Recombinant pro-urokinase requires heparin for optimal clot lysis and restoration of blood flow in a canine femoral artery thrombosis model

Heparin is often used as an adjunct to thrombolytic therapy in order to prevent reocclusion of the patent vessels in patients with thrombotic disease. Controversy exists as to whether heparin is required for effective clot lysis with tissue-type plasminogen activator, while in vitro data and small scale clinical trials have suggested an enhancement of pro-urokinase efficacy by heparin. The present study was conducted to determine whether heparin pre-treatment is required to produce optimal clot lysis and blood flow restoration in response to recombinant pro-urokinase (r-proUK). In four groups of dogs, blood clots labelled with ¹²⁵Iodine were formed in the femoral artery and were monitored continuously for loss of counts as an indicator of clot lysis. Femoral artery blood flow was measured simultaneously. Group 1 received vehicle (n=5), while group 2 was given vehicle + heparin (n=6; 500U bolus + 350U/h). This dose of heparin increased the activated partial thromboplastin time (APTT) by at least 1.5 times the control level for the 4h observation period. Group 3 received r-proUK alone at a dose of 100,000U/kg (50% given as a 1-min bolus injection, 50% as a 30 min infusion) (n=8), while group 4 was treated with the same dose of r-proUK in the presence of heparin as described (n=8). Clot lysis at 4h in groups 1 and 2 was 26±3% and 28±5%, respectively; flow was not restored in either group. In group 3, clot lysis was 50±4% while group 4 showed lysis of 85±5% (p<0.05). However, flow was not restored in any dog in group 3, while five of eight dogs in group 4 showed complete restoration of blood flow. In the remaining three dogs, flow was restored to 70-91% of control levels. The data suggest that a regimen of heparin pretreatment with continued infusion markedly increases the efficacy of r-proUK in this model and results in significant restoration of blood flow.