Abstract-Several recent studies have proposed that coagulation is triggered during cardiopulmonary bypass surgery by extrinsic pathway activation involving factor VIIa generation, but the methodology was indirect. Therefore, 12 patients were studied during routine cardiac and cardiopulmonary bypass surgery. Samples were taken before, during, and after bypass from the perfusate, from the aorta (retrograde cardiac drainage), pericardium, and collected suction fluid originating from the whole operative field. These samples were analyzed by enzyme-linked immunosorbent assay for 2-chain factor VIIa, by prothrombin F 1ϩ2 assay, by thrombin-antithrombin (TAT) assay, and for heparin concentration. Factor VIIa, F 1ϩ2 , and TAT levels in samples from the pericardium were greatly elevated (mean, 0.92 to 1.01, 227 to 334, and 399 to 526 g/L, respectively; preoperative mean, 0.33, 32.3, and 1.90 g/L, respectively; PϽ0.05 for all), whereas levels in suction fluid were less consistently high. Factor VIIa and both F 1ϩ2 and thrombin-antithrombin levels in samples from the aorta, pericardium, and suction fluid were significantly correlated (rϭ0. 57, PϽ0.001, nϭ111; and rϭ0.51, PϽ0.001, nϭ105, respectively), and all were inversely correlated with heparin levels (rϾϪ0.35, PϽ0.001, nϾ92). There was no evidence of factor VIIa generation in the circuit during bypass surgery, and both F 1ϩ2 and thrombin-antithrombin levels rose only Ϸ2-fold, probably because heparin levels were higher than they were in the pericardium (PϽ0.05). We concluded that appreciable activation of factor VII occurs on the pericardium and that this is associated with increased thrombin generation. Ineffective local heparinization may be partly responsible. These results suggest that pericardium-induced activation of factor VII should be the target of anticoagulant strategies during cardiopulmonary bypass surgery. (Arterioscler Thromb Vasc Biol. 1999;19:248-254.)