(Circulation. 1995;91:1175-1181.)
© 1995 American Heart Association, Inc.
Articles |
Thrombolysis and Reocclusion in Experimental Jugular Vein and Coronary Artery Thrombosis
Effects of a Plasminogen Activator Inhibitor Type 1–Neutralizing Monoclonal Antibody
From the Center for Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research (B.J.B., M.L., J.W.t.C.); the Department of Experimental Cardiology (R.C., M.J.J.); and the Department of Biochemistry (H.P.), Academic Medical Center, University of Amsterdam, the Netherlands.
Correspondence to Bart J. Biemond, MD, Center for Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic Medical Center, F4-237, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Background Thrombolytic therapy for acute myocardial
infarction is often complicated by reocclusion of the initially
reperfused artery. Platelets have been shown to play an important role
in this process. We determined the contribution of plasminogen
activator inhibitor type 1 (PAI-1), stored in the 
-granules of
platelets, to thrombolysis resistance and to reocclusion.
Methods and Results In a rabbit jugular vein thrombosis model, the effect of a PAI-1–neutralizing monoclonal antibody (CLB-2C8) on thrombolysis and thrombus growth was assessed. The effect on reperfusion, reocclusion, and duration of vessel patency was studied in a canine model of coronary artery thrombosis superimposed on a high-grade stenosis and endothelial damage. In the rabbit jugular vein model, the intravenous administration of 1 mg/kg anti–PAI-1 antibody significantly enhanced the endogenous thrombolysis from 5.5±1.3% in the animals treated with a nonspecific monoclonal antibody (control) to 13.7±2.6% in the animals treated with the anti–PAI-1 antibody. Thrombus growth was reduced significantly, from 41.3±2.6% in the control animals to 22.8±2.8% in the animals treated with the anti–PAI-1 antibody. In combination with a single bolus injection of recombinant tissue-type plasminogen activator (rTPA; 0.25 mg/kg), the anti–PAI-1 antibody reduced thrombus growth significantly, from 21.5±2.7% in the animals treated with rTPA alone to 12.2±2.6% in the animals treated with rTPA and the antibody. No additional effect of the anti–PAI-1 antibody was observed on rTPA-induced thrombolysis. In the canine coronary artery thrombosis model, the administration of a suboptimal dose of rTPA (0.45 mg/kg) induced reperfusion in 7 of the 8 dogs after 19.5±8.2 minutes. Reperfusion was followed by reocclusion in all animals after 3.3±2.6 minutes. Administration of the anti–PAI-1 antibody in combination with rTPA significantly reduced time to reperfusion (8.1±5.2 minutes) and delayed the occurrence of reocclusion to 11.6±12.5 minutes.
Conclusions Administration of the anti–PAI-1 antibody (CLB-2C8) results in increased endogenous thrombolysis and inhibition of thrombus growth in a venous thrombosis model in rabbits and facilitated reperfusion and reduction of reocclusion in a canine model of coronary artery thrombosis.
Key Words: plasminogen activators • occlusions • arteries • thrombosis
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