Improved understanding of the molecular mechanisms of fibrinolysis has led to major advances in fibrinolytic and antifibrinolytic therapy. Characterization of the genes for all the major fibrinolytic proteins has revealed the structure of the relevant serine proteases, their inhibitors, and their receptors. The development of genetically engineered animals deficient in one or more fibrinolytic protein(s) has revealed both expected and unexpected functions. In addition, we now have a catalog of acquired and inherited disorders reflective of either fibrinolytic deficiency with thrombosis or fibrinolytic excess with hemorrhage. These advances have led to development of more effective and safer protocols for both pro- and antifibrinolytic therapy in a variety of circumstances.
BASIC CONCEPTS OF FIBRINOLYSIS
In response to vascular injury, fibrin, the insoluble end product of the action of thrombin on fibrinogen, is deposited in blood vessels, thus stemming the flow of blood. Once the vessel has healed, the fibrinolytic system is activated, converting fibrin to its soluble degradation products through the action of the serine protease, plasmin (Fig. 25–1A). Fibrinolysis is subject to precise control because of the actions of multiple activators, inhibitors, and cofactors.1 In addition, receptors expressed by endothelial, monocytoid, and myeloid cells provide specialized, protected environments where plasmin can be generated without compromise by circulating inhibitors (Fig. 25–1B).2,3 Beyond its more traditional role in fibrin degradation, the fibrinolytic system also supports a variety of tissue remodeling mechanisms. This chapter reviews the fundamental features of plasmin generation, considers the major clinical syndromes resulting from abnormalities in fibrinolysis, and discusses approaches to fibrinolytic and antifibrinolytic therapy.
Overview of the fibrinolytic system. A. Fibrin-based plasminogen activation. The zymogen plasminogen (Plg) is converted to the active serine protease, plasmin (PN), through the action of tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). The activity of t-PA is greatly enhanced by its assembly with Plg through lysine residues (K) on a fibrin-containing thrombus. u-PA acts independently of fibrin. Both t-PA and u-PA can be inhibited by plasminogen activator inhibitor-1 (PAI-1), the main physiologic regulator of plasminogen activator activity. By binding to fibrin, PN is protected from its major inhibitor, α2-plasmin inhibitor (α2–PI). Fibrin-bound plasmin degrades crosslinked fibrin, giving rise to soluble fibrin degradation products (FDPs). B. Cell surface plasminogen activation. Although many cell types express receptors for Plg, urokinase, and t-PA, only the endothelial cell is depicted here. The annexin A2 heterotetramer, consisting of two copies each of annexin A2 (A2) and protein p11 (p11), binds both t-PA and Plg, thereby augmenting the efficiency of plasmin generation on endothelial cells. Plg may also bind to other endothelial cell receptors, including histone H2B (H2B) and α-enolase, and may be activated by u-PA bound to its receptor, uPAR, to effect plasmin generation.