The clotting and fibrinolytic systems are activated by tissue factor and by tissue-type plasminogen activator in the pericardial cavity, where the thrombogenicity is greater than that of the surface of modern extracorporeal circuits. This local activation may have consequences for the systemic activation processes during cardiopulmonary bypass. To test this hypothesis, we investigated blood activation by interrupting the blood suction from the pericardial cavity during cardiopulmonary bypass in clinical coronary artery bypass operations. In blood collected in the pericardial cavity, thrombin-antithrombin III complex (p < 0.01), tissue-type plasminogen activator antigen (p < 0.05), fibrinogen degradation products (p < 0.01), and fibrin degradation products (p < 0.01) were significantly higher than in the systemic blood. Plasma heparin was significantly consumed in the pericardial cavity (p < 0.01). Once the pericardial blood was returned to the systemic circulation after resumed suction during cardiopulmonary bypass, thrombin-antithrombin III complex (p < 0.05), fibrinogen degradation products (p < 0.05), and fibrin degradation product (p < 0.05) concentrations increased significantly in the systemic blood. The effects of pericardial tissue on activation of clotting and fibrinolysis were also studied in vitro. When human plasma was incubated for 5 minutes with rabbit pericardium at reduced heparin concentrations, we found significant generation of thrombin (p < 0.05) and plasmin (p < 0.05). If the thrombin inhibitor hirudin was added, plasmin generation was also inhibited (p < 0.05). The results of the clinical and experimental study are in agreement with our hypothesis that tissue factor and tissue-type plasminogen activator accelerate the activation of clotting and sequentially of fibrinolysis under conditions of low heparin concentrations in the pericardial cavity and that this local activation contributes highly to the systemic activation, affecting hemostasis during cardiopulmonary bypass. Topical use of heparin in the pericardial cavity therefore seems indicated to reduce blood activation during cardiopulmonary bypass.