Factor VIII Inhibitors in Patients with Congenital Factor VIII Deficiency

At a Glance

A factor VIII inhibitor is an antibody directed against factor VIII. The factor VIII inhibitor is quantitated in Bethesda units. One Bethesda unit of factor VIII inhibitor produces a residual factor VIII concentration of 50%. A second Bethesda unit reduces the level to 25-50%, and so forth, with each additional Bethesda unit. Thus, seven Bethesda units results in a factor VIII level of less than 1% of normal.

With rare exceptions, factor VIII inhibitors do not decrease the concentration of von Willebrand factor. Antibodies to factor VIII can appear in hemophilia A patients, and they can also appear spontaneously in nonhemophiliac patients. Of the hemophiliac patients who develop inhibitors to factor VIII, the lower the concentration of factor VIII in the patient’s plasma at baseline, the more prone that patient is to developing an inhibitor.

There is no correlation between transfusion requirement and the development of a factor VIII inhibitor. Some patients develop antibodies to factor VIII after the first exposure to factor VIII, and others develop antibodies only after many transfusions. Approximately 10-15% of hemophilia A patients develop factor VIII inhibitors. Some patients develop large amounts of antibody and are called high responders, whereas others generate little antibody and are considered low responders. Patients who have previously developed a factory inhibitor can show an anamnestic rise in Bethesda units after re-exposure to factor VIII.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

For the diagnosis of a factor VIII inhibitor, the partial thromboplastin time (PTT) must be increased, the factor VIII must be decreased, the PTT mixing studies should show either partial or complete correction immediately after mixing and the correction should fade toward an elevated PTT after 30 minutes to 1 hour of incubation of the mixed plasma at 37°C. This is a classic pattern for the mixing study that is different from the pattern seen with the lupus anticoagulant or a simple factor deficiency.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

A lupus anticoagulant, if present, will not usually show correction into the normal range at any time in the PTT mixing study, unlike the factor VIII inhibitor. The presence of a lupus anticoagulant should result in a positive lupus anticoagulant test, but a factor VIII inhibitor can produce a false-positive lupus anticoagulant test. Thus, the pattern of the mixing study is an important point of differentiation between a lupus anticoagulant and a factor VIII inhibitor. In addition, a factor to inhibitor shows a relatively selective decrease in factor VIII, whereas a lupus anticoagulant can produce low levels of factors VIII, IX, XI and/or XII.

What Lab Results Are Absolutely Confirmatory?

The presence of a Bethesda unit level of at least 1 unit per ML, in the presence of a decreased factor VIII and in the absence of a lupus anticoagulant confirms the presence of a factor VIII inhibitor. When a factor VIII inhibitor is present, it is essential to know the number of Bethesda units, because the treatment depends on the number of Bethesda units in the patient’s plasma.