Tyr346→Cys mutation results in factor VIII:C assay discrepancy and a normal bleeding phenotype – is this mild haemophilia A?

Summary. Patients with mild haemophilia A may have a discrepancy in the factor VIII (FVIII) level when measured with a one-stage assay (FVIII:C1) compared with a two-stage assay (FVIII:C2). This discrepancy usually results in the one-stage level being higher than the two-stage level. A F8 mutation resulting in a Tyr346→Cys substitution within the a1 interdomain region has been described which results in the converse assay discrepancy. We report four individuals (three families) who have this mutation. Mean FVIII:C1 level was 25 IU dL⁻¹ compared with a mean FVIII:C2 level of 63 IU dL⁻¹. These individuals had presented opportunistically and did not have a clinically significant bleeding disorder. The bleeding phenotype correlated with the two-stage assay result rather than the one-stage result. FVIII replacement therapy does not appear to be required for these individuals.