Procoagulant imbalance in patients with non-alcoholic fatty liver disease

Abstract

Background & aims: Non-alcoholic fatty liver disease (NAFLD) is characterized by increased risk of cardiovascular events and liver-fibrosis. Both could be explained by a procoagulant-imbalance that was surmised but never directly demonstrated. We investigated 113 patients with varying histological liver damage [steatosis (n=32), steatohepatitis (n=51), metabolic-cirrhosis (n=30)], 54 with alcoholic/viral-cirrhosis and 179 controls.

Methods: Plasma was evaluated for levels of pro- and anti-coagulants, and for thrombin-generation assessed as endogenous-thrombin-potential (ETP) with and without thrombomodulin or Protac® as protein C activators. The procoagulant-imbalance was defined as ETP-ratio (with-to-without thrombomodulin) or as Protac®-induced-coagulation-inhibition (PICI%). High ETP-ratios or low PICI% indicate resistance to thrombomodulin or Protac® and hence a procoagulant-imbalance.

Results: ETP-ratio increased from controls [0.57 (0.11-0.89)] to steatosis [0.72 (0.33-0.86)] and metabolic-cirrhosis [0.80 (0.57-0.95)], (p<0.001), the latter being comparable to that for alcoholic/viral-cirrhosis [0.80 (0.57-0.95) vs. 0.80 (0.44-0.96)]. Factor VIII (a potent procoagulant for thrombin-generation) increased from steatosis [99% (71-150)] to metabolic-cirrhosis [157% (64-232)], p<0.001. Protein C (a powerful anticoagulant) decreased from steatosis [103% (77-228)] to metabolic-cirrhosis [77 (17-146)], p<0.001. As a consequence, factor VIII-to-protein C ratio increased from steatosis [0.96 (0.36-1.60)] to metabolic-cirrhosis [2.05 (0.81-12.1)], p<0.001 and was correlated with the ETP-ratio (rho=0.543, p<0.001). Similar results were obtained for PICI%. Patients with procoagulant-imbalance detected as ETP-ratio greater or PICI% lower than the median value of controls tended to have a higher risk of metabolic-syndrome, higher intima-media thickness, fibrosis, steatosis or lobular inflammation, all considered clinical manifestations of NAFLD.

Conclusion: NAFLD is characterized by a procoagulant-imbalance progressing from the less severe (steatosis) to the most severe form of the disease (metabolic-cirrhosis). This imbalance appears to result from increased factor VIII and reduced protein C and might play a role in the risk of cardiovascular events and liver-fibrosis commonly observed in NAFLD.

Keywords: Factor VIII; Protac®; Protein C; Thrombin generation; Thrombomodulin.