Abstract Number: PB0811
Meeting: ISTH 2020 Congress
Background: Haemophilia A and B are X-linked haemorrhagic disorders caused by mutations in F8 and F9 genes. Due to recessive inheritance, males are affected, while female carriers are usually asymptomatic and express about half of normal factor VIII and IX activity. The phenotypic expression of the disease in female carriers is extremely variable. This variability might be attributable to several genetic mechanisms, including skewed X chromosome inactivation (XCI).
Aims: To investigate whether the low activity of FVIII or FIX (≤50 IU/dL) could be related to XCI in haemophilia carriers with bleeding symptoms.
Methods: XCI status was determined by indirect DNA-based methylation analysis (HUMARA assay). Bleeding tendency was evaluated using the standardized ISTH bleeding assessment tools (BAT score). BAT score ≥6 has been considered abnormal in adult females.
Results: The HUMARA assay was tested in 73 symptomatic female carriers of haemophilia A and B with a clotting activity of FVIII or FIX ≤50 IU/dL. Approximately 20% of haemophilia carriers showed an extremely skewed XCI (≥90:10), while 33% showed a skewed pattern of ≥80:20.
Data on bleeding manifestations were available for 65 haemophilia carriers.
A statistical association between XCI pattern and FVIII and FIX levels was observed, with a value of Person’s r=-0.60. Especially the group of female carriers with very low coagulant activity (≤20 IU/dL) and high XCI pattern (≥80:20) showed a BAT score of 15 (IQR: 8-18), while female carriers with factor level >20 IU/dL and XCI pattern < 80:20 had a BAT score of 5 (IQR: 2-8) (Figure).
Conclusions: Our study demonstrates that XCI could have a great influence on the phenotype and expression of X-linked diseases, but random XCI not fully negate bleeding tendency in haemophilia carriers, underling the complexity of female carriers phenotype.
To cite this abstract in AMA style:Garagiola I, Mortarino M, Siboni SM, Boscarino M, Peyvandi F. X Chromosome Inactivation: A Modifier of Factor VIII and IX Plasma Levels in Haemophilia Carriers [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/x-chromosome-inactivation-a-modifier-of-factor-viii-and-ix-plasma-levels-in-haemophilia-carriers/. Accessed October 1, 2023.
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