Coagulation
Hereditary bleeding disorders
Factor IX deficiency (hemophilia B)

Authors: Kendall Crookston, M.D., Ph.D., Julie Gober-Wilcox, M.D. (see Authors page)

Revised: 28 April 2016, last major update September 2010

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: Factor IX deficiency[title] AND Hemophilia B [title]

Definition / General
  • Factor IX deficiency (hemophilia B) is the second most common congenital bleeding disorder that is inherited as an X-linked recessive trait
  • Characterized by mild, moderate or severe bleeding episodes
Terminology
  • Also known as Christmas disease
Epidemiology
  • 1 in 30,000 male births
  • Almost exclusively affects males
  • Rarely affects females (see etiology)
  • Female carriers are unaffected
Sites
  • Bleeding into muscle, soft tissue or joints (hemarthrosis), GI / GU tract bleeding, easy bruising, excessive bleeding after surgery, trauma, dental procedures or circumcision; epistaxis, poor wound healing, intracranial hemorrhage, scalp hematoma, development of pseudotumors with repetitive hematoma formation, menorrhagia

  • Incidence of sites of bleeding:
    • Hemarthrosis: 70 - 80%
    • Muscle/soft tissue: 10 - 20%
    • Other major bleeds: 5 - 10%
    • Central nervous system: < 5%

  • Incidence of bleeding into joints:
    • Knee: 45%
    • Elbow: 30%
    • Ankle: 15%
    • Shoulder: 3%
    • Wrist: 3%
    • Hip: 2%
    • Other: 2%
Pathophysiology
  • Factor IX is a vitamin K-dependent serine protease produced in the liver
  • It circulates in the plasma in its inactive form
  • It is activated by factor VIIIa, and catalyzes the conversion of factor X to Xa
  • It can also be activated directly by the Tissue Factor-Factor VIIa complex in the extrinsic pathway
  • Factor IX has normal plasma activity of 50% - 150% (0.5 - 1.5 IU/mL)
  • Its biologic half life is 18 - 24 hrs
Etiology
  • Factor IX deficiency is inherited as an X-linked recessive trait, but 30% of cases are due to spontaneous mutations
  • The gene for factor IX is located on a fragile region of the X chromosome
  • More than 300 mutations have been identified; the most common are single point mutations; numerous point and deletion mutations produce defective, nonfunctional but immunologically detectable factor IX
  • Large gene deletions and nonsense mutations are most susceptible to formation of factor IX alloantibodies

  • Hemophilic females develop disease due to:
    • High degree of X-inactivation in carriers
    • Hemizygosity of the X chromosome in females with Turner syndrome (XO karyotype)
    • Homozygosity in female progeny of a hemophilia B carrier and an affected hemophilic male
Clinical Features
  • Clinical severity is dependent on factor levels:
    • Mild (> 5% activity; > 0.05 IU/mL); occurs in 30% - 40%; presents with bleeding after surgery or trauma
    • Moderate (1%-5% activity; 0.01-0.05 IU/mL); occurs in 10%; presents with bleeding after surgery or trauma and less commonly with spontaneous bleeding
    • Severe (< 1% activity; < 0.01 IU/mL); occurs in 50%; presents with spontaneous bleeding into joints, muscles and with life-threatening hemorrhage
    • 30% of cases are due to spontaneous mutations and have no family history of bleeding
    • 1% - 4% of patients with hemophilia B will develop alloantibody inhibitors after replacement therapy
Laboratory
  • Prolonged PTT with correction after mixing study (at 0 and 2 hr)
  • Normal PT and bleeding time
  • Measure both factor VIII and IX activity by functional plasma clot-based assay or chromogenic substrate-based assay
  • Note: diagnosis is confounded in neonates since factor IX levels are significantly reduced at birth and up to 6 months post-partum
  • Rule out vWD by vWF antigen and ristocetin cofactor activity
  • Bethesda assay for quantitation of inhibitor
  • Candidates for genetic testing include patients who have a diagnosis of hemophilia A or B, at-risk women who are related to an affected man (proband) who has a known mutation, and female carriers of hemophilia A or B seeking prenatal diagnosis
  • Genetic testing uses RFLP analysis
Prognostic Factors
  • Chronic complications of hemophilia include musculoskeletal problems (e.g. chronic synovitis, arthropathy, fractures, contractures), inhibitor formation (which complicates treatment), and transfusion-related infections (e.g. HIV, HBV, HCV, etc.)
Case Reports
Treatment
  • Need 50 - 80% of normal levels for surgical hemostasis with major surgery or major bleeding, 40% postoperatively, 30 - 50% to prevent minor bleeding

  • Plasma-derived or recombinant factor IX concentrates (1 unit/kg raises levels in vivo by 1%):
    • Major surgery/bleeding - 50 - 80 units factor IX concentrate/kg every 12 - 24 hours as necessary, usually for 7 - 10 days
    • Postoperatively - 40 units/kg every 12 - 24 hours, usually for 7 days
    • Minor bleeding - postoperatively; 30 - 40 units/kg every 12 - 24 hours as necessary
    • Prophylaxis in severe hemophilia B - 25 - 40 units/kg two times weekly

  • Treatment of acute bleeding episodes in patients with inhibitors:
    • For low-titer inhibitors: high dose factor IX (to overwhelm inhibitor), porcine factor IX (if no cross reactivity with inhibitor)
    • For high-titer inhibitors: factor IX bypassing agents (prothrombin complex concentrates, FEIBA, recombinant factor VIIa
Differential Diagnosis