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

Authors

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

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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