Thrombolysis with recombinant tissue plasminogen activator in atherosclerotic thrombotic occlusion

Human tissue plasminogen activator holds promise for the dissolution of coronary thrombi by intravenous administration and without systemic anticoagulation. Prior animal experiments have been conducted only in vessels without disease. To test the thrombolytic efficacy of recombinant tissue plasminogen activator in the presence of diseased intima, an established model of atherosclerosis was utilized. The aorta of 16 New Zealand white rabbits (2 to 3 kg) was made atherosclerotic by balloon endothelial denudation and concurrent 1% cholesterol feeding for 8 weeks. An aged (24 hour) heterologous (human) clot, labeled with 1-125 fibrinogen was injected into the distal aorta and produced thrombotic occlusion. After 1 hour of thrombosis (control period), recombinant tissue plasminogen activator (100,000 IU ≌ 1 mg protein, n = 6) or streptokinase (100,000 IU, n = 5) or saline solution (n = 5) was systemically infused over 30 minutes. Serial blood samples, obtained to determine fractional change in blood radioactivity over time, showed a fourfold increase of blood radioactivity after tissue plasminogen activator and streptokinase infusion compared with the control period (47,400 ± 3,300 [mean ± standard error] versus 11,800 ± 300 counts/min, p ã 0.001). Time to 50% of maximal thrombolysis was 41 ± 14 minutes (± standard deviation) for tissue plasminogen activator versus 63 ± 16 minutes for streptokinase (p < 0.01). In six of six rabbits receiving tissue plasminogen activator and four of five rabbits receiving streptokinase, reestablishment of distal aortic flow was detected via the indwelling catheter within 25 minutes of drug infusion. In the five control rabbits, reperfusion did not occur and there was no change in blood radioactivity over time (up to 2 hours). Gross and histologic studies of the aortas confirmed thrombolysis and diffuse intimai disease at the site of balloon denudation. Thus, in atherosclerotic arteries, intravenous infusion of recombinant tissue plasminogen activator rapidly lysed human thrombus and resulted in reperfusion.