title: Cysteine-mutations in von Willebrand factor associated with increased clearance.
abstract: BACKGROUND
  von Willebrand disease (VWD) is a bleeding disorder caused by the decrease of functional von Willebrand factor (VWF). Low levels of VWF can result from decreased synthesis, impaired secretion, increased clearance or combinations thereof. Several mutations lead to impaired synthesis or secretion of VWF, however, little is known about the survival of VWF in the circulation.
  
  
  OBJECTIVE
  To evaluate the effect of several VWF mutations on VWF clearance.
  
  
  METHODS
  The effect of three cysteine-mutations (C1130F, C1149R or C2671Y) on the in vivo survival of VWF was studied in patients carrying these mutations and in a VWF-deficient mice model.
  
  
  RESULTS
  In patients carrying these mutations, we observed increased propeptide/mature VWF ratios and rapid disappearance of VWF from the circulation after desmopressin treatment. Detailed analysis of in vivo clearance of recombinant VWF in a VWF-deficient mice model revealed a fourfold increased clearance rate of the mutants. The mutations C1130F, C1149R and C2671Y are each associated with reduced survival of VWF in the circulation. Detailed analysis of the recombinant mutant VWF demonstrated that increased clearance was not due to increased proteolysis by ADAMTS-13. We did not identify functional or structural characteristics that the mutant proteins have in common and could be associated with the phenomenon of increased clearance.
  
  
  CONCLUSIONS
  Cysteine-mutations in VWF may result in reduced in vivo survival. The observation that various mutations are associated with increased in vivo clearance may have major implications for the therapeutic strategies that rely on the rise of endogenous VWF after desmopressin administration.
authors.affiliation: Department of Haematology, Laboratory for Thrombosis and Haemostasis, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: Schooten
authors.forename: P
authors.initials: P
authors.lastname: Tjernberg
authors.forename: E
authors.initials: E
authors.lastname: Westein
authors.forename: V
authors.initials: V
authors.lastname: Terraube
authors.forename: G
authors.initials: G
authors.lastname: Castaman
authors.forename: J A
authors.initials: JA
authors.lastname: Mourik
authors.forename: M J
authors.initials: MJ
authors.lastname: Hollestelle
authors.forename: H L
authors.initials: HL
authors.lastname: Vos
authors.forename: R M
authors.initials: RM
authors.lastname: Bertina
authors.forename: H M
authors.initials: HM
authors.lastname: Berg
authors.forename: J C J
authors.initials: JC
authors.lastname: Eikenboom
authors.forename: P J
authors.initials: PJ
authors.lastname: Lenting
authors.forename: C V
authors.initials: CV
authors.lastname: Denis
mesh_terms: D000071120:ADAMTS13 Protein; D000818:Animals; D003545:Cysteine / Q000235:genetics*; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D006801:Humans; D008660:Metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics*; D014841:von Willebrand Factor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; D003894:Deamino Arginine Vasopressin; D003545:Cysteine