Extrinsic Prothrombin Activation Pathway

When a blood vessel is injured, bleeding is stopped by coagulation factors which form a thrombus/clot. 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 to the cut edges of the damaged blood vessel. In this way, a platelet plug is formed and external bleeding stops. Next, the protein based coagulation cascade serves to stabilize the clot that has formed and further seal up the wound. All of the protein factors of this cascade 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, which in turn is required for the conversion of fibrinogen to fibrin.Thrombin resides in the cell in an inactive form called prothrombin. Prothrombin is activated in the coagulation cascade by the formation of a complex called the prothrombin activator complex. The formation of this complex can be brought about by two different pathways: the intrinsic or the extrinsic 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 activator complex. Two components are unique to the extrinsic Pathway: TF (Tissue Factor) or FIII and FVII. 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. 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 which is then activated to FVIIa to form a complex of TF, FVIIa, calcium and phospholipid; this complex rapidly activates FX to FXa. FV is a cofactor in the formation of the prothrombin activator complex which 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 which converts prothrombin to active thrombin. Thrombin activates circulating fibrinogen to fibrin. Fibrin monomers polymerize spontaneously to form an insoluble gel. Polymerized fibrin is stabilized by FXIIIa, a factor produced by the action of thrombin on FXIII. The fibrin mesh conjoined with aggregated platelets blocks the damaged blood vessel and prevents further bleeding.The main function of the extrinsic pathway is to magnify the activity of the intrinsic pathway. 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. The extrinsic pathway is inhibited by certain factors and proteins. Antithrombin serves to block the actions of multiple clotting factors involved in the formation of the prothrombin activator complex. TFPI acts as an important inhibitor of the TF-FVIIa complex. Newly formed thrombin activates the formation of a complex of protein-C, protein-S and 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. Thus, inhibition is essential in order to prevent excessive clotting.