Thrombolytic Properties of Pro-Urokinase, Plasminogen Proactivator (PPA)

Thrombolytic properties of highly purified plasminogen proactivator (PPA) isolated from culture medium of human kidney cells were compared with those of human urinary urokinase(u-UK). When 125-I-PPA or u-UK was added to whole blood perfusion medium containing preformed thrombi made from whole blood by Chandler loop method, the rates of uptake by the thrombi of PPA and u-UK for 4 hrs were only 2.5% and 2.7% respectively. Using the same thrombi and perfusion medium, an in vitro thrombolytic effect of PPA was examined over a 4 hr period. In early perfusion time, a lag phase was observed in the lysis-time curve of PPA, but not of u-UK. After the lag phase, the lysis by PPA increased linearly without early reaching a low level plateau that was characteristic of the lysis by u-UK. At 4hr, the PPA percent lysis was higher than the u-UK figure. Half lives in rabbit of 125-I-labelled PPA and u-UK iv doses were 5.1±0.2 min and 7.3±0.2 min respectively.

The thrombolytic ability of PPA in vivo was evaluated in rabbit pulmonary embolism induced by iv 125-I-fibrin suspension as well as cynomolgus monkey femoral vein thrombosis produced by formation of 125-I-fibrinogen labelled clot in an isolated segment of the vein. In both models, PPA was as effective in thrombolysis as u-UK. However conversion to active UK form, consumptions of plsminogen and PI, fibrinogenolysis and prolongation of APTT in plasma were minor in the PPA group, but not in the u-UK group. It is thus suggested that PPA may cause a local activation limited on the fibrin to lead to a lysis of the thrombi without incurring systemic fibrinolysis