Tissue Factor

This issue of Seminars in Thrombosis and Hemostasis focuses on tissue factor (TF) in hemostasis and thrombosis, on the physiological importance of TF and its source in the organism, and on its role in infections and sepsis, atherosclerosis, trauma, and cancer.

In the first article, Tilley and Mackman review the role of TF in hemostasis and thrombosis. TF is the major initiator of the clotting process and is released by many tissues. Tissue expression varies, however, and some express little, whereas others express more. Studies in mice that express low levels of TF confirmed that low levels protect against thrombosis, and are associated with bleeding and disturbances of the reproductive cycle. Of special interest is the presence of blood-borne TF because it appears to play a role in thrombogenesis. Abnormal TF expression is seen in patients with atherosclerosis, cancers, and sepsis. Disturbances also contribute to pregnancy complications. This brief review should give readers an appreciation of the role of TF in health and disease.

Østerud and Bjørklid describe the sources of TF. There is great variability in the quantities of TF in various organs, and highly vascularized organs appear to have the highest concentrations. In contrast to the prevailing concept that TF is released from endothelial cells upon injury, these cells appear to contain very little TF. Most of it is found in the adventitia of blood vessels. Recent studies suggest that there is TF in the circulating blood, likely derived from monocytes and microparticles. In addition, platelets appear to be devoid of TF, but platelets are involved in decrypting TF activity from monocytes; in this process, TF is transferred to activated platelets. This article sheds a new light on the role of TF in coagulation.

In the next article Versteeg and Ruf explore the role of TF in other physiological and pathological events. TF plays a major role in inflammation, tumor growth, and angiogenesis. The complexes of TF and factor VIIa facilitate direct and indirect cell signaling that is an essential part of the nonhemostatic functions. The complexes activate protease-activated receptor 2 and thereby regulate gene transcription and protein translation, cell proliferation and survival, and cell motility and integrin activation. These complex events are reviewed expertly in this article.

Levi and coworkers review the role of TF in inflammatory conditions. The interrelationship between coagulation and inflammation has become better understood in the last few years, and there appears to be considerable cross-talk between the two systems. An inflammatory response leads to activation of the clotting system, potentially resulting in disseminated intravascular coagulation and multiple organ system failure. Activation of the coagulation system, in turn, leads to the release of inflammatory cytokines that further stimulate the coagulation system. TF is a key player in these events and its relationship to tissue factor pathway inhibitor (TFPI) is of great importance. This review addresses these interrelationships superbly.

van der Wal and associates review the role of TF in the process of atherosclerosis and its consequences (i.e., coronary artery disease, unstable angina, and myocardial infarction). The role of TF in atherosclerosis goes far beyond its ability to trigger local thrombi formation at sites of atherosclerotic plaque ruptures. TF appears to be involved directly in plaque formation and propagation. The authors comprehensively discuss these issues with considerable emphasis on vulnerable plaques that seem to be the morphologic and functional basis for most complications of coronary artery disease.

Gando describes the role of TF in organ dysfunction in trauma patients. TF appears to play a pivotal role in this process by triggering the activation of the coagulation system leading to intravascular fibrin deposition and by triggering the inflammatory responses. Elevated TF levels have been described frequently in trauma patients. TF may derive from injured tissues or from monocytes and macrophages. In addition, a downregulation of physiological inhibitor mechanisms, most notably TFPI, further contributes to organ dysfunction. The author corroborates these events by extensive studies of hemostasis and inflammatory markers in trauma patients. The multiple organ dysfunction syndrome appears to be closely linked to the availability of TF in trauma patients.

Rak and coworkers review the role of TF in cancer and angiogenesis comprehensively. Cancer and thrombosis have long been recognized as closely related events and TF undoubtedly plays a major role in the pathogenesis of thrombosis, especially venous thromboembolism. However, TF appears also to be linked to tumor growth, metastasis, and angiogenesis. Cancer cells express high levels of TF and oncogenic events in cancer cells increase TF levels. These interrelationships are discussed extensively by the authors. Based on the present understanding, anti-TF treatment may potentially become an additional modality to the management of cancer patients.

Laterre and associates summarize the data available on the pharmacological inhibition of TF. Both antibodies to TF and recombinant TFPI (rTFPI) have been studied in animal models of sepsis. rTFPI has also been investigated in healthy volunteers and in patients with sepsis. Most data support the potential benefit of rTFPI on the coagulation disturbances seen in sepsis, on inflammation, and at least in animal models, on survival. Limited clinical data did not reveal an improvement in survival, but more studies are needed to evaluate the therapeutic potential of TF blockade fully.

My thanks and appreciation go to Professor Marcel Levi for assembling this interesting and thought-provoking issue, and to the authors who expertly reviewed the role of TF in health and disease.