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

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 proteolytic 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 tissue necrosis factor, interleukins, adhesion molecules and many other intracellular signals in different cell types. Such resulting 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 cardiovascular 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 protein 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-inflammation circuit, offering not only antithrombotic but anti-inflammatory significance in the prevention of cardiovascular complications.

Genetic Determined Low Response to Thienopyridines is Associated with Higher Systemic Inflammation in Smokers

“…It has been well established that inflammation can cause thrombosis and thrombosis can mediate inflammation [30]. These processes have several connecting points of which tissue factor (TF) has been shown to be critical for and plays a central role in the inflammationthrombosis circuit [31]. The role of TF in inflammation is mediated by blood coagulation.…”

Pathogenesis, clinical and laboratory aspects of thrombosis in cancer

“…Upregulation of TF, defined as the result of enhanced TF expression/availability for exposure to FVII zymogen inducing FVII activation [16] is a hallmark of malignancy. A variety of oncogenic events in cancer cells (e.g., expression of mutant K-ras, EGFR, PTEN or p53) lead to an increase in TF levels and activity [17].…”

Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody–induced fetal injury

“…1 Tissue factor (TF), the major cellular initiator of the coagulation protease cascade, plays important roles in both thrombosis and inflammation. 2 The coagulation cascade is initiated by the complex of TF and factor VIIa (FVIIa). The TF:FVIIa complex activates its substrates factor X and factor IX by limited proteolysis.…”