The protein Z/protein Z-dependent protease inhibitor complex

Summary

Protein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 but it has no enzymatic activity. It is a cofactor of a serpin, the protein Z-dependent protease inhibitor (ZPI), and the complex PZ/ZPI inhibits activated factor X on phospholipid surfaces. In mice, the disruption of PZ or ZPI gene is asymptomatic, but enhances the thrombotic phenotype and mortality of other thrombotic risk factors. Most of the clinical studies focused on PZ. Despite conflicting results, a recent meta-analysis indicated that PZ deficiency could be a risk for venous and arterial thrombosis and early fetal loss. However, these conclusions are drawn from case-control studies of small size, constituting an important limitation. Recently, it was shown that PZ and/or ZPI are synthesised by normal kidney and different cancer cells, suggesting that the complex PZ/ZPI could play a role in inhibiting the tissue deposition of fibrin. The physiopathological consequences of these observations remain to be established. At this time, the measurement of plasma PZ and ZPI or analysis of their gene polymorphisms should not be performed routinely for the exploration of thrombophilia.

Zusammenfassung

Das Protein Z (PZ) ist ein Vitamin-K-abhängiger Faktor, der 1984 im humanen Plasma identifiziert wurde, ohne dass eine enzymatische Aktivität nachgewiesen wurde. Es ist ein Kofaktor eines Serpins, des Protein-Z-abhängigen Protease-Inhibitors (ZPI), wobei der Komplex PZ/ ZPI den aktivierten Faktor X auf Phospholipid-Oberflächen inhibiert. Bei Mäusen ist die Ausschaltung des PZ-oder ZPI-Gens asymptomatisch, fördert aber den thrombotischen Phänotyp und die Mortalität infolge anderer thrombotischer Risikofaktoren. Die Mehrzahl der klinischen Studien konzentrierte sich auf PZ. Trotz widersprüchlicher Resultate zeigte eine aktuelle Metaanalyse, dass PZ-Mangel ein Risikofaktor für venöse und arterielle Thrombose sowie frühe Aborte sein könnte. Allerdings stammen diese Folgerungen aus kleinen Fall-Kontrollstudien, was eine wesentliche Limitierung darstellt. Kürzlich konnte gezeigt werden, dass PZ und/oder ZPI von normalen Nieren- und verschiedenen Krebszellen synthetisiert werden. Dies deutet darauf hin, dass der Komplex PZ/ ZPI eine Rolle bei der Vermeidung von Fibrinablagerungen im Gewebe spielen könnte. Die physiopathologischen Konsequenzen dieser Beobachtungen sind noch zu ermitteln. Zurzeit sollte die Bestimmung von PZ und ZPI im Plasma oder die Analyse ihrer Polymorphismen nicht routinemäßig zum Thrombophilie-Screening durchgeführt werden.

Keywords

Protein Z - protein Z-dependent protease inhibitor - thrombosis - cancer

Schlüsselwörter

Protein Z - Protein-Z-abhängiger Protease-Inhibitor - Thrombose - Krebs

• References

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