title: Hyperfibrinolysis in alcoholic cirrhosis: relative plasminogen activator inhibitor type 1 deficiency.
abstract: BACKGROUND
  Over activity of the fibrinolytic system (hyperfibrinolysis) occurs in cirrhosis and has been shown to correlate with the risk of variceal hemorrhage. We have developed a model for assessing acute tissue plasminogen activator (t-PA) release in vivo in man. The aims of the study were to assess the contribution of basal and stimulated t-PA release to hyperfibrinolysis in patients with alcoholic cirrhosis.
  
  
  METHODS
  Bilateral forearm blood flow and plasma fibrinolytic variables were measured in 8 patients with biopsy proven alcohol induced cirrhosis, ascites and portal hypertension, and 8 age and sex matched healthy controls during infusion of bradykinin (100-900 pmol/min; endothelium-dependent vasodilator that releases t-PA) followed by sodium nitroprusside (SNP 2-8 microg/min; a control endothelium-independent vasodilator).
  
  
  RESULTS
  Baseline plasma t-PA antigen concentrations were higher in patients (14+/-2 vs 9+/-1 ng/mL; p<0.05) whereas plasma plasminogen activator inhibitor type-1 (PAI-1) antigen concentrations were similar (59+/-16 vs 55+/-11 ng/mL; p=NS). This resulted in an increased t-PA activity (3+/-1 vs 0+/-0 IU/mL; p<0.05) and reduced PAI-1 activity (9+/-2 vs 21+/-2 AU/mL; p<0.05) indicating a relative deficiency of PAI-1 in patients with cirrhosis. Bradykinin and SNP caused dose-dependent vasodilatation (p<0.001 for both) that did not differ between the two groups. Bradykinin caused a similar release of t-PA antigen (p<0.05 for both) in both patients and controls (24+/-17 vs 23+/-7 ng/100 mL/min; p=ns) without affecting PAI-1 concentrations. Local t-PA activity was increased in patients following acute stimulated t-PA release (5+/-1 vs 3+/-1 IU/mL; p<0.05). SNP caused no significant change in fibrinolytic parameters.
  
  
  CONCLUSIONS
  Patients with alcoholic cirrhosis have a higher basal plasma t-PA activity because of a failure to increase plasma concentrations of its inhibitor, PAI-1. Furthermore, despite releasing normal amounts of t-PA acutely, higher t-PA activity remained due to the relative deficiency of PAI-1. This suggests that the pathogenesis of hyperfibrinolysis in alcoholic cirrhosis is the result of a relative PAI-1 deficiency and enhanced basal t-PA release.
authors.affiliation: Department of Hepatology, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SU, UK. j.w.ferguson@ed.ac.uk
authors.forename: James W
authors.initials: JW
authors.lastname: Ferguson
authors.forename: Ahmed
authors.initials: A
authors.lastname: Helmy
authors.forename: Christopher
authors.initials: C
authors.lastname: Ludlam
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hayes
authors.forename: David C
authors.initials: DC
authors.lastname: Newby
mesh_terms: D001920:Bradykinin / Q000494:pharmacology; D005260:Female; D005342:Fibrinolysis; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000172:deficiency*; D010959:Tissue Plasminogen Activator / Q000097:blood
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D009599:Nitroprusside; D010959:Tissue Plasminogen Activator; D001920:Bradykinin