Hemophilia A

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.

1. Individuals with severe hemophilia A 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.

2. Individuals with moderate hemophilia A seldom have spontaneous bleeding, although it varies between individuals; however, they do 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.

3. 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.

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 on molecular genetic testing in a male proband confirms the diagnosis. Identification of a heterozygous F8 pathogenic variant on molecular genetic testing in a symptomatic female confirms the diagnosis.

Management: Treatment of manifestations: Referral to a hemophilia treatment center (HTC) to facilitate treatment (intravenous infusion of factor VIII concentrate is most effective when infused within one hour of bleeding onset); training to facilitate home infusions administered by parents or affected individuals; immune tolerance therapy. For those with mild disease, immediate treatment of bleeding with intravenous or nasal desmopressin acetate in those who have been shown to respond to desmopressin acetate or factor VIII concentrate.

Prevention of primary manifestations: For those with severe hemophilia A and those with moderate hemophilia A and frequent bleeding, prophylactic treatment with factor VIII concentrate infusions or subcutaneous administration of emicizumab. Adeno-associated viral (AAV)-mediated gene therapy for hemophilia A (valoctocogene roxaparvovec) was approved by the FDA for adults with severe disease in 2023.

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. Comorbidities may require more frequent visits.

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, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.