Tissue factor upregulation drives a thrombosis–inflammation circuit in relation to cardiovascular complications

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Abstract
The extrinsic coagulation is recognized as an 'inducible' signalling cascade resulting from tissue factor (TF) upregulation by exposure to clotting zymogen FVII upon inflammation or tissue injury. Following the substantial initiation, an array of pro- teolytic activation generates mediating signals (active serine proteases: FVIIa, FXa and FIIa) that lead to hypercoagulation with fibrin overproduction manifesting thrombosis. In addition, TF upregulation plays a central role in driving a thrombosis- inflammation circuit. Coagulant mediators (FVIIa, FXa and FIIa) and endproduct (fibrin) are proinflammatory, eliciting tis- sue necrosis factor, interleukins, adhesion molecules and many other intracellular signals in different cell types. Such result- ing inflammation could ensure 'fibrin' thrombosis via feedback upregulation of TF. Alternatively, the resulting inflammation triggers platelet/leukocyte/polymononuclear cell activation thus contributing to 'cellular' thrombosis. TF is very vulnerable to upregulation resulting in hypercoagulability and subsequent thrombosis and inflammation, either of which presents car- diovascular risks. The prevention and intervention of TF hypercoagulability are of importance in cardioprotection. Blockade of inflammation reception and its intracellular signalling prevents TF expression from upregulation. Natural (activated pro- tein C, tissue factor pathway inhibitor, or antithrombin III) or pharmacological anticoagulants readily offset the extrinsic hypercoagulation mainly through FVIIa, FXa or FIIa inhibition. Therefore, anticoagulants turn off the thrombosis-inflam- mation circuit, offering not only antithrombotic but anti-inflammatory significance in the prevention of cardiovascular com- plications. Copyright # 2004 John Wiley & Sons, Ltd. abbreviations — AcAP, ancylostoma caninum anticoagulant protein; ACE, angiotensin-converting enzyme; AP-1, activator protein-1; APC, activated protein C; AT II, angiotensin-II; AT III, antithrombin III; Cox-1(2), cycloxygenase-1(2); CPB, cardiopulmonary bypass; CRP, C-reactive protein; Egr-1, early growth reponse-1; FBG, fibrinogen; FIIa, thrombin; FVIIa, activated factor VII; FVIIai, active-site inhibited FVIIa; FXa, activated factor X; HC II, heparin cofactor II; HDL, high density lipoprotein; HUVEC, human univernile endothelial cell; ICAM, intracellular adhesion molecule; IL, interleukin; LDL, low density lipoprotein; LMWH, low molecular weight heparin; Lp(a), lipoprotein (a); LPS, lipopolysac- charide; bacterial endotoxin; MAPK, mitogenic activating protein kinase; MCP, monocyte chemotractic protein; NF-B, nuclear factor-kappa B; OxLDL, oxidizaed LDL; PAF, platelet activating factor; PAR, protease activated receptor; PC, protein C; PDE, phosphodiesterase; PDGF, platelet derived growth factor; PGI, protacyclin; PGJ2, prostaglandin J2; PS, protein S; PTK, protein tyrosine kinase; SMC, smooth muscle cell; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TGF, transforming growth factor; TNF-, tissue necrosis factor-alpha; VCAM, vascular adhesion molecule; VEC, vascular endothelial cell; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell

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