Severe and moderate haemophilia A and B in US females

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia Vol. 20; no. 2; pp. e136 - e143
• Main Authors: Di Michele, D. M., Gibb, C., Lefkowitz, J. M., Ni, Q., Gerber, L. M., Ganguly, A.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2014
• Subjects: Cytogenetic Analysis; Factor IX - genetics; Factor VIII - genetics; Female; females; genotype; haemophilia A; haemophilia B; Hemophilia A - complications; Hemophilia A - diagnosis; Hemophilia A - drug therapy; Hemophilia A - epidemiology; Hemophilia B - complications; Hemophilia B - diagnosis; Hemophilia B - drug therapy; Hemophilia B - epidemiology; Humans; Male; moderate haemophilia; Mutation; Phenotype; Quality of Life; Registries; Risk Factors; severe haemophilia; Severity of Illness Index; United States - epidemiology; United States; haemophilia B; haemophilia A; severe haemophilia; moderate haemophilia; females; genotype
• ISSN: 1351-8216; 1365-2516; 1365-2516
• DOI: 10.1111/hae.12364

Summary Haemophilia A and B are rare X‐lined hemorrhagic disorders that typically affect men. Women are usually asymptomatic carriers, but may be symptomatic and, rarely, also express severe (factor VIII (FVIII) or factor IX (FIX) <0.01 U mL−1) or moderately severe (FVIII/FIX 0.01–0.05 U mL−1) phenotypes. However, data on clinical manifestations, genotype and the psychosocial ramifications of illness in severely affected females remain anecdotal. A national multi‐centre retrospective study was conducted to collect a comprehensive data set on affected US girls and women, and to compare clinical observations to previously published information on haemophilic males of comparable severity and mildly affected haemophilic females. Twenty‐two severe/moderate haemophilia A/B subjects were characterized with respect to clinical manifestations and disease complications; genetic determinants of phenotypic severity; and health‐related quality of life (HR‐QoL). Clinical data were compared as previously indicated. Female patients were older than male patients at diagnosis, but similarly experienced joint haemorrhage, disease‐ and treatment‐related complications and access to treatment. Gynaecological and obstetrical bleeding was unexpectedly infrequent. F8 or F9 mutations, accompanied by extremely skewed X‐chromosome inactivation pattern (XIP), were primary determinants of severity. HR‐QoL was diminished by arthropathy and viral infection. Using systematic case verification of participants in a national surveillance registry, this study elucidated the genetics, clinical phenotype and quality of life issues in female patients with severe/moderate haemophilia. An ongoing international case‐controlled study will further evaluate these observations. Novel mechanistic questions are raised about the relationship between XIP and both age and tissue‐specific FVIII and FIX expression.