New agents for thromboprotection

Summary

Blood coagulation is essential for hemostasis, however excessive coagulation can lead to thrombosis. Factor XII starts the intrinsic coagulation pathway and contact-induced factor XII activation provides the mechanistic basis for the diagnostic aPTT clotting assay. Despite its function for fibrin formation in test tubes, patients and animals lacking factor XII have a completely normal hemostasis. The lack of a bleeding tendency observed in factor XII deficiency states is in sharp contrast to deficiencies of other components of the coagulation cascade and factor XII has been considered to have no function for coagulation in vivo. Recently, experimental animal models showed that factor XII is activated by an inorganic polymer, polyphosphate, which is released from procoagulant platelets and that polyphosphate-driven factor XII activation has an essential role in pathologic thrombus formation. Cumulatively, the data suggest to target polyphosphate, factor XII, or its activated form factor XIIa for anticoagulation. As the factor XII pathway specifically contributes to thrombosis but not to hemostasis, interference with this pathway provides a unique opportunity for safe anticoagulation that is not associated with excess bleeding.

The review summarizes current knowledge on factor XII functions, activators and inhibitors.

Zusammenfassung

Die Blutgerinnung ist notwendig zur Blutstillung bei Verletzungen, kann aber auch zu Thrombosen führen. Faktor XII startet die intrinsische Blutgerinnungskaskade und dieser Mechanismus ist die Basis für den millionenfach eingesetzten aPTT-Gerinnungstest. Trotz seiner Bedeutung für die Fibrinbildung im Reagenzglas ist ein Mangel an Faktor XII we-der bei Mensch noch Tier mit einer erhöhten pathologischen Blutungsneigung assoziiert. Daher dachte man über Jahrzehnte, dass Faktor XII keine Funktion für die Blutgerinnung in vivo habe. In den vergangenen Jahren haben experimentelle Tiermodelle gezeigt, dass Faktor XII durch das anorganische Polymer Polyphosphat auf prokoagulanten Thrombozyten aktiviert wird. Die Polyphosphat-getriebene Faktor-XII-vermittelte Fibrinbildung hat eine essenzielle Funktion für die Bildung von Thromben, aber keine Funktion für hämostatische Mechanismen. Daher sind Polyphosphat, Faktor-XII-Zymogen und die aktive Protease attraktive Zielstrukturen für sichere Antikoagulanzien, die im Gegensatz zu aktuellen Medikamenten nicht mit Blutungsnei-gung assoziiert sind.

Diese Übersichtsarbeit fasst das aktuelle Wissen über Faktor XII, seinen Aktivator Polyphosphat und Inhibitoren dieser beiden Substanzen zusammen.

Keywords

Factor XII - contact system - anticoagulants - polyphosphate

Schlüsselwörter

Faktor XII - Kontaktphasesystem - Antikoagulanz - Polyphosphat

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