Intrahepatic fibrin(ogen) deposition drives liver regeneration after partial hepatectomy in mice and humans

Abstract

K E Y P O I N T Sl Liver-associated tissue factor drives rapid intrahepatic coagulation after PHx.l Intrahepatic fibrin(ogen) deposition, but not thrombin-mediated platelet activation, promotes liver regeneration after PHx.Platelets play a pivotal role in stimulating liver regeneration after partial hepatectomy in rodents and humans. Liver regeneration in rodents is delayed when platelets are inhibited. However, the exact mechanisms whereby platelets accumulate and promote liver regeneration remain uncertain. Thrombin-dependent intrahepatic fibrin(ogen) deposition was recently reported after partial hepatectomy (PHx) in mice, but the role of fibrin(ogen) deposits in liver regeneration has not been investigated. We tested the hypothesis that fibrin(ogen) contributes to liver regeneration by promoting intrahepatic platelet accumulation and identified the trigger of rapid intrahepatic coagulation after PHx. PHx in wildtype mice triggered rapid intrahepatic coagulation, evidenced by intrahepatic fibrin(ogen) deposition. Intrahepatic fibrin(ogen) deposition was abolished in mice with liver-specific tissue factor deficiency, pinpointing the trigger of coagulation after PHx. Direct thrombin activation of platelets through protease-activated receptor-4 did not contribute to hepatocyte proliferation after PHx, indicating that thrombin contributes to liver regeneration primarily by driving intrahepatic fibrin(ogen) deposition. Fibrinogen depletion with ancrod reduced both intrahepatic platelet accumulation and hepatocyte proliferation after PHx, indicating that fibrin(ogen) contributes to liver regeneration after PHx by promoting intrahepatic platelet accumulation. Consistent with the protective function of fibrin(ogen) in mice, low postoperative plasma fibrinogen levels were associated with liver dysfunction and mortality in patients undergoing liver resection. Moreover, increased intrahepatic fibrin(ogen) deposition was evident in livers of patients after liver resection but was remarkably absent in patients displaying hepatic dysfunction postresection. The results suggest a novel mechanism whereby coagulation-dependent intrahepatic fibrin(ogen) deposition drives platelet accumulation and liver regeneration after PHx. (Blood. 2019;133(11):1245-1256

<p>Clinical Implications of Thrombocytopenia for the Cirrhotic Patient</p>

“…Increased intrahepatic fibrin(ogen) deposition is present in livers of patients after liver resection but absent in patients displaying postresection hepatic dysfunction. 112 Experimental and clinical studies support the importance of platelets on regeneration in cirrhosis. Pretreatment of cirrhotic rats with thrombopoietin prior to partial hepatectomy is associated with accumulation of platelets within the liver and correction of the impaired regeneration that is otherwise observed.…”

Platelets in chronic liver disease, from bench to bedside

“…A recent elegant work indicates that fibrin contributes to liver regeneration by promoting intrahepatic platelet accumulation. 38 In this work, the authors showed that the tissue factor produced by hepatocytes after partial hepatectomy is critical for activating a coagulation cascade that leads to intrahepatic fibrin deposition and platelet accumulation in the remnant liver. Accordingly, thrombocytopenia was shown to impair hepatocyte proliferation in a surgical murine model of liver regeneration and many studies based on therapeutic enrichment of platelets during partial hepatectomy indicate pro-regenerating beneficial effects.…”

Hemostasis and Liver Regeneration

“…1). As mentioned previously, hepatic platelet accumulation is very rapid after PHx, peaking within 30 minutes, 25,63 and platelet accumulation in the liver shortly after PHx is most impactful with respect to liver regeneration. Indeed, timing seems to be of critical relevance as platelet depletion prior to PHx significantly reduced hepatocyte proliferation, whereas antibody-mediated thrombocytopenia initiated 2 hours after PHx had a much less impact.…”

“…For example, we have shown that depletion of plasma fibrinogen with ancrod also prevented hepatic platelet accumulation. 63 This suggests that in addition to adhesive proteins such as VWF, coagulation factors are critical drivers of platelet accumulation in the liver after PHx, a potential basis for prior studies associating blood coagulation with liver regeneration. 63,64 Coagulation Factors in Liver Regeneration Activation of coagulation has been shown to promote liver regeneration.…”