Tissue Distribution of Factor VIII Gene Expression In Vivo – A Closer Look

Abstract

SummaryPrevious studies have shown that factor VIII (FVIII) is expressed by multiple tissues. However, little is known about its cellular origin or its level of expression in different organs. In the present study, we examined FVIII gene expression in different tissues on a quantitative basis. Most of the tissues, especially liver and kidney, expressed high levels of FVIII mRNA compared to their level of expression of other hemostatic proteins, including von Willebrand factor (VWF). This was unexpected since FVIII is a trace protein. In situ hybridization analysis confirmed that liver and kidney were rich in FVIII mRNA. In the liver, a clear hybridization signal was detected in cells lining the sinusoids. FVIII mRNA analysis of purified liver cells confirmed the expression of FVIII mRNA by sinusoidal endothelial cells and Kupffer cells. Low but significant levels of FVIII mRNA were also detected in the hepatocytes. VWF mRNA was not detectable in these cells. Similarly, immunohistochemical staining of liver tissue revealed that FVIII protein is primarily associated with sinusoidal cells. VWF protein was predominantly located in the endothelium of larger vessels. In the kidney, FVIII synthesis was localized to the glomeruli and to tubular epithelial cells. Taken together, these results suggest that besides hepatocytes, non-parenchymal cells (e.g. sinusoidal endothelial cells) contribute to FVIII synthesis. VWF synthesis is primarily confined to extra-hepatic tissues.

Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

“…Our current understanding of the mechanism of FVIII biosynthesis in mice is limited by the lack of a positive correlation between FVIII mRNA and FVIII protein levels. 39,40 Because FVIII mRNA and LRP mRNA have been identified in the same cell type, 3,4,16,41 we cannot exclude the possibility that LRP plays an as-yet-unidentified role along the intracellular secretory pathway of FVIII. This would be consistent with the recent observation that the LDL receptor within the endoplasmic reticulum mediates the presecretory degradation of its ligand apolipoprotein B.…”

“…FVIII is synthesized in various tissues, including liver, spleen, and kidney. 3,4 In plasma, FVIII circulates in complex with its carrier protein von Willebrand factor (VWF), which is produced and secreted by vascular endothelial cells. 5,6 VWF serves a predominant role in stabilizing FVIII and prevents its premature clearance.…”

Idiopathic Non-Cirrhotic Intrahepatic Portal Hypertension (NCIPH)—Newer Insights into Pathogenesis and Emerging Newer Treatment Options

“…In the normal state, von-Willebrand Factor (vWF) immunostaining is usually positive in large vessels but negative in the sinusoidal endothelial cells in the liver. 28 On the occurrence of liver injury accompanied by a necroinflammatory process, the sinusoidal endothelial cell becomes positive for vWF, presumably in association with the capillarization of hepatic sinusoids. 29 In an interesting in-vitro experiment, human umbilical vein endothelial cells were treated with interleukin 6 (IL-6), IL-8, or tumor necrosis factor alpha (TNF-a), and the formation of platelet-decorated ULvWF strings were quantitated.…”

Allogeneic bone marrow transplantation in a child with severe aplastic anemia and hemophilia A

“…Bone marrow FVIII mRNA expression has not been evaluated. 12 Our patient's donor was his unaffected brother. Four months after allo-BMT, clotting parameters and the FVIII level remained similar to pretransplant values, suggesting that bone marrow does not make a major contribution to circulating FVIII levels.…”