Safety of catheter-delivered plasmin in patients with acute lower extremity arterial or bypass graft occlusion: Phase I results

Abstract

Background: Current treatment of acute peripheral artery or bypass graft occlusion utilizes catheter-directed thrombolysis of a plasminogen activator (PA). Plasmin is a direct-acting thrombolytic with a striking safety advantage over PA in preclinical models. Objectives: To report the first use of purified plasmin for acute lower extremity arterial or bypass graft thrombosis in a phase I dose-escalation study of a catheter-delivered agent. Methods: Eighty-three patients with non-embolic occlusion of infrainguinal native arteries or bypass grafts were enrolled (safety population) into seven sequential dose cohorts to receive 25-175mg of plasmin by intrathrombus infusion over 5h. Arteriograms were performed at baseline, 2h, and 5h, and subjects were monitored for 30 days for clinical outcomes and laboratory parameters of systemic fibrinolysis. Results: Major bleeding occurred in four patients (4.8%), and minor bleeding alone in 13 (15.7%), with no trend towards more bleeding at higher dosages of plasmin. There was a trend towards lower plasma concentrations of fibrinogen, α2-antiplasmin and α2-macroglobulin with increasing doses of plasmin, but the nadir fibrinogen concentration was >350mgdL-1 at the highest plasmin dose. Individual nadir values were above 200mgdL-1 in 82 of 83 subjects, and were not different in patients with or without bleeding. Thrombolysis (≥50%) occurred in 79% of subjects receiving 125-175mg of plasmin, as compared with 50% who received 25-100mg. Conclusions: Catheter-delivered plasmin can be safely administered to patients with acute lower extremity arterial occlusion at dosages of 25-175mg. © 2012 International Society on Thrombosis and Haemostasis.