About the condition

Description/definition:

Hemophilia B is a hereditary X-linked chromosomal disorder of varying severity caused by the deficiency or absence of coagulation factor IX (FIX), characterized by spontaneous, postoperative, or posttraumatic bleeding. Reported incidence of hemophilia B is 1 in 20,000 to 1 in 30,000 live male births (accounts for 18% of people with hemophilia)

Classified as:

Mild

• FIX activity > 5%-40%
• Usually diagnosed later in life
• Characterized by prolonged bleeding following major trauma or surgery

Moderate

• FIX activity 1%-5% (0.01-0.05 units/mL)
• Usually diagnosed between age 5 and 6 years
• Characterized by bleeding following minor trauma but may present with spontaneous bleeding

Severe

• FIX activity < 1% (< 0.01 units/mL)
• Usually diagnosed in the first 2 years of life
• May present with spontaneous mild or life-threatening bleeding

Pathophysiology:

• FIX is a vitamin K–dependent enzyme that is essential for normal thrombin generation. It is synthesized in the liver.
• Mutations in the F9 gene on the X chromosome, resulting in deficiency or absence of coagulation factor IX (FIX). Over 1000 known pathogenic variants in the FIX gene reported, especially missense and frameshift changes.
• Inherited recessive mutations in about 70% of cases, spontaneous mutations in about 30% of cases (called sporadic cases).
• About 10% of female carriers with 1 F9 disease-causing mutation and 1 normal allele have about 30% factor IX activity and mild bleeding disorder.
• Severity of disease and bleeding complications inversely proportional to factor IX activity

Diagnosis:

Suspect diagnosis of hemophilia A in a patient with:

• Spontaneous bleeding usually into joints, muscles, and soft tissue
• Excessive, prolonged, or intermittent bleeding following trauma or surgery, including heel stick, intramuscular injection, venipuncture
• Family history of bleeding
• Intracranial bleeding in absence of major trauma
• Infant with intracranial hemorrhage or bleeding post circumcision
• Prolonged or renewed bleeding after tooth extraction, circumcision, or mouth injury
• Unexplained gastrointestinal bleeding or hematuria
• Prolonged nosebleeds (particularly recurrent and bilateral)

Confirm diagnosis:

• Factor IX activity level in plasma using a one-stage clot-based or chromogenic substrate assay
• genetic testing identifies disease-causing mutations in 99% of individuals with hemophilia B

Coagulation profile testing may include:

• Elevated aPTT – usually prolonged but may be normal in mild hemophilia B
• Reduced FIX activity level – used for definitive diagnosis, classification of disease severity
• FIX inhibitor testing – if aPTT prolonged
  • Alloimmune inhibitors may be present in patients who have been previously exposed to FIX concentrates
  • Elevated aPTT will not correct if inhibitor against FIX present
  • in contrast to factor VIII inhibitors, factor IX inhibitors are not time-dependent

Differential diagnosis

• Other causes of low FIX activity:
  • Normal neonates and premature infants
  • Vitamin K deficiency at any life stage
  • Inherited deficiency of vitamin K-dependent factors (an autosomal disorder)anticoagulant therapy with vitamin K antagonists
  • Liver disease
• Compared with hemophilia A

Treatment:

General principles of management:

• The overall goal of hemophilia B treatment involves utilization of exogenous clotting factor concentrates, or other novel therapies (not currently approved), to achieve hemostasis
• The mainstay of therapy for hemophilia B is to replace the deficient clotting factor to:
  • Prevent bleeding (called prophylactic treatment)
  • Control bleeding (called on-demand or episodic treatment)
• FIX concentrates include
  • Plasma-derived
  • Recombinant

Treatment of active bleeding:

• Patients with hemophilia should receive immediate care for potential bleeding events with strong consideration of treatment with clotting factor concentrates before any imaging
• In patients without inhibitors
  • In patients with major bleeding, the goal is to replace factor IX activity to ≥ 100%
  • Factor IX concentrate (plasma derived) 1 unit/kg increases factor IX activity by 1%, but dosing of factor IX varies by type of product due to different recovery rates (the amount of factor IX concentrate that is required to achieve a similar plasma level is approximately twice that of an FVIII product)
  • Recombinant human factor VIIa may be given if patient has history of previous allergic reaction to factor IX
  • Antifibrinolytic monotherapy or adjuvant therapy dosing for mild mucosal or skin bleeding (for example, during dental surgery)
• In patients with inhibitors
  • For low-titer inhibitor patients (< 5 Bethesda units/mL)
    • Factor IX concentrate – high-dose or high-frequency  with the goal in patients with major bleeding to replace factor IX activity to ≥ 100%
  • For high-titer inhibitor patients (> 5 Bethesda units/mL)
    • Recombinant hFVIIa or APCC (FEIBA)
  • Antifibrinolytic monotherapy (tranexamic acid or aminocaproic acid) for mucosal or skin bleeding

Prophylactic treatment

• Considered standard of care in all patients with severe hemophilia B
• Historically involves the routine administration of factor IX concentrate to maintain at least a 1% trough FIX activity in between dosing
• For patients without inhibitors, consider factor IX – typical initial dosing 15-40 units/kg IV twice weekly; regimens are often individually tailored
• For patients with inhibitors (> 5 Bethesda units/mL) consider either:
  • factor VIIa (recombinant) – typical dosing 90 mcg/kg IV given once daily
  • aPCC – typical dosing 50-85 units/kg IV every other day or 3 times weekly
  • if treatment failure occurs, consider giving the alternate agent