title: Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis.
abstract: OBJECTIVE
  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.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy. armando.tripodi@unimi.it
authors.forename: Armando
authors.initials: A
authors.lastname: Tripodi
authors.forename: Massimo
authors.initials: M
authors.lastname: Primignani
authors.forename: Laura
authors.initials: L
authors.lastname: Lemma
authors.forename: Veena
authors.initials: V
authors.lastname: Chantarangkul
authors.forename: Pier Mannuccio
authors.initials: PM
authors.lastname: Mannucci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D001779:Blood Coagulation Factors / Q000378:metabolism; D001780:Blood Coagulation Tests; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008103:Liver Cirrhosis / Q000097:blood* / Q000150:complications; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology; D011486:Protein C / Q000378:metabolism* / Q000627:therapeutic use; D020151:Protein C Deficiency / Q000097:blood / Q000150:complications / Q000188:drug therapy; D012307:Risk Factors; D013917:Thrombin / Q000096:biosynthesis; D018180:Thrombomodulin / Q000097:blood; D054556:Venous Thromboembolism / Q000097:blood / Q000209:etiology / Q000517:prevention & control
chemical_list: D001779:Blood Coagulation Factors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011486:Protein C; D018180:Thrombomodulin; C049647:snake venom protein C activator; D013917:Thrombin
keywords: ETP; Factor VIII; PICI; Protac®; Protac®-induced-coagulation inhibition; Thrombin generation; Thrombomodulin; endogenous thrombin potential