Abstract
Acetaminophen (APAP) overdose is a leading cause of acute liver failure. Multiple changes are evident in the hemostatic system of APAP overdose patients and changes in some hemostatic tests are associated with a poor outcome. Experimental APAP‐induced liver injury in mice is associated with activation of the coagulation cascade and intrahepatic fibrin(ogen) deposition. The overall goal of this talk will be to summarize recent results from our studies seeking to define the precise role of fibrin(ogen) in APAP‐induced liver injury and repair. We were surprised to observe that the protection afforded by anticoagulants in APAP‐treated mice was transient, and prolonged anticoagulation increased peak liver injury alongside evidence of delayed repair. Linking this observation to fibrin(ogen), mice lacking fibrin(ogen) had delayed liver repair after APAP overdose. The mechanism whereby fibrin(ogen) stimulated liver repair was determined to involve fibrin(ogen) engagement of the leukocyte αMβ2 integrin and induction of macrophage matrix metalloproteinase activity. The results highlight a novel pathway of liver repair after APAP overdose and the talk will highlight proof‐of‐concept pharmacologic studies targeting of this pathway to improve liver repair after APAP overdose.
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