Past, Present, and Future

This issue of Arteriosclerosis, Thrombosis, and Vascular Biology contains 4 reviews on tissue factor (TF) and 1 on tissue factor pathway inhibitor (TFPI). One review on TF will be published in a later issue. In this editorial, we will briefly revisit the major advances in the field, highlight some of the current controversies, and discuss some of the future challenges. TF (also known as tissue thromboplastin or coagulation factor III) was first identified as a constituent of tissue that when added to plasma activated the clotting cascade— hence the name tissue factor. TF was first purified in 1985,1 and this subsequently led to the cloning of the TF cDNA and gene.2–5 In 1989 Drake and colleagues6 proposed that TF around blood vessels forms a “hemostatic envelope” that initiates clotting after vessel injury. The crystal structure of the extracellular domain of TF bound to Factor VIIa (FVIIa) was reported in 1996.7 In the same year it was discovered that inactivation of the mouse TF gene resulted in embryonic lethality.8–10 Taken together, these studies indicated that TF was essential for hemostasis. Activation of the clotting cascade leads to the generation of thrombin that cleaves fibrinogen to fibrin as well as activates platelets (Figure). In 1999, the late Yale Nemerson and colleagues11 reported that there was TF in blood of healthy individuals. They showed that this so-called “blood-borne” or “circulating” TF enhanced thrombosis in an ex vivo model. It was argued that, unlike vessel wall TF, circulating TF would be continuously delivered to the clot and participate in its growth.12,13 Butenas and colleagues14 believe that levels of circulating TF in healthy individuals are extremely low and unlikely to contribute to clotting. However, Monroe and colleagues noted that TF was present throughout thrombotic clots whereas it was only present at the edges of hemostatic clots, suggesting that circulating TF is incorporated into thrombotic clots.15 Clearly, further studies are needed to determine the roles of circulating TF in hemostasis and thrombosis in health and disease. Other reports indicated that platelets contain very low levels of TF (possibly by binding TF-positive microvesicles, also referred to as microparticles), contain a premRNA (that can be spliced into a mature TF mRNA on activation of the cells), and can synthesize TF (albeit very low levels).16–18 In contrast, other investigators could not detect TF activity in platelets.14 Similar to circulating TF, platelet TF has been proposed to provide an additional source of TF that may enhance the clotting reaction. However, at present there is no experimental evidence to support this hypothesis. Another controversy arose after the description of a new form of TF called alternatively spliced TF (altTF; also called soluble TF).19 Initial reports suggested that altTF was thrombotic.20 To date this protein has not been isolated from human plasma. Importantly, this truncated protein lacks exon 5 (which encodes the substrate binding site) and exon 6 (which encodes the transmembrane domain that localizes TF in the membrane), both of which are required for TF cofactor activity.21 Indeed, subsequent studies indicate that altTF has no procoagulant activity.22 Therefore, it seems that altTF is unlikely to contribute to either hemostasis or thrombosis. One study suggested a role for altTF in tumor growth and angiogenesis.14 From the Division of Hematology and Oncology, Department of Medicine (N.M.), University of North Carolina at Chapel Hill; and Aab Cardiovascular Research Institute and Department of Medicine (M.T.), University of Rochester, NY. Correspondence to Nigel Mackman, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7035. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2009;29:1986-1988.) © 2009 American Heart Association, Inc.