Tissue Factor in the Pathogenesis of Atherosclerosis

Abstract

Thrombosis is integral to the development and progression and clinical sequelae of atherosclerosis. Acute thrombosis can occur spontaneously, leading to catastrophic arterial occlusion and resulting in myocardial infarction, unstable angina, stroke, and sudden death (1,2). Acute thrombosis also occurs as a complication of arterial bypass surgery, balloon angioplasty, atherectomy, or coronary artery stenting (3-5). Non-occlusive thrombus is an important component of the atherosclerotic plaque. Thrombus is comprised principally of platelets and fibrin. White blood cells and circulating proteins are also trapped within the platelet-fibrin thrombus. Activated platelets release a variety of growth factors and cytokines that have been implicated in vessel inflammation and in vascular smooth muscle cell (SMC) proliferation and migration (6,7). Thrombin (8) and factor XlXa (9,10) also have direct effects on SMC and may play a role in the development of intimal hyperplasia. In addition, products secreted by leukocytes trapped within the thrombus may have direct effects on the vessel wall. Tissue factor (TF) is a membrane-bound glycoprotein that initiates coagulation (11,12).Human TF consists of three domains: a short cytoplasmic domain of 19 residues, a single transmembrane domain of 23 residues, and a large extracellular domain of 219 residues. In addition, there is a 32 residue amino-terminal leader sequence which is cleaved to produce the mature molecule. TF binds to factor VIIA/IIa, and the resulting complex acts as a catalyst for the conversion of factors IX and X to IXa and Xa respectively, triggering the clotting cascade. This ultimately leads to the generation of thrombin, which in turn cleaves fibrinogen to fibrin, the major ingredient of the thrombus. Recent studies suggest that the accumulation of TF in atherosclerotic plaques plays a major role in determining plaque thrombogenicity. TF is also rapidly induced in the vessel wall as a consequence of acute arterial injury. Both phenomena may be important in the thrombotic complications of atherosclerotic heart disease.

The role of tissue factor in normal pregnancy and in the development of preeclampsia: A review

“…Today, a wide range of other biological effects of TF is under study. Hyperexpression of TF with subsequent shift of the hemostatic equilibrium towards hypercoagulation has been observed in cardiovascular diseases, diabetes, metabolic syndrome, inflammatory conditions, generalization of malignant diseases, and also in cases of pregnancy complications such as repeated miscarriages and preeclampsia 20,21 . In all of these clinical situations, two basic pathogenic mechanisms associated with the activation of TF apply and they potentiate each other: thrombotization and inflammation 1 .…”

Native and Oxidized Low Density Lipoprotein Induction of Tissue Factor Gene Expression in Smooth Muscle Cells Is Mediated by Both Egr-1 and Sp1

“…[1][2][3]. In atherosclerotic plaques, enhanced TF expression has been detected in association with smooth muscle cells (SMC), macrophages, the lipid-rich necrotic core, and the endothelium overlying the plaque (4 -7).…”

Resveratrol, a Polyphenolic Compound Found in Wine, Inhibits Tissue Factor Expression in Vascular Cells

“…21,22 Accumulation of TF in atherosclerotic plaques is thought to play a major critical role in determining plaque thrombogenicity. 17 Because thrombosis is the integral part of the atherosclerosis and coronary artery disease, it is possible that the decreased risk of coronary heart disease associated with consumption of red wine, in part, could be caused by its ability to suppress the expression of TF in the arterial wall. In the present study, we have examined the effect of resveratrol on induction of TF expression in both endothelial cells and monocytes.…”