Extrinsic pathway of blood coagulation

Factor X is a plasma protein involved in both the intrinsic and extrinsic pathways of blood coagulation. Factor X has a mass of 55kDa and the activated Xa of 40kDa. The normal concentration in plasma is 6-8 pg/ml. Post-translational modifications of the protein involve y-carboxylation of specific glutamic acid residues, 3-hydroxylation of one aspartic acid residue, and N- and 0-linked glycosylation. 

Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vase Biol 2007 27(8) 1687-93. 

Figure 51-1. The pathways of blood coagulation. The intrinsic and extrinsic pathways are indicated. The events depicted below factor Xa are designated the final common pathway, culminating in the formation of cross-linked fibrin. New observations (dotted arrow) include the finding that complexes of tissue factor and factor Vila activate not only factor X (in the classic extrinsic pathway) but also factor IX in the intrinsic pathway, in addition, thrombin and factor Xa feedback-activate at the two sites indicated (dashed arrows). (PK, prekallikrein HK, HMW kininogen PL, phospholipids.) (Reproduced, with permission, from Roberts HR, Lozier JN New perspectives on the coagulation cascade. Hosp Pract [Off Ed] 1992Jan 27 97.)...

The extrinsic pathway of coagulation is activated when circulating factor VII encounters tissue factor. Tissue factor is a transmembrane glycoprotein, which is normally expressed by subendothelial fibroblast-like cells, which surround the blood vessel. An intact endothelium normally shields the circulating blood from exposure to tissue factor. The tissue factor molecule consists of a 219 amino acid hydrophilic extracellular domain, a 23 amino acid hydrophobic region that spans the membrane, and a 21 amino acid cytoplasmic tail that anchors the molecule to the cell membrane (15,16). Other sites of tissue factor expression include activated monocytes, activated endothelial cells, and atherosclerotic plaques. 

Initiation of blood coagulation (clotting) occurs through the contact activation pathway (intrinsic pathway) and the tissue factor (TF) pathway (extrinsic pathway). The contact activation pathway is quantitatively the most important, but is much slower to initiate the TF pathway is considered to be the primary pathway for the initiation of blood coagulation and affords a more rapid response (the so-called thrombin burst), which augments the contact activation pathway. Both pathways share a common pathway that converges at factor X with the production of thrombin (Figure 11.1). 

During blood coagulation either an intrinsic (all blood) system or an extrinsic (tissue juice-lipoprotein) system is activated.. In either case the pathways meet at the activation of Factor X, forming a proteolytic enzyme Factor X. This enzyme in the presence of cofactors (calcium ion, phospholipid and Factor V) will form thrombin from prothrombin. Heparin is a cofactor for a protein called antithrombin III which circulates in the plasma and is an inhibitor of both Factor Xg and thrombin. Antithrombin III neutralizes these 2 enzymes by molecular combination heparin increases the rate of this neutralization. In the past 2 years work has continued on the mechanism of blood coagulation More... 

Rao, K.W.M. 1987. Studies of mechanisms inhibiting the initiation of extrinsic pathway of coagulation. Blood 69 645-651. 

Lipids and blood coagulation - In Fig. 1 is shown a simplified scheme of blood coagulation, subdivided into the extrinsic and intrinsic pathways of prothrombin activation. 

Lipids play an essential role in both the intrinsic and extrinsic pathways of proArombin activation. They enter the coagulation sequence after it has been initiated by surface contact and other protein interactions. There is no evidence that they initiate the coagulation process. The lipid is normally derived from the blood platelet where it probably exists as lipoprotein. It exerts a surface catalytic action on the plasma coagulation proteins with which it may bind in the presence of calciiun. The resulting complex could contain platelet liproprotein or its lipid moiety alone and may mediate prothrombin activation. 

Factor VII. This is a vitamin K-dependent serine protease that functions in the extrinsic coagulation pathway and catalyzes the activation of Factors IX and X. Factor VII is present constitutively in the surface membrane of pericytes and fibroblasts in the adventitia of blood vessels, vascular endothehum, and monocytes. It is a single-chain glycoprotein of approximately 50,000 daltons. 

Two coagulation factors function uniquely in the extrinsic pathway factor III (tissue factor) and factor VII. Tissue factor is an integral membrane protein present in a wide variety of tissue types (particularly lung and brain). This protein is exposed to blood constituents only upon rupture of... 

Figure 12.1 Schematic diagram of the initial steps of the extrinsic blood coagulation pathway. See text for details (TF tissue factor)...

Simultaneously, activation of the extrinsic coagulation cascade occurs as a result of exposure of blood to the thrombogenic lipid core and endothelium, which are rich in tissue factor. This pathway ultimately leads to the formation of a fibrin clot composed of fibrin strands, cross-linked platelets, and trapped red blood cells. 

Extrinsic pathway Coagulation is activated by release of tissue thromboplastin, a factor not found in circulating blood. Clotting occurs in seconds because factor III bypasses the early reactions. 

Extrinsic pathway This pathway has fewer steps than the intrinsic pathway and occurs rapidly, within a matter of seconds if the trauma is severe. It is called the extrinsic pathway because a protein tissue factor, also called thromboplastin or coagulation factor III, takes into the blood stream from outside and initiates the formation of prothrombinase. Tissue factor is released from the surface of the damaged cells. It activates factor VII. Factor VII combines with factor X, activating it. Factor X in the presence of Ca combines with factor V to give active enzyme prothrombinase. 

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