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What Do Inhibitors Do in Hemophilia B?

Medically reviewed by Todd Gersten, M.D.
Posted on February 28, 2023

Hemophilia B is a genetic bleeding disorder in which a person’s blood is unable to clot properly, leading to uncontrolled bleeding episodes. It’s caused by an insufficient amount of factor IX (9) in the blood. You will usually see Roman numerals in any discussion of clotting factors. Clotting factors, like factor IX, are substances that form clots and stop bleeding.

A person can receive clotting factors to treat hemophilia, administered via an infusion. However, some people develop inhibitors, or antibodies that target and destroy the infused factors. Inhibitors prevent treatment from working, which can lead to uncontrolled bleeding and make the management of hemophilia difficult.

MyHemophiliaTeam members have shared questions about 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.”

What Are Inhibitors for Hemophilia B?

Blood is made up of many substances, including clotting factors. People with hemophilia B have low levels of clotting factor IX. The lower the levels of clotting factors in the blood, the more severe the hemophilia can be.

Inhibitors are antibodies produced by the immune system that target infused clotting factors. Normally, the immune system makes antibodies to target foreign invaders, like bacteria and viruses, to help destroy them and keep us healthy. However, some forms of antibodies can work against helpful substances, such as clotting factors for treating hemophilia. They’re called inhibitors because they “inhibit” the blood-clotting process by destroying the infused clotting factors.

Hemophilia treatments focus mainly on replacing the missing clotting factors. In severe cases, a person may receive a clotting factor transfusion to help prevent bleeding episodes.

There are two main types of clotting factor treatments for the condition:

  • Plasma-derived factors — Derived from human blood and plasma donations
  • Recombinant factors — Produced in a lab

Symptoms of an Inhibitor in Hemophilia B

If, following a clotting factor infusion treatment, you experience a bleeding episode that doesn’t seem to get better — or gets worse — you may have an inhibitor.

People with hemophilia B who have an inhibitor are at higher risk of an anaphylactic reaction to a clotting factor infusion. This refers to a severe, potentially life-threatening allergic reaction by the immune system, characterized by symptoms such as breathing difficulties, rash, nausea, and shock.

Why Does a Person Develop Inhibitors?

A person’s risk of developing inhibitors depends mainly on what type of hemophilia they have and its severity. According to the Hemophilia Federation of America, around 1 percent to 4 percent of people with severe hemophilia B may develop an inhibitor. By comparison, around 30 percent of people with severe classic hemophilia develop inhibitors, as do about 5 percent of those with mild to moderate classic hemophilia.

Typically, inhibitors develop during childhood, usually between the ninth and 50th infusion treatment. In rare cases, inhibitors may develop later in life after treatment is complete.

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

  • Being Black or Hispanic
  • 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

Two types of blood tests can help determine if a person with hemophilia B has an inhibitor: the Nijmegen-Bethesda and Bethesda assays. They measure how much inhibitor is in the blood (known as an inhibitor titer) in units called Bethesda units (BUs).

People with inhibitors are broken into two groups based on their concentration of inhibitors: They have either low-titer (low-responding) or high-titer (high-responding) inhibitors.

A person with low-titer inhibitors (lower than 5 BUs) can sometimes continue to use factor replacement therapy for treating bleeding, but they’ll need more. Sometimes, low-titer inhibitors resolve on their own.

Those with high titers (greater than 5 BUs) won’t benefit from any amount of factor replacement treatment. In such cases, a bypassing agent (BPA) may help control bleeding.

To be safe, it’s recommended that people with hemophilia B get tested for inhibitors at least once a year. Inhibitor symptoms are not always obvious, so it’s important to monitor for their development. According to the Centers for Disease Control and Prevention (CDC), federally funded hemophilia treatment centers offer free inhibitor testing to those who qualify.

How Are Inhibitors Treated?

Inhibitor development 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, BPAs, and immune tolerance induction (ITI) therapy.

Treatments for Low-Titer Inhibitors

If you have low-titer inhibitors, your doctor may give you high doses of clotting factor concentrates. High doses can overcome the inhibitors and provide extra clotting factors so your blood 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 consider your type of hemophilia and the severity of your bleeding 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.

The class of treatments known as bypassing agents works by “bypassing” the need for factor VIII or factor IX to help clot blood. 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 VIII or factor IX, this treatment activates a different clotting pathway in the body.
  • Anti-inhibitor coagulant complex (Feiba) — This medication contains a combination of factors IIa, VIIa, IXa, and Xa to help clot blood.
  • Emicizumab-kxwh (Hemlibra) — This artificial antibody brings together factors IXa and X to help clot blood.
  • Coagulation factor VIIa (recombinant)-jncw (Sevenfact) — This medication contains a synthetic version of the factor VIIa protein used to treat people with both main types of hemophilia.

People taking BPAs require close monitoring to ensure their blood isn’t clotting in the wrong areas or too much, according to the CDC.

MyHemophiliaTeam members have shared their experiences with inhibitor treatment. One member said, “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 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 classic hemophilia and inhibitors — around 70 percent become tolerant to infused clotting factors. Unfortunately, the treatment works in only about 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 medical bills, talk with your doctor. They can 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.

    Posted on February 28, 2023
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    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.
    Ted Samson is a copy editor at MyHealthTeam. Learn more about him here.

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