Integrated cross-linking by TG2 and FXIII generates hepatoprotective fibrin(ogen) deposits in injured liver

• Tissue transglutaminase synergistically drives unique in vitro fibrin crosslinking with thrombin-activated coagulation factor XIII

• Tissue transglutaminase contributes to hepatoprotective extravascular fibrin(ogen) accumulation and crosslinking in acute liver injury

The transglutaminase coagulation factor XIII (FXIII) is critical for the stability and function of intravascular fibrin clots. Pro-repair extravascular fibrin(ogen) deposits are potentially subject to crosslinking by FXIII as well as other transglutaminases not typically resident in plasma. However, the impact of these alternative modifiers on fibrin(ogen) structure and function is not known. We tested the hypothesis that tissue transglutaminase (TG2) modifies FXIII-directed fibrin(ogen) crosslinking in vitro and within injured tissue. Global proteomic analysis following experimental acetaminophen (APAP)-induced acute liver injury revealed that intrahepatic fibrin(ogen) deposition was associated with hepatic TG2 levels that exceeded that of FXIII. Mass spectrometry-based crosslink mapping of in vitro fibrin matrices uncovered the first evidence of synergistic fibrin(ogen) a-a crosslinking catalyzed by both transglutaminases. Fibrin(ogen) crosslinking was increased in livers from patients with APAP-induced acute liver failure. APAP-challenged TG2-/- mice displayed an altered pattern of FXIII-dependent fibrin(ogen)-g and fibrin(ogen)-a chain crosslinking aligned with the impact of TG2 on fibrin crosslinking in vitro. This shift in fibrin(ogen) crosslinking exacerbated pathologies including hepatic necrosis and sinusoidal congestion. The results are the first to indicate that TG2 impacts FXIII-directed fibrin(ogen) crosslinking, both in vitro and in vivo. The results suggest that TG2 functions to dynamically alter the structure of extravascular fibrin(ogen) to mitigate liver damage, a novel mechanism likely applicable across types of tissue injury.