Glucocorticoid Directly Enhances mRNA Levels of Endogenous Coagulation Factor VIII in Human Liver Sinusoidal Endothelial Cells

Abstract

Background: Increased coagulation factor VIII (FVIII:C) activity is potentially associated with the pathogenesis of glucocorticoid (GC)-induced coagulopathy. However, the mechanism underlying the increase in FVIII:C activity remains unclear.
Objectives: We analyzed the changes in coagulation parameters, including FVIII and von Willebrand factor (VWF), in pediatric patients with immune thrombocytopenic purpura (ITP) treated with GC. The influence of GC treatment on mRNA expression of the FVIII (F8) and VWF (VWF) genes was examined in human liver sinusoidal endothelial cells (HLSEC/ciJ) and umbilical vein endothelial cells (EA. hy926).
Methods: Activated partial thromboplastin time (APTT) and levels of FVIII:C, FVIII antigen (FVIII:Ag), and VWF antigen (VWF:Ag) were compared before and after GC treatment in patients with ITP. Changes in F8 and VWF mRNA levels in HLSEC/ciJ and EA. hy926 cells before and after dexamethasone (DEX) treatment were quantified by reverse transcription polymerase chain reaction. Changes in FVIII protein levels were also evaluated in the lysates of DEX-treated HLSEC/ciJ cells.
Results: Values of APTT significantly decreased after GC treatment in ITP patients; significant increases in FVIII:C and FVIII:Ag levels were observed (p<0.05). Notably, no significant increase in VWF:Ag level was observed. F8 and VWF mRNA expressions in HLSEC/ciJ cells increased following DEX treatment (1 and 100 μM) (p<0.05), with the most significant increase seen in F8 mRNA levels (100 μM DEX; p<0.01). These increases were nullified by pretreatment with the GC receptor (GR) antagonist RU486. Additionally, VWF mRNA, but not F8 mRNA, expression increased after treating EA. hy926 cells with 1 μM DEX (p<0.05). No significant increase in FVIII protein level was observed in HLSEC/ciJ cells after treatment with 100 μM DEX.
Conclusions: Direct enhancement of mRNA levels of endogenous FVIII by GC via GR activation is, at least in part, a mechanism underlying the increase in FVIII levels during GC treatment.