Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis

J Hepatol. 2013 Aug;59(2):265-70. doi: 10.1016/j.jhep.2013.03.036. Epub 2013 Apr 11.


Background & aims: Cirrhosis is associated with a plasmatic procoagulant imbalance, detected in vitro by thrombin generation tests performed in the presence vs. absence of such activators of protein C as thrombomodulin or Protac. This imbalance is thought to be due to decreased protein C and increased factor VIII, but this has never been directly demonstrated. To test this hypothesis we analyzed plasma from 50 patients with cirrhosis before and after in vitro addition of purified protein C meant to restore normal levels.

Methods: Results for two thrombin generation assays were expressed as ratios of endogenous thrombin potential (ETP) with-to-without thrombomodulin or as Protac-induced coagulation inhibition (PICI%). By definition, high ETP ratios or low PICI% reflect a resistance to the anticoagulant action of thrombomodulin or Protac, respectively, and can be taken as indexes of in vitro procoagulant imbalance.

Results: The median (range) protein C level before addition was 40% (4-101%) and increased to 156% (110-305) after addition (p<0.001). The procoagulant imbalance, which was high before protein C addition [ETP ratio=0.83 (0.44-1.00)], was reduced after addition [ETP ratio=0.60 (0.14-0.84)], p<0.001. ETP-ratios were inversely correlated with protein C activity (rho=-0.46, p<0.001). Similar results were obtained with the Protac assay.

Conclusions: The results provide evidence that low protein C contributes to the procoagulant imbalance in plasma from patients with cirrhosis. The findings may have clinical implications for the treatment or prophylaxis of thrombosis in these patients.

Keywords: ETP; Factor VIII; PICI; Protac®; Protac®-induced-coagulation inhibition; Thrombin generation; Thrombomodulin; endogenous thrombin potential.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Blood Coagulation Factors / metabolism
  • Blood Coagulation Tests
  • Blood Coagulation* / drug effects
  • Blood Coagulation* / physiology
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / complications
  • Male
  • Middle Aged
  • Peptides / pharmacology
  • Protein C / metabolism*
  • Protein C / therapeutic use
  • Protein C Deficiency / blood
  • Protein C Deficiency / complications
  • Protein C Deficiency / drug therapy
  • Risk Factors
  • Thrombin / biosynthesis
  • Thrombomodulin / blood
  • Venous Thromboembolism / blood
  • Venous Thromboembolism / etiology
  • Venous Thromboembolism / prevention & control


  • Blood Coagulation Factors
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Protein C
  • Thrombomodulin
  • snake venom protein C activator
  • Thrombin