Clinical data have shown that the evaluation of fibrin degradation products (FbDP) does not reflect the efficiency of thrombolytic therapy in vivo. In this study, we found that the addition of plasminogen activators to normal plasma resulted in generation of FbDP and release of fibrinopeptide A (FpA) as shown by ELISA and HPLC. This FpA release was concomitant with fibrinogen degradation, and was not inhibited by thrombin inhibition or by prothrombin depletion in plasma. Thus, the increase in FpA did not result from coagulation activation and may result from the plasmin-induced release of FpA from fibrinogen degradation product E1. The generation of cross-linked FbDP after tPA addition occurred in normal plasma as well as in factor-XIII-deficient plasma and quickly reached a plateau. It was not inhibited by hirudin. Therefore FbDP in these plasmas probably derived from the plasmin degradation of cellular transglutaminase cross-linked fibrin/fibrinogen derivatives present in plasma.