Plasmin-mediated Cleavage of High Molecular Weight Kininogen Contributes to Acetaminophen-Induced Acute Liver Failure

Abstract

Acetaminophen (APAP)-induced liver injury is associated with activation of coagulation and fibrinolysis. In mice, both tissue factor-dependent thrombin generation and plasmin activity have been shown to promote liver injury after APAP overdose. However, the contribution of the contact and intrinsic coagulation pathways has not been investigated in this model. Mice deficient in individual factors of the contact (FXII and PK) or intrinsic coagulation (FXI) pathway were administered a hepatotoxic dose of 400 mg/kg of APAP. Neither FXII, FXI, nor prekallikrein deficiency mitigated coagulation activation or hepatocellular injury. Interestingly, despite the lack of significant changes to APAP-induced coagulation activation, markers of liver injury and inflammation were significantly reduced in APAP-challenged high molecular weight kininogen-deficient (HK-/-) mice. Protective effects of HK deficiency were not reproduced by inhibition of bradykinin-mediated signaling, whereas reconstitution of circulating levels of HK in HK-/- mice restored hepatotoxicity. Fibrinolysis activation was observed in mice after APAP administration. Western blotting, ELISA, and mass spectrometry analysis demonstrated that plasmin efficiently cleaves HK into multiple fragments in buffer or plasma. Importantly, plasminogen deficiency attenuated APAP-induced liver injury and prevented HK cleavage in the injured liver. Finally, enhanced plasmin generation and HK cleavage, in the absence of contact pathway activation, were observed in plasma of patients with acute liver failure due to APAP overdose. In summary, extrinsic, but not intrinsic pathway activation drives the thromboinflammatory pathology associated with APAP-induced liver injury in mice. Furthermore, plasmin mediated cleavage of HK contributes to hepatotoxicity in APAP-challenged mice independently of thrombin generation or bradykinin signaling.

Tranexamic acid: Beyond antifibrinolysis

“…46 Henderson et al have recently found that plasmin-generated proteolytic fragments of high-molecular-weight kininogen induce the apoptotic death of endothelial cells and proinflammatory activation of leukocytes. 94 The degradation of ECM by plasmin results in the liberation of vessel permeability regulators, such as VEGF and TGF-β. 91 Plasmin has also been shown to activate protease-activated receptors (PAR), directly or through plasmin-activated MMP-1.…”

“…Thus, plasmin cleaves IL‐8 to a more potent form for granulocyte activation and cleaves CCL21 chemokine bound to ECM to generate a soluble chemotactic fragment 46 . Henderson et al have recently found that plasmin‐generated proteolytic fragments of high‐molecular‐weight kininogen induce the apoptotic death of endothelial cells and proinflammatory activation of leukocytes 94 . The degradation of ECM by plasmin results in the liberation of vessel permeability regulators, such as VEGF and TGF‐β 91 .…”

Assessment of plasmin and inducible nitric oxide synthase in the patients with COVID-19

“…Infection with CoV-2 By cleaving the spike proteins of the SARS-CoV-2 virus, plasmin increases its virulence and infectivity. [6].…”

An Update on Safe Anticoagulation

“…41 In contrast to FXII, HK has recently been shown to have a role in experimental liver inflammation. 42 Together the data reveal differential roles of contact system proteins in distinct inflammatory disease states. 43…”