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

Dafna Groeneveld, David Pereyra, Zwanida Veldhuis, Jelle Adelmeijer, Petra Ottens, Anna K. Kopec, Patrick Starlinger, Ton Lisman and James P. Luyendyk

Key points

  • Liver-associated tissue factor drives rapid intrahepatic coagulation after partial hepatectomy.

  • Intrahepatic fibrin(ogen) deposition, but not thrombin-mediated platelet activation, promotes liver regeneration after partial hepatectomy.

Abstract

Platelets play a pivotal role in stimulating liver regeneration following 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 remains uncertain. Thrombin-dependent intrahepatic fibrin(ogen) deposition was recently reported after partial hepatectomy in mice (PHx), but the role of fibrin(ogen) deposits in liver regeneration has not been tested. 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 wild-type 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 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 remarkably, was absent in patients displaying hepatic dysfunction post-resection. The results suggest a novel mechanism whereby coagulation-dependent intrahepatic fibrin(ogen) deposition drives platelet accumulation and liver regeneration after partial hepatectomy.

  • Submitted August 10, 2018.
  • Accepted January 9, 2019.