If you or someone you know has a bleeding disorder, it’s important to have an understanding of inhibitors, as some people with hemophilia or von Willebrand disease (VWD) type 3 can develop them.
So what exactly are inhibitors, who do they affect, how do they develop, and what effects do they have? Read on for answers to these questions and more.
What is an inhibitor?
An inhibitor is an antibody that your immune system creates in response to the infusion of clotting factor concentrates. Clotting factor concentrates are infused to help your blood clot normally, which means inhibitors make standard treatment ineffective and it becomes more difficult to stop a bleeding episode. Those with inhibitors need special treatment until their body stops making them. That special treatment can be costly: The Centers for Disease Control and Prevention (CDC) states that the excess cost of care for each person with hemophilia and an inhibitor is over $800,000 per year.
Inhibitors usually develop during the first 50 times a person is treated with clotting factor concentrates, but they can appear at any time. Inhibitors can cause major health complications: People with bleeding disorders who develop an inhibitor are twice as likely to be hospitalized for a bleeding episode because the clotting factor treatment doesn’t work as well to stop the bleeding.
How and why do inhibitors form?
Inhibitors are antibodies, and your immune system produces antibodies to defend against diseases and other foreign substances. Those antibodies then work to destroy the foreign substances—often viruses and bacteria—in your body. But sometimes, the immune system builds antibodies to destroy things that were meant to help the body, such as medication. So in some cases, when a person receives replacement factor treatment, the body's immune system perceives the normal clotting factor as a threat and creates antibodies—inhibitors—to destroy it.
Inhibitors can develop in anyone with hemophilia and VWD, no matter the type or the severity of the bleeding disorder. But scientists don’t know exactly why they develop in some people but not others. Experts point to a few risk factors that increase the likelihood of developing an inhibitor:
- Genetics: People with certain types of hemophilia gene mutations are more likely to develop an inhibitor
- Number of times you have used clotting factor concentrates in your lifetime
- Increased frequency and dose of treatment
- Black race or Hispanic ethnicity
- Family history of inhibitors (other family members who have had inhibitors)
How common are inhibitors?
About 1 in 5 people with severe hemophilia A and about 3 in 100 people with hemophilia B will develop inhibitors. Approximately 5.8% to 9.5% of patients with type 3 VWD have developed inhibitors.
For those with hemophilia B, inhibitors are less common, but the effects are often much more severe: About half of people with hemophilia B who have inhibitors will develop an anaphylactic reaction to infused factor IX.
How do I get tested for inhibitors?
Inhibitors are diagnosed with a blood test that measures if an inhibitor is present along with the amount of inhibitor present (called an inhibitor titer) in the blood. Inhibitors are measured using a test called the Bethesda assay, which gives a numeric value and refers to the inhibitor level. This number is quantified in Bethesda units: One Bethesda unit is defined as the amount of inhibitor in a plasma sample that can neutralize 50% of one unit of factor VIII activity in normal plasma after two hours at 37 degrees Celsius.
If you have more than 5 Bethesda units, you have a high-titer inhibitor, which means your body has a strong response against the factor, so traditional treatments don’t work. If you have less than 5 Bethesda units, you have a low-titer inhibitor, which means your body doesn’t have a strong response against the clotting factor product.
Signs of an inhibitor include frequent bleeds while on a regular treatment schedule, and
What bleeding disorders treatments are available for people with inhibitors?
If you have a low-titer inhibitor, continued therapy with factor replacement is often effective, though sometimes a change in size and frequency is necessary. If you have high-titer inhibitors, there are a few options:
- Plasmapheresis: A temporary treatment that involves physicians removing antibodies from the body, lowering the level of antibodies to allow treatment with factor concentrate to treat the bleed. While similar, plasmapheresis and plasma exchange are not exactly the same. Plasmapheresis separates the plasma from the blood either by centrifugation or membrane filtration. Once separated the plasma can be manipulated in a variety of ways. Plasma exchange refers to discarding the plasma and substituting a replacement fluid.
- Bypassing agents: Treatments that bypass the need for clotting factor treatment so the body can clot the blood normally.
- Immune Tolerance Induction (ITI) Therapy: A treatment with the goal of stopping the inhibitor from blocking factor in the blood and teaching the body to accept factor as a normal part of blood.