title: Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: influence of glycosylation, proteolysis and gene mutations.
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.
authors.affiliation: Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Department of Haematology, Royal Free Campus, University College and Royal Free Medical School, London, United Kingdom. E-mail: c.millar@medsch.ucl.ac.uk
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Millar
authors.forename: Anne F
authors.initials: AF
authors.lastname: Riddell
authors.forename: Simon A
authors.initials: SA
authors.lastname: Brown
authors.forename: Richard
authors.initials: R
authors.lastname: Starke
authors.forename: Ian
authors.initials: I
authors.lastname: Mackie
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Bowen
authors.forename: P Vincent
authors.initials: PV
authors.lastname: Jenkins
authors.forename: Jan A
authors.initials: JA
authors.lastname: van Mourik
mesh_terms: D051722:ADAM Proteins / Q000097:blood*; D000071120:ADAMTS13 Protein; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003894:Deamino Arginine Vasopressin / Q000008:administration & dosage*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006031:Glycosylation; D006207:Half-Life; D006490:Hemostatics / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009154:Mutation; D010641:Phenotype; D037121:Plant Lectins / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000097:blood; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D016896:Treatment Outcome; D014842:von Willebrand Diseases / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D006490:Hemostatics; D037121:Plant Lectins; D011498:Protein Precursors; C017707:Ricinus communis agglutinin-1; D014841:von Willebrand Factor; C067003:von Willebrand factor propolypeptide; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D003894:Deamino Arginine Vasopressin