Intrinsic pathways

CAD is subsequently released from the mitochondria and translocates to the nucleus, where, after cleavage by caspase 3, it leads to oligonucleosomal DNA fragmentation and a more pronounced and advanced chromatin condensation. This later and more pronounced chromatin condensation is referred to as stage II condensation. 

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Factor IX. This factor is dependent on the presence of vitamin K for its activity as a biologicaUy functional procoagulant glycoprotein. Factor IX is converted to its active form by XIa in the classic scheme of the intrinsic pathway. However, it can also be activated via interaction with Factor Xa or the complex Factor III plus Factor VII in the presence of calcium. 

Formerly, the clotting cascade had been divided into an extrinsic and intrinsic pathway. Although useful for... 

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. ... 

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... 

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 intrinsic pathway (Figure 51-1) involves factors XII, XI, IX, VIII, and X as well as prekallikrein, high-molecular-weight (HMW) kininogen, Ca, and platelet phospholipids. It results in the production of factor Xa (by convention, activated clotting factors are referred to by use of the suffix a). 

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. 

The pathophysiology of hemophilia is based on the factor VIII or IX deficiency resulting in inadequate thrombin generation and an impaired intrinsic-pathway coagulation cascade (see... 

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. 

The intrinsic pathway appears to be initiated when factor XII is activated by contact with surface proteins exposed at the site of damage. High molecular mass kininogen also appears to form part of this initial activating complex (Figure 12.2). 

Figure 12.2 The steps unique to the intrinsic coagulation pathway. Factor Xlla can also convert prekal-likrein to kallikrein by proteolysis, but this is omitted for the sake of clarity. Full details are given in the main text. The final steps of the coagulation cascade, which are shared by both extrinsic and intrinsic pathways, are outlined in Figure 12.3...

Factor XIa, in turn, activates factor IX. Factor IXa then promotes the activation of factor X, but only when it (i.e. IXa) is associated with factor Villa. Factor Villa is formed by the direct action of thrombin on factor VIII. The thrombin will be present at this stage because of prior activation of the intrinsic pathway. 

In Chapter 3 we described the intrinsic pathways of de-excitation of a molecule M the sum fey of the rate constants for these processes is equal to the reciprocal of the excited-state lifetime to1 ... 

Intrinsic pathway All the protein factors necessary for coagulation are present in circulating blood. Clot formation may take several minutes and is initiated by activation of factor XII. 

C. Both extrinsic and intrinsic pathways can lead to programmed cell death (Figure 14-8). 

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.

The intrinsic pathway responds to stress, usually resulting in the cell s inability to repair extensive DNA damage, sparking a decision to commit suicide. 

Although the final steps of the blood elotting cascade are identical, the initial steps can occur via two distinct pathways the extrinsic and intrinsic pathways. 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. 

Pathways affected Intrinsic pathway and common pathway Extrinsic pathway and common pathway... 

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