Fibrinolysis: Biochemistry, Clinical Aspects, and Therapeutic Potential.

The fibrinolytic system is responsible for physiological lysis of hemostatic plugs once vascular integrity has been restored after injury. The formation and regulation of plasmin proceeds in a very similar way to the formation and regulation of thrombin in the coagulation cascade.1 Complex regulatory pathways, which include cell surfaces, the fibrin surface, the structure of the fibrin clot, and circulating inhibitors regulate physiological clot lysis. The physiological relevance of the fibrinolytic system is evidenced by rare bleeding disorders due to accelerated fibrinolysis such as Quebec platelet disorder, congenital deficiencies of antiplasmin and plasminogen activator inhibitor type 1 (PAI-1), and acquired hyperfibrinolytic states such as observed in acute promyelocytic leukemia.2 In addition, efficacy of exogenous administration of plasminogen activators to lyse pathological thrombi underlines the therapeutic importance of the fibrinolytic system. Further to the physiological role of fibrinolysis in intravascular clot lysis, components of the fibrinolytic system play an important role in many physiological and pathological processes unrelated to intravascular clot lysis.3 In this issue of Seminars of Thrombosis & Hemostasis, we have assembled articles dealing with new developments in biochemistry, clinical aspects, and the therapeutic potential of thefibrinolytic system. This collection of articles describes new developments and covers topics not included in a recent issue of the journal in 2013.4 Although primary, secondary, and tertiary hemostases were traditionally viewed as separate processes, each acting on a different timescale, we currently understand that all components of hemostasis act simultaneously and have complex interactions. The first part of this issue discusses new insights into the biochemistry of fibrinolysis. In the first article, by Whyte et al, the role of platelets in clot stability and lysis is outlined.5 The authors discuss recent insights in platelet-mediated modulation of fibrinolysis by secretion of fibrinolytic proteins from platelet granules and by plateletsurface modulation of fibrinolysis. Importantly, platelets appear to have both proand antifibrinolytic properties, the net effect of which is incompletely understood. The next article by Vallier et al describes recent observations on the profibrinolytic properties of microparticles shed from various cell types.6 In addition to the well-known procoagulant properties of microparticles, there is accumulating data showing that microparticles can initiate plasmin generation. The potential role of fibrinolytic microparticles in detection and pathogenesis of cancer is also discussed. The next part of this issue deals with functions of the fibrinolytic system beyond lysis of hemostatic plugs or pathological thrombi. The article by Foley discusses the role of the fibrinolytic system in inflammation and as a regulator of the complement system.7 Specifically, the article deals with the roles of fibrinolytic components in infection, woundhealing, and inflammation and includes diseases such as atherosclerosis. Draxler et al then further describe the role of plasmin as a modulator of the immune response and specifically address the role of plasmin in tissue homeostasis and the detrimental effects of dysregulated plasmin generation in chronic and acute inflammatory states.8 The possibility that antifibrinolytic agents act also as antiinflammatory drugs is discussed. This additional function of antifibrinolytic agents may be relevant for patients with trauma or undergoing major surgery that receive antifibrinolytic drugs. The next article by Fredriksson et al deals with nonfibrinolytic effects of tissue plasminogen activator (tPA) in the central nervous system.9 Some controversy on the