Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose

Hepatology. 2018 Nov;68(5):1991-2003. doi: 10.1002/hep.30070. Epub 2018 Sep 20.


The serine protease plasmin degrades extracellular matrix (ECM) components both directly and indirectly through activation of matrix metalloproteinases. Excessive plasmin activity and subsequent ECM degradation cause hepatic sinusoidal fragility and hemorrhage in developing embryos. We report here that excessive plasmin activity in a murine acetaminophen (APAP) overdose model likewise compromises hepatic sinusoidal vascular integrity in adult animals. We found that hepatic plasmin activity is up-regulated significantly at 6 hours after APAP overdose. This plasmin up-regulation precedes both degradation of the ECM component fibronectin around liver vasculature and bleeding from centrilobular sinusoids. Importantly, administration of the pharmacological plasmin inhibitor tranexamic acid or genetic reduction of plasminogen, the circulating zymogen of plasmin, ameliorates APAP-induced hepatic fibronectin degradation and sinusoidal bleeding. Conclusion: These studies demonstrate that reduction of plasmin stabilizes hepatic sinusoidal vascular integrity after APAP overdose. (Hepatology 2018; 00:1-13).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / poisoning*
  • Analgesics, Non-Narcotic / poisoning*
  • Animals
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology
  • Disease Models, Animal
  • Drug Overdose / metabolism
  • Drug Overdose / pathology*
  • Fibrinolysin / metabolism*
  • Fibronectins / metabolism
  • Fluorescent Antibody Technique
  • Immunoblotting
  • Liver / blood supply
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Real-Time Polymerase Chain Reaction


  • Analgesics, Non-Narcotic
  • Fibronectins
  • Acetaminophen
  • Fibrinolysin