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J Thromb Haemost. 2018 Nov 11. doi: 10.1111/jth.14330. [Epub ahead of print]

Chronic liver injury drives non-traditional intrahepatic fibrin(ogen) cross-linking via tissue transglutaminase.

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Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan, ; USA.
Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.
Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, Sydney, NSW, 2010, Australia.
Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.



Intravascular fibrin clots and extravascular fibrin deposits are often implicated in the progression of liver fibrosis. However, evidence supporting a pathological role of fibrin in hepatic fibrosis is indirect and based largely on studies using anticoagulant drugs that inhibit activation of the coagulation protease thrombin, which has other downstream targets that promote fibrosis. Therefore, the goal of this study was to determine the precise role of fibrin deposits in experimental hepatic fibrosis.


Liver fibrosis was induced in mice expressing mutant fibrinogen insensitive to thrombin-mediated proteolysis (i.e., locked in the monomeric form), termed FibAEK mice, and Factor XIII A2 subunit-deficient mice (FXIII-/- ). Female wild-type mice, FXIII-/- mice, and homozygous FibAEK mice were challenged with carbon tetrachloride (CCl4 ), twice weekly for 4 or 6 weeks (1 ml/kg, ip).


Hepatic injury and fibrosis induced by CCl4 challenge were unaffected by FXIII deficiency or inhibition of thrombin-catalyzed fibrin polymer formation (in FibAEK mice). Surprisingly, hepatic deposition of cross-linked fibrin(ogen) was not reduced in CCl4 -challenged FXIII-/- mice or FibAEK mice compared to wild-type mice. Rather, deposition of cross-linked hepatic fibrin(ogen) following CCl4 challenge was dramatically reduced in tissue transglutaminase-deficient mice (TGM2-/- mice). However, the reduction in cross-linked fibrin(ogen) in TGM2-/- mice did not affect CCl4 -induced liver fibrosis.


These results indicate that neither traditional fibrin clots, formed by the thrombin:FXIIIa pathway, nor atypical TGM2-cross-linked fibrin(ogen) contribute to experimental CCl4 -induced liver fibrosis. Collectively, the results indicate that liver fibrosis occurs independently of intrahepatic fibrin(ogen) deposition. This article is protected by copyright. All rights reserved.


Coagulation; factor XIII; fibrin; fibrosis; thrombin


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