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Hemophilia B.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2000 Oct 2 [updated 2017 Jun 15].

Author information

1
Associate Chief Scientific Officer, Bloodworks Northwest, Seattle, Washington
2
Genomics Laboratory, Bloodworks Northwest, Seattle, Washington

Excerpt

CLINICAL CHARACTERISTICS:

Hemophilia B is characterized by deficiency in factor IX clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor IX clotting activity. In individuals with severe hemophilia B, spontaneous joint or deep-muscle bleeding is the most frequent sign. Individuals with severe hemophilia B are usually diagnosed during the first two years of life; without prophylactic treatment, they may average up to two to five spontaneous bleeding episodes each month. Individuals with moderate hemophilia B seldom have spontaneous bleeding; however, they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies from once a month to once a year. Individuals with mild hemophilia B do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia B are often not diagnosed until later in life. In any individual with hemophilia B, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. Approximately 30% of heterozygous females have factor IX clotting activity lower than 40% and are at risk for bleeding (even if the affected family member has mild hemophilia B), although symptoms are usually mild. After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity.

DIAGNOSIS/TESTING:

The diagnosis of hemophilia B is established in individuals with low factor IX clotting activity. Identification of a hemizygous F9 pathogenic variant on molecular genetic testing in a male proband confirms the diagnosis. Identification of a heterozygous F9 pathogenic variant on molecular genetic testing in a symptomatic female confirms the diagnosis.

MANAGEMENT:

Treatment of manifestations: Referral to a hemophilia treatment center (HTC) for assessment, education, genetic counseling, and treatment. Intravenous infusion of plasma-derived or recombinant factor IX for bleeding episodes within an hour of noticing symptoms. Training and home infusions for those with severe hemophilia B. Prevention of primary manifestations: For those with severe disease, prophylactic infusions of factor IX concentrate twice weekly to maintain factor IX clotting activity higher than 1% nearly eliminates spontaneous bleeding and prevents chronic joint disease. Some individuals require higher trough levels for this effect. Longer-acting products that allow weekly or biweekly dosing are now available. Prevention of secondary complications: Recombinant factor IX produced without human- or animal-derived proteins and virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV and hepatitis B and C viruses. Surveillance: For individuals with severe or moderate hemophilia B, assessments every six to 12 months at an HTC; for individuals with mild hemophilia B, assessments at least every two to three years. Agents/circumstances to avoid: Circumcision of at-risk males until hemophilia B is either excluded or treated with factor IX concentrate regardless of severity; intramuscular injections; activities with a high risk of trauma, particularly head injury; aspirin and all aspirin-containing products. Cautious use of other medications and herbal remedies that affect platelet function. Evaluation of relatives at risk: To clarify genetic status of females at risk before pregnancy or early in pregnancy in order to facilitate management. Pregnancy management: Maternal factor IX levels do not increase during pregnancy and heterozygous females are more likely to need factor infusion support for delivery or to treat or prevent postpartum hemorrhage; monitor heterozygous mothers for delayed bleeding post partum. Therapies under investigation: Clinical trials of additional longer-acting recombinant factor IX concentrates and gene therapy using intravenous infusion of an adeno-associated viral vector expressing factor IX are underway. Other: Vitamin K does not prevent or control bleeding in hemophilia B.

GENETIC COUNSELING:

Hemophilia B is inherited in an X-linked manner. The risk to sibs of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the F9 pathogenic variant in each pregnancy. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant are carriers. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Carrier testing for family members at risk and prenatal testing for pregnancies at increased risk are possible if the F9 pathogenic variant has been identified in a family member or if informative intragenic linked markers have been identified.

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