Plasma hypercoagulability in the presence of thrombomodulin but not of activated protein C in patients with cirrhosis

Abstract

Cirrhosis significantly changes all hemostasis steps. Recent studies suggest that cirrhosis is associated with a coagulopathy leading to a hypercoagulable state. The underlying mechanisms are not fully understood, but protein C deficiency is probably a major determinant of this phenotype. The aim of this study was to compare the results of thrombin generation assays performed with addition of thrombomodulin or activated protein C to assess the effect of by-passing the protein C activation step in cirrhotic patients and healthy controls. Fifty-eight patients with cirrhosis and 26 healthy controls were prospectively included in this study. Thrombin generation was determined in platelet-poor plasma using 5 pM of tissue factor and 4 nM of phospholipids, without and with external addition of 1 nM thrombomodulin or 4 nM activated protein C. All results were normalized with the values of a pool of normal plasma samples to limit inter-plate variability. When thrombin generation assays were performed in the presence of thrombomodulin, endogenous thrombin potential (ETP) and ETP with/ETP without TM ratio were significantly higher in cirrhotic patients than in healthy controls (P < 0.0001). Moreover, these values progressively increased with cirrhosis severity. When thrombin generation assays were performed with activated protein C, all thrombin generation parameters were comparable between healthy controls and cirrhotic patients, despite an acquired protein S deficiency. In the presence of activated protein C, no hypercoagulability was observed, adding to the current evidence that acquired protein C deficiency plays a key role in the coagulation imbalance.