Hepatocyte tissue factor contributes to the hypercoagulable state in a mouse model of chronic liver injury.
OBJECTIVE
Patients with chronic liver disease and cirrhosis have a dysregulated coagulation system and are prone to thrombosis. The basis for this hypercoagulable state is not completely understood. Tissue factor (TF) is the primary initiator of coagulation in vivo. Patients with cirrhosis have increased TF activity in white blood cells and circulating microparticles. The aim of our study was to determine the contribution of TF to the hypercoagulable state in a mouse model of chronic liver injury.


METHODS
We measured levels of TF activity in the liver, white blood cells and circulating microparticles, and a marker of activation of coagulation (thrombin-antithrombin complexes (TATc)) in the plasma of mice subjected to bile duct ligation for 12days. We used wild-type mice, mice with a global TF deficiency (low TF mice), and mice deficient for TF in either myeloid cells (TF(flox/flox),LysMCre mice) or in hepatocytes (TF(flox/flox),AlbCre).


RESULTS
Wild-type mice with liver injury had increased levels of white blood cell, microparticle TF activity and TATc compared to sham mice. Low TF mice and mice lacking TF in hepatocytes had reduced levels of TF in the liver and in microparticles and exhibited reduced activation of coagulation without a change in liver fibrosis. In contrast, mice lacking TF in myeloid cells had reduced white blood cell TF but no change in microparticle TF activity or TATc.


CONCLUSIONS
Hepatocyte TF activates coagulation in a mouse model of chronic liver injury. TF may contribute to the hypercoagulable state associated with chronic liver diseases in patients.
Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France. Electronic address: pierre-emmanuel.rautou@inserm.fr.
Pierre-Emmanuel
PE
Rautou
Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kohei
K
Tatsumi
Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Silvio
S
Antoniak
Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
A Phillip
AP
Owens
Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Erica
E
Sparkenbaugh
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lori A
LA
Holle
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Alisa S
AS
Wolberg
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA.
Anna K
AK
Kopec
Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Rafal
R
Pawlinski
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA.
James P
JP
Luyendyk
Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Nigel
N
Mackman
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008107:Liver Diseases / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019851:Thrombophilia / Q000209:etiology*; D013925:Thromboplastin / Q000502:physiology*
D013925:Thromboplastin
Coagulation; Liver injury; Microparticle; Thrombosis