What is the pathophysiology of factor VIII (FVIII) in hemophilia A?

Updated: Jan 14, 2019
  • Author: Douglass A Drelich, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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Answer

Primary sites of factor VIII (FVIII) production are thought to be the vascular endothelium in the liver and the reticuloendothelial system. Liver transplantation corrects FVIII deficiency in persons with hemophilia.

FVIII messenger RNA has been detected in the liver, spleen, and other tissues. [2] Studies of FVIII production in transfected cell lines have shown that following synthesis, FVIII moves to the lumen of the endoplasmic reticulum, where it is bound to several proteins that regulate secretion, particularly immunoglobulin binding protein, from which it has to dissociate in an energy-dependent process.

Cleavage of FVIII's signal peptide and the addition of oligosaccharides also occur in the endoplasmic reticulum. The chaperone proteins, calnexin and calreticulin, enhance both FVIII secretion and degradation.

A part of the factor FVIII protein in the endoplasmic reticulum is degraded within the cell. The other part enters the Golgi apparatus, where several changes occur to produce the heavy and light chains and to modify the carbohydrates. The addition of sulfates to tyrosine residues of the heavy and light chains is necessary for full procoagulant activity, with the sulfated region playing a role in thrombin interaction. This posttranslational sulfation of tyrosine residues impacts the procoagulant activity of factor VIII and its interaction with von Willebrand factor (vWF).


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