Thrombin activatable fibrinolysis inhibitor

Summary

Thrombin activatable fibrinolysis inhibitor (TAFI) was discovered two decades ago as a consequence of the identification of an unstable carboxypeptidase (CPU), which was formed upon thrombin activation of the respective pro-enzyme (proCPU). The antifibrinolytic function of the activated form (TAFIa, CPU) is directly linked to its capacity to remove C-terminal lysines from the surface of the fibrin clot. No endogenous inhibitors have been identified, but TAFIa activity is regulated by its intrinsic temperature-dependent instability with a half-life of 8 to 15 min at 37 °C. A variety of studies have demonstrated a role for TAFI/TAFIa in venous and arterial diseases. In addition, a role in inflammation and cell migration has been shown. Since an elevated level of TAFIa it is a potential risk factor for thrombotic disorders, many inhibitors, both at the level of activation or at the level of activity, have been developed and were proven to exhibit a profibrinolytic effect in animal models. Pharmacologically active inhibitors of the TAFI/TAFIa system may open new ways for the prevention of thrombotic diseases or for the establishment of adjunctive treatments during thrombolytic therapy.

Zusammenfassung

Der Thrombin-aktivierbare Fibrinolyseinhibitor (TAFI) wurde schon vor 20 Jahren bei der Identifizierung einer instabilen Carboxypeptidase (CPU) entdeckt, die sich nach Thrombinaktivierung des entsprechenden Proenzyms (proCPU) bildet. Die antifibrinolytische Wirkung der aktivierten Form (TAFIa, CPU) steht direkt mit der Funktion in Verbindung, C-terminale Lysine von der Oberfläche eines Fibringerinnsels zu entfernen. Endogene Inhibitoren gegen TAFI konnten nicht identifiziert werden, die Aktivität von TAFIa wird jedoch über dessen temperaturabhängige Instabilität reguliert, die Halbwertszeit bei 37 °C beträgt 8–15 min. Die Rolle von TAFI/TAFIa bei Venenund Arterienerkrankungen konnte in zahlreichen Studien nachgewiesen werden. Darüber hinaus spielt der Inhibitor nachweislich bei Entzündungen und Zellmigration eine Rolle. Da erhöhte TAFIa-Spiegel einen potenziellen Risikofaktor für thrombotische Störungen darstellen, wurden sowohl auf der Aktivierungsals auch auf der Aktivitätsebene zahlreiche Inhibitoren entwickelt, deren profibrinolytische Wirkung in Tiermodellen nachgewiesen werden konnte. Pharmakologisch aktive Inhibitoren des TAFI/TAFIa-Systems bieten möglicherweise neue Wege für die Prävention von Thromboseerkrankungen oder für die Einführung von Begleittherapien zur thrombolytischen Therapie.

Keywords

Thrombin activatable fibrinolysis inhibitor - TAFI - proCPU - fibrinolysis

Schlüsselwörter

Thrombin-aktivierbarer Fibrinolyseinhibitor - TAFI - proCPU - Fibrinolyse

• References

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