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.
Conclusion: 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.