Coagulation
Hereditary bleeding disorders
Factor IX deficiency (hemophilia B)
Last author update: 1 September 2010
Last staff update: 28 September 2020
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PubMed Search: Factor IX deficiency[title] AND Hemophilia B [title]
Table of Contents
Definition / general | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Laboratory | Prognostic factors | Case reports | Treatment | Differential diagnosis | Additional referencesCite this page: Crookston K, Gober-Wilcox J. Factor IX deficiency (hemophilia B). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coagulationfactorIXdef.html. Accessed December 4th, 2024.
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
- Spontaneous hemopericardium in a patient with hemophilia B (J Invasive Cardiol 2008;20:E296)
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
- Acquired hemophilia B: autoantibody against factor IX
- Factor VIII deficiency (hemophilia A)
- Other factor deficiencies: XI, XII
- von Willebrand Disease: particularly type 2N or type 3)
