Jr I

VIIIa

Activated platelets

Prothrombin

Activated platelets

Thrombin

FIGURE 14-73

Two clotting pathways—called intrinsic and extrinsic—merge and can lead to the generation of thrombin. Under most physiological conditions, however, factor XII and the contact activation step that begin the intrinsic pathway probably play little, if any, roles in clotting. Rather, clotting is initiated solely by the extrinsic pathway, as described in the text. You might think that factors IX and X were accidentally transposed in the intrinsic pathway, but such is not the case; the order of activation really is XI, IX, and X. For the sake of clarity, the roles of calcium in clotting are not shown.

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Circulation CHAPTER FOURTEEN

Circulation CHAPTER FOURTEEN

TABLE 14-14 Official Designations for Clotting Factors Along with Synonyms More Commonly Used

Factor I (fibrinogen) Factor Ia (fibrin) Factor II (prothrombin) Factor IIa (thrombin)

Factor III (tissue factor, tissue thromboplastin) Factor IV (Ca2+)

Factors V, VII, VIII, IX, X, XI, XII, and XIII are the inactive forms of these factors; the active forms add an "a" (for example, factor XIIa). There is no factor VI. Platelet factor (PF)

underlying damaged endothelium. The contact activation of factor XII to XIIa is a complex process that requires the participation of several other plasma proteins not shown in Figure 14-73. (Contact activation also explains why blood coagulates when it is taken from the body and put in a glass tube: This has nothing whatever to do with exposure to air, but happens because the glass surface acts like collagen and induces the same activation of factor XII and aggregation of platelets as a damaged vessel surface. A silicone coating markedly delays clotting by reducing the activating effects of the glass surface.)

Factor XIIa then catalyzes the activation of factor XI to factor XIa, which activates factor IX to factor IXa. This last factor then activates factor X to factor Xa, which is the enzyme that converts prothrombin to thrombin. Note in Figure 14-73 that another plasma protein—factor VIIIa—serves as a cofactor (not an enzyme) in the factor IXa-mediated activation of factor X. The importance of factor VIII in clotting is emphasized by the fact that the disease hemophilia, in which excessive bleeding occurs, is usually due to a genetic absence of this factor. (In a smaller number of cases, hemophilia is due to an absence of factor IX.)

Now we turn to the extrinsic pathway for initiating the clotting cascade (upper right of Figure 14-73). This pathway begins with a protein called tissue factor, which is not a plasma protein. It is located instead on the outer plasma membrane of various tissue cells, including fibroblasts and other cells in the walls of blood vessels below the endothelium. The blood is exposed to these subendothelial cells when vessel damage disrupts the endothelial lining, and tissue factor on these cells then binds a plasma protein, factor VII, which becomes activated to factor VIIa. The complex of tissue factor and factor VIIa on the plasma membrane of the tissue cell then catalyzes the activation of factor X. In addition, it catalyzes the activation of factor IX, which can then help activate even more factor X by plugging into the intrinsic pathway.

In summary, theoretically clotting can be initiated either by the activation of factor XII or by the generation of the tissue factor-factor VIIa complex. The two paths merge at factor Xa, which then catalyzes the conversion of prothrombin to thrombin, which catalyzes the formation of fibrin. As shown in Figure 14-73, thrombin also contributes to the activation of: (1) factors XI and VIII in the intrinsic pathway; and (2) factor V, with factor Va then serving as a cofactor for factor Xa. Not shown in the figure is the fact that thrombin also activates platelets.

As stated earlier, under physiological conditions, the two pathways just described actually are brought into play sequentially. How this works can be understood by turning again to Figure 14-73; hold your hand over the first part of the intrinsic pathway so that you can eliminate the contact activation of factor XII and then begin the next paragraph's description at the top of the extrinsic pathway in the figure.

(1) The extrinsic pathway, with its tissue factor, is the usual way of initiating clotting in the body, and factor XII—the beginning of the full intrinsic pathway— normally plays little if any role (in contrast to its initiation of clotting in test tubes or, within the body in several unusual situations). Accordingly, thrombin is initially generated only by the extrinsic pathway. The amount of thrombin is too small, however, to produce adequate, sustained coagulation. (2) It is large enough, though, to trigger thrombin's positive-feedback effects on the intrinsic pathway—activation of factors XI and VIII and of platelets. (3) This is all that is needed to trigger the intrinsic pathway independently of factor XII, and this pathway then generates the large amounts of thrombin required for adequate coagulation. Thus, the extrinsic pathway, via its initial generation of small amounts of thrombin, provides the means for recruiting the more potent intrinsic pathway without the participation of factor XII. In essence, thrombin eliminates the need for factor XII. Moreover, thrombin not only recruits the intrinsic pathway but facilitates the prothrombin-thrombin step itself by activating factor V and platelets.

Finally it should be noted that the liver plays several important indirect roles in clotting (Figure 14-74), and persons with liver disease frequently have serious bleeding problems. First, the liver is the site of production for many of the plasma clotting factors. Second, the liver produces bile salts (Chapter 17), and these are important for normal intestinal absorption of the lipid-soluble substance vitamin K. The liver requires this vitamin to produce prothrombin and several other clotting factors.

PART THREE Coordinated Body Functions

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART THREE Coordinated Body Functions

Fuction Lipids Human Body

FIGURE 14-74

Roles of the liver in clotting.

FIGURE 14-74

Roles of the liver in clotting.

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