DIFFERENTIAL EFFECTS OF LYS- AND MINI-PLASMINOGEN ON CLOT LYSIS INDUCED BY RECOMBINANT UROKINASE AND RECOMBINANT PRO-UROKINASE IN A CANINE THROMBOSIS MODEL

Abstract

These studies were conducted to examine the lytic efficacy of recombinant urokinase (r-UK) and pro-urokinase (r-proUK) in the presence and absence of truncated forms of plasminogen. Due to differences in their structures, these modified proteins are more readily activated to plasmin than the circulating form of plasminogen. Use of such modified substrates for plasminogen activators may improve the clinical outcome in patients treated for a variety of thrombotic diseases. Lys-plasminogen (46 units) or mini-plasminogen (in units of equivalent chromogenic activity), in conjunction with r-UK (7,500 units), were administered in the absence of heparin to dogs (9 – 11 kg) in which a radiolabelled thrombus was formed in a femoral artery. Fibrinolysis was measured as a loss of radioactivity from the clot. After intra-arterial administration of the agents, clot lysis was 48 ± 8%, 50 ± 9% and 75 ± 2% in the presence of r-UK + vehicle, r-UK + lys-plasminogen, and r-UK + mini-plasminogen, respectively. When these treatment groups were examined in the presence of heparin (500 units + 350 units/hour) in a second study, r-UK (2,000 units) produced clot lysis of 54 ± 35; addition of lys- or mini-plasminogen to the regimen resulted in lysis of 62 ± 9% and 46 ± 10%, respectively. A third phase of the study examined r-proUK (1,000 units) with heparin; in this case, lysis was 51 ± 9% in the presence of vehicle, but 55 ± 17% and 10 ± 5% when lys- and mini-plasminogen were administered, respectively. Flow restoration, measured in the femoral artery in each experiment, generally paralleled the lytic profile. The results indicate that supplementation with mini-plasminogen is only useful when added to a lytic regimen in the absence of heparin, and that lys-plasminogen, in conjunction with either of the lytic agents, does not improve clot lysis in this canine model.