Inhibitors are antibodies that the immune system develops because it sees the infused clotting factor as a foreign substance that needs to be destroyed. Antibodies are proteins that eat up the activated factor before it has time to stop the bleeding.
Who is at risk?
Approximately 30% of people with severe hemophilia A are affected by inhibitors at some point in their lives. An inhibitor usually occurs between the 5th and 50th infusion of factor concentrate, but in rare cases can also be developed later in life.
While people with severe hemophilia are more likely to develop inhibitors, approximately 5-8% of people with mild or moderate hemophilia A develop inhibitors. The antibodies destroy not only the factor concentrate infused but also the small percentage of factor protein that the body was producing naturally. So, a person with mild or moderate hemophilia who develops an inhibitor now, in effect, has severe hemophilia (<1% circulating factor).
Approximately 2-3% of people with hemophilia B develop inhibitors. While inhibitors in people with hemophilia B are less common than hemophilia A, it can be even more challenging as about half of hemophilia B inhibitor patients will develop an anaphylactic reaction to infused factor IX, which can be life-threatening.
In addition to the type and severity of hemophilia someone has, here are other risk factors:
- Age and number of exposures to factor product
- Family history of an inhibitor
- Race and ethnicity (people of African American and Hispanic descent are at a higher risk of developing an inhibitor)
- Gene mutation (may indicate a higher risk of inhibitor development)
- Intensive factor therapy related to surgery or trauma
What are the symptoms of an inhibitor?
Inhibitors destroy the infused factor concentrate as well as the factor produced naturally by the body in people with mild and moderate hemophilia. A person who doesn’t have inhibitors will heal from injuries or feel better soon after the factor concentrate is infused. A person with an inhibitor does not get better after receiving a dose of factor that is appropriate for their weight.
How are inhibitors detected?
Children should be tested for inhibitors regularly, at least once per year. A blood test called activated partial thromboplastin time (APTT) is performed soon after factor concentrate is infused to calculate the time it takes for the person’s blood to clot. If clotting time is outside the range expected after an infusion, a second test called Bethesda assay is performed to confirm the diagnosis and to determine the level of inhibitor that the person has developed.
Inhibitor testing should be initiated if a patient is responding poorly to treatment. Some Hemophilia Treatment Centers (HTC) test more frequently in the early days of treatment, and many test before every surgery and at annual comprehensive clinic visits.
Are inhibitors all the same?
No. Inhibitors come in different degrees of severity. Inhibitors are measured in titer (the amount of inhibitors present in a person’s blood) and immune response strength (how the immune system responds to additional infusions of factor concentrate).
The inhibitor “titer” is measured in Bethesda units (BU). This number represents the amount of inhibitors in the person’s body. Inhibitors are classified as follows:
- Low Titer: amount in the blood is less than 5 BU. The number, and therefore strength, of the inhibitor is low. People with low titer inhibitors can sometimes continue to use factor VIII or factor IX products to treat bleeds; they just need a lot more of it. Low titer inhibitors can sometimes resolve on their own.
- High Titer: amount of inhibitors found in the blood is greater than 5 BU. The number, and therefore strength of the inhibitor, is high. People with a high titer inhibitor get no benefit from factor VIII or factor IX, no matter how much they infuse.
Once an inhibitor is present, the strength with which the body reacts to further exposure of factor concentrate, also called anamnestic response, can further classify the inhibitor type.
- Low Responder: when people with low-responding inhibitors receive factor VIII or factor IX, the inhibitor titer does not rise. Because the titer stays low, they may be able to control bleeding by using larger quantities of those factor concentrates.
- High Responder: when people with high-responding inhibitors are exposed to factor VIII or factor IX the immune system quickly triggers even more inhibitor development.