Classical hemophilia A (HA) is characterized by absence
or decrease in factor VIII activity. F8 is an essential cofactor
of F9 to activate F10. Most known genetic mutations
that lead to HA phenotype can be traced to the F8 gene
itself. However, in some cases, mutations in chaperon
proteins, such as LMNA1 and MCFD2, cause a decrease
in secretion of both F5 and F8 resulting in a combined
F5/F8 deficiency. Moreover, mutations in the domain of
von Willebrand factor (VWF) that interact with F8 cause a
HA-like syndrome known as type 2N (Normandy) von
Willebrand disease (VWD-2N). Still, in a minority of HA
cases, no mutations could be attributed to any of the
genes known to be involved in the F8 pathway. In this article
we will give an overview of these cases and outline
future efforts needed to identify the molecular defects in
such patients.