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What Do Inhibitors Do in Hemophilia A?

Updated on October 18, 2022
Medically reviewed by
Todd Gersten, M.D.
Article written by
Emily Wagner, M.S.

Hemophilia A is a rare bleeding disorder in which the blood doesn’t clot properly. People with hemophilia don’t have enough clotting factors — substances that form clots and stop bleeding — in their blood.

To treat hemophilia, clotting factors can be given through an infusion. However, some people develop inhibitors, or antibodies that target and destroy the infused factors. Inhibitors prevent treatment from working. They can lead to uncontrolled bleeding and hemophilia that’s difficult to treat.

MyHemophiliaTeam members have shared their questions and experiences with developing inhibitors. One member asked, “I always make my day the best it can be, but I’m getting curious if I could possibly have developed an inhibitor. Is that likely at my age? I have been infusing a lot lately, and nothing seems to be changing.”

Others have shared experiences of their loved ones developing inhibitors. “I am the uncle of an 18-month-old boy diagnosed with severe hemophilia A in 2016, with no prior history of hemophilia. During the last week, we discovered that my nephew has inhibitors,” wrote one member. Another responded, “That really sucks, but there is hope. My son had the same problem. They gave him a 100 percent clotting factor per pound for about one or two years, and he no longer has an inhibitor.”

What Are Inhibitors for Hemophilia A?

Blood is made up of many substances, including factors that help it clot to stop bleeding. People with hemophilia A have low levels of a clotting factor called factor 8. The lower the levels of clotting factors in the blood, the more severe the hemophilia will be.

Hemophilia treatments are mainly focused on replacing the missing blood clotting factors. In severe cases, clotting factor transfusions are given to help prevent bleeding episodes. Two main types of clotting factors are given to treat hemophilia: plasma-derived factors (derived from human blood and plasma donations) and recombinant factors (produced in a lab).

Inhibitors are antibodies made by the immune system that target infused clotting factors. Normally, the immune system makes antibodies to target foreign invaders like bacteria or viruses to help destroy them and keep us healthy. However, antibodies can also be formed against helpful substances we put into our bodies, such as clotting factors for treating hemophilia. They are called inhibitors because they “inhibit” the blood-clotting process by destroying the infused clotting factors.

Why Does a Person Develop Inhibitors?

The risk of developing inhibitors mainly depends on the type and severity of hemophilia you have. According to the Hemophilia Federation of America, around 30 percent of people with severe hemophilia A will develop inhibitors at some point. Typically, inhibitors develop during childhood, especially within the first 50 infusion treatment days. In some cases, inhibitors may develop later in life after treatment is complete, but this is rare.

Although it is less common, people with mild to moderate hemophilia can also develop inhibitors. It’s estimated that between 5 percent to 8 percent of those with mild to moderate hemophilia A may develop inhibitors. Even less common is developing inhibitors with hemophilia B. This only occurs in 2 percent to 3 percent of cases.

Certain risk factors can increase the likelihood of developing inhibitors. These include:

  • Being of African American or Hispanic descent
  • Having a family history of inhibitors
  • Receiving higher doses of clotting factors due to trauma or surgery
  • Being younger
  • Having certain gene mutations

Testing for Inhibitors

The most obvious symptom of having inhibitors is uncontrolled bleeding that doesn’t stop even after treatment. This is known as breakthrough bleeding. Your body also may not heal as well after an injury.

If your doctor thinks you may have inhibitors, they will perform a blood test known as the Bethesda assay. This test measures how much inhibitor is in the blood (known as an inhibitor titer).

To be safe, it’s recommended that people with hemophilia and von Willebrand disease type 3 who are treated with clotting factor infusions get tested once a year for inhibitors. Inhibitor symptoms are not always obvious, so testing is important to monitor for their development. According to the Centers for Disease Control and Prevention, free inhibitor testing is offered through federally funded hemophilia treatment centers to those who qualify.

People with inhibitors are broken into two groups based on their concentration of inhibitors: They either have low-titer (low-responding) inhibitors or high-titer (high-responding) inhibitors. A person with low-titer inhibitors is more likely to respond well to inhibitor treatment. Those with high titers are less likely to have successful treatment.

How Are Inhibitors Treated?

Developing inhibitors after hemophilia treatment can be difficult to deal with. Fortunately, several treatment options can help resolve inhibitors and teach the immune system to not attack factor infusions. These include high-dose clotting factor concentrates, bypassing agents, and immune tolerance induction therapy.

Treatments for Low-Titer Inhibitors

If you have low-titer inhibitors, your doctor may give you high doses of clotting factor concentrates. These high doses can overcome the inhibitors in your blood and provide extra clotting factors so it may clot effectively. You may need more frequent treatments for this method to work.

Treatments for High-Titer Inhibitors

High-titer inhibitors can make treatment more complicated. Your doctor will take the type of hemophilia you have and the severity of your bleeding into consideration when making a treatment plan. In emergencies, plasmapheresis can filter high concentrations of inhibitors out of the blood. However, this is only a temporary solution, as the body will continue to make new inhibitors.

One class of treatments known as bypassing agents (BPAs) works by “bypassing” the need for factor 8 or factor 9 to help clot blood. To date, the U.S. Food and Drug Administration (FDA) has approved four BPAs to treat people with inhibitors:

  • Coagulation factor VIIa (recombinant) (NovoSeven RT) — Used in people who have developed inhibitors against factor 8 or factor 9, this treatment activates a different clotting pathway in the body.
  • Anti-inhibitor coagulant complex (Feiba) — This medication contains a combination of factors 2a, 7a, 9a, and 10a to help clot blood.
  • Emicizumab-kxwh (Hemlibra) — This artificial antibody brings together factor 9a and factor 10 to help clot blood.
  • Coagulation factor 7a (recombinant)-jncw (Sevenfact) — This medication contains a synthetic version of the factor 7a protein used to treat people with hemophilia A or B.

MyHemophiliaTeam members have shared their experiences with inhibitor treatment. One member shared, “I am on Hemlibra now and have been bleed-free for a little over two years … it’s now October 2018, and Hemlibra has changed my life.” Another wrote, “I’ve been on Hemlibra since March 2017. No treatable bleeds and no side effects.”

Immune Tolerance Induction Therapy

To target the cause of inhibitors, some people undergo immune tolerance induction (ITI) therapy. This therapy familiarizes the immune system with clotting factors so it doesn’t make antibodies against them. During ITI therapy, clotting factors are infused daily over weeks to months to expose the immune system.

Your doctor may also prescribe medications that suppress the immune system so it doesn’t overreact during ITI therapy. ITI therapy is generally successful in people with hemophilia A and inhibitors — around 70 percent become tolerant to infused clotting factors. On the other hand, this treatment only works in around 30 percent of those with hemophilia B and inhibitors.

Talk to Your Doctor About Inhibitors

Depending on the type of hemophilia you have, you may be at a higher risk of developing inhibitors. Be sure to talk to your doctor about yearly testing, as well as what it means for you if you develop an inhibitor toward your treatment.

The cost of inhibitor treatment can be expensive, especially when combined with other hemophilia treatments. If you’re concerned about the cost of treatment, discuss this with your doctor. They will connect you with a hemophilia treatment center or social worker who can help you learn more about coverage, costs, and any available resources.

Find Your Team

On MyHemophiliaTeam, more than 6,000 people living with hemophilia come together to ask questions, give advice, and share their stories with others who understand life with the condition.

Have you or a loved one developed inhibitors after treatment? How did you manage and treat them? Share your hemophilia journey in the comments below, or start a conversation by posting on your Activities page.

All updates must be accompanied by text or a picture.
Todd Gersten, M.D. is a hematologist-oncologist at the Florida Cancer Specialists & Research Institute in Wellington, Florida. Review provided by VeriMed Healthcare Network. Learn more about him here.
Emily Wagner, M.S. holds a Master of Science in biomedical sciences with a focus in pharmacology. She is passionate about immunology, cancer biology, and molecular biology. Learn more about her here.

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