Protein Z-dependent regulation of coagulation

Protein Z (PZ) is a 62 kDa vitamin K-dependent plasma protein that serves as a cofactor for the inhibition of factor Xa by protein Z-dependent protease inhibitor (ZPI). ZPI is a recently identified 72 kDa member of the serpin superfamily of proteinase inhibitors that contains a tyrosine at its reactive center. PZ circulates in plasma in a complex with ZPI. Inhibition of factor Xa by ZPI in the presence of phospholipids and Ca⁺⁺ is enhanced 1000-fold by PZ, but ZPI also inhibits factor XIa in a process that does not require PZ, phospholipids or Ca⁺⁺. ZPI activity is consumed during coagulation through proteolysis mediated by factor Xa with PZ and factor XIa. Concomitant PZ deficiency dramatically increases the severity of the prothrombotic phenotype of factor V_Leiden mice. Studies to determine the potential roles of PZ and ZPI deficiency in human thrombosis are in progress.