Resection of the liver (i.e., partial hepatectomy; PHx) is a common surgical procedure used to treat multiple forms of liver disease, including removal of tumors caused by liver cancer and metastases. The liver can regenerate to restore normal hepatic function, ensuring a complication-free recovery in most patients. However, a significant number of patients suffer from failed liver regeneration leading to serious complications, including post-hepatectomy liver failure (PHLF), a condition where the liver remnant cannot sustain critical hepatic functions. Biomarkers of the development of PHLF after liver resection are not universally predictive. More importantly, there are no targeted therapies available to stimulate liver regeneration. This proposal seeks to discover innovative strategies to better predict PHLF and simultaneously uncover novel putative therapeutic targets to promote liver regeneration in patients undergoing PHx. Our strong preliminary results, generated using experimental PHx in mice and intraoperative liver and plasma samples from liver resection patients from a well-defined repository, suggest that rapid activation of intrahepatic blood coagulation is a central determinant of liver regeneration. Specifically, we hypothesize that cross-linked fibrin polymers, formed in the remnant liver as a result of increased coagulation activity, promote hepatic platelet accumulation that stimulates liver regeneration. Our approach includes innovative analysis of the interplay between fibrinogen and platelets in immediately available human liver and plasma samples, previously collected in precise sequence during surgical liver resection, comprehensive mechanistic assessment of fibrin(ogen) structure and hemostatic functions in experimental and clinical liver resection samples, genetically-modified mice expressing fibrin(ogen) proteins with specific functional mutations, comprehensive analyses linking failed regeneration to hepatic dysfunction, and application of FDA-approved fibrinogen concentrates as a novel pro-regenerative therapeutic. The investigative team comprises internationally-recognized researchers and physician-scientists at the nexus of coagulation in liver disease. The combined expertise of the investigative team in mechanistic studies of liver injury and regeneration, coagulation and fibrin(ogen) biochemistry/function, and leading-edge clinical/translational investigation maximizes impact of the proposed studies. In our proposed studies we will:
(Aim 1) Determine the mechanism linking blood coagulation to liver regeneration after PHx;
(Aim 2) Identify modifications of fibrinogen hemostatic function connected to outcome in patients after liver resection;
and (Aim 3) Determine the potential of fibrinogen supplementation as a novel pro-regenerative therapy in experimental PHx. The expected outcome of these Specific Aims is the discovery of a novel mechanistic link between coagulation and liver regeneration. The proposed studies are potentially transformative, because they would suggest that changes in blood coagulation, largely considered secondary to the surgery, can be measured and therapeutically controlled to drive patient recovery and prevent liver failure.
Some patients who have unhealthy tissue (e.g., a tumor) removed from their liver using a surgical procedure called partial hepatectomy develop complications because the remaining liver tissue does not sufficiently regenerate to recover its normal function. Our studies suggest that partial hepatectomy is associated with activation of blood clotting in the liver of humans and mice, and that a specific blood clotting protein, fibrinogen, can promote liver regeneration. The primary goal of this research is to discover how fibrinogen promotes liver regeneration so that we can discover new strategies to predict, prevent and ultimately treat liver dysfunction in patients after partial hepatectomy.