Das TAFI-System

Zusammenfassung

Ziel der Blutgerinnung ist die Verhinderung eines Blutverlustes. Das Fibrinolysesystem dient dazu, das Produkt der Blutgerinnung, das Fibringerinnsel, zu beseitigen. Eine wichtige Verbindung zwischen Gerinnungsaktivierung und Fibrinolyse ist der Thrombin-aktivierbare Fibrinolyse-Inhibitor (TAFI). TAFI wird durch Thrombin aktiviert, wobei Thrombomodulin als Kofaktor wirken kann. TAFIa hemmt die Aktivierung von Plasminogen und die Proteolyse von Fibrin, indem es vom Fibrin Lysinreste abspaltet, die für die Bindung von t-PA, Plasminogen und Plasmin entscheidend sind. Hohe Thrombinkonzentrationen begünstigen die TAFI-Aktivierung und führen so zu Gerinnseln mit hoher Resistenz gegenüber der Fibrinolyse. Niedrige Thrombinkonzentrationen, bei Patienten mit hämorrhagischer Diathese, oder gerinnungshemmender Therapie, führen zu verminderter TAFIa-Aktivität und damit zu einer gesteigerten Fibrinproteolyse. Aus der Erforschung des TAFI-Systems ergeben sich neue therapeutische Ansätze, sowohl für die Behandlung von Blutungen, als auch für die Behandlung von Thrombosen, Embolien oder disseminierter intravasaler Gerinnung.

Summary

The primary focus of the blood coagulation system is the prevention of blood loss. The system is regulated by various inhibitors, and by the fibrinolytic system, which removes the final product of the blood coagulation system, the fibrin clot. The fibrinolytic system is activated in the course of coagulation activation. The thrombin-activated fibrinolysis inhibitor (TAFI) is an important regulator of fibrinolysis. TAFI is activated by thrombin, and activation is enhanced in the presence of thrombomodulin. TAFIa, the product of TAFI activation, removes lysine residues from fibrin, which are essential for the binding of t-PA, plasminogen, and plasmin to fibrin. The fibrin loses its cofactor activity in t-PA-induced plasminogen activation, resulting in less plasmin, and the remaining plasmin finds less binding sites on fibrin, resulting in an increased resistance of the clot towards plasmin proteolysis.

High concentrations of thrombin result in high TAFIa-activity and consequently in highly resistant fibrin clots. Patients with hyperprothrombinaemia consequently display elevated TAFIa-levels, which may contribute to the risk for thrombosis. Treatment with recombinant factor VIIa also leads to high concentrations of thrombin, resulting in fibrin clots with enhanced resistance towards fibrinolysis. At low thrombin concentration, as observed in patients with bleeding disorders or patients treated with anticoagulant drugs, less TAFIa is produced in the course of coagulation activation, and the clots are less resistant towards fibrinolysis. TAFIa-inhibitors are currently being developed for the treatment of throboembolic disorders or hypofibrinolytic DIC. Enhancement of TAFIa-activity may be helpful in patients with bleeding.

Schlüsselwörter

Gerinnung - Fibrinolyse - TAFI

Keywords

Coagulation - fibrinolysis - TAFI

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