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Severe and moderate haemophilia A and B in US females

Authors

  • D. M. Di Michele,

    Corresponding author
    1. Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA
    Current affiliation:
    1. Division of Blood Diseases and Resources, National Heart, Lung and Blood Institute.
    • Correspondence: Donna DiMichele, MD, Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, National Institutes of Health, 6701 Rockledge Drive, Room 9132, Bethesda, MD 20892-7950, USA.

      Tel.: +1 (301) 435 0080; fax: +1 (301) 480 0867;

      e-mail: dimicheledm@nhlbi.nih.gov

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  • C. Gibb,

    1. Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA
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  • J. M. Lefkowitz,

    1. Department of Social Work, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY, USA
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  • Q. Ni,

    1. Department of Public Health, Weill Cornell Medical College, New York, NY, USA
    Current affiliation:
    1. Allergan Inc, Irvine, CA, USA
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  • L. M. Gerber,

    1. Department of Public Health, Weill Cornell Medical College, New York, NY, USA
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  • A. Ganguly

    1. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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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.

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