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Hemophilia A.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
2000 Sep 21 [updated 2014 Jun 05].

Excerpt

CLINICAL CHARACTERISTICS:

Hemophilia A is characterized by deficiency in factor VIII 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 VIII clotting activity. In severe hemophilia A, spontaneous joint or deep-muscle bleeding is the most frequent symptom. Individuals with severe hemophilia A 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 A 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, usually from once a month to once a year. Individuals with mild hemophilia A do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding episodes varies widely, typically from once a year to once every ten years. Individuals with mild hemophilia A are often not diagnosed until later in life. In any individual with hemophilia A, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. Approximately 10% of carrier females are at risk for bleeding (even if the affected family member is mildly affected) and are thus symptomatic carriers, 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 A is established in individuals with low factor VIII clotting activity in the presence of a normal von Willebrand factor (VWF) level. Molecular genetic testing of F8, the gene encoding factor VIII, identifies pathogenic variants in as many as 98% of individuals with hemophilia A.

MANAGEMENT:

Treatment of manifestations: Referral to one of the approximately 140 federally funded hemophilia treatment centers (HTCs) in the USA or worldwide for assessment, education, and genetic counseling and to facilitate management. Training and home infusions administered by parents followed by patient self-infusion are critical components of comprehensive care; especially for those with severe disease, intravenous infusion of factor VIII concentrate is most effective when infused within one hour of the onset of bleeding. For those with mild disease, including most symptomatic carriers, immediate treatment of bleeding or prophylaxis with intravenous or nasal desmopressin (DDAVP [1-deamino-8-D-arginine vasopressin]) or factor VIII concentrate. Prevention of primary manifestations: For those with severe disease, prophylactic infusions of factor VIII concentrate three times a week or every other day to maintain factor VIII clotting activity higher than 1% nearly eliminates spontaneous bleeding and prevents chronic joint disease. Prevention of secondary complications: Reduction of bleeding and chronic joint disease is achieved by prophylactic treatment and prompt effective treatment of bleeding, including home therapy. Surveillance: For individuals with severe or moderate hemophilia A, assessments every six to 12 months at an HTC are recommended; for individuals with mild hemophilia A, at least every two to three years. Agents/circumstances to avoid: Circumcision of at-risk males until hemophilia A is either excluded or treated with factor VIII 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 and to facilitate management. Pregnancy management: Monitor carrier mothers for delayed bleeding postpartum unless it is known that their baseline factor VIII clotting activity is normal. Therapies under investigation: Ongoing clinical trials of longer-acting factor VIII concentrates. Other: Vitamin K does not prevent or control bleeding in hemophilia A; cryoprecipitate contains factor VIII but does not undergo viral inactivation so is no longer used to treat hemophilia A; no clinical trials for gene therapy in hemophilia A are currently in progress although several improved approaches are in pre-clinical testing.

GENETIC COUNSELING:

Hemophilia A 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 F8 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 at-risk family members and prenatal testing for pregnancies at increased risk are possible if the F8 pathogenic variant has been identified in a family member or if informative intragenic linked markers have been identified.

Copyright © 1993-2016, University of Washington, Seattle. All rights reserved.

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