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Inhibitor Testing and the Road to Prevention
By Fiona Bethea, MPH, Centers for Disease Control (CDC)
I nhibitor development is a serious complication of treatment NBA. When laboratories use different testing methods, it is
for people with hemophilia and von Willebrand disease not possible to compare results from one laboratory to another.
(vWD) type 3. Approximately 1 in 5 people with hemophilia Additionally, in 2014, researchers found that about 1 in 3 NBA
A, and 3 in 100 people with hemophilia B, will develop an in- tests had positive inhibitor test results when an inhibitor was
hibitor. The current goal for inhibitor elimination is identify- not actually present; this is called a false positive test result.
ing inhibitors early through testing and then promptly start-
ing treatment, which can lead to a more successful response to In order to overcome these limitations, CDC developed a mod-
treatment. A priority for the Centers for Disease Control and ified NBA method that added a heat treatment step. This new
Prevention (CDC) is working to eliminate inhibitors among step allows everyone to be tested for inhibitors, regardless of
people with bleeding disorders. This article provides informa- when they were last infused with factor. CDC performs inhibi-
tion about inhibitors, inhibitor testing, and current efforts to tor testing with the new method at the CDC laboratory to en-
monitor the occurrence of inhibitors among people with bleed- sure that test results from across the country are comparable
ing disorders. for monitoring purposes. In 2015, the National Hemophilia
Foundation (NHF) Medical and Scientific Advisory Council
What is an inhibitor? (MASAC) recommended that NASCOLA promote standard-
Inhibitors are antibodies that attack infused clotting factor ized inhibitor testing, including the implementation of the
used to treat or prevent bleeding episodes. Antibodies are pro-
teins in the blood that are made by a person’s immune system CDC-NBA method. The CDC-NBA method is current-
to attack intruders not recognized as being a normal ly being disseminated to clinical laboratories
part of the body. When a person develops an inhibi-
tor, their body attacks the clotting factor so it doesn’t and developed in a kit form to aid in local testing.
work as well to stop and prevent bleeding episodes.
Symptoms of an inhibitor can include bleeding that Who can get an inhibitor?
becomes more difficult to control over time with the
usual dose of clotting factor. CDC performed the Hemophilia Inhibitor Research
Study (HIRS) from 2006–2012. HIRS found that all
How are you tested for an inhibitor and people with hemophilia A and hemophilia B are at
what are the limitations? risk for developing an inhibitor, regardless of age, dis-
All testing methods use a blood sample, collected from an indi- ease severity, and number of infusions. Additionally, more
vidual, to detect if an inhibitor is present. In 1998, the Interna- than half of the people who developed an inhibitor in the study
tional Society on Thrombosis and Hemostasis recommended had no symptoms of an inhibitor when it was detected. There-
the Nijmegen-Bethesda assay (NBA) as the gold standard in- fore, the CDC-modified NBA test can be used to screen people
hibitor testing method. The NBA measures inhibitor levels, for inhibitors before symptoms show up. Inhibitors diagnosed
called inhibitor titers, in the blood. The amount of inhibitor early and below 10 NBU are more likely to be successfully
is measured in Nijmegen-Bethesda units (NBU). The higher treated. In 2015, the MASAC also recommended that, at a mini-
the number of NBU, the more inhibitor that is present. This mum, all individuals with hemophilia receive annual inhibitor
test has limitations, however. The NBA cannot accurately test testing.
for an inhibitor if a person received traditional clotting factor
therapy within 72 hours of testing. This is a problem for people What does a positive test result mean?
on prophylaxis (routine treatment of hemophilia given to pre-
vent bleeding before it starts), and those who treated a bleed Currently, a single positive inhibitor test, especially with an in-
prior to their clinic visit. Another limitation, based on a survey hibitor titer of less than 2.0 NBU, cannot predict how this result
performed by the North American Specialized Coagulation may impact a person’s life. A positive inhibitor test result could
Laboratory Association (NASCOLA), showed that only 20% of be due to either a clinically significant inhibitor, a transient
laboratories used the established method to perform the NBA. inhibitor, or a false positive test result. A clinically significant
Seventy percent of laboratories used their own version of the inhibitor is one in which the inhibitor prevents the infused
treatment product from working effectively to stop or pre-
vent bleeding episodes. A clinically significant inhibitor will
require special treatment to successfully eliminate the inhibi-
tor. A transient inhibitor is one in which multiple low-positive
test results occur, but the infused treatment continues to work
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