Prominent protein Z-induced thrombin inhibition in cirrhosis: A new functional assay for hypercoagulability assessment

Background and Aims Protein Z (PZ) is an anticoagulant that accelerates the inhibitory effect of PZ-dependent protease inhibitor (ZPI) on coagulation factor Xa. We assessed functional status of PZ system in 158 patients with liver cirrhosis and 59 healthy controls. Methods Plasma PZ and ZPI levels were measured by enzyme immunoassay. Thrombin generation assays (TGA) were performed with and without thrombomodulin (TM) or PZ, and the ratios were calculated by dividing TGA values with TM or PZ by values without TM or PZ. Results PZ and ZPI levels were reduced and elevated in advanced cirrhosis, respectively. The lag time ratio–PZ was significantly higher in cirrhosis patients than controls and correlated with the model for end-stage liver disease score. The peak thrombin ratio–PZ and endogenous thrombin potential (ETP) ratio–PZ were significantly lower in cirrhosis patients than controls and correlated with the severity of liver cirrhosis. The peak thrombin ratio–PZ was dramatically reduced in advanced cirrhosis. Cirrhosis patients had a significantly higher ETP ratio–TM than the controls, although the ratio was not correlated with cirrhosis severity. The lag time ratio–PZ and peak time ratio–PZ were significantly correlated with the levels of all coagulation and anticoagulation factors. Interestingly, the lag time ratio–PZ and peak thrombin ratio–PZ were significantly associated with thrombotic events. Conclusion The anticoagulant role of PZ is insufficient in advanced stages of cirrhosis. Our newly developed functional assay for measuring the PZ system is expected to reflect the ongoing hypercoagulability of cirrhosis.