Tissue factor on the loose.

The enzymatic complex of tissue factor (TF) and the blood coagulation factor VIIa is generally considered to be the initiator of coagulation. Coagulation that occurs at the site of luminal injury to an artery is, along with platelet deposition, the cause of arterial thrombosis, which is the leading cause of death in Western society. Under pathological conditions the intima, the neointima and the atherosclerotic plaque contain active TF. Therefore the initiation of thrombosis is believed to be due to TF present in the wall of the pathologically changed artery. This classical view of thrombosis has been challenged. In this article we review the evidence for the presence of TF activity in various tissues outside the vessel wall, in extracellular form, in encrypted form, and even in plasma. We found TF expression in a variety of cells in culture after growth factor or cytokine stimulation. This TF was often also present in the extracellular matrix, and in addition we found latent TF on the outside of unbroken smooth muscle cells. Freeze-thawing the cells or detergent lysis could activate this TF. We also found TF activity in native whole blood and in plasma. Inhibition of this circulating TF prevented formation of thrombi on collagen-coated glass slides in an ex vivo perfusion system. Furthermore, in a thrombosis model in which rat aorta was injured, TF was found on the intimal surface of the injured aorta. TF activity was measured in a flow chamber, and it was shown that all measurable activity was extracellular. We conclude that blood-borne TF plays a major role in thrombosis. Encryption of TF present in circulation could be a mechanism that prevents thrombosis. Alternatively, circulating TF may be active but below the threshold required for the initiation of blood coagulation.