Background: Intravascular fibrin clot formation proceeds in a well-ordered series of reactions catalyzed by thrombin cleavage of fibrinogen leading to fibrin polymer formation and cross-linking by the transglutaminase factor XIIIa (FXIIIa). Extravascular fibrin(ogen) deposition is also a common feature in injured tissues, however, the mechanisms regulating fibrino(ogen) polymerization and cross-linking in this setting are poorly understood.

Aims: The objective of this study was to determine the mechanisms of fibrin polymerization and cross-linking in an established setting of acute liver injury induced by acetaminophen (APAP) overdose.

Methods: Mice were challenged with a hepatotoxic dose of APAP (300 mg/kg) or saline. Hepatic fibrin(ogen) deposition and cross-linking was measured following APAP overdose in wildtype mice, mice lacking the catalytic subunit of FXIII (FXIII^-/-), and in Fib^AEK mice, which express a mutant fibrinogen insensitive to thrombin-mediated fibrin polymer formation.

Results: Hepatic fibrin(ogen) deposition was similar in APAP-challenged wild-type and FXIII^-/- mice, yet cross-linking of hepatic fibrin(ogen) was dramatically reduced (>90%) by FXIII deficiency. Hepatic fibrin(ogen) deposition was partially reduced (~50%) in APAP-challenged Fib^AEK mice, but most of the residual fibrin(ogen) deposits were still cross-linked. This result in Fib^AEK mice suggests that cross-linked fibrin(ogen) deposits in the APAP-injured liver may not all be in the form of polymerized fibrin. We then tested the hypothesis that the oxidative environment in the injured liver, which contains high levels of reactive mediators (e.g., peroxynitrite), modifies fibrinogen such that fibrin polymerization is impaired without impacting FXIII-mediated cross-linking. Notably, fibrin(ogen) modified with 3-nitrotyrosine adducts was identified in the APAP-injured liver. In biochemical assays, peroxynitrite inhibited thrombin-mediated fibrin polymerization in a concentration-dependent manner but did not block fibrin(ogen) cross-linking over time.

Conclusions: Collectively, these studies depict a unique disease state wherein defective thrombin-catalyzed fibrin polymerization is circumvented to allow tissue deposition and FXIII-dependent cross-linking of fibrin(ogen).

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/factor-xiii-cross-links-fibrinogen-independent-of-fibrin-polymerization-in-experimental-acute-liver-injury/