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Coagulation

Acquired bleeding disorders

Factor VIII inhibitor


Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Lizabeth Rosenbaum, MD, University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 9 April 2013, last major update June 2010
Copyright: (c) 2002-2013, PathologyOutlines.com, Inc.

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

Terminology
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When challenged with factor VIII 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
● High responders are patients who develop a high titer of inhibitor (>5 BU)

● "Bypassing agents" are coagulation factor treatment products that do not contain factor VIII

Epidemiology
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● Develops in 10-20% of patients with severe hemophilia A after infusion of factor VIII containing products, less often with mild/moderate disease
● Rarely occurs de novo in patients without hereditary hemophilia, causing acquired hemophilia A (click here for topic)

Risk factors for development of inhibitors:
● Specific factor VIII genotype (i.e major deletions or rearrangements have higher risk than those with small deletions or missense mutations)
● Increased severity of hemophilia A (most likely due to more aggressive treatment)
● Younger age
● Race (blacks and Hispanics more affected than whites)
● Family history of factor VIII inhibitors

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

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
● Are predominantly polyclonal IgG, but isolated instances of IgM and IgA have been reported
● Titer of inhibitor often increases after treatment with factor VIII containing products - this does not happen with autoimmune factor VIII inhibitor
● 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)

Laboratory
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● Prolonged PTT that does not correct with mixing studies. Note: PTT may initially be normal and then increase after 1-2 hours 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 VIII 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 high-titer inhibitor (>5 BU) are less likely to respond to treatment
● Factor VIII genotypes that includes large gene deletions, inversions, nonsense and splice site mutations show less response to treatment (J Thromb Haemost 2009;7:1809)
● Data is inconclusive regarding relative inhibitor risk of plasma-derived vs. recombinant factor concentrates-both can lead to formation

Case reports
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● Acquired factor VIII inhibitor in association with myelodysplastic syndrome (Intern Med J 2009;39:e7)

Treatment
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● Acute bleeding episodes can be treated with high dose human factor VIII for low titer patients (to overwhelm inhibitor) or porcine factor VIII (if no cross reactivity with inhibitor)
● For high-titer inhibitors, factor VIII 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)
● Immunosuppression for autoimmune based inhibitors, with a possible role for 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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Am J Clin Pathol 2009;131:552, Clin Rev Allergy Immunol 2009;37:58, Blood 2009;113:11, eMedicine

End of Coagulation > Acquired bleeding disorders > Factor VIII inhibitor


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