It is a phenomenon that occurs in the blood when it stops having its usual characteristics, as is its liquid consistency, to begin to become viscous.
This type of coagulation triggers an effect on the enzymes that in turn affect other molecules of the body created thus, in this way, what has been called avalanche point, as the evolution of coagulation is compromising its passage always a greater number of cells in crescendo.
Hence, it is called a coagulation cascade.
Damage to the walls of blood vessels exposes cells that contain tissue factors from the cell layers underlying the bloodstream.
The Factor of Tissue (TF for its acronym in English) is able to bind in the presence of calcium to Factor VII (FVII), which circulates at low levels in the bloodstream, calcium forming a bridge between TF and FVII.
This triggers an extracellular cascade involving sequential activations of serine protease: TF / FVII is activated by automatic cleavage to TF / FVIIa, which together with FVIIIa (cofactor) converts FIX into FIXa, which converts FX into FXa (although TF / FVIIa can also convert FX directly to FXa).
Together with FVa (cofactor) converts FII (prothrombin) into FIIa (thrombin), which converts fibrinogen to fibrin , which causes fibrin deposition and activation of platelets to form blood clots (activation of FXIII FXIIIa stabilizes the clot of fibrin when crossing it).
Inhibition by feedback
The tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that acts as a Kunitz-type serine protease inhibitor. TFPI is a dual inhibitor, which binds to the TF / FVIIa complex to prevent it from acting on its FIX and FX substrates.
It also directly inhibits FXa – in fact, the TFPI / FXa complex is a more effective inhibitor of TF / FVIIa than TFPI alone, possibly forming a large TFPI / FXa / TF / FVIIa complex.
Therefore, FXa exercises a 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 posterior part of the cascade.
So, therefore, the TFPI action is not absolute. It is thought that TFPI is important for modulating TF-induced thrombogenesis, since inadequate thrombus formation in blood vessels can cause cardiovascular diseases such as myocardial infarction, stroke and pulmonary embolism, among others.
A link between blood clotting and inflammation
The tissue factor also has an important role to play in inflammation, since the initiation of the signaling pathway of extracellular blood coagulation can trigger a signaling pathway of intracellular inflammation.
The activated coagulation factors FVIIa, FXa and FIIa (thrombin) are proinflammatory, capable of inducing an inflammatory state through protease activated receptors (PAR) found on the surface of several cell types.
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), among others.
PARs are G-protein coupled receptors (GPCR), where PAR-1, 3 or 4 transmits FIIa signaling, PAR-1, 2 or 3 transmits FXa signaling, and PAR-2 transmits FVIIa signaling.
Fibrin can also promote an inflammatory response. In addition to activation of the PAR receptor, phosphorylation of the cytoplasmic domain of tissue factor can lead to intracellular signaling events.
In addition, inflammation can promote coagulation through a feedback cycle in the expression of TF: several inflammatory signals, such as AP-1, Erg-1 and NFkB, can increase TF expression, improving its availability for binding of FVII or FVIIa.
This creates, finally, a cycle of coagulation-inflammation, where each path promotes the other, a reaction triggers another and so on.