Tissue factor at the crossroad of coagulation and cell signaling

Abstract

The tissue factor (TF) pathway plays a central role in hemostasis and thrombo-inflammatory diseases. Although structure-function relationships of the TF initiation complex are elucidated, new facets of the dynamic regulation of TF's activities in cells continue to emerge. Cellular pathways that render TF non-coagulant participate in signaling of distinct TF complexes with associated proteases through the protease-activated receptor (PAR) family of G protein-coupled receptors. Additional co-receptors, including the endothelial protein C receptor (EPCR) and integrins, confer signaling specificity by directing subcellular localization and trafficking. We here review how TF is switched between its role in coagulation and cell signaling through thiol-disulfide exchange reactions in the context of physiologically relevant lipid microdomains. Inflammatory mediators, including reactive oxygen species, activators of the inflammasome, and the complement cascade play pivotal roles in TF procoagulant activation on monocytes, macrophages and endothelial cells. We furthermore discuss how TF, intracellular ligands, co-receptors and associated proteases are integrated in PAR-dependent cell signaling pathways controlling innate immunity, cancer and metabolic inflammation. Knowledge of the precise interactions of TF in coagulation and cell signaling is important for understanding effects of new anticoagulants beyond thrombosis and identification of new applications of these drugs for potential additional therapeutic benefits.

Accumulation of tissue factor in endothelial cells promotes cellular apoptosis through over-activation of Src1 and involves β1-integrin signalling

“…The accumulation of TF within the endothelial cells has been reported to contribute to the progression of chronic pathological disorders including cardiovascular disease [1][2][3][4] and cancer [4][5][6][7]. This occurs in addition to the procoagulant property of TF and is associated with the ability to regulate cellular processes such as migration and proliferation [8][9][10][11][12][13][14].…”

Xenotransplantation: Current Status in Preclinical Research

“…In the context of xenotransplantation, the assault by antibodies and complement-activated pig endothelial cells converts endothelial cells from an anticoagulant phenotype to a procoagulant state, leading to vascular destruction, and infiltration by various immune cells (87). Both recipient-and donor-derived TF contribute to activation of the extrinsic coagulation cascade (85,88). The molecular incompatibilities between primate and pig coagulation-anticoagulation systems exaggerate this process ( Figure 3B).…”

“…The porcine TF (pTF) pathway inhibitor is an ineffective inhibitor of the human Xa factor and may ineffectively shut down the activation of the major TF. Pig TBM (pTBM) binds only weakly to primate thrombin, leading to levels of activated PC that are insufficient to inhibit coagulation, resulting in thrombotic microangiopathy in pig grafts within a matter of weeks (85). Porcine vWF spontaneously could aggregate primate platelets through GPIb receptors even in the absence of shear stress (86).…”

COVID‐19 hypothesis: Activated protein C for therapy of virus‐induced pathologic thromboinflammation

“…In only the past 7 years have the terms thromboinflammation and immunothrombosis been used 7‐9 . These terms are useful to denote extensive interactions between the body’s innate and acquired immune systems and coagulation systems; notably, plasma coagulation proteases have a wide range of direct and indirect effects on many immune system cell types, which enable crosstalk between circulating proteases and host defense immune cell responses 7‐13 . Healthy crosstalk between circulating proteases and cells is critical for providing the optimal benefits of protective inflammation reactions and protective coagulation reactions to combat invading pathogens, such as SARS‐CoV‐2.…”