SCIENTIFIC BACKGROUND
Hemophilia A is an X-linked recessive coagulation disorder caused by a deficiency of coagulation factor VIII (FVIII). This leads to a disturbance in the intrinsic pathway of the coagulation cascade and hemorrhagic diathesis with prolonged activated partial thromboplastin time (aPTT).
Phenotypically, hemophilia A is indistinguishable from hemophilia B (factor IX deficiency). The two syndromes can be differentiated by biochemical measurement of the respective enzyme activity. Factor XIII activity should be measured before genetic testing. Since von Willebrand factor deficiency can also lead to decreased FVIII activity, von Willebrand factor should also be determined biochemically for a differential diagnosis.
More than 2,500 pathogenic variants in the F8 gene are known to lead to hemophilia A. Depending on the type of variant, there is a varying degree of impairment of enzyme activity; as a result the disease is classified into different levels of severity:
- Severe hemophilia A: factor VIII activity <1%
- Moderate hemophilia A: factor VIII activity 1-5%
- Mild hemophilia A: factor VIII activity 6-40%
Due to X-linked inheritance, males are predominantly affected. The estimated prevalence is approximately 1:6,000. In rare cases, heterozygous carriers may also express symptoms in the presence of unequal X inactivation. Approximately 30% of hemophilia A cases are due to new mutations. Mild forms and about 50% of severe forms of the disease are caused by point mutations in the F8 gene. About half of the severe hemophilia cases are caused by gene inversions in intron 1 or intron 22. Therapy involves intravenous substitution with recombinant factor VIII.
References
Konkle et al. 2000 Oct 2 [Updated 2017 Jun 15]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. Gene Reviews®, [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK1495 / Jenkins et al. 2012, Eur J Hum Genet 20:5 / Oldenburg et al. 2008, Hämostaseologie 28:335 / Keeney et al. 2005, Haemophilia 11:87 / http://www.dhg.de/