title: Ancrod and fibrin formation: perspectives on mechanisms of action.
abstract: OBJECTIVE
  Ancrod, derived from Malayan pit viper venom, has been tested as ischemic stroke treatment in clinical trials with inconsistent results. We studied the actions of ancrod on fibrinolysis pathways in patient plasma samples and endothelial cell culture systems.
  
  
  METHODS
  We analyzed fibrinogen levels during the first 6 hours of ancrod infusion in patients entered in the Stroke Treatment with Ancrod Trial. For the in vitro study, human brain microvascular endothelial cells incubated with plasminogen or with human brain microvascular endothelial cell-conditioned medium were co-incubated with ancrod and fibrinogen under normal or oxygen-glucose deprivation conditions over 6 hours.
  
  
  RESULTS
  Fibrinogen levels decreased both in vivo and in vitro. Ancrod generated fibrinopeptide A, caused visible clot formation, and reduced levels of tissue-type plasminogen activator antigen in the human brain microvascular endothelial cell system and in a cell-free system with conditioned media.
  
  
  CONCLUSIONS
  The in vitro results indicate that ancrod causes local fibrin formation and secondary depletion of tissue-type plasminogen activator by binding to fibrin clot. Ancrod-induced fibrin formation could result in cerebral microvascular occlusion and may explain the suboptimal clinical effects of ancrod in human stroke trials.
authors.affiliation: Department of Anatomy & Neurobiology, University of California Irvine, Irvine, CA, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Liu
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Marder
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.forename: Shur-Jen
authors.initials: SJ
authors.lastname: Wang
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Annlia
authors.initials: A
authors.lastname: Paganini-Hill
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Fisher
mesh_terms: D000721:Ancrod / Q000627:therapeutic use*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D020521:Stroke / Q000097:blood* / Q000188:drug therapy*
chemical_list: D017077:Culture Media, Conditioned; D005337:Fibrin; D000721:Ancrod