F8 (Coagulation Factor VIII Intrinsic Tenase Cofactor Gene)
F8 (coagulation factor VIII; HGNC:3546, NCBI Gene ID 2157) is a human locus mapped to chromosome band Xq28 that encodes coagulation Factor VIII procofactor glycoprotein (2,332 mature aa; ~280 kDa). F8 acts in intrinsic coagulation cascade cofactor for Factor IXa in Factor X activation, together with F9 (Coagulation Factor IX Gene), F2 (Prothrombin / Thrombin Gene), and F5 (Coagulation Factor V Gene). Encodes coagulation factor VIII; X-linked mutations cause hemophilia A, treated by AAV5-hF8-SQ gene therapy and bispecific antibodies.
Approved Symbol
F8
Chromosomal Locus
Xq28
Encoded Product
Coagulation Factor VIII procofactor glycoprotein (2,332 mature aa; ~280 kDa)
Primary Pathway
Intrinsic coagulation cascade cofactor for Factor IXa in Factor X activation
Clinical / Therapeutic Role
Hemizygous mutations/intron 22 inversions cause Hemophilia A; target of valoctocogene roxaparvovec (Roctavian) AAV5 gene therapy
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 26-exon gene spanning 186 kb at the telomeric tip of chromosome Xq28, featuring a 3.1 kb exon 14 that encodes the heavily glycosylated, dispensable central B domain (domain organization A1-A2-B-A3-C1-C2) and harboring homologous intronic repeats in intron 22 and intron 1 prone to flip inversions.
Cellular & Tissue Expression Profile: Synthesized and secreted into plasma primarily by hepatic sinusoidal endothelial cells (rather than hepatocytes) and extrahepatic vascular endothelial cells, circulating tightly bound to von Willebrand factor (vWF) which protects FVIII from premature proteolysis.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Upon trace thrombin (F2) cleavage at Arg372, Arg740, and Arg1689, activated Factor VIIIa dissociates from vWF and binds negatively charged phosphatidylserine on activated platelet membranes as the non-enzymatic cofactor for serine protease Factor IXa (F9)—forming the intrinsic tenase complex that accelerates Factor X activation by >200,000-fold.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Hemizygous loss-of-function mutations in F8 cause X-linked recessive Hemophilia A (~1 in 5,000 male births), with homologous recombination inversion of intron 22 accounting for ~45% of severe cases (<1% FVIII activity) and spontaneous hemarthroses.
Therapeutic & Clinical Pharmacology: Because full-length F8 cDNA (7.0 kb) exceeds AAV packaging limits, deletion of the non-essential exon 14 B-domain yielded B-domain-deleted F8-SQ (4.4 kb), now FDA-approved as the single-dose AAV5 gene therapy valoctocogene roxaparvovec (Roctavian) alongside the FVIIIa-mimetic bispecific antibody emicizumab (Hemlibra).