(Circulation. 1996;93:1913-1918.)
© 1996 American Heart Association, Inc.
Articles |
Monoclonal Antibody Against Tissue Factor Shortens Tissue Plasminogen Activator Lysis Time and Prevents Reocclusion in a Rabbit Model of Carotid Artery Thrombosis
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993, and previously published in abstract form (Circulation. 1993;88[pt 2]:I-615).
From the Department of Internal Medicine, Division of Cardiology, 2nd School of Medicine, University of Naples, Italy, and the Department of Internal Medicine, Division of Cardiology, Yale University, New Haven, Conn (M.D.E., A.B.P.).
Correspondence to Paolo Golino, MD, PhD, Division of Cardiology, 2nd School of Medicine, University of Naples, Via Sergio Pansini 5, 80131 Naples, Italy.
Background Tissue factor (TF)–dependent activation of the coagulation is important in the pathophysiology of intravascular thrombus formation. We tested the effects of a monoclonal antibody against TF (AP-1) on lysis time induced by tissue-type plasminogen activator (TPA) and on reocclusion rate in a rabbit model of carotid artery thrombosis.
Methods and Results Intravascular thrombosis was obtained by placing an external constrictor around carotid arteries with endothelial injury. Carotid blood flow velocity was measured continuously with a Doppler flow probe. Thirty minutes after thrombus formation, the rabbits received either AP-1 (0.15 mg/kg IV, n=8) or placebo (n=8). All rabbits also received TPA (80 µg/kg bolus plus 8 µg·kg-1·min-1 infusion for up to 90 minutes or until reperfusion was achieved) and heparin (200 U/kg IV as a bolus). At reperfusion, TPA was discontinued, and the rabbits were followed for an additional 90 minutes. AP-1 shortened lysis time from 44±8 minutes (mean±SEM) in control rabbits to 26±7 minutes in AP-1–treated rabbits (P<.01). Reocclusion occurred in all control rabbits in 10±3 minutes, whereas it occurred in only two of eight AP-1–treated rabbits in 72 and 55 minutes (P<.01). No changes in prothrombin time and ex vivo platelet aggregation in response to various agonists were observed after AP-1 administration, indicating the absence of systemic effects by this antibody.
Conclusions TF exposure and activation of the extrinsic coagulation pathway play an important role in prolonging lysis time and mediating reocclusion after thrombolysis in this model. AP-1, a monoclonal antibody against TF, might be suitable as adjunctive therapy to TPA.
Key Words: thrombolysis • tissue factor • coagulation
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