For many parents of children newly diagnosed with hemophilia, the word “inhibitors” soon becomes part of their vocabulary. And although they may not know at first what an inhibitor is, they may have learned to associate the word with something fearful. But for people with hemophilia A and inhibitors, things aren’t as bad as they once were.
What exactly is an inhibitor? Who gets them? What happens when you get an inhibitor? How do you treat bleeds if you have an inhibitor? Do inhibitors go away on their own, or can you grow out of them or eliminate them?
What Is an Inhibitor?
Inhibitors are specialized proteins called antibodies. They’re a part of the immune system that protects us from bacteria, viruses, and foreign proteins—in other words, anything that the body identifies as not belonging, and as being potentially harmful. But sometimes the immune system makes mistakes: it may even attack the body itself, as in autoimmune diseases including rheumatoid arthritis or multiple sclerosis. With hemophilia, the immune system also makes a mistake: it misidentifies a helpful agent—infused clotting factor—as something harmful, and then mounts an immune response against the factor to neutralize it and mark it for removal from the body.
Inhibitors are very efficient. When an inhibitor is present in hemophilia, some or all of the infused factor is neutralized within minutes. This prevents the factor from participating in the clotting process to stop bleeding. And it means that people with inhibitors can’t use standard clotting factor concentrates to control bleeds.
Unfortunately, the alternative therapies we have for treating bleeds with inhibitors aren’t as effective as standard factor at controlling bleeds. As a result, people with inhibitors tend to bleed longer, develop target joints (joints that bleed frequently), and suffer from joint damage more often than people without inhibitors. Fortunately, for people with hemophilia A and inhibitors, treatment has improved dramatically over the past three years.
How do you know if you have an inhibitor? There are usually no outward signs. Inhibitors are sometimes diagnosed during routine hemophilia treatment center (HTC) clinic visits; and sometimes inhibitors are suspected after you notice that factor infusions fail to adequately control bleeding. Your HTC should test for inhibitors at least annually and always before any surgery, and you should request a test whenever you feel that bleeds aren’t being controlled effectively with your usual dose of factor.1
When an inhibitor is suspected, a diagnostic test called a mixing study (activated partial thromboplastin time, or aPTT) is performed: the patient’s blood plasma is mixed with normal plasma to see if this corrects the clotting time. In someone with hemophilia without an inhibitor, a mixing study results in a normal clotting time; but if an inhibitor is present, then the clotting time is abnormally prolonged. If this happens, then another test, the Bethesda inhibitor assay, is done to determine how much of the inhibitor-causing antibody is present.2 The Bethesda assay is a quantitative assay, meaning that it measures the amount of inhibitor and the results are expressed in numbers.
Note: Testing for inhibitors is a bit tricky. It’s best to have a Bethesda assay done at an HTC, because the lab techs there have more experience performing the tests, and the results are more likely to be accurate when compared to tests done at other hospitals.
Strength of the Inhibitor
To develop a strategy for treating bleeds, your doctor will need to know the strength, or concentration, of the inhibitor. The inhibitor strength is reported as a “titer” and is expressed in Bethesda Units (BU).3 Inhibitor titers can be as low as 1 BU or higher than 10,000 BU.
An inhibitor titer less than or equal to 5 BU (≤5 BU) is considered a low-titer inhibitor. An inhibitor greater than 5 BU (>5 BU) is considered a high-titer inhibitor. If you have a low-titer inhibitor, you can still use standard factor to treat bleeds, although in higher doses to accommodate for some of the factor being neutralized by the inhibitor. If you have a high-titer inhibitor, standard factor concentrates are not effective because all the factor is quickly neutralized after an infusion.
In addition to the inhibitor titer, inhibitors are categorized by how the immune system responds to infused factor. For some people, the inhibitor titer stays more or less stable and doesn’t rise after the patient is exposed to factor. If your child has an inhibitor titer ≤5 BU, and it remains at or below 5 BU for several days after an infusion, he is a low responder.
For others, when factor is infused, the immune system quickly ramps up inhibitor production in an effort to neutralize the infused factor. This results in an increase of the inhibitor titer within four to seven days of exposure to factor, peaking within one to three weeks. This ramping up of inhibitors after factor exposure is an anamnestic response (meaning a memory or recall response). If, after exposure to factor, the inhibitor titer rises above 5 BU over a few days, then your child is classified as a high responder. High-responding inhibitors are more challenging to treat than low-responding inhibitors because normal factor concentrates are useless with high-titer, high-responding inhibitors. Treating bleeds with these inhibitors requires special factor concentrates called bypassing agents, such as FEIBA or NovoSeven.
But there’s one case where standard factor can be used to treat bleeds in high responders. In high responders, the immune system often produces fewer and fewer antibodies over time if it isn’t exposed to factor. If someone hasn’t been exposed to factor for several months, then the inhibitor titer may have decreased to a level low enough that normal factor concentrates may be used to treat bleeds successfully for a few days—that is, before the anamnestic response kicks in and the inhibitor titer increases again, making the factor ineffective.
1. You can get free inhibitor testing at federally funded HTCs by participating in the Centers for Disease Control and Prevention’s (CDC) Community Counts Registry for Bleeding Disorders Surveillance program. 2. There are several different types of inhibitor assays; the Bethesda assay is the most widely used. 3. A Bethesda Unit (BU) is the amount of an inhibitor that will neutralize 50% of factor VIII in normal plasma after 120 minutes’ incubation at 37°C.