The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment

Abstract

The fibrinolytic system is a key player in keeping the haemostatic balance, and changes in fibrinolytic capacity can lead to both bleeding-related and thrombosis-related disorders. Our knowledge of the fibrinolytic system has expanded immensely during the last 75 years. From the first successful use of thrombolysis in myocardial infarction in the 1960s, thrombolytic therapy is now widely implemented and has reformed treatment in vascular medicine, especially ischemic stroke, while antifibrinolytic agents are used routinely in the prevention and treatment of major bleeding worldwide. Despite this, this research field still holds unanswered questions. Accurate and timely laboratory diagnosis of disturbed fibrinolysis in the clinical setting remains a challenge. Furthermore, despite growing evidence that hypofibrinolysis plays a central role in, e.g., sepsis-related coagulopathy, coronary artery disease, and venous thromboembolism, there is currently no approved treatment of hypofibrinolysis in these settings. The present review provides an overview of the fibrinolytic system and history of its discovery; measurement methods; clinical relevance of the fibrinolytic system in diagnosis and treatment; and points to future directions for research.

Keywords: diagnostic tests; fibrinolysis; plasmin; plasminogen.

Figure 1

Schematic overview of activators and regulators of fibrinolysis. As a result of coagulation activation, fibrinogen A and B domains are cleaved from fibrinogen by thrombin, giving rise to fibrin monomers, which subsequently polymerise to form the fibrin clot. The clot is then stabilised by covalent crosslinking of D-domains induced by coagulation factor (F) XIIIa. Plasmin is the main enzyme responsible for fibrin clot degradation (fibrinolysis) and is activated by tissue-type plasminogen activator (tPA) in the presence of fibrin, or by urokinase-type plasminogen activator (uPA) in the presence of its cellular receptor (uPAR). Important regulators of fibrinolysis are plasminogen activator inhibitors (PAI)-1 and -2, which inhibit tPA and uPA activity; α2-antiplasmin binds and inhibits plasmin directly, and thrombin-activatable fibrinolysis inhibitor (TAFI) cleaves lysine residues from the fibrin clot and thereby impedes plasminogen binding to fibrin. (a) denotes activated enzyme.