Clinical Information

Hemophilia A (HA) is caused by a deficiency of clotting factor VIII (FVIII). HA is an X-linked recessive bleeding disorder that affects approximately 1 in 5000 male individuals. Male patients are typically affected with bleeding symptoms, whereas female carriers generally do not have bleeding symptoms but are at risk of having affected sons. Rarely, approximately 10% of female carriers have FVIII activity levels below 35% and are at risk for bleeding.

Bleeding, the most common clinical symptom in individuals with HA, correlates with FVIII activity levels. FVIII activity levels below 1% are associated with severe disease, 1% to 5% activity with moderate disease, and 5% to 40% with mild disease. In male patients with severe deficiency, spontaneous bleeding may occur. In individuals with mild HA, bleeding may occur only after surgery or trauma.

FVIII is encoded by the factor VIII (F8) gene. Approximately 98% of patients with a diagnosis of HA are found to have a variant in F8 (ie, intron 1 and 22 inversions, point mutations, insertions, and deletions). The intron 1 inversion variant accounts for approximately 5% of variants associated with severe HA. These inversions are typically not identified in patients with mild or moderate HA.

Intron 1 inversion known variant analysis is only recommended for individuals when an intron 1 inversion has already been identified in the family.

If a familial mutation has not been identified in a severely affected HA patient, the F8 gene intron 1 and 22 inversion analysis (F8INV / Hemophilia A F8 Gene, Intron 1 and 22 Inversion Mutation Analysis, Whole Blood) should be ordered.

If the intron 1 inversion analysis is negative, the tested individual has not inherited the familial variant.

It is recommended that the F8 variant be confirmed in the affected male patient or obligate female carrier prior to testing at-risk individuals. Affected male patients are identified by FVIII activity (F8A / Coagulation Factor VIII Activity Assay, Plasma) and clinical evaluation, while obligate female carriers are identified by family history assessment. If the intron inversion assays do not detect an inversion in these individuals, additional analysis (ie, F8 sequencing) may be able to identify the familial variant. Of note, not all women with an affected son are germline carriers of a F8 variant, as de novo variants in F8 do occur. Approximately 20% of mothers of isolated cases do not have an identifiable germline F8 variant. Importantly, there is a small risk for recurrence even when the familial F8 variant is not identified in the mother of the affected patient due to the possibility of germline mosaicism.