik
Affiliations
Controlled Clinical Trial

Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: influence of glycosylation, proteolysis and gene mutations

Carolyn M Millar et al. Thromb Haemost. 2008 May.

Abstract

Reduced plasma survival of von Willebrand factor (VWF) may contribute towards the pathogenesis of type 1 von Willebrand disease (VWD). However, little is known about mechanism(s) of VWF clearance and factors that may affect it. The half-life of VWF-related parameters following the administration of DDAVP was measured in 26 patients with type 1 VWD and 10 haemophilia A controls. Binding of lectins Ricinus communis (RCA-I) and Erythina crystagalli (ECA) agglutinins to VWF and VWF susceptibility to ADAMTS-13-mediated proteolysis were investigated. Sequence analysis of targeted regions of the VWF gene was performed to inspect for mutations that have been associated with increased clearance. Post-DDAVP clearance of VWF was increased approximately three-fold in the type 1 VWD cohort overall. However this was not shown to consistently associate with steady-state VWF antigen (VWF:Ag) levels. Furthermore, increased VWF clearance was not consistently associated with increased ratios of VWF propeptide (VWFpp) to VWF:Ag indicating that a normal ratio does not necessarily reflect normal post-DDAVP survival in type 1 VWD patients. RCA-I and ECA binding to VWF were increased in type 1 VWD patients and, although inversely correlated with VWF levels, this was independent of VWF clearance. There was no association between VWF clearance and ADAMTS-13-mediated proteolysis. Three novel candidate mutations with an increased clearance phenotype were identified. The data are consistent with heterogeneity in pathogenic mechanisms in type 1 VWD and are consistent with type 1 VWD representing a complex genetic trait.

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