Inhibition of tissue factor limits the growth of venous thrombus in the rabbit.
Antibody mediated inhibition of tissue factor (TF) function reduces thrombus size in ex vivo perfusion of human blood over a TF-free surface at venous shear rates suggesting that TF might be involved in the mechanism of deep vein thrombosis. Moreover, TF-bearing monocytes and polymorphonuclear (PMN) leukocytes were identified in human ex vivo formed thrombi and in circulating blood. To understand the role of TF in thrombus growth, we applied a rabbit venous thrombosis model in which a collagen-coated thread was installed within the jugular vein or within a silicon vein shunt. The effect of an inhibitory monoclonal antirabbit TF antibody (AP-1) or Napsagatran, a specific inhibitor of thrombin, was quantified by continuously monitoring 125I-fibrinogen incorporation into the growing thrombi. The antithrombotic effect obtained with the anti-TF antibody was comparable to the effect observed with the thrombin inhibitor napsagatran suggesting that in this animal model the thrombus propagation is highly TF dependent. Immunostaining revealed that TF was mostly associated with leukocytes within the thrombi formed in the jugular vein or in the silicon vein shunt. Ex vivo perfusion experiments over collagen-coated coverslips demonstrated the presence of TF-bearing PMN leukocytes in circulating blood. The results suggest that in rabbits venous thrombus growth is mediated by clot-bound TF and that blocking the TF activity can inhibit thrombus propagation.
Himber
J
J
Hoffmann-La Roche Ltd, Pharma Division, Preclinical Research, Basel, Switzerland. jacques.himber@roche.com
Wohlgensinger
C
C
Roux
S
S
Damico
L A
LA
Fallon
J T
JT
Kirchhofer
D
D
Nemerson
Y
Y
Riederer
M A
MA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001807:Blood Vessel Prosthesis; D005340:Fibrinogen / Q000378:metabolism; D007150:Immunohistochemistry; D007601:Jugular Veins; D007962:Leukocytes / Q000737:chemistry; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D013925:Thromboplastin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D020246:Venous Thrombosis / Q000209:etiology* / Q000473:pathology
D000911:Antibodies, Monoclonal; D009281:Naphthalenes; D010880:Piperidines; D005340:Fibrinogen; D013925:Thromboplastin; C087198:napsagatran