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; Anne F. Riddell; Simon A. Brown; Richard Starke; Ian Mackie; Derrick J. Bowen; P. Vincent Jenkins; Jan A. van Mourik

doi:10.1160/TH07-09-0565

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 99(05): 916-924
DOI: 10.1160/TH07-09-0565

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

¹Katharine Dormandy Haemophilia Centre and Thrombosis Unit, University College and Royal Free Medical School, London, UK

,

Anne F. Riddell

¹Katharine Dormandy Haemophilia Centre and Thrombosis Unit, University College and Royal Free Medical School, London, UK

,

Simon A. Brown

¹Katharine Dormandy Haemophilia Centre and Thrombosis Unit, University College and Royal Free Medical School, London, UK

,

Richard Starke

²Haemostasis Research Unit, University College London, London, UK

,

Ian Mackie

²Haemostasis Research Unit, University College London, London, UK

,

Derrick J. Bowen

³Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK

,

P. Vincent Jenkins

¹Katharine Dormandy Haemophilia Centre and Thrombosis Unit, University College and Royal Free Medical School, London, UK

,

Jan A. van Mourik

⁴Department of Plasma Proteins, Sanquin Research, Amsterdam and Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

› Author Affiliations

Abstract

Summary

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.

Keywords

Clearance - glycosylation - proteolysis - von Willebrand factor - von Willebrand disease

Full Text

References

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