Orthotopic liver transplantation is frequently associated with hyperfibrinolysis, the origin and clinical relevance of which is largely unknown. In 20 orthotopic liver transplantations, we studied the occurrence and systemic effects of hyperfibrinolysis. Severe fibrinolysis was defined to be present when the euglobulin-clot lysis time and the whole-blood-clot lysis time, as measured by thrombelastography, were shorter than 60 and 90 min, respectively, at some time during the operation. Based on these criteria, 7 patients had minimal fibrinolysis (group I), and 13 patients had severe fibrinolysis (group II). In group II a gradual increase of tissue-type plasminogen activator (t-PA) activity was seen during the anhepatic stage, followed by an "explosive" increase immediately after graft reperfusion (P = 0.0004, compared with group I), and a reduction of plasminogen activator inhibitor (PAI) activity. Plasma degradation products of fibrinogen and fibrin increased parallel to t-PA activity, and levels were significantly higher at 45 min after graft reperfusion in group II compared with group I (P less than 0.04). Thrombin-antithrombin III complexes showed an identical steady increase in both groups, indicating that increased t-PA activity was not related to thrombin formation. A combination of increased endothelial release and reduced hepatic clearance may have caused the increased t-PA activity. The t-PA-associated destruction of fibrinogen and fibrin after graft reperfusion is consistent with the clinical signs of severe oozing often seen in this period. These observations may have important clinical implications for the treatment of bleeding in patients undergoing orthotopic liver transplantation.