Extrinsic Prothrombin Activation Pathway
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Extrinsic Prothrombin Activation Pathway

Thrombin/TFIIa (Activated Factor-II) is a coagulation protein that has many effects in the Coagulation cascade, the homeostatic process of greatest interest. It is a multifunctional serine proteinase best known for its ability to cleave Fibrinogen to Fibrin. Fibrin forms an essential component of the Blood Clot. When a blood vessel is injured, bleeding is stopped by clotting factors which form a Thrombus/Clot of Fibrin threads that trap platelet aggregates. A clot is a jelly-like mass of thickened blood composed of Fibrin and platelet aggregates. The first step in clotting is adhesion of platelets, which are fragments of blood cells that circulate in the blood, to the cut edges of a damaged blood vessel. In this way, a platelet plug is formed and external bleeding stops. Next, the protein based system (the coagulation cascade) serves to stabilize the clot that has formed and further seal up the wound. All of the factors have an inactive and an active form. Once activated, the factor will serve to activate the next factor in the sequence until Fibrin is formed. The goal of the clotting pathway is the production of Thrombin (from its inactive form, Prothrombin), which is required for the conversion of Fibrinogen to Fibrin. Fibrin will form a mesh within the platelet aggregate to stabilize the clot (Ref.1 & 2).

Thrombin resides in the cell in an inactive form, called Prothrombin. This Prothrombin is activated by the coagulation cascade, by the formation of a complex, called Prothrombin Activator Complex. The formation of Prothrombin Activator Complex can be brought about by two different pathways: The Intrinsic Prothrombin Activation Pathway, and the Extrinsic Prothrombin Activation pathway. Though the ultimate goal of both the pathways is the generation of the Prothrombin Activator Complex, they use alternate routes, each giving rise to a different form of the Prothrombin activator. Two components are unique to the Extrinsic Pathway: TF (Tissue Factor) or FIII (Factor-III), and FVII (Factor-VII). TF is a transmembrane protein of the vessel wall that does not normally come into contact with blood and circulating clotting factors until vascular injury occurs. Once in contact with blood, TF rapidly activates the Extrinsic Coagulation pathway, thus initiating the thrombogenic response. TF is present in most human cells bound to the cell membrane. It is expressed by smooth muscle cells in and surrounding blood vessels, and at low levels by blood cells or activated endothelial cells that line blood vessels. At sites of vascular injury, the released TF comes in contact with the plasma coagulation factor FVII (Factor-VII), which is then activated to form a complex of TF, FVIIa (Activated FVII), Calcium, and a Phospholipid, and this complex then rapidly activates FX (Factor-X). The TF interacts with FVIIa, to activate FX (Factor-X) to FXa (Activated Factor-X). Calcium ions and Phospholipids aid in enhancement of the process.FV (Factor-V) is a cofactor in the formation of the Prothrombin Activator Complex. FV is activated to FVa (Activated Factor-V) by means of minute amounts and is inactivated by increased levels of Thrombin. FVa binds to specific receptors on the surfaces of activated platelets and forms a complex with FXa. The complex thus formed, consisting of FXa, TF, FVIIa, and the cofactor FVa is termed as the Prothrombin Activator Complex. This complex, specifically FXa, along with the cofactor FVa, then converts Prothrombin to active Thrombin, which converts circulating Fibrinogen to Fibrin. The Fibrin monomers, thus formed polymerize spontaneously to form an insoluble gel. The polymerized Fibrin is stabilized by the FXIIIa, produced by the action of Thrombin on FXIII. These insoluble Fibrin mesh conjoined with aggregated Platelets block the damaged blood vessel and prevent further bleeding. Not surprisingly, therefore, the absence of any of these clotting factors (TF, FVIIa, FVa, FXa, Prothrombin, and/or Fibrinogen) predisposes animals to severe, often life-threatening, bleeding disorders (Ref.3, 4 & 5).

In contrast, the Intrinsic pathway consists of the clotting factors: FVIII (Factor-VIII), FIX, FX, FXI,FXII, FV and Prothrombin (FII), which is converted to Thrombin (FIIa). In this case, Prothrombin Activator Complex consists of FXa, FVa, FVIIIa, and PL (Phopspholipid). The two pathways are interconnected, and there is cross-talk between the two pathways at several points. For example, the FXIIa, a factor involved in the Intrinsic Pathway, indirectly facilitates the Extrinsic pathway by converting FVII to FVIIa. The activation of FVII also occurs through the action of Thrombin or FXa, mostly generated though the Intrinsic pathway. The ability of FXa to activate FVII creates a link between the Intrinsic and Extrinsic pathways. In reality, the main function of the Extrinsic pathway is to magnify the activity of the Intrinsic pathway. The Extrinsic pathway is an alternative route in order to activate the cascade of coagulation. It provides a rapid response to tissue injury, generating activated FXa almost instantaneously, compared to the seconds or even minutes required for the Intrinsic pathway to activate FX (Ref. 6, 7 & 8). The Extrinsc pathway suffers a setback in clotting, through the intervention of some factors and proteins. Antithrombin serves to block the actions of multiple clotting factors, involved in the formation of the Prothrombin Activator Complex. TFPI (TF Pathway Inhibitor) acts as an important inhibitor of TF-FVIIa complex. The newly formed Thrombin activates the formation of a complex of Protein-C, Protein-S and TM (Thrombomodulin) that can inactivate FV, thus affecting the clotting cascade negatively. As enhanced coagulation and thrombosis are linked to a variety of cardiovascular and metabolic diseases, as well as to cancer, inhibition is essential in order to keep a check on excessive clotting, and hence, the unwanted clots (Ref.1, 9 & 10).