PB1122 - Regulation of coagulation factor VIII activity in a murine model of steatohepatitis

Background: The liver is a major organ that produces coagulation factors. Most coagulation factors are produced by hepatocytes, but only coagulation factor VIII (FVIII) is produced by liver sinusoidal endothelial cells. FVIII does not decrease in liver dysfunction such as cirrhosis, and its unique regulation of activity has attracted much attention.

Aims: We aimed to clarify the regulatory mechanism of FVIII activity during liver injury using a murine model of diet-induced steatohepatitis.

Methods: Male C57BL/6 (wild type, WT) and von Willebrand factor (VWF)-deficient mice were fed a high-fat diet (choline-deficient methionine-reduced high-fat diet, CDAHFD) or normal chow diet (NCD) for 12 weeks. Plasma coagulation factor activity was measured by a one-stage clotting assay. mRNA expression of coagulation factors was analyzed with quantitative RT-PCR. FVIII clearance in mice was assessed by measuring human FVIII antigen after administration of human FVIII.

Results: FVIII activity, but not coagulation factor IX (FIX) activity, increased 2.5-fold during the CDAHFD feeding in WT mice. However, F8 mRNA expression was unchanged in the liver, and its compensatory increase was not observed in other organs, including the lung, kidney, and spleen. On the other hand, plasma VWF was significantly increased in CDAHFD-fed mice, and its mRNA expression enhanced in the liver, but not other organs. As expected from the increase in plasma VWF, FVIII clearance after the administration of human FVIII was significantly prolonged in CDAHFD-fed mice. Unexpectedly, Vwf-deficient mice also showed a transient increase in FVIII activity and a decrease in FVIII clearance after CDAHFD feeding.

Conclusion(s): FVIII activity in steatohepatitis is enhanced by the reduction of FVIII clearance associated with an increase in plasma VWF produced from the liver. In addition, a mechanism regulating VWF-independent FVIII clearance is also involved in the increase of FVIII activity in steatohepatitis.