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Coagulation

Hereditary bleeding disorders

Factor IX deficiency (Hemophilia B)


Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 16 October 2010, last major update September 2010
Copyright: (c) 2002-2010, PathologyOutlines.com, Inc.

Definition
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● 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
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● Also known as Christmas disease

Epidemiology
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● 1 in 30,000 male births
● Almost exclusively affects males
● Rarely affects females (see etiology)
● Female carriers are unaffected

Sites
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● 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
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● 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
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● 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
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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
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● 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
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● 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
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● Spontaneous hemopericardium in a patient with hemophilia B (J Invasive Cardiol 2008;20:E296)

Treatment
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● 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
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von Willebrand Disease (particularly type 2N or type 3)
Factor VIII deficiency (hemophilia A)
● Acquired hemophilia B (autoantibody against factor IX)
● Other factor deficiencies (XI, XII)

Additional references
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Haemophilia 2010;16 Suppl 6:1, Haemophilia 2010;16 Suppl 6:13, World Federation of Hemophilia. Guidelines for the management of hemophilia, Consultative Hemostasis and Thrombosis: Elsevier, 2007

End of Coagulation > Hereditary bleeding disorders > Factor IX deficiency (Hemophilia B)


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