Tissue Factor

The Blood Coagulation Cascade

Damage to blood vessel walls exposes Tissue Factor-containing cells from underlying cell layers to the bloodstream. Tissue Factor (TF) is then able to bind in the presence of calcium to Factor VII (FVII), which circulates at low levels in the bloodstream, the calcium forming a bridge between TF and FVII. This sets off an extracellular cascade involving sequential serine protease activations: TF/FVII is activated by auto-cleavage to TF/FVIIa, which along with FVIIIa (cofactor) converts FIX to FIXa, which converts FX to FXa (although TF/FVIIa can also directly convert FX to FXa), which along with FVa (cofactor) converts FII (prothrombin) to FIIa (thrombin), which converts fibrinogen to fibrin, leading to fibrin deposition and the activation of platelets to form blood clots (the activation of FXIII to FXIIIa stabilises the fibrin clot by cross-linking it):

Blood Coagulation Cascade

Feedback Inhibition

Tissue Factor Pathway Inhibitor (TFPI) is an anti-coagulation protein that acts as a Kunitz-type serine protease inhibitor. TFPI is a dual inhibitor, binding to the TF/FVIIa complex to prevent it from acting on its FIX and FX substrates, and by directly inhibiting FXa as well - in fact, the TFPI/FXa complex is a more effective inhibitor of TF/FVIIa than TFPI alone, possibly by forming a large TFPI/FXa/TF/FVIIa complex. Therefore FXa exerts negative feedback on its own production. With the inhibition of the TF/FVIIa complex, additional FIXa and FXa can only be produced through the action of FXIa, which is generated from FXI by thrombin in the later part of the cascade. Therefore, the action of TFPI is not absolute. TFPI is thought to be important in modulating TF-induced thrombogenesis, since inappropriate thrombus formation in blood vessels can cause cardiovascular diseases such as myocardial infarction, stroke, and pulmonary embolism, amongst others.

Inhibition of the Tissue Factor Pathway

A Link between Blood Coagulation and Inflammation

Tissue Factor also has an important role to play in inflammation, since the initiation of the extracellular blood coagulation signalling pathway can trigger an intracellular inflammation-signalling pathway. The activated coagulation factors FVIIa, FXa and FIIa (thrombin) are pro-inflammatory, capable of inducing an inflammatory state via protease-activated receptors (PAR) found on the surface of several cell types. The activation of PAR receptors can induce the expression of a variety of inflammatory molecules, including tissue necrosis factor, interleukins, adhesion molecules (MCP-1, ICAM-1, VCAM-1), and growth factors (VEGF, PDGF, bFGF), amongst others. PARs are G-protein-coupled receptors (GPCRs), where PAR-1, 3 or 4 transmits FIIa signalling, PAR-1, 2 or 3 transmits FXa signalling, and PAR-2 transmits FVIIa signalling. Fibrin is also able to promote an inflammatory response. In addition to PAR receptor activation, the phosphorylation of the cytoplasmic domain of Tissue Factor can lead to intracellular signalling events.

Furthermore, inflammation can promote coagulation through a feedback loop on TF expression: various inflammatory signals, such as AP-1, Erg-1 and NFkB, can increase TF expression, enhancing its availability for FVII or FVIIa binding. This creates a coagulation-inflammation cycle, where each pathway promotes the other.

Inflammation and Blood Coagulation Pathways

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