F8 – Mild Hemophilia A

Coagulation factor VIII (encoded by F8) is a multidomain glycoprotein essential for intrinsic tenase complex assembly. Mild hemophilia A is defined by factor VIII coagulant activity (FVIII:C) between 5% and 40% of normal and often presents with discrepant one-stage versus two-stage or chromogenic assay results ([PMID:10554831]).

F8-related mild hemophilia A follows an X-linked recessive inheritance pattern, with hemizygous males affected and heterozygous females usually asymptomatic or mildly deficient. Rare Turner syndrome cases reveal apparent homozygosity for F8 missense variants manifesting as mild FVIII deficiency masked by standard one-stage assays ([PMID:21707934]).

A spectrum of missense variants has been identified in mild hemophilia A. Notable examples include p.His1954Leu in the A3 domain disrupting assay concordance, p.Arg1708His (c.5123G>A (p.Arg1708His)) in exon 14 associated with mild deficiency, and p.Arg2182His recurring independently in three unrelated families with variable severity ([PMID:10215414]).

Segregation analysis of p.Arg2182His demonstrated co-segregation with mild to moderate bleeding phenotypes across three kindreds (totaling five affected males), supporting the variant’s pathogenicity and X-linked transmission ([PMID:10215414]).

Functional studies reveal that many mild hemophilia A variants accelerate A2 subunit dissociation from activated FVIII heterotrimer, reducing two-stage activity, while C-domain mutations impair von Willebrand factor binding and secretion. Structural modeling and in vitro assays consistently show impaired FIXa interaction and reduced proteolytic activation, aligning with clinical assay discrepancies ([PMID:9864159]).

Clinical utility of these findings underscores the need for combined one-stage and chromogenic assays when evaluating suspected mild hemophilia A. F8 sequencing confirms diagnosis, informs carrier status, and guides therapeutic management in patients with assay-discordant FVIII activity.

References

• International journal of laboratory hematology • 2012 • Investigation of inflicted injury in a young girl reveals mild haemophilia A and Turner's syndrome. PMID:21707934
• Human Mutation • 1998 • Independent occurrence of the novel Arg2163 to His mutation in the factor VIII gene in three unrelated families with haemophila A with different phenotypes. PMID:10215414
• Blood • 1999 • Mild hemophilia A caused by increased rate of factor VIII A2 subunit dissociation: evidence for nonproteolytic inactivation of factor VIIIa in vivo. PMID:9864159
• British journal of haematology • 1999 • Diagnostic importance of the two-stage factor VIII:C assay demonstrated by a case of mild haemophilia associated with His1954-->Leu substitution in the factor VIII A3 domain. PMID:10554831

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