Anticlotting Systems

Earlier we described how the release, by endothelial cells, of prostacyclin and nitric oxide inhibit platelet aggregation. Since this aggregation is an essential precursor for clotting, these agents reduce the magnitude and extent of clotting. In addition, however, the body has mechanisms for limiting clot formation, itself, and for dissolving a clot after it has formed.

Factors That Oppose Clot Formation

There are at least three different mechanisms that oppose clot formation, once underway, thereby helping to limit this process and prevent it from spreading excessively. Defects in any of these natural anticoagulant mechanisms are associated with abnormally high risk of clotting (hypercoagulability).

The first anticoagulant mechanism acts during the initiation phase of clotting and utilizes the plasma protein called tissue factor pathway inhibitor (TFPI), which is secreted mainly by endothelial cells. This substance binds to tissue factor-factor Vila complexes and inhibits the ability of these complexes to generate factor Xa. This anticoagulant mechanism is the reason that the extrinsic pathway by itself can generate only small amounts of thrombin.

Thrombomodulin

FIGURE 14-75

Thrombin indirectly inactivates factors VIIIa and Va via protein C. To activate protein C, thrombin must first bind to a thrombin receptor, thrombomodulin, on endothelial cells; this binding also eliminates thrombin's procoagulant effects.

Factor VIIIa

Factor Va

FIGURE 14-75

Thrombin indirectly inactivates factors VIIIa and Va via protein C. To activate protein C, thrombin must first bind to a thrombin receptor, thrombomodulin, on endothelial cells; this binding also eliminates thrombin's procoagulant effects.

The second anticoagulant mechanism is triggered by thrombin. As illustrated in Figure 14-75, thrombin can bind to an endothelial cell receptor known as thrombomodulin. This binding eliminates all of thrombin's clot-producing effects and causes the bound thrombin to bind a particular plasma protein, protein C (distinguish this from protein kinase C, Chapter 7). The binding to thrombin activates protein C, which, in combination with yet another plasma protein, then inactivates factors VIIIa and Va. Thus, we saw earlier that thrombin directly activates factors VIII and V, and now we see that it indirectly inactivates them via protein C. Table 14-15 summarizes the effects— both stimulatory and inhibitory—of thrombin on the clotting pathways.

A third naturally occurring anticoagulant mechanism is a plasma protein called antithrombin III, which inactivates thrombin and several other clotting factors. To do so, circulating antithrombin III must itself be activated, and this occurs when it binds to hep-arin, a substance that is present on the surface of en-dothelial cells. Antithrombin III prevents spread of a clot by rapidly inactivating clotting factors that are carried away from the immediate site of the clot by the flowing blood.

The Fibrinolytic System

TFPI, protein C, and antithrombin III all function to limit clot formation. The system to be described now, however, dissolves a clot after it is formed.

A fibrin clot is not designed to last forever. It is a transitory device until permanent repair of the vessel occurs. The fibrinolytic (or thrombolytic) system is the

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

Circulation CHAPTER FOURTEEN

Circulation CHAPTER FOURTEEN

TABLE 14-15 Actions of Thrombin

Procoagulant

Cleaves fibrinogen to fibrin

Activates clotting factors XI, VIII, V, and XIII

Stimulates platelet activation

Anticoagulant

Activates protein C, which inactivates clotting factors VIIIa and Va

principal effector of clot removal. The physiology of this system (Figure 14-76) is analogous to that of the clotting system: It constitutes a plasma proenzyme, plasminogen, which can be activated to the active enzyme plasmin by protein plasminogen activators. Once formed, plasmin digests fibrin, thereby dissolving the clot.

The fibrinolytic system is proving to be every bit as complicated as the clotting system, with multiple types of plasminogen activators and pathways for generating them, as well as several inhibitors of these plasminogen activators. In describing how this system can be set into motion, we restrict our discussion to one example—the particular plasminogen activator known as tissue plasminogen activator (t-PA), which is secreted by endothelial cells. During clotting, both plasminogen and t-PA bind to fibrin and become incorporated throughout the clot. The binding of t-PA to fibrin is crucial because t-PA is a very weak enzyme in the absence of fibrin. The presence of fibrin profoundly increases the ability of t-PA to catalyze the generation of plasmin from plasminogen. Thus, fibrin is an important initiator of the fibrinolytic process that leads to its own dissolution.

The secretion of t-PA is the last of the various an-ticlotting functions exerted by endothelial cells that we have mentioned in this chapter. They are summarized in Table 14-16.

Fibrinolytic Pathway

FIGURE 14-76

Basic fibrinolytic system. There are many different plasminogen activators and many different pathways for bringing them into play.

FIGURE 14-76

Basic fibrinolytic system. There are many different plasminogen activators and many different pathways for bringing them into play.

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Responses

  • mathilda ruoho
    What factors oppose clotting?
    8 years ago
  • chica
    What is the anticlotting system in the body?
    8 years ago
  • Rosamunda
    What are factors of the anti clotting system?
    8 years ago
  • miska
    What is the function of thrombin in our body?
    7 years ago

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