Tissue Factor in Cardiovascular Diseases

Abstract

Abstract-Tissue factor (TF), formerly known as thromboplastin, is the key initiator of the coagulation cascade; it binds factor VIIa resulting in activation of factor IX and factor X, ultimately leading to fibrin formation. TF expression and activity can be induced in endothelial cells, vascular smooth muscle cells, and monocytes by various stimuli such as cytokines, growth factors, and biogenic amines. These mediators act through diverse signal transduction mechanisms including MAP kinases, PI3-kinase, and protein kinase C. Cellular TF is present in three pools as surface, encrypted, and intracellular protein. TF can also be detected in the bloodstream, referred to as circulating or blood-borne TF. Elevated levels of TF are observed in patients with cardiovascular risk factors such as hypertension, diabetes, dyslipidemia, and smoking as well as in those with acute coronary syndromes. TF may indeed be involved in the pathogenesis of atherosclerosis by promoting thrombus formation; in addition, it can induce migration and proliferation of vascular smooth muscle cells. As a consequence, therapeutic strategies have been developed to specifically interfere with the action of TF such as antibodies against TF, site-inactivated factor VIIa, or recombinant TF pathway inhibitor.

Tissue factor gene promoter haplotype associates with carotid intima-media thickness in subjects in cardiovascular risk prevention

“…Moreover, although evaluation in silico in another study did not indicate effects of the 4 investigated polymorphisms on transcription factor binding [11], gel shift experiments by Terry et al indeed demonstrated such effects of the Del-1208Ins polymorphism, providing a possible explanation for the genotypic differences in TF expression and activity [17]. An influence on local TF activity in the vessel wall may in turn modulate processes involved in atherosclerosis such as inflammation and VSMC migration and proliferation [2,9,10,[25][26][27][28][29][30], which could result in measurable differences in C-IMT as observed in this study. We cannot rule out, however, that the observed effect of A/G TF promoter haplotype on C-IMT may be explained by linkage disequilibrium with other genetic variants influencing the atherosclerotic process.…”

“…Indeed, experimental studies in vitro and in vivo have shown involvement of TF in inflammation and VSMC migration/proliferation mediated via intracellular signalling by the TF cytoplasmic tail and/or TF:FVIIa-promoted extracellular proteolytic cascades and activation of protease-activated receptors (PARs) [2,9,10,[25][26][27][28][29][30]. The association between tertiles of TF and C-IMT, tested by multivariable linear regression analysis, was analysed in the subgroup of subjects (n = 120) who underwent plasma TF level determinations.…”

“…In the normal vessel, TF is constitutively expressed in adventitial fibroblasts and at low levels in scattered cells in the tunica media [1]. TF expression can be induced in both vascular and non-vascular cells by numerous pro-atherogenic stimuli [2,3]; in atherosclerotic vessels, enhanced TF expression is indeed observed in vascular smooth muscle cells (VSMC), monocytes/macrophages, Abbreviations: Bif, bifurcation; C-IMT, carotid intima-media thickness; CCA, common carotid artery; HDL, high-density lipoprotein; ICA, internal carotid artery; LDL, low-density lipoprotein; MI, myocardial infarction; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism; TF, tissue factor.…”

“…foam cells and endothelial cells [1][2][3][4][5]. Furthermore, TF is present in the necrotic core of atherosclerotic lesions, mainly associated with macrophage or lymphocyte-derived microparticles [5,6], and is considered to be an important determinant of plaque thrombogenicity upon rupture [7,8].…”

“…Furthermore, TF is present in the necrotic core of atherosclerotic lesions, mainly associated with macrophage or lymphocyte-derived microparticles [5,6], and is considered to be an important determinant of plaque thrombogenicity upon rupture [7,8]. Recent findings also indicate important non-hemostatic functions of TF in inflammation, cell migration and proliferation [2,9,10]. This suggests a role of TF not only in latestage thrombotic events, but also at early stages in the process of atherosclerosis.…”