Altered fibrinogen γ-chain cross-linking in mutant fibrinogen-γΔ5 mice drives acute liver injury

Hepatic deposition of cross-linked fibrin(ogen) occurs alongside platelet accumulation as a hallmark of acetaminophen (APAP)-induced liver injury. We sought to define the precise role of the fibrinogen γ-chain C-terminal integrin αIIbβ3 binding domain in APAP-induced liver injury. Mice expressing mu...

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Bibliographic Details
Published in:Journal of thrombosis and haemostasis 2023-08, Vol.21 (8), p.2175-2188
Main Authors: Poole, Lauren G., Schmitt, Lauren R., Schulte, Anthony, Groeneveld, Dafna J., Cline, Holly M., Sang, Yaqiu, Hur, Woosuk S., Wolberg, Alisa S., Flick, Matthew J., Hansen, Kirk C., Luyendyk, James P.
Format: Article
Language:English
Subjects:
acetaminophen
acute liver injury
cross-linking
fibrinogen
mouse model
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Summary:Hepatic deposition of cross-linked fibrin(ogen) occurs alongside platelet accumulation as a hallmark of acetaminophen (APAP)-induced liver injury. We sought to define the precise role of the fibrinogen γ-chain C-terminal integrin αIIbβ3 binding domain in APAP-induced liver injury. Mice expressing mutant fibrinogen incapable of engaging integrin αIIbβ3 due to a C-terminal fibrinogen γ-chain truncation (mutant fibrinogen-γΔ5 [FibγΔ5] mice) and wild-type mice were challenged with APAP (300 mg/kg, intraperitoneally). We observed an altered pattern of fibrin(ogen) deposition in the livers of APAP-challenged FibγΔ5 mice. This led to the unexpected discovery that fibrinogen γ-chain cross-linking was altered in the livers of APAP-challenged FibγΔ5 mice compared with that in wild-type mice, including absence of γ-γ dimer and accumulation of larger molecular weight cross-linked γ-chain complexes. This finding was not unique to the injured liver because activation of coagulation did not produce γ-γ dimer in plasma from FibγΔ5 mice or purified FibγΔ5 fibrinogen. Sanger sequencing predicted that the fibrinogen-γΔ5 γ-polypeptide would terminate at lysine residue 406, but liquid chromatography tandem mass spectrometry analysis revealed that this critical lysine residue was absent in purified fibrinogen-γΔ5 protein. Interestingly, hepatic deposition of this uniquely aberrantly cross-linked fibrin(ogen) in FibγΔ5 mice was associated with exacerbated hepatic injury, an effect not recapitulated by pharmacologic inhibition of integrin αIIbβ3. The results indicate that fibrinogen-γΔ5 lacks critical residues essential to form γ-γ dimer in response to thrombin and suggest that hepatic accumulation of abnormally cross-linked fibrin(ogen) can exacerbate hepatic injury. •Mutant fibrinogen-γΔ5 (FibγΔ5) lacks the γ-chain C-terminal integrin αIIBβ3 binding domain.•The role of this domain in acetaminophen-induced liver injury is unknown.•FibγΔ5 lacks lysine 406 required for γ-γ dimer formation and forms altered cross-links.•Altered fibrin(ogen) cross-linking in FibγΔ5 mice is associated with elevated acute liver injury.
ISSN:1538-7836
1538-7836
DOI:10.1016/j.jtha.2023.04.003