Recombinant Pro-Urokinase Requires Heparin for Optimal Clot Lysis and Restoration of Blood Flow in a Canine Femoral Artery Thrombosis Model

Abstract

SummaryHeparin 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; 500 U bolus + 350 U/h). This dose of heparin increased the activated partial thromboplastin time (APTT) by at least 1.5 times the control level for the 4 h observation period. Group 3 received r-proUK alone at a dose of 100,000 U/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 4 h 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.

PROACT: A Phase II Randomized Trial of Recombinant Pro-Urokinase by Direct Arterial Delivery in Acute Middle Cerebral Artery Stroke

“…25 The thrombolytic potential remains confined to the thrombus but is apparently augmented by the concomitant use of heparin. 21,26 In a canine femoral artery thrombosis model, rpro-UK plus heparin produced a significant increase in thrombus lysis compared with rpro-UK, vehicle plus heparin, and vehicle alone 26 and minimized further thrombus accretion. Other experimental data suggest that heparin doses sufficient to increase the activated partial thromboplastin time by 1.5 times control markedly increase the recanalization efficacy of rpro-UK.…”

A pilot study on systemic thrombolysis followed by low molecular weight heparin in ischemic stroke

“…New strategies to increase the likelihood of complete and partial recanalization are justified because unsatisfactory recanalization rates have been reported with intravenous rt‐PA alone [4–9]. Anticoagulation (AC) therapy, concomitant to rt‐PA treatment, with either unfractionated heparin or low molecular weight heparin (LMWH) could potentially decrease re‐occlusion, as well as increase recanalization rates [10].…”

Intraarterial Thrombolysis Trials in Acute Ischemic Stroke

“…The thrombolytic effect of urokinase is augmented with heparin (18,19). The best thrombolytic drug for use in acute stroke has yet to be determined.…”