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INTRODUCTION

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Fibrinolysis is a biological process that aims to degrade clot formation. This is done in balance with coagulation, which aims to induce clot formation. Many pathologic conditions occur when the balance between these two systems is altered, usually leading to the extremes of their respective purposes, that is, severe bleeding or severe clotting. On the other hand, coagulation, or clotting, is the process in which blood transitions from a liquid state to gel, leading to hemostasis. This is usually done when the endothelium tissue suffers an injury.

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Coagulation prevents bleeding and activates the repair system of cells. Coagulation is executed by platelet aggregation and fibrin formation. Fibrin is formed via two pathways: tissue factor pathway (extrinsic) and contact activation pathway (intrinsic). Both pathways rely on series of coagulation factors that work in synchrony to eventually activate fibrin at the necessary site within the vasculature. Factor X is the coagulation factor that unites both pathways onto a common pathway to ultimately convert prothrombin into activated thrombin. In turn, thrombin is now active and converts fibrinogen into fibrin. Fibrin then auto-polymerizes into several fibrin strands to stabilize the clot formation, with the aid of platelet aggregation.

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PHYSIOLOGY OF FIBRINOLYSIS

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Once a stable clot is formed within the vasculature, the balance can begin to shift towards stimulation of fibrinolysis. Plasminogen is released from the liver, where it is produced, and imbeds itself into the stable clot. Even though plasminogen can bind to the clot, it is unable to cleave it until it is converted into plasmin. Over several days during the clot lifespan, damaged endothelium begins to secrete urinary plasminogen activator (also referred to as u-PA or urokinase) and tissue plasminogen activator (t-PA). These two enzymes convert plasminogen into its active form, plasmin. Plasmin then degrades fibrin into fibrin degradation products (FDP). A positive feedback loop ensues as FDP leads to further upregulation of urokinase and t-PA. However, both enzymes, u-PA and t-PA, are inhibited by plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) (Figure 99-1).

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FIGURE 99-1

Fibrinolysis. (Reproduced with permission from Brunton L, Chabner BA, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill Education, Inc.; 2011: Fig. 30-3.)

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Plasmin continues to cleave fibrin into FDP, thus degrading the clot, until other proteases begin inactivating plasmin. These enzymes include alpha 2-macroglobulin and alpha 2-antiplasmin. Both enzymes are produced and secreted by the liver. Interestingly, alpha 2-macroglobulin also inhibits thrombin as well. Aside from the t-PA and u-PA activation of plasmin, there are several other endothelial molecules that aid in promoting an anticoagulant state within the body. Some of these molecules include prostacyclin and nitric oxide. Both are well known to act as powerful endothelial vasodilators; however, they also appear to play a role ...

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