Hemophilia A

Excerpt

Clinical characteristics: Hemophilia A is characterized by deficiency in factor VIII clotting activity that results in prolonged bleeding 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.

Severe hemophilia A: Individuals are usually diagnosed during the first two years of life following oral or soft tissue bleeding either with procedures or due to a known family history of hemophilia. Without prophylactic treatment, individuals may average up to two to five spontaneous bleeding episodes each month including spontaneous joint bleeds or deep-muscle hematomas, and prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.

Moderate hemophilia A: Less frequent spontaneous bleeding, although it varies between individuals. Affected individuals have prolonged or delayed bleeding 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.

Mild hemophilia A: Individuals generally 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.

Heterozygous females: Approximately 30% of heterozygous females have factor VIII clotting activity below 40% and are at risk for bleeding (even if males in the family are only mildly affected). After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity. In addition, 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency.

Diagnosis/testing: The diagnosis of hemophilia A is established in an individual with low factor VIII clotting activity in the presence of a normal, functional von Willebrand factor level. Identification of a hemizygous F8 pathogenic variant by molecular genetic testing in a male proband confirms the diagnosis. Identification of a heterozygous F8 pathogenic variant by molecular genetic testing in a symptomatic female confirms the diagnosis.

Management: Targeted therapies: For those with severe hemophilia A and those with moderate or mild hemophilia A and frequent bleeding, prophylactic treatment with factor VIII concentrate infusions or subcutaneous administration of emicizumab; other non-factor prophylactic therapies (marstacimab, concizumab, and fitusiran) are approved in those age 12 years and older. Desmopressin acetate in those with mild hemophilia A and documented response to this therapy. Immune tolerance therapy in those with inhibitors. Adeno-associated viral (AAV)-mediated gene therapy for hemophilia A (valoctocogene roxaparvovec) was approved by the FDA for adults with severe disease in 2023.

Supportive care: Referral to a hemophilia treatment center (HTC) for assessment, education, genetic counseling, and treatment. Training to facilitate home infusions administered by parents or affected individuals should be provided for individuals affected by moderate and severe hemophilia; physical therapy for evaluation and treatment of musculoskeletal disease; standard treatments for pain with help from a pain specialist as needed; standard treatments for transfusion-related infections contracted prior to virucidal treatment of plasma-derived concentrates.

Surveillance: For individuals with severe or moderate hemophilia A, assessments including inhibitor screen every six to 12 months at an HTC; for individuals with mild hemophilia A, assessment at an HTC every one to two years. Children and individuals with comorbidities may require more frequent visits. The assessment should include a review of bleeding episodes, adjustment of treatment plans as needed, a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, and a discussion of any other issues related to the individual's hemophilia A as well as family and community support. Screening for alloimmune inhibitors is performed during initial ten to 20 treatment days in children with severe hemophilia then on recommended schedule or in individuals with a suboptimal clinical response to treatment.

Agents/circumstances to avoid: Circumcision of at-risk males until hemophilia A is either excluded or treated with factor VIII concentrate regardless of severity; activities with a high risk of trauma, particularly head injury; cautious, if any, use of medications and herbal remedies that affect platelet function, including aspirin; use precaution with intramuscular injections (apply pressure; intramuscular injection may be scheduled after factor VIII treatment or while on emicizumab therapy).

Evaluation of relatives at risk: It is appropriate to evaluate asymptomatic male and female at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment, preventive measures, and surveillance. It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.

Pregnancy management: Monitor affected females during pregnancy and for delayed bleeding post partum unless it is known that their baseline factor VIII clotting activity is normal prior to pregnancy and there are no symptoms of bleeding.

Genetic counseling: Hemophilia A is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. The risk to sibs of a female proband depends on the genetic status of the mother and father. If the mother of the proband has an F8 pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. If the father of the proband has an F8 pathogenic variant, he will transmit it to all his daughters and none of his sons. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant are heterozygotes and may be at risk for bleeding. Once the F8 pathogenic variant has been identified in an affected family member, genetic testing for at-risk family members and prenatal/preimplantation genetic testing are possible.