Clotting intrinsic pathway

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

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 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 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. 

Figure 17.2 The intrinsic and extrinsic pathways involved in blood clotting. Both pathways converge to activate thrombin. Solid arrows represent biochemical conversions whereas dotted arrows represent either catalytic or activating actions. Fibrin is formed as monomers which polymerise to form fibrils. Within the fibrils, the fibrin monomers associate laterally which is facilitated by active XIII (ie Xllla). Thrombin activates XIII.

Two separate pathways, intrinsic and extrinsic, lead to the formation of a fibrin clot. Both pathways must function for hemostasis. 

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. 

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. 

Hemostasis begins with the formation of the platelet plug, followed by activation of the clotting cascade, and propagation of the clot. One of the major multicomponent complexes in the coagulation cascade consists of activated factor IX (factor IXa) as the protease, activated factor VIII (factor Villa), calcium, and phospholipids as the cofactors, and factor X as the substrate. Factor IXa can be generated by either factor Xa activation of the intrinsic pathway or by the tissue factor/factor Vila complex. 

The ideal anticoagulant drug would prevent pathologic thrombosis and limit reperfusion injury, yet allow a normal response to vascular injury and limit bleeding. Theoretically this could be accomplished by preservation of the TF-VIIa initiation phase of the clotting mechanism with attenuation of the secondary intrinsic pathway propagation phase of clot development. At this... 

Why do we have the intrinsic pathway when the tissue factor pathway provides rapid clot formation The answer seems to be that the tissue factor pathway is needed immediately after injury but that it is turned off quickly by the anticoagulation systems of the body. As a result the protease plasmin begins to dissolve (lyse) the clot within a few hours. The intrinsic pathway is apparently needed to maintain the clot for a longer period.514... 

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.)... 

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. ... 

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). 

The intrinsic pathway is involved in the clotting of blood in glass tubes and in the undesirable intravascular clotting that results in thrombosis. Control of the clotting mechanism is thus central to hemostasis to avoid bothhemorrhage and thrombosis. 

Figure 10.37. Blood-Clotting Cascade. A fibrin clot is formed by the interplay of the intrinsic, extrinsic, and final common pathways. The intrinsic pathway begins with the activation of factor XII (Hageman factor) by contact with abnormal surfaces produced by injury. The extrinsic pathway is triggered by trauma, which activates factor VII and releases a lipoprotein, called tissue factor, from blood vessels. Inactive forms of clotting factors are shown in red their activated counterparts (indicated by the subscript "a") are in yellow. Stimulatory proteins that are not themselves enzymes are shovm in blue. A striking feature of this process is that the activated form of one clotting factor catalyzes the activation of the next factor.

The extrinsic pathway is activated by tissue injury and is not of major concern in the clinical use of membrane devices. The intrinsic pathway, however, is initiated by a multitude of factors. Including interactions between serum proteins and exogenous materials. Hydrodynamic forces acting on platelets may also lead to the release of platelet factors that trigger the intrinsic pathway. Thus, the selection of membrane materials to minimize thrombogenesls cannot be fully separated from the design of devices to contain them because of this potential for shear forces to activate the clotting cascade. 

Blood Clotting Is Accomplished by a Cascade of intrinsic pathway... 

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