Haemophilia A

Haemophilia A is inherited in an X-linked manner. Males with an F8 pathogenic variant are affected; female carriers may also present with bleeding symptoms, as approximately 30% have factor VIII clotting activity below 40% and a further 25% with normal activity report an increased bleeding tendency. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Laboratory screening typically shows a prolonged activated partial thromboplastin time (aPTT) with a normal prothrombin time and normal platelet count. Further analysis shows reduced factor VIII coagulant activity (FVIII:C) and/or antigen levels. Especially in patients with low FVIII:C and disproportionally higher factor (vWF) antigen, von Willebrand syndrome type 2N should be ruled out by measuring the von Willebrand factor’s Factor VIII binding capacity (VWF:FVIIIB).

Main differential diagnoses include:

• Haemophilia B: clinically indistinguishable from hemophilia A, but caused by deficiency of factor IX rather than factor VIII
• Type 2N : low FVIII:C indistinguishable from mild hemophilia A; differentiated by molecular genetic testing or by measuring factor VIII binding capacity of VWF (VWF:FVIIIB)
• Type 3 von Willebrand disease: frequent mucous-membrane bleeding plus joint and muscle bleeding similar to hemophilia A, but with complete or near-complete quantitative deficiency of von Willebrand factor (factor VIII clotting activity most commonly 2-8 %)

• Identification of a hemizygous (males) or heterozygous (females) pathogenic or likely pathogenic variant by molecular genetic testing confirms the diagnosis, supports phenotype and inhibitor-risk prediction, and enables family studies.
• Allowing predictive testing of at-risk family members once the familial pathogenic variant has been identified, supporting informed reproductive and clinical decisions within the family.

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