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 of inhibitor development?
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, there are other risk factors:
- age/number of exposures to factor product
- family history of an inhibitor
- race/ethnicity (people of African American and Hispanic descent are at a higher risk of developing an inhibitor)
- gene mutation (there are ongoing studies that indicate the type of genetic mutation one has may indicate a higher risk of inhibitor development)
- intensive factor therapy related to surgery or trauma
The journal Haemophilia has published the results of a six-year study called the Hemophilia Inhibitor Research Study (HIRS) that was designed to test the feasibility of conducting national monitoring for inhibitors among people with hemophilia in the United States. In the study, investigators from 17 hemophilia treatment centers located across the United States enrolled 1,163 people with hemophilia and followed them for up to 6 years to learn the best way to determine who was at risk for developing an inhibitor. HIRS investigators and CDC researchers found that people with hemophilia of all ages were at risk for developing an inhibitor and that unless people are regularly tested for an inhibitor, they can have one and not know it until it causes a severe bleeding problem.
Read the Hemophilia Inhibitor Research Study (HIRS) in its entirety.
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).
- Titer: 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.
- Anamnestic Response: 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.
Inhibitor Track at HFA Symposium
To view the presentations from the 2014 Inhibitor Track at the HFA Symposium, please click HERE.
To view the presentations from the 2015 Inhibitor Track at the HFA Symposium, please click HERE.
Personal Stories about Living with An Inhibitor
CDC’s National Center on Birth Defects and Developmental Disabilities (NCBDDD) hosts a Flickr Album featuring the stories of people with hemophilia who have also experienced life with the added challenge of an inhibitor. This Flickr Album provides powerful, personal testimonials on what it’s like to live with hemophilia and an inhibitor, and is aimed at raising awareness of this serious bleeding disorder complication, the need for continued inhibitor research, and of the importance of routine inhibitor screening.
For more information about inhibitors:
- Center for Disease Control and Prevention (CDC) website, including results of the CDC’s six year, Hemophilia Inhibitor Research Study (HIRS), which tested the feasibility of conducting national monitoring for inhibitors among people with hemophilia in the United States.
- World Federation of Hemophilia Inhibitor Primer
- Canadian Hemophilia Society Inhibitor Guide
- Managing Your Child’s Inhibitor: A Practical Guide for Parents, by Laureen A. Kelley
- CLINICAL TRIALS – There may be some current clinical trials in hemophilia with inhibitors. Click here for more information on clinical trials