title: Endogenous tissue plasminogen activator enhances fibrinolysis and limits thrombus formation in a clinical model of thrombosis.
abstract: OBJECTIVE
  Using a clinical model of deep arterial injury, we assessed the ability of exogenous and endogenous tissue plasminogen activator (t-PA) to limit acute in situ thrombus formation.
  
  
  RESULTS
  Ex vivo thrombus formation was assessed in the Badimon chamber at low and high shear rates in 2 double-blind randomized cross-over studies of 20 healthy volunteers during extracorporeal administration of recombinant t-PA (0, 40, 200, and 1000 ng/mL) or during endogenous t-PA release stimulated by intra-arterial bradykinin infusion in the presence or absence of oral enalapril. Recombinant t-PA caused a dose-dependent reduction in thrombus area under low and high shear conditions (P<0.001 for all). Intra-arterial bradykinin increased plasma t-PA concentrations in the chamber effluent (P<0.01 for all versus saline) that was quadrupled in the presence of enalapril (P<0.0001 versus placebo). These increases were accompanied by an increase in plasma D-dimer concentration (P<0.005 for all versus saline) and, in the presence of enalapril, a reduction in thrombus area in the low shear (16±5; P=0.03) and a trend toward a reduction in the high shear chamber (13±7%; P=0.07).
  
  
  CONCLUSIONS
  Using a well-characterized clinical model of coronary arterial injury, we demonstrate that endogenous t-PA released from the vascular endothelium enhances fibrinolysis and limits in situ thrombus propagation. These data support a crucial role for the endogenous fibrinolytic system in vivo and suggest that continued exploration and manipulation of its therapeutic potential are warranted.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4SU, United Kingdom. andrewjohnlucking@gmail.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lucking
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Gibson
authors.forename: Elspeth E
authors.initials: EE
authors.lastname: Paterson
authors.forename: Dana
authors.initials: D
authors.lastname: Faratian
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ludlam
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Boon
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000293:Adolescent; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000502:physiology; D005342:Fibrinolysis; D006801:Humans; D013927:Thrombosis / Q000209:etiology*; D010959:Tissue Plasminogen Activator / Q000502:physiology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D010959:Tissue Plasminogen Activator; D001920:Bradykinin