Antifibrinolytic Therapy and Perioperative Considerations

Abstract

Fibrinolysis is a physiologic component of hemostasis that functions to limit clot formation. However, after trauma or surgery, excessive fibrinolysis may contribute to coagulopathy, bleeding, and inflammatory responses. Antifibrinolytic agents are increasingly used to reduce bleeding, allogeneic blood administration, and adverse clinical outcomes. Tranexamic acid is the agent most extensively studied and used in most countries. This review will explore the role of fibrinolysis as a pathologic mechanism, review the different pharmacologic agents used to inhibit fibrinolysis, and focus on the role of tranexamic acid as a therapeutic agent to reduce bleeding in patients after surgery and trauma.

Figure 1

Simplified fibrinolysis pathway. For clot formation, the principal event is fibrin formation following vascular injury, tissue factor binding to factor VIIa and activation of the Xase complex for hemostatic activation and thrombin generation. Thrombin stimulates endothelial release of tissue plasminogen activator (tPA), but also increased vascular flow, kinins, and other factors will release tissue plasminogen activator. Plasmin is released by formation of a plasminogen-tissue plasminogen activator complex that assembles on fibrin and binds to lysine sites on fibrin clot. Once assembled, tissue plasminogen activator cleaves plasminogen to its active form plasmin. Plasmin can also be generated by other mechanisms including urokinase, contact activation, and kallikrein mediated protease activation. Fibrinolysis is inhibited by plasminogen activator inhibitors (PAI 1 and PAI 2), and by thrombin binding to thrombomodulin to release and activate thrombin-activatable fibrinolysis inhibitor (not shown). Abbreviations: TF—tissue factor, VIIa-factor VIIa, X- factor X, Va-factor Va, tPA—tissue plasminogen activator, PAI—plasminogen activator inhibitor

Figure 2

Multiple pathways are responsible for generation of plasmin, including endothelial activation and release of tissue plasminogen activator (tPA), contact activation, and kallikrein-mediated plasmin activation. Plasmin generation and activity are also inhibited by plasminogen activator inhibitor1 (PAI1), thrombin-activatable fibrinolysis inhibitor (TAFI), lysine analogues (tranexamic acid and ε-aminocaproic acid [EACA]), and α₂-antiplasmin. Plasmin generation after tissue injury can induce many other responses, including thrombin generation and cleavage of fibrinogen to fibrin. Plasmin also binds and activates monocytes, neutrophils, platelets, and endothelial cells, to increase proinflammatory responses and multiorgan system-failure. Attenuation of these pathophysiological responses with tranexamic acid might provide additional mechanisms to restore hemostatic balance and control of plasmin generation and fibrinolysis, as shown in CRASH–2.PMNs=polymorphonuclear leucocytes. After trauma, tissue injury shifts the complex balance of fibrinolysis to additional plasmin generation, and activation that increases coagulopathy, inflammatory responses, and bleeding. (from Levy JH Lancet reference )