Comparative study of the activity of high and low molecular weight urokinase in the presence of fibrin.

The fibrinolytic or thrombolytic activity of low molecular weight urokinase (LMW-UK) and high molecular weight urokinase (HMW-UK) is not significantly different when measured in a bovine fibrin plate method, in a circulating plasma system containing a 125I-labelled human fibrin clot, or on 125I-fibrin films in culture plates using normal or alpha 2-antiplasmin depleted human plasma. In a human fibrin plate method however HMW-UK was found to be more active than LMW-UK. In a purified system on human 125I-fibrin films the activation of native or modified human plasminogen by HMW-UK was also found to be more effective than by LMW-UK. Using a clot lysis test system we did not observed a different inhibition of LMW-UK and HMW-UK upon incubation in human plasma. This is in contrast with previous reports that HMW-UK is inhibited more rapidly in human plasma than LMW-UK. In a purified system the inhibition rate of LMW-UK and HMW-UK by alpha 2-antiplasmin is the same (rate constants at 25 degree C of 167 +/- 9 M-1s-1 and 171 +/- 5 M-1s-1 respectively). The clinical trials available at present used doses of urokinase which were in excess of those required to obtain a maximal fibrinolytic effect. This might explain why in these trials no difference was observed between the thrombolytic effect of LMW-UK and HMW-UK, while in vitro HMW-UK appeared to be more effective. However, one should always be careful to extrapolate in vitro observations as such to the in vivo situation encountered during thrombolytic therapy.