A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries.
Tissue factor (TF) is a transmembrane protein that binds factor VII/VIIa, thus activating the extrinsic blood coagulation pathway. Since this pathway appears to be involved in the formation of intravascular thrombi, the anti-rabbit TF monoclonal antibody, AP-1, was produced and tested as an antithrombotic agent in a rabbit model of recurrent intravascular thrombosis. In this model, a plastic constrictor is positioned around the injured rabbit carotid arteries, and flow is monitored with a Doppler flow probe. This produces cyclic flow variation (CFV) in the carotid artery, which is caused by recurrent formation and dislodgment of thrombi at the site of the stenosis. After monitoring CFV pattern for 30 minutes, AP-1 was infused intravenously into nine rabbits at doses of 0.05 to 1.5 mg/kg body weight, and a control monoclonal antibody that does not react with rabbit TF was infused into four additional rabbits. In all rabbits receiving AP-1, CFV was abolished, and a steady normal blood flow was restored, indicating that thrombus formation had been blocked by AP-1. By contrast, in all rabbits that received the control monoclonal antibody, CFV continued unaltered. There was no change in the partial thromboplastin time and ex vivo platelet aggregation to several different agonists after infusion of AP-1, indicating an absence of systemic effects on the coagulation process. We conclude that activation of the extrinsic coagulation pathway has a key role in triggering intravascular thrombosis and that an anti-TF monoclonal antibody is an effective antithrombotic agent that could have therapeutic potential for humans.
Pawashe
A B
AB
Department of Internal Medicine, Yale University, New Haven, Conn. 06510.
Golino
P
P
Ambrosio
G
G
Migliaccio
F
F
Ragni
M
M
Pascucci
I
I
Chiariello
M
M
Bach
R
R
Garen
A
A
Konigsberg
W K
WK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D002339:Carotid Arteries / Q000378:metabolism; D016893:Carotid Stenosis / Q000150:complications* / Q000628:therapy*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D011817:Rabbits; D013925:Thromboplastin / Q000276:immunology* / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D013925:Thromboplastin