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Coagulation

Acquired bleeding disorders

Factor IX inhibitor


Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Lizabeth Rosenbaum, M.D., University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 30 September 2014, last major update August 2010
Copyright: (c) 2006-2014, PathologyOutlines.com, Inc.

Definition
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● An acquired anti-factor IX alloantibody (“antibody produced by one individual that reacts with alloantigens of another individual of the same species”) that develops following infusion of factor IX concentrates (plasma derived and recombinant) causing either increased clearance from the circulation or interference with coagulation function (e.g. inhibition of interaction of factor IX with phospholipid, etc.)

Terminology
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● When challenged with factor IX concentrate, inhibitor patients are either low or high responders
● Low responders are patients who develop a low titer of inhibitor (<5 Bethesda Units/BU); 50% of inhibitors are low titer and transient
● “Bypassing agents” are coagulation factor treatment products that do not contain factor IX

Epidemiology
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● Develops in 1.5-3% of patients with severe hemophilia B after transfusion of factor IX containing products, less commonly with mild/moderate disease
● The lower inhibitor rate in hemophilia B is due to the lower proportion of severe cases of hemophilia B (~30%) compared with hemophilia A (~60%)
● Rarely arises in non-hemophilia patients with autoimmune disorders causing acquired hemophilia B

Risk factors for development of inhibitors:
● Specific factor IX genotype (i.e. major deletions or nonsense mutations have higher risk than those with small deletions or missense mutations)
● Increased severity of hemophilia B (most likely due to more aggressive treatment)
● Younger age
● Race (particularly individuals of Scandinavian descent)
● Family history of factor IX inhibitors

Sites
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● Typically associated with intra-articular and soft tissue bleeding, similar to hemophilia A

Etiology
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● Multiple genetic and environmental factors (see above)

Clinical features
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● Occurs after at least one infusion of factor concentrate, at a median of 9-12 exposures
● Antibodies are predominantly polyclonal IgG
● Titer of inhibitor often increases after treatment with factor IX containing products
● The presence of an inhibitor should be suspected when a hemophilia patient shows a decreased response to replacement therapy (i.e. when a sufficient dose of factor concentrate does not control an acute bleeding episode)
● With the development of inhibitors, some patients may experience allergic or anaphylactic reactions following exposure to concentrate

Laboratory
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● Prolonged PTT that does not correct with mixing studies
● Note: with factor VIII inhibitors, the PTT may initially be normal and then increase after 1-2 hours incubation; in contrast, factor IX inhibitors immediately inactivate factor IX activity and therefore do not require prolonged incubation
● Normal PT
● A nonlinear curve in a factor assay is often a clue to the presence of an inhibitor
● The Bethesda assay is performed to detect and quantitate the presence of inhibitor by diluting inhibitor patient plasma with pooled normal plasma
● Each Bethesda unit indicates a decrease of factor IX concentration in assay by 50% (1 unit: reduction from 100% to 50%; 2 units: to 25%; 3 units: to 12.5%, etc.)
● The Nijmegen assay is also used (Thromb Haemost 1995;73:247)

Prognostic factors
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● Patients with a high titer of inhibitor (>5 BU) are less likely to respond to treatment
● Data is inconclusive regarding the relative inhibitor risk of plasma-derived vs. recombinant factor concentrates - both can lead to formation of inhibitors

Case reports
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● Development of an IgA factor IX inhibitor (Am J Hematol 1984;17:321)

Treatment
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● Treatment is primarily supportive; aggressive treatment should be aimed at correcting the underlying cause
● Acute bleeding episodes can be treated with high dose human factor IX for low titer patients (to overwhelm the inhibitor) or porcine factor IX (if no cross reactivity with inhibitor)
● For high titer inhibitors, factor IX bypassing agents (prothrombin complex concentrates, FEIBA or recombinant factor VIIa (J Thromb Haemost 2004;2:899)
● FEIBA can also be used for minor or major surgical procedures (Haemophilia 2009;15:1300)
● For autoimmune based inhibitors, use immunosuppression and possibly plasmapheresis

Differential diagnosis
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● Occasionally a lupus-like anticoagulant can cause a false-positive inhibitor screen by prolonging the PTT and leading to a nonlinear curve in a factor assay

Additional references
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Semin Thromb Hemost 2009;35:760

End of Coagulation > Acquired bleeding disorders > Factor IX inhibitor


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