any factor IX–containing products in a facil-
ity equipped to treat anaphylactic shock.70–72 A
comparison of inhibitors in hemophilia A and
B is shown in Table 3.
TREATMENT OF ACUTE BLEEDS IN PATIENTS WITH
FACTOR VIII INHIBITORS
The available therapeutic agents for treatment of acute hemorrhage in children with
hemophilia A with an inhibitor include high-dose recombinant or plasma-derived factor VIII
concentrate, activated prothrombin complex
concentrates (aPCCs), and recombinant activated factor VII (rFVIIa). In addition, antifibrinolytics may be used as an adjunct therapy.
Patient response to each treatment varies widely, with some patients responding well to one
treatment and less well to another. Neither the
patient's history nor standard lab tests can assist in making the best choice for the patient.
A personalized approach to factor selection is
used, and the dosing of that particular agent is
often determined primarily by clinical assessment.
Inhibitors are quantitated using the Bethesda
inhibitor assay and clinically are classified as
low- and high-responding inhibitors (Table 4).
Inhibitor screening should be done prior to invasive procedures and periodically during the first
50 days of treatment since the risk for inhibitor
development is highest during this period.
A low-responding inhibitor is one in which
inhibitor titers are < 5 Bethesda units (BU)/mL;
patients with low-responding inhibitors can generally be treated with factor VIII concentrates at
higher doses.73 Because the effect of factor VIII
inhibitor is usually delayed, the Bethesda titer
in plasma is determined after a 2-hour incubation period. As a result of this time delay, continuous administration of factor VIII is usually
found to be effective.74 For a serious limb- or
life-threatening bleeding episode, a bolus infusion of 100 IU of factor VIII per kg of body
weight is administered, and the level is maintained by treatment at a rate of 20 IU/kg/hr.
An assay for factor VIII should be performed 1
hour after the bolus infusion and at least daily
thereafter. As the antibody titer drops, the daily
level of factor VIII may rise and thus downward
adjustment of the continuous infusion rate
may be required. For routine joint and muscle
hemorrhage, patients can usually be managed
with infusions at twice the usual dosage. Routine inhibitor assays should be performed after
exposure to factor VIII to determine whether an
anamnestic response has occurred.
Most clinicians caring for patients with limb- or
life-threatening bleeding episodes prefer to use
Table 3. Comparison of Inhibitors in Hemophilia A and B
Inhibitors in Factor VIII Deficiency Inhibitors in Factor IX Deficiency
Incidence of inhibitor development
Severe disease 20%–30% of patients Low incidence (2%–4% of patients)
Moderate to mild disease 3% to 13% of patients Extremely rare
Impact of race Increased incidence in people of African
descent and Hispanics
No conclusive evidence of racial difference in
Frequency of infusion-associated
Rare Occurs in ~60% of patients with inhibitors
Success of immune tolerance therapy 60%–70% of patients 15%–30% of patients
Complications of immune tolerance
Well tolerated Nephrotic syndrome (especially in patients with
a history of infusion reactions)
Adapted from Tandra A, Shapiro AD. Treatment of inhibitors in hemophilia B. In: Lee CA, Berntorp EE, Hoots K, eds. Textbook of hemophilia. 2nd ed.
Hoboken (NJ): John Wiley and Sons; 2010: 97.