title: Severe and moderate haemophilia A and B in US females.
abstract: 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.
authors.affiliation: Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Di Michele
authors.forename: C
authors.initials: C
authors.lastname: Gibb
authors.forename: J M
authors.initials: JM
authors.lastname: Lefkowitz
authors.forename: Q
authors.initials: Q
authors.lastname: Ni
authors.forename: L M
authors.initials: LM
authors.lastname: Gerber
authors.forename: A
authors.initials: A
authors.lastname: Ganguly
mesh_terms: D020732:Cytogenetic Analysis; D005164:Factor IX / Q000235:genetics; D005169:Factor VIII / Q000235:genetics; D005260:Female; D006467:Hemophilia A / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology*; D002836:Hemophilia B / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology*; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D011788:Quality of Life; D012042:Registries; D012307:Risk Factors; D012720:Severity of Illness Index; D014481:United States / Q000453:epidemiology
chemical_list: D005169:Factor VIII; D005164:Factor IX
keywords: females; genotype; haemophilia A; haemophilia B; moderate haemophilia; severe haemophilia