Fibrinolysis-Mediated Pathways in Acute Liver Injury

Abstract

Acute liver injury (ALI), that is, the development of reduced liver function in patients without preexisting liver disease, can result from a wide range of causes, such as viral or bacterial infection, autoimmune disease, or adverse reaction to prescription and over-the-counter medications. ALI patients present with a complex coagulopathy, characterized by both hypercoagulable and hypocoagulable features. Similarly, ALI patients display a profound dysregulation of the fibrinolytic system with the vast majority of patients presenting with a hypofibrinolytic phenotype. Decades of research in experimental acute liver injury in mice suggest that fibrinolytic proteins, including plasmin(ogen), plasminogen activators, fibrinolysis inhibitors, and fibrin(ogen), can contribute to initial hepatotoxicity and/or stimulate liver repair. This review summarizes major experimental findings regarding the role of fibrinolytic factors in ALI from the last approximately 30 years and identifies unanswered questions, as well as highlighting areas for future research.

Figure 1.. Plasmin inhibition with tranexamic acid (TXA) attenuates acetaminophen-induced acute liver injury in Fib^γΔ5 mice.

Wild-type and Fib^γΔ5 mice were challenged with a hepatotoxic dose of acetaminophen (300 mg/kg, i.p.) as described. Tranexamic acid (1200 mg/kg, i.p.) or vehicle (saline) 2 h and 8 h after acetaminophen challenge. (A) Representative photomicrographs of formalin-fixed paraffin-embedded liver tissues stained with hematoxylin and eosin illustrate robust sinusoidal congestion and hemorrhage (arrows) in vehicle-treated Fib^γΔ5 mice 24 h after acetaminophen challenge, which is reduced by TXA treatment. The area of hepatocellular necrosis and congestion and hemorrhage were quantified in the entire left lateral lobe as described. Results are presented as mean ± SEM with individual mice presented as circles (saline) or squares (tranexamic acid), **p<0.05

Figure 2.. Fibrinolytic factors can initiate, promote, or resolve acute liver injury (ALI).

Intrahepatic fibrinolysis can have divergent effects on ALI. On one hand, excessive intrahepatic plasmin generation can exacerbate ALI. “Dysfunctional fibrinogen,” resulting from experimentally-imposed mutations or physiologically-occurring post-translational modifications (i.e., oxidation) may promote plasmin generation. On the other hand, fibrinolytic factors including tPA, uPA, and plasmin(ogen) also promote tissue repair and regeneration to resolve ALI. tPA= tissue plasminogen activator, uPA= urokinase plasminogen activator, α₂-AP= alpha-2 antiplasmin, PAI-1 = plasminogen activator inhibitor-1, TAFI= thrombin-activatable fibrinolysis inhibitor. Created with BioRender.com