The Extrinsic Pathway

Following the recruitment and activation of platelets by injured capillaries, their soft clot aggregates provide a surface for plasma proteins to interact and activate thrombin, which transforms soluble fibrinogen to a fibrin clot. Thrombin is activated by two blood coagulation pathways, extrinsic and intrinsic. A defective extrinsic path is incompatible with life, whereas defects of the intrinsic path cause hemophilia. 

The extrinsic pathway is mediated by tissue factor (TF), also known as thromboplastin or factor HI (Fig. 11.6a). Tissue factor is not present in blood plasma, i.e., it is extrinsic or outside of the vascular system. TF is a membrane protein that becomes exposed to the blood by trauma to the endothelial surface of blood vessels. It is especially rich in the membranes of pericytes, platelets, and leukocytes, but present in lesser amounts in most cells. It is absent from striated muscle cells and chondroblasts. 

When TF is exposed to blood, it spontaneously binds factor VII, a serine protease of the coagulation system that possesses a gla domain (Table 11.1). The TF VII complex therefore adheres to the negatively charged surface of activated platelets. About 0.4% of factor VII is activated in blood by fatty acid- or triglyceride-mediated activation of factor IX and binds similarly to TF. The TF Vila complex (Fig. 11.6a) has proteolytic activity and cleaves (converts) another gla protein that also binds to the activated platelets, factor X. Factor Xa is a serine protease that converts the remainder of the TF VII complex, generating additional Xa proteolytic activity that ultimately converts prothrombin to thrombin for 

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Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

Two pathways lead to fibrin clot formation the intrinsic and the extrinsic pathways. These pathways are not independent, as previously thought. However, this artificial distinction is retained in the following text to fa-cihtate their description. 

Initiation of the fibrin clot in response to tissue injury is carried out by the extrinsic pathway. How the intrinsic pathway is activated in vivo is unclear, but it involves a negatively charged surface. The intrinsic and extrinsic pathways converge in a final common path-vray involving the activation of prothrombin to thrombin and the thrombin-catalyzed cleavage of fibrinogen to form the fibrin clot. The intrinsic, extrinsic, and final common pathways are complex and involve many different proteins (Figure 51-1 and Table 51-1). In... 

The Extrinsic Pathway Also Leads to Activation of Factor X But by a Different Mechanism... 

In the final common pathway, factor Xa, produced by either the intrinsic or the extrinsic pathway, activates prothrombin (factor II) to thrombin (factor Ila), which then converts fibrinogen to fibrin (Figure 51-1). 

A number of laboratory tests are available to measure the phases of hemostasis described above. The tests include platelet count, bleeding time, activated partial thromboplastin time (aPTT or PTT), prothrombin time (PT), thrombin time (TT), concentration of fibrinogen, fibrin clot stabifity, and measurement of fibrin degradation products. The platelet count quantitates the number of platelets, and the bleeding time is an overall test of platelet function. aPTT is a measure of the intrinsic pathway and PT of the extrinsic pathway. PT is used to measure the effectiveness of oral anticoagulants such as warfarin, and aPTT is used to monitor heparin therapy. The reader is referred to a textbook of hematology for a discussion of these tests. 

Although the final steps of the blood clotting cascade are identical, the initial steps can occur via two distinct pathways extrinsic and intrinsic. Both pathways are initiated when specific clotting proteins make contact with specific surface molecules exposed only upon damage to a blood vessel. Clotting occurs much more rapidly when initiated via the extrinsic pathway. 

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... 

The initial steps of the intrinsic pathway are somewhat more complicated. This system requires the presence of clotting factors VIII, IX, XI and XII, all of which, except for factor VIII, are endo-acting proteases. As in the case of the extrinsic pathway, the intrinsic pathway is triggered upon exposure of the clotting factors to proteins present on the surface of body tissue exposed by vascular injury. These protein binding/activation sites probably include collagen. 

Partially responsible for inhibition of the extrinsic pathway. Inactivates factors V and VIII and promotes fibrinolysis. Activity declines following warfarin administration. cofactor to accelerate the anticoagulant activity of protein C. Decreased levels occur following warfarin administration. ... 

The extrinsic pathway involves response to an external signal. 

Figure 14-8. Overview of pathways that regulate programmed cell death. Apoptosis may occur in response to signaling through either the extrinsic pathway or the intrinsic pathway. In each case, proteolytic cleavage activates an initiator caspase, caspase 8 or 9, either of which can cleave an effector caspase such as caspase 3. Apaf-1 is part of a large complex called the apoptosome that mediates the intrinsic pathway. Binding of an extracellular death ligand to its cell-surface receptor activates the extrinsic pathway.

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. 

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

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. 

The extrinsic pathway consists of a series of events initially induced by death receptors located on the cell surface. It is initiated by interaction of extracellular death ligands with their respective receptors, located on the surface of the plasma membrane. The death ligands are members of the tumor necrosis factor (TNF)/nerve growth factor (NGF) superfamily. TNF-R1, Fas (Apo-l/CD95), TRAIL-R1, TRAIL-R2, and NGF-R are examples of death receptors. They are transmembrane proteins consisting of an external domain, where the ligand associates, and a cytoplasmic domain, which contains the DD (death domain). 

But it still seems we haven t made much progress—now we have to go back and ask what activates Stuart factor. It turns out that it can be activated by two different routes, called the intrinsic and the extrinsic pathways. In the intrinsic pathway, all the proteins required for clotting are contained in the blood plasma in the extrinsic pathway, some clotting proteins occur on cells. Let s first examine the intrinsic pathway. (Please follow along using Figure 4-3.)... 

Like the intrinsic pathway, the extrinsic pathway is also a cascade. The extrinsic pathway begins when a protein called proconvertin is turned into convertin by activated Hageman factor and thrombin. In the presence of another protein, tissue factor, convertin... 

The intrinsic and extrinsic pathways cross over at several points. Hageman factor, activated by the intrinsic pathway, can switch on proconvertin of the extrinsic pathway. Convertin can then feed back into the intrinsic pathway to help activated PTA activate Christmas factor. Thrombin itself can trigger both branches of the clotting cascade by activating antihemophilic factor, which is required to help activated Christmas factor in the conversion of Stuart factor to its active form, and also by activating proconvertin. ... 

The extrinsic pathway, which is initiated by thromboplastin released from injured tissues and the protease proconvertin (Factor VII). 

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