Thrombolytic Therapy with Tissue Plasminogen Activator: Why Prolonged Continuous Infusion is not the Best Approach

Abstract

Continuous infusion has been assumed to be the optimal way of administering every thrombolytic agent approved for clinical use. However, this simplistic approach fails to take advantage of differences in properties of thrombolytic agents that could be exploited to increase efficacy as well as safety. In particular, continuous infusion is not necessary when using thrombolytic agents with strong fibrin binding and is not the optimal way of administering recombinant tissue plasminogen activator (r-tPA or alteplase). Once given by intraclot injection, alteplase binds to fibrin clot, and once bound to clot, its activity as a plasminogen activator increases several hundred-fold, also known as fibrin selectivity. Once the clot has been laced with tPA, prolonged fibrinolysis ensues, obviating the need for prolonged infusions. Forty-five patients with subclavian, jugular, or central venous thrombosis (SJ-CVT) and 56 patients with acute deep vein thrombosis of the lower extremity (DVT-LE) were treated with once daily intraclot pulse spray injection of tPA without prolonged infusions of tPA, but with full systemic anticoagulation. Initial protocols used high doses of tPA (20-40 mg/day for SJ-CVT, and up to 50 mg/day for DVT-LE) but were reduced five- to ten-fold to a maximum of 4 mg/day tPA for SJ-CVT and a maximum of 10 mg/day tPA for DVT-LE after pharmacokinetic studies indicated the higher doses greatly exceeded the amount of tPA that could bind to acute fibrin clot. Venous patency was restored in 34 of 45 (76%) SJ-CVT patients after an average of 2.1 days/treatments and 51 of 56 (91%) of acute DVT-LE patients after an average of 2.7 days/treatments. There was no loss of efficacy with decrease in dose of tPA. No major bleeding complications requiring transfusion were found at either dosing schedule. Elimination of prolonged continuous infusion from thrombolytic regimens using tPA has two advantages. When many venous divisions are thrombosed, the catheter can be moved from one division to the next to load each segment of clot with tPA quickly, instead of having to leave the catheter in one division for prolonged infusion. This allows thrombolysis of many divisions in almost parallel fashion instead of the serial fashion required with conventional thrombolytic therapy. The second advantage is safety, because with termination of intraclot injection, any tPA that reached the systemic circulation during injection is cleared rapidly due to its short half-life (T.5 ≈ 5 min) shortening the duration of circulating tPA, whereas with conventional thrombolytic therapy, elevated systemic tPA levels and suppressed plasminogen activator inhibitor-1 levels are likely to persist as long as the prolonged infusion continues.