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Almost half of severe hemophilia A (HA) cases are caused by an intron-22 inversion mutation (Int22Inv), which truncates the 26-exon F8mRNA after exon 22. Another F8transcript, F8B, is initiated from within F8-intron-22. F8BmRNA consists of a short exon spliced to exons 23-26 and is expressed in multiple human cell types. It has been hypothesized that Int22Inv patients have self-tolerance to partial FVIII proteins expressed from these two transcripts. FVIII is expressed in endothelial cells, primarily in liver and lung. Several studies have reported FVIII expression in other cell types, although this has been controversial.