Protein Z, a protein seeking a pathology

Abstract

Protein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 characterized by an homology with other vitamin K-dependent factors (factor VII, IX, X, protein C). In contrast to these factors, PZ does not possess any enzymatic activity but is involved as a cofactor in the down-regulation of coagulation by forming a complex with the protein Z-dependent protease inhibitor (ZPI). ZPI inhibits the activated factor X (FXa) on phospholipid surface. In mice, the disruption of PZ gene is asymptomatic, but the association with the factor V Leiden mutation leads to a quasi complete mortality during the neonatal period with microvascular thrombosis. In humans, PZ is characterized by an unusual wide distribution in plasma, and a major decrease induced by warfarin. Isolated PZ deficiency does not seem to constitute a risk for venous thrombosis, but a severe PZ deficiency could increase the risk of well recognized venous thrombotic risk factors such as factor V Leiden, G20210A mutation or hyperhomocysteinemia. Unexpectedly, a relationship between PZ deficiency and ischemic arterial diseases such as stroke, acute coronary syndromes or peripheral arterial disease was described but not confirmed by all studies. PZ deficiency could be also a risk factor for early fetal losses, and increases the arterial risk in antiphospholipid syndrome. This review analyzes the different studies so far published and discusses the various results obtained in order to understand whether or not protein Z deficiency could be considered as an arterial ischemic risk factor.