ACQUIRED FACTOR

VIII INHIBITORS
PNH HAEMATOLOGY WEDNESDAY TEACHING

SHAREEF SHAH
Same as Acquired
Haemophilia A
 AUTOANTIBODIES

• These are autoantibodies, not alloantibodies

• Inhibitors that developed in haemophilia patients are alloantibodies
EFFECT OF THE AUTOANTIBODIES

• Inhibit the activity of Factor VIII

OR

• Increase the clearance of Factor VIII

FACTOR VIII INHIBITORS : THE MOST COMMON

• The most common autoantibodies that affect clotting factor activity

TYPE OF IMMUNOGLOBULINS

• Mostly IgG that do not bind complement

• Different IgG subclassess
TARGET OF AUTOANTIBODIES

Less
• Epitopes on the factor VIII molecule. often

• Mostly bind to C2 domain

• Less often to A2 domain
• C2 domain binds to the proagulant
phospholipid phosphatidylserine on
activated platelets and endothelial cell and
to vWF leads to reduced procoagulant
activity. Most common
EPIDEMIOLOGY

• Incidence = 1.3 to 1.5 cases per million population per year

• Mostly age >50, except for women who were pregnant or postpartum
MAJOR IDENTIFIABLE CAUSES

• pregnancy
• Post partum period
• Rheumatoid Arthritis
• Malignancy
• SLE
• Drug reactions
• 50% no underlying disorder
FACTORS PREDICTING FOR IMPROVED OS

• Attainment of complete remission

• Age <65
• Post partum status
CLINICAL FEATURES

• Bleeding, in some cases is first noted after a surgical procedure.

• Most bleeding occur spontaneously without apparent provocation.
• Symptomatic patients often present with large hematomas, extensive ecchymoses or
severe mucosal bleeding (including epistaxis, GI bleed, gross haematuria)
• Spontaneous hemarthroses are unusual
WHEN TO SUSPECT?

The sudden presence of large hematomas or extensive

ecchymoses in an older individual without significant
trauma or known bleeding disorder should always raise
the clinical suspicioun of an acquired factor VIII
inhibitor.
DIAGNOSTIC TESTS

• Coagulation tests (prolonged aPTT, normal PT)

• Inhibitor screen (mixing test)
• Bethesda assay
INHIBITOR SCREEN (MIXING TEST)

• varying amounts of patient plasma and pooled normal plasma are mixed and the aPTT measured.
• After mixing, measurement of the aPTT should be performed not only immediately but also after
incubation at 37ºC for one to two hours. The second measurement is necessary to detect factor VIII
inhibitors with slow reaction kinetics
• Correction of the prolonged aPTT with pooled normal plasma= a factor deficiency or VWD
• Persistent prolongation of the aPTT with pooled normal plasma = the presence of an inhibitor.
• Correction of the aPTT with phospholipid in mixed plasma = presence of antiphospholipid
antibodies. If the aPTT does not correct, the Bethesda assay is performed.
BETHESDA ASSAY

• The Bethesda assay both establishes the diagnosis of a factor VIII inhibitor and quantifies the
antibody titer. By standardizing the strength of factor VIII inhibitors, this assay also permits
comparison between different treatment regimens.
• serial dilutions of patient plasma are incubated with pooled normal plasma at 37ºC for 2 hours
• factor VIII activity is then measured using a clotting assay as one would in a patient with
hereditary factor VIII deficiency.
• The reciprocal dilution of patient plasma that results in 50 percent factor VIII activity is defined as
one Bethesda unit (BU). The stronger the inhibitor, the greater the dilution required to allow
for factor VIII activity.
TREATMENT

1) CONTROL OF BLEEDING

AND

2) ELIMINATION OF THE INHIBITOR

AND

3) AVOIDANCE OF ACTIONS THAT MIGHT PROVOKE BLEEDING (e.g. IM injection)

CONTROL OF ACTIVE BLEEDING

• Desmopressin (DDAVP)
• Factor VIII concentrates
• aPCC e.g. FEIBA
• Recombinant human factor VIIa (novoseven)
• Recombinant porcine sequence Factor VIII concentrate
 CONTROL OF ACTIVE BLEEDING

Severity of bleeding Inhibitors titre Treatment

Invasive procedures DDAVP 0.3mcg/kg SC OD 3-5 days

Non life threatening bleeding Low DDAVP 0.3mcg/kg SC OD 3-5 days

Bypassing agents (FEIBA Or Novoseven)
Severe bleeding Low Recombinant Factor VIII
(<5 Bethesda Human Factor VIII concentrate
Units) Bypassing agents (FEIBA Or Novoseven)

Severe bleeding High Bypassing agents (FEIBA Or Novoseven)

Porcine Factor VIII
 ELIMINATION OF THE INHIBITOR

Immunosuppresive CR Median times to CR Adverse events

agents No evidence of one better than the other.
-Glucocorticoid alone 48% 5 weeks 25% Choice should be based on titre level.
Preferred in pregnancy Some inhibitors will regress spontaneously
without treatment
Glucocorticoid + 70% 5 weeks 41%
Cyclophosphamide 2nd line therapy was successful in
Glucocorticoid + 59% ~10 weeks 37% approximately 60% of cases that failed
Rituximab first-line therapy; outcome was not
affected by the choice of 1st line therapy
MONITORING RESPONSE TO TREATMENT

• Primary goal = cessation of bleeding, followed by a decrease in the titer of the inhibitor
• Adequate response = complete absence of the inhibitor (not always achieved)
• Titers drop very slowly following successful treatment. Recheck every 2-4 weeks
• Recheck factor VIII activity level after approximately 4 weeks of immunosuppressive
therapy to determine if factor activity is detectable.
WITHHOLDING IMMUNOSUPPRESSIVE THERAPY

• Although spontaneous recovery is possible, it is not advisable to withhold

immunosuppresants due to continued risk of bleeding
NATURAL HISTORY (MOST ON IMMUNOSUPPRESSIVE AGENTS)

• The relapse rate after a 1st CR ~20%

• 70% of such relapsing patients achieve a 2nd CR
• The relapse rate of pregnancy-associated factor VIII inhibitors appears to be lower [84]. Relapse of pregnancy-
associated acquired factor VIII inhibitors may rarely occur in subsequent pregnancies;
• the antibody may affect fetal factor VIII levels, resulting in life-threatening hemorrhage in a subsequent fetus
because of transplacental transfer of IgG antibodies.
• Patients with low antibody titers (ie, <5 Bethesda units) tend to have remissions within months, whereas those with
higher titers may have antibody persistence for years [24].
• In at least one case, treatment of the underlying condition (eg, malignancy) has resulted in disappearance of the
inhibitor [87].