Monoclonal antibody against tissue factor shortens tissue plasminogen activator lysis time and prevents reocclusion in a rabbit model of carotid artery thrombosis.

Abstract

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 ws 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 microg/kg bolus plus 8 microg x kg(-1) x 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 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.

• Authors: M Ragni, P Cirillo, I Pascucci, A Scognamiglio, D D'Andrea, N Eramo, M D Ezekowitz, A B Pawashe, M Chiariello, P Golino
• Journal: Circulation (Circulation) Vol. 93 Issue 10 Pg. 1913-8 (May 15 1996) ISSN: 0009-7322 [Print] United States
• PMID: 8635271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Fibrinopeptide A
• Fibrinogen
• Thromboplastin
• Plasminogen Activators
• Tissue Plasminogen Activator

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Carotid Artery Thrombosis (therapy)
• Female
• Fibrinogen (analysis)
• Fibrinopeptide A (analysis)
• Male
• Plasminogen Activators (therapeutic use)
• Platelet Aggregation
• Rabbits
• Thromboplastin (physiology)
• Tissue Plasminogen Activator (pharmacology)