Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis

Activation of the coagulation system by contact of circulating blood with tissue factor, a component of the extrinsic blood coagulation pathway that is produced in the vessel wall, may represent a pathway for the initiation of thrombosis in atherosclerotic vessels. This hypothesis was tested in vivo in a rabbit femoral artery eversion (inside-out) graft model, in which the adventitia, with its tissue factor, was exposed to circulating blood. Intra-arterial infusion of a neutralizing monoclonal antibody against tissue factor (D3) at a rate of 12 mg/kg over 15 minutes prevented thrombosis of a 7-8-mm eversion graft within a 2-hour observation period in four of five rabbits, whereas with a control antibody infusion (MA-15C5), occlusion occurred within 2 hours in five of six rabbits. In vitro immersion before reinsertion of the arterial segment in a solution containing 2 mg/ml of the control antibody for 30 minutes was associated with occlusion in all six rabbits, whereas pretreatment with D3 was associated with persistent patency in three of nine rabbits. Stepwise logistic-regression analysis of the results with perfusion status as the dependent variable and type of antibody (D3 or MA-15C5), application method (infusion versus immersion), and graft segment length as independent variables yielded a significant difference in frequency of occlusion with the two antibodies (p = 0.016). It is concluded that exposure of tissue factor to flowing blood may constitute a trigger mechanism for platelet-mediated arterial thrombosis.