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 +/- 3%; 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.