title: Procoagulant imbalance in patients with non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy. Electronic address: armando.tripodi@unimi.it.
authors.forename: Armando
authors.initials: A
authors.lastname: Tripodi
authors.affiliation: Metabolic Liver Diseases Center, Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi di Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Fracanzani
authors.affiliation: First Division of Gastroenterology; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Primignani
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Veena
authors.initials: V
authors.lastname: Chantarangkul
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Marigrazia
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Scientific Direction; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Pier Mannuccio
authors.initials: PM
authors.lastname: Mannucci
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.affiliation: Metabolic Liver Diseases Center, Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi di Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bertelli
authors.affiliation: Metabolic Liver Diseases Center, Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi di Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.affiliation: Metabolic Liver Diseases Center, Department of Pathophysiology and Transplantation, Section of Internal Medicine, Università degli Studi di Milano, Italy; IRCCS Cà Granda Maggiore Hospital Foundation, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology; D016022:Case-Control Studies; D005169:Factor VIII / Q000378:metabolism; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000209:etiology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000150:complications; D011486:Protein C / Q000378:metabolism; D012307:Risk Factors; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000097:blood; D055815:Young Adult
chemical_list: D001779:Blood Coagulation Factors; D011486:Protein C; C546931:THBD protein, human; D018180:Thrombomodulin; D005169:Factor VIII; D013917:Thrombin
keywords: Factor VIII; Protac®; Protein C; Thrombin generation; Thrombomodulin