PB0665 - A Case of Discrepant One-stage and Chromogenic Factor VIII Activity Assay in a Patient with a Hemizygous Arg550His Mutation in the F8 Gene

Background: Missense mutations in the F8 gene are known to cause discrepant one-stage and chromogenic assays of Factor VIII (FVIII) activity. Lower FVIII activity (>2-fold difference) when measured with the chromogenic substrate assay compared to the one-stage assay has been described with mutations in the A1-A2-A3 domains of F8. These mutations are thought to disrupt FVIII heterodimer stability and FVIIIa heterotrimer stability.

Aims: We describe a clinical case of discrepant one-stage and chromogenic substrate assay for factor VIII activity in a patient with mild Hemophilia A with a c.1649G>A(p.Arg550His) mutation in the F8 gene.

Methods: The electronic medical record was retrospectively reviewed.

Results: A 50-year-old man with prior history of hemarthrosis, recurrent epistaxis, prolonged bleeding with skin lacerations and prolonged bleeding after tooth extraction presented to our center for evaluation. He had a normal INR of 1.16 and mild prolongation in PTT of 43.8 that fully corrected on mixing study. He had a normal Thrombin Time. He had multiple prior one-stage assays of FVIII activities that ranged from 57-71%. At the time of evaluation, his one-stage FVIII assay was 57%. A chromogenic FVIII activity was checked and found to be 27%. The patient was given a diagnosis of mild Hemophilia A and genetic testing was ordered. He was found to have a hemizygous missense mutation for a c.1649G>A (p.Arg550His) in exon 11 of the F8 gene, consistent with mild Hemophilia A.

Conclusion(s): The c.1649G>A (p.Arg550His) mutation in F8 has been described to cause discrepant results between one-stage and chromogenic substrate assays along with other missense mutations in the A1-A2-A3 domain interfaces, and chromogenic assays should be considered in patients with high clinical suspicion for Hemophilia A even with a normal one-stage FVIII activity assay.