Inhibition of tissue factor limits the growth of venous thrombus in the rabbit

Abstract

Summary. 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 125 I-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 TFbearing 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.

Tissue factor and tissue factor pathway inhibitor

“…In a study of venous thrombosis in a rabbit model in which fibrin deposition was quantified on collagencoated threads within either the jugular vein or a siliconcoated vein shunt, an inhibitory monoclonal antibody to tissue factor was as effective as a specific thrombin inhibitor (napsagatran) in blocking thrombus formation [97]. The fact that inhibiting tissue factor activity had such an impact on thrombus growth in the silicon vein shunt is significant and indicates the transfer of active tissue factor from some active component of blood to the surface of the growing thrombus [98].…”

A Selective, Slow Binding Inhibitor of Factor VIIa Binds to a Nonstandard Active Site Conformation and Attenuates Thrombus Formation in Vivo

“…Recently, the tissue factor (TF)-factor VIIa (FVIIa) complex has emerged as an appealing molecular target for various thrombosis-related disorders, including unstable angina, acute myocardial infarction, myocardial ischemia-reperfusion injury, venous thrombosis, sepsis, and glomerulonephritis (7)(8)(9)(10)(11)(12). In addition, there is evidence for a role of TF⅐FVIIa in tumor growth and metastasis (13,14) (reviewed in Ref.…”

Stress repair mechanism activity explains inflammation and apoptosis

“…Factor VII activation by tissue factor initiates the enzymatic interaction and determines its magnitude and location [208,209,212]. Factors IX and X amplify Factor VII thrombin production to moderate levels that energize tissue repair [27,121,215].…”