Inactivation of single-chain urokinase-type plasminogen activator by thrombin in human subjects

Thrombin cleaves single-chain urokinase-type plasminogen activator (scu-PA) into a virtually inactive two-chain form (tcu-PA/T), a process that may protect a blood clot from early fibrinolysis. It is not known under what circumstances tcu-PA/T can be generated in vivo. We have studied the occurrence of tcu-PA/T in human subjects with a varying degree of hypercoagulability. tcu-PA/T was assessed in the plasma of patients with disseminated intravascular coagulation (DIC), endotoxin-treated volunteers, patients with unstable angina pectoris, and patients selected for hip replacement. Relationships between tcu-PA/T and several markers reflecting thrombin generation were examined. tcu-PA/T was observed only in the plasma of patients with DIC and was associated with all thrombin markers and with scu-PA and urokinase antigen. Prothrombin fragment 1 + 2 and urokinase antigen were independent predictors of tcu-PA/T. The fact that tcu-PA/T could not be detected in the other three groups was explained by a lower extent of thrombin generation, a greater inhibition of thrombin by antithrombin, or less available urokinase antigen in these groups. The contribution of scu-PA to total urokinase antigen was decreased in the patients with DIC because of inactivation by thrombin, which may be an additional explanation for the inadequate fibrinolysis observed in these patients. These findings show that scu-PA can be inactivated in the circulation under severe pathophysiologic circumstances and that the process of inactivation depends not only on the generation of thrombin but also on the control of thrombin activity by its inhibitor antithrombin.