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Chapter 178

## Abstract

Abstract

1. The fibrinolytic system plays a central role in hemostasis through the controlled dissolution of the fibrin blood clot. Clot lysis is achieved by the direct action of the protease plasmin, which is, in turn, activated through proteolytic cleavage of its inactive zymogen, plasminogen. The known physiologic activators of plasminogen are tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In addition, a number of nonphysiologic plasminogen activators have been identified, including several bacterial gene products that may play important roles in microbial pathogenesis. The fibrinolytic system constitutes a primary mechanism for the defense against extensive intravascular thrombosis and is tightly regulated at many levels. The specific serine protease inhibitors α2-antiplasmin (α2AP) and plasminogen activator inhibitors (PAIs) target plasmin and the PAs, respectively. In addition, cellular receptors for uPA (the uPA receptor [uPAR]), tPA, and plasmin, together with specific interactions of fibrinolytic system components with fibrin, serve to localize and fine-tune the process of clot lysis.

2. Acquired or inherited disorders of fibrinolytic system components can result in pathologic bleeding or thrombosis. The proteases of the fibrinolytic system are all homologous members of the serine protease family with similar structures. Plasminogen is activated to plasmin by specific cleavage at the Arg560-Val561 peptide bond. Plasminogen is synthesized primarily in the liver and circulates at high concentrations in plasma. Plasminogen binds to its substrate, fibrin, through “lysine-binding” sites in kringle domains 1 and 4. tPA also has a high affinity for fibrin, with the presence of fibrin markedly enhancing the rate of plasminogen activation. tPA appears to be the primary physiologic activator of plasminogen within the vascular space, whereas uPA activity may be required primarily at extracellular sites. α2AP efficiently inhibits plasmin in the circulation, whereas clot-bound plasmin is relatively resistant. The combined effect of these interactions is to localize plasmin activity to the fibrin clot and to protect circulating fibrinogen from degradation.

3. Though partial deficiency of plasminogen has been described as predisposing to thrombosis, this has not been consistently observed. However, complete deficiency of plasminogen was recently shown to explain a distinct clinical syndrome previously known as ligneous conjunctivitis. The predominant manifestations of this disorder are ocular. Surprisingly, widespread vascular thrombosis has not been observed in these patients. Several mutations leading to complete loss of plasminogen antigen and activity have been identified in patients with ligneous conjunctivitis. The absence of clinically evident vascular thrombosis in these patients, in contrast to observations in plasminogen-deficient mice, suggests that alternative mechanisms for clot lysis and the clearance of fibrin may exist in humans.

4. Deficiency states for α2AP and PAI-1 have been described in a limited number of patients. Both of these disorders are autosomal recessive and associated with inactivating mutations in the corresponding genes. Clinical manifestations are mild to moderate bleeding, particularly after trauma. Patients can be successfully treated with inhibitors of plasmin activity, including ε-aminocaproic acid (EACA) and tranexamic acid.

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