Hemostasis and Liver Regeneration

Abstract

The liver is unique in its remarkable regenerative capacity, which enables the use of liver resection as a treatment for specific liver diseases, including removal of neoplastic liver disease. After resection, the remaining liver tissue (i.e, liver remnant) regenerates to maintain normal hepatic function. In experimental settings as well as patients, removal of up to two-thirds of the liver mass stimulates a rapid and highly coordinated process resulting in the regeneration of the remaining liver. Mechanisms controlling the initiation and termination of regeneration continue to be discovered, and many of the fundamental signaling pathways controlling the proliferation of liver parenchymal cells (i.e., hepatocytes) have been uncovered. Interestingly, while hemostatic complications (i.e., bleeding and thrombosis) are primarily thought of as a complication of surgery itself, strong evidence suggests that components of the hemostatic system are, in fact, powerful drivers of liver regeneration. This review focuses on the clinical and translational evidence supporting a link between the hemostatic system and liver regeneration, and the mechanisms whereby the hemostatic system directs liver regeneration discovered using experimental settings.

Figure 1:

Mechanisms linking hemostatic factors to liver regeneration: Platelets rapidly accumulate in the liver remnant after partial hepatectomy. Accumulation of platelets in the liver appears to depend on multiple factors including von Willebrand factor (VWF), and on fibrin deposits formed as a result of intrahepatic coagulation. Experimental evidence suggests that platelets contribute to liver regeneration through multiple mechanisms including 1) degranulation and release of serotonin and other growth factors, 2) transfer of RNA by direct interactions with hepatocytes and 3) potentially through cell-cell interactions with leukocytes or other non-parenchymal cells. Among the gaps in knowledge include the source of VWF responsible for driving platelet accumulation (plasma, endothelial cells or platelets themselves), and whether fibrin drives regeneration through mechanisms independent of its role in platelet accumulation. TF = Tissue factor VWF = von Willebrand factor EC = Endothelial Cell HPC = Hepatocyte