title: Severe dengue is associated with consumption of von Willebrand factor and its cleaving enzyme ADAMTS-13.
abstract: BACKGROUND
  Thrombocytopenia, bleeding and plasma leakage are cardinal features of severe dengue. Endothelial cell activation with exocytosis of Weibel-Palade bodies (WPBs) may play an etiological role in this condition.
  
  
  RESULTS
  In a cohort of 73 Indonesian children with dengue hemorrhagic fever (DHF), of which 30 with dengue shock syndrome (DSS), we measured plasma levels of the WPB constituents von Willebrand factor antigen (VWF:Ag), VWF propeptide and osteoprotegerin (OPG), together with activity levels of the VWF-cleaving enzyme ADAMTS-13 and the amount of VWF in a platelet binding conformation (VWF activation factor). Compared with healthy controls (n = 17), children with DHF/DSS had significantly higher levels of VWF:Ag, VWF propeptide and OPG and decreased ADAMTS-13 activity. The VWF activation factor was also significantly higher in DHF/DSS and highest in children who died. There were significant differences in the kinetics of the various WPB constituents: VWF propeptide and OPG levels decreased toward discharge, while VWF:Ag levels were lower than expected at enrollment with plasma levels increasing toward discharge. Moreover, VWF propeptide levels correlated better with markers of disease severity (platelet count, liver enzymes, serum albumin and pleural effusion index) than corresponding VWF levels. Together, these findings suggest that there is consumption of VWF in DHF/DSS. In 4 out of 15 selected children with low ADAMTS-13 levels on admission, we found a remarkable reduction in the large and intermediate VWF multimers in the discharge blood samples, consistent with an acquired von Willebrand disease.
  
  
  CONCLUSIONS
  These findings suggest that severe dengue is associated with exocytosis of WPBs with increased circulating levels of VWF:Ag, VWF propeptide and OPG. High circulating levels of VWF in its active conformation, together with low ADAMTS-13 activity levels, are likely to contribute to the thrombocytopenia and complications of dengue. During the convalescence phase, qualitative defects in VWF with loss of larger VWF multimers may develop.
authors.affiliation: Department of Parasitology, Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
authors.forename: Kis
authors.initials: K
authors.lastname: Djamiatun
authors.forename: Andre J A M
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.forename: Sultana M H
authors.initials: SM
authors.lastname: Faradz
authors.forename: D
authors.initials: D
authors.lastname: Hapsari
authors.forename: Wil M V
authors.initials: WM
authors.lastname: Dolmans
authors.forename: Silvie
authors.initials: S
authors.lastname: Sebastian
authors.forename: Rob
authors.initials: R
authors.lastname: Fijnheer
authors.forename: Quirijn
authors.initials: Q
authors.lastname: de Mast
mesh_terms: D051722:ADAM Proteins / Q000097:blood*; D000071120:ADAMTS13 Protein; D000293:Adolescent; D001774:Blood Chemical Analysis; D002648:Child; D002675:Child, Preschool; D003715:Dengue / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007214:Indonesia; D008297:Male; D053244:Osteoprotegerin / Q000097:blood; D014841:von Willebrand Factor / Q000032:analysis*
chemical_list: D053244:Osteoprotegerin; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human