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

A hallmark of hemophilia is bleeding within joints and muscles that in the past often resulted in disability (permanent joint damage)

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
Diagram of factor IX (FIX) gene and protein structure. (A) FIX gene (F9). (B). FIX protein showing amino acids numbered by Human Genome Variation Society nomenclature. (C). Activated FIX (FIXa). Domains include signal peptide (Signal), propeptide (Pro), gamma-carboxyglutamic acid (Gla), hydrophobic segment (H), epidermal growth factor (EGF) 1, EGF 2, linker peptide (L), activation peptide (Act), serine protease. (From Appl Clin Genet. 2021; 14: 445–454.)

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
From Hematol Oncol Clin North Am. 2021 Dec;35(6):1143-1155.

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
From Hematol Oncol Clin North Am. 2021 Dec;35(6):1143-1155.

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