Differential Diagnosis

A detailed history of bleeding episodes can help determine if an individual has a lifelong, inherited bleeding disorder or an acquired (often transient) bleeding disorder. Increased bleeding with trauma, tonsillectomy, or for a few hours following tooth extraction may be seen in individuals without a bleeding disorder. In contrast, prolonged or intermittent bleeding that lasts several days following tooth extraction or mouth injury, renewed bleeding or increased pain and swelling several days after an injury, or development of a wound hematoma several days after surgery almost always indicates a coagulation problem. An older individual with severe or moderate hemophilia A may have joint deformities and muscle contractures. Large bruises and subcutaneous hematomas for which no trauma can be identified may be present. Individuals with a mild bleeding disorder have no outward signs except during an acute bleeding episode. Note: Petechial hemorrhages indicate severe thrombocytopenia and are not a feature of hemophilia A. Table 3. Inherited Bleeding Disorders with Low Factor VIII Clotting Activity

Source: GeneReviews — "Hemophilia A"

Management Guidelines

Clinical practice guidelines for hemophilia A have been published .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hemophilia A, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Hemophilia A: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Hematologic

| • Personal family history of bleeding to help predict disease severity

• CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage

• Referral to HTC

• F8 molecular testing to aid in determining disease severity, likelihood of inhibitor development, testing of family members

|

Musculoskeletal

| Joint muscle eval, esp if person reports history of hemarthrosis or deep-muscle hematomas |

Infectious

disease | Screening for hepatitis A, B, C as well as HIV if blood products or plasma-derived clotting factor concentrates were administered prior to 1990 |

Genetic

counseling | By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of hemophilia A to facilitate medical personal decision making

CBC = complete blood count; GI = gastrointestinal; HTC = hemophilia treatment center; MOI = mode of inheritance

Source: GeneReviews — "Hemophilia A"

Clinical Guidance

The following agents/circumstances should be avoided:

• Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure. The benefit versus the risk of factor VIII exposure in early life should be considered.

• Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as in individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely .

• Intramuscular injections without factor treatment should be avoided. Pressure on the site after intramuscular injection in children has been reported without factor VIII coverage. Individuals on prophylactic therapy may be given intramuscular injections.

• Activities that involve a high risk of trauma, particularly of head injury, should be avoided.

Source: GeneReviews — "Hemophilia A"

Therapies Under Investigation

Clinical trials for gene therapy for hemophilia A are under way; one product, valoctocogene roxaparvovec, received conditional marketing authorization by the European Medicines Agency in 2022 and approval by the FDA in 2023. The gene therapies currently in or having recently completed Phase III trials use liver-targeted adeno-associated (AAV) vectors. Therapeutic levels have been achieved in many (although not all) individuals in studies to date, and short-term steroids are often needed for elevated transaminases. Long-term durability as well as safety need further study . Additional approaches to gene therapy are under study in preclinical models and early-phase trials, including with lentiviral vectors .

Source: GeneReviews — "Hemophilia A"