Clinical Guidance

Disease severity

• Large deletions, nonsense variants, and most frameshift variants cause severe disease.

• Missense variants can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved.

Alloimmune inhibitors

• Alloimmune inhibitors occur with the greatest frequency (40%-60%) in individuals with large partial (50 bp) deletions, whole-gene deletions, or early-termination variants (100 predicted amino acids) .

• Missense variants are rarely associated with inhibitors.

Source: GeneReviews — "Hemophilia B"

Penetrance

All males with an F9 pathogenic variant are affected and will have hemophilia B of approximately the same severity as all other affected males in the family; however, other genetic and environmental effects may modify the clinical severity to some extent. Approximately 30% of heterozygous females have factor IX clotting activity below 40% and are at risk for bleeding; mild bleeding can occur in carriers with low-normal factor IX activity .

Source: GeneReviews — "Hemophilia B"

Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care .

Suggestive Findings

Hemophilia B should be suspected in a male or female proband with any of the following clinical features, laboratory features, and/or family history.

Clinical features

Source: GeneReviews — "Hemophilia B"

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 oozing 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 B may have joint deformities and muscle contractures.

Source: GeneReviews — "Hemophilia B"

Management Guidelines

Clinical practice guidelines for hemophilia B have been published .

Evaluations Following Initial Diagnosis

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

Table 4.

Hemophilia B: 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

• F9 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 B to facilitate medical personal decision making

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

Source: GeneReviews — "Hemophilia B"

Clinical Guidance

The following agents/circumstances should be avoided:

• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.

• Use precaution with intramuscular injections without factor IX treatment. Pressure on the site after intramuscular injection in children has been reported to be effective without factor IX coverage. Individuals on prophylaxis may be given intramuscular injections.

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

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

Older, intermediate-purity plasma-derived "prothrombin complex" concentrates should be used cautiously (if at all) in hemophilia B because of their thrombogenic potential.

Source: GeneReviews — "Hemophilia B"

Therapies Under Investigation

Gene therapy for hemophilia B. Clinical trials for gene therapy for hemophilia B are under way, and two products have been approved by the FDA, although one is not being marketed . Long-term durability and safety need further study . Additional studies of gene therapy products and approaches are under way in preclinical studies and later-phase clinical trials . Hemostasis rebalancing agents. Several products are under study that alter the balance of hemostasis so that individuals in which hemostasis is defective, such as those with hemophilia B, can have a more normal hemostatic response . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Hemophilia B"

Surveillance Guidelines

Persons with hemophilia followed at an HTC have lower mortality than those who are not . Young children with severe or moderate hemophilia B should be evaluated at an HTC (accompanied by their parents/guardians) every six to 12 months and as needed to review their history of bleeding episodes and adjust treatment plans. Early signs and symptoms of possible bleeding episodes are reviewed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, a discussion of any other issues related to the individual's hemophilia B, and family and community support. Because of the risk of severe allergic reactions with development of alloantibodies, it is recommended that the first 20 factor replacement treatments be given in a medical setting where resuscitation medications and equipment are available. Risk can be stratified if the genetic variant is known. Those with large partial deletions, complete gene deletions, and early termination variants (100 predicted amino acids) are at highest risk . Screening for alloimmune inhibitors is performed after treatment with factor IX concentrates has been initiated for either bleeding or prophylaxis . Testing for inhibitors should also be performed in any individual with hemophilia B whenever a suboptimal clinical response to treatment is suspected.

Source: GeneReviews — "Hemophilia B"