title: Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome.
abstract: BACKGROUND
  HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome is a severe complication of pre-eclampsia in pregnancy, characterized by microvascular platelet thrombi. Activation of the endothelium is thought to play a key role in pre-eclampsia and HELLP syndrome. Activation of endothelial cells may lead to release of von Willebrand factor (VWF) multimers, which are highly reactive with platelets. Normally, newly released multimers are cleaved by ADAMTS13, resulting in less reactive derivatives.
  
  
  OBJECTIVE
  We hypothesized that HELLP syndrome is characterized by increased amounts of active VWF compared with healthy pregnancy and pre-eclampsia, due to acute activation of endothelial cells. This might contribute to thrombocytopenia and thrombotic microangiopathy.
  
  
  METHODS
  Active VWF and ADAMTS13 activity were measured in healthy pregnant volunteers (n = 9), patients with pre-eclampsia (n = 6) and patients with HELLP syndrome (n = 14) at similar gestational ages. To study the role of endothelial cell activation, the propeptide/mature VWF ratio was determined, and VWF released by cultured endothelial cells was analyzed.
  
  
  RESULTS
  Active VWF levels were increased 2.1-fold in HELLP syndrome compared with healthy pregnant volunteers (P < 0.001) and 1.6-fold compared with patients with pre-eclampsia (P = 0.001). ADAMTS13 activity was moderately decreased in patients with HELLP syndrome compared with healthy pregnant volunteers (P < 0.004), but not compared with patients with pre-eclampsia. The propeptide/mature VWF ratio was increased 1.7-fold compared with healthy pregnant volunteers (P < 0.001) and 1.5-fold compared with patients with pre-eclampsia (P < 0.05). A significant correlation was found between this ratio and the activation factor of VWF (r = 0.68, P < 0.001). The amount of active VWF was increased 1.4-fold in medium of stimulated endothelial cells when compared with non-stimulated cells (P < 0.05).
  
  
  CONCLUSIONS
  Acute endothelial cell activation in HELLP syndrome and decreased ADAMTS13 activity result in increased amounts of active VWF. This might explain the consumptive thrombocytopenia and thrombotic microangiopathy associated with HELLP syndrome. Inhibition of circulating active VWF could be a potential new approach in the treatment of patients with HELLP syndrome.
authors.affiliation: Department of Haematology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: J J J
authors.initials: JJ
authors.lastname: Hulstein
authors.forename: P J
authors.initials: PJ
authors.lastname: van Runnard Heimel
authors.forename: A
authors.initials: A
authors.lastname: Franx
authors.forename: P J
authors.initials: PJ
authors.lastname: Lenting
authors.forename: H W
authors.initials: HW
authors.lastname: Bruinse
authors.forename: K
authors.initials: K
authors.lastname: Silence
authors.forename: Ph G
authors.initials: PG
authors.lastname: de Groot
authors.forename: R
authors.initials: R
authors.lastname: Fijnheer
mesh_terms: D051722:ADAM Proteins / Q000097:blood / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000328:Adult; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005865:Gestational Age; D017359:HELLP Syndrome / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex; D011225:Pre-Eclampsia / Q000097:blood / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014842:von Willebrand Diseases / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D011498:Protein Precursors; C094990:adhesion receptor; D014841:von Willebrand Factor; C067003:von Willebrand factor propolypeptide; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D013755:Tetradecanoylphorbol Acetate