Some people with hemophilia and von Willebrand disease type 3 will develop inhibitors. Inhibitors make it more difficult to stop a bleeding episode because they prevent the treatment from working.
If you have hemophilia or VWD type 3, you should be tested for inhibitors once a year. You can receive free inhibitor testing at federally funded hemophilia treatment centers (HTCs) through the CDC Community Counts
Registry for Bleeding Disorders Surveillance program.
People with hemophilia have a better quality of life today than ever before, but medical complications can still occur. Approximately 1 in 5 people with hemophilia A1 and about 3 in 100 people with hemophilia B2 will develop an antibody—called an inhibitor—to the product (medicine) used to treat or prevent their bleeding episodes. People with von Willebrand disease (VWD) type 3 may also develop inhibitors. Developing an inhibitor is one of the most serious and costly medical complications of a bleeding disorder because treatment of bleeds becomes less effective.
People with hemophilia, and many with VWD type 3, use treatment products called clotting factor concentrates (“factor”). These treatment products improve blood clotting, and they are used to stop or prevent a bleeding episode. When a person develops an inhibitor, the body stops accepting the factor treatment product as a normal part of blood. The body thinks the factor is a foreign substance and tries to destroy it with an inhibitor. The inhibitor keeps the treatment from working which makes it more difficult to stop a bleeding episode. A person who develops an inhibitor will require special treatment until his or her body stops making inhibitors. Inhibitors most often appear during the first 50 times a person is treated with clotting factor concentrates, but they can appear at any time.
Cost of Treatment for People with Inhibitors
Treatment for people with an inhibitor poses special challenges. The healthcare costs associated with inhibitors can be staggering because of the amount and type of treatment product required to stop bleeding. Also, people with hemophilia who develop an inhibitor are twice as likely to be hospitalized for a bleeding complication, and they are at increased risk of death.3,4, 5
Risk Factors and Causes
All persons with hemophilia and VWD type 3 are at risk of developing an inhibitor. Scientists do not know exactly what causes inhibitors. Multiple research studies have shown that people with certain types of hemophilia gene mutations6 are more likely to develop an inhibitor.
Genes are inside all the cells of the body, and they contain the instructions for the development and functioning of all living things. The genes that a person inherits from his or her parents can determine many things. For example, genes affect what a person will look like and whether the person might have certain diseases. Hemophilia is caused by changes, called mutations, within the genes that control normal blood clotting.
Some studies have found other characteristics that possibly play a role in increasing the risk of inhibitor development among people with hemophilia. These include7
- Number of lifetime exposures to clotting factor concentrates,
- Increased frequency and amount of treatment,
- Black race or Hispanic ethnicity, and
- Family history of inhibitors.
Inhibitors are diagnosed with a blood test. The blood test determines if a person has an inhibitor, and it can measure the amount of inhibitor present (called an inhibitor titer) in the blood. Inhibitor titers are measured in Nijmegen-Bethesda units (NBU) or Bethesda units (BU), depending on the type of test performed. The higher the inhibitor titer, the more inhibitor is present in the blood. Test results of 5.0 NBU/BU or lower are called “low titer” inhibitors, whereas test results of greater than 5.0 NBU/BU are called “high titer” inhibitors. People diagnosed with low titer inhibitors are more likely to have shorter and more successful inhibitor treatment than those with high titer inhibitors.8 It is important that all people with hemophilia or VWD type 3 who use clotting factor concentrates are tested for inhibitors at least once a year. Eligible individuals can receive free inhibitor testing at federally funded HTCs through the Community Counts Registry for Bleeding Disorders Surveillance.
Treating people who have an inhibitor is complex, and it remains one of the biggest challenges in in the care of people with bleeding disorders. Some inhibitors, called “transient” inhibitors, may disappear on their own, without treatment. If possible, a person with an inhibitor should be cared for at an HTC. HTCs are specialized healthcare centers that bring together a team of doctors, nurses, and other health professionals experienced in treating people with bleeding disorders.
Some treatments for people with inhibitors include the following:
- High-Dose Clotting Factor Concentrates: People with low titer inhibitors may be treated with higher amounts or increased frequency of factor to overcome the inhibitor and yet have enough left over to form a clot.
- Bypassing Agents: Special blood products, called bypassing agents, are used to treat bleeding episodes for people with high titer inhibitors. Instead of replacing the missing factor, they go around (or bypass) the factors that are blocked by the inhibitor to help the body form a normal clot. People taking bypassing agents should be monitored closely to make sure that their blood is not clotting too much or clotting in the wrong places in the body.
Immune Tolerance Induction (ITI) Therapy: The goal of ITI therapy is to stop the inhibitor from blocking factor in the blood and to teach the body to accept factor as a normal part of blood. With ITI therapy, people receive large amounts of factor every day for many weeks or months.
Learn more about ITI »
All inhibitor treatment options require specialized medical expertise. Treatment can be costly, particularly bypass agents and ITI. People who are being treated for inhibitors should have their blood tested often to measure their inhibitor titers to be sure that treatment is working. HTCs can serve a vital role in supporting patients who undergo an intensive treatment regimen for inhibitors, such as ITI.
CDC is learning more about why certain people, but not others, develop inhibitors and how inhibitors can be prevented. The Hemophilia Inhibitor Research Study (HIRS) began in 2006 and ended in 2016. During the 10 year study period, 37 federally funded hemophilia treatment centers across the United States enrolled approximately 1900 persons with hemophilia. Key findings and accomplishments from the HIRS study include the following:
- Confirmed certain hemophilia A and hemophilia B gene mutations (changes in the genes) are linked to inhibitor development.6
- Developed an inhibitor test method that can successfully test people for inhibitors after they receive clotting factor treatment.9 This test method was implemented as centralized inhibitor testing for all federally funded HTCs in the CDC bleeding disorders monitoring program, Community Counts.10
- Demonstrated the accuracy of several inhibitor test methods (chromogenic & fluorescence immunoassay) that can be used to confirm test results of the standard Nijmegen Bethesda Assay.11, 12
- Assembled databases that contain more than 2,000 factor VIII (factor 8) gene mutations and over 1,000 factor IX (factor 9) gene mutations (CHAMP and CHBMP, respectively) that have been reported worldwide.13, 14
- Demonstrated that all persons with hemophilia, regardless of age, disease severity, or number of product treatment exposures, were at risk for inhibitor development.15
Through additional research, researchers and clinicians hope to increase the knowledge about inhibitors. Knowing more about why some people develop inhibitors and others do not may help predict treatment options that will prevent individuals from developing an inhibitor. The goal is to reduce the number of people who develop inhibitors, decrease healthcare costs, and ensure that all treatment products are safe and effective for people with bleeding disorders.
Did You Know?
There are many places people with inhibitors and their families can seek support.
- The National Hemophilia Foundation (NHF) Inhibitor Education Summits. These summits are intended for patients, caregivers, and staff members from hemophilia treatment centers and NHF chapter organizations. The summits allow attendees to learn from each other’s experiences and from experts. Past topics have addressed new drugs in development, tips for parents, sports and exercise, immune tolerance therapy, and needs of older adults with hemophilia and an inhibitor. For more information, visit https://www.hemophilia.org/Events-Educational-Programs/Inhibitor-Education/Inhibitor-Education-Summits
- The NHF’s Inhibitor Education Summits Webinar Series. This webinar series is designed to enhance and expand upon the education provided at NHF’s annual Inhibitor Education Summits. For more information, visit https://www.hemophilia.org/Events-Educational-Programs/Inhibitor-Education/Inhibitor-Education-Webinars.
- The Hemophilia Federation of America’s Helping Hands Program. This program offers financial assistance to those in need to pay for attendance at eligible national and state bleeding disorder educational meetings; travel for necessary medical procedures, surgeries and second opinions; and tutoring or education-related expenses. To learn more, visit http://www.hemophiliafed.org/programs/helping-hands/helping-hands-inhibitor-support/
- CDC’s Flickr Album. This album features stories of people with hemophilia who have also experienced life with the added challenge of an inhibitor. To read their stories, visit https://www.flickr.com/photos/cdcsocialmedia/sets/72157654059374830
- Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003; 9(4):418-435.
- Puetz J, Soucie JM, Kempton CL, Monahan PE, and Hemophilia Treatment Center Network Investigators. Prevalent inhibitors in hemophilia B subjects enrolled in the Universal Data Collection database. Haemophilia. 2015; 20(1):25-31.
- Guh S, Grosse SD, McAlister S, Kessler CM, Soucie JM. Health care expenditures for males with haemophilia and employer-sponsored insurance in the United States. Haemophilia. 2012; 18(2):268-275.
- Guh S, Grosse SD, McAlister S, Kessler CM, Soucie JM. Health care expenditures for Medicaid-covered males with haemophilia in the United States, 2008. Haemophilia. 2012; 18(2):276-283.
- Walsh CE, Soucie JM, Miller CH; United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia A mortality in the United States. American Journal of Hematology. 2015; 90:400-405.
- Miller CH, Benson J, Ellingsen D, Driggers J, Payne A, Kelly FM, Soucie JM, Hooper CW, and the Hemophilia Inhibitor Research Study Investigators. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012; 18:375-382.
- Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Therapeutic Advances in Hematology. 2013; 4(1):59-72.
- Hay CR, DiMichele DM, International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012; 119(6):1335-1344.
- Miller CH, Platt SJ, Rice AS, Kelly FM, Soucie JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance. Journal of Thrombosis and Haemostasis. 2012; 10:1055-1061.
- Soucie JM, Miller CH, Kelly FM, Oakley M, Brown DL, Kucab P. A public health approach to the prevention of inhibitors in hemophilia. American Journal of Preventive Medicine. 2014; 47:669-673.
- Miller CH, Rice AS, Boylan B, Shapiro AD, Lentz SR, Wicklund BM, Kelly FM, Soucie JM, and the Hemophilia Inhibitor Research Study Investigators. Comparison of clot-based, chromogenic, and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study. Journal of Thrombosis and Haemostasis. 2013; 11:1300-1309.
- Boylan B, Rice AS, Dunn AL, Tarantino MD, Brettler DB, Jarrett JC, Miller CH, and the Hemophilia Inhibitor Research Study Investigators. Characterization of the anti-factor VIII immunoglobulin profile in patients with hemophilia A by use of a fluorescence-based immunoassay. Journal of Thrombosis and Haemostasis. 2014; 13:47-53.
- Payne AB, Miller CH, Kelly FM, Soucie JM, Hooper CW. The CDC Hemophilia A Mutation Project (CHAMP) mutation list: a new online resource. Human Mutation. 2012; E2382-E2392.
- Li T, Miller CH, Payne AB, Hooper CW. The CDC Hemophilia B mutation project mutation list: a new online resource. Molecular Genetics and Genomic Medicine. 2013; 1(4):238-245.
- Soucie JM, Miller CH, Kelly FM, Payne AB, Creary M, Bockenstedt PL, Kempton CL, Manco-Johnson MJ, Neff AT, and the Haemophilia Inhibitor Research Study Investigators. A study of prospective surveillance for inhibitors among persons with haemophilia in the United States. Haemophilia. 2014; 20:230-237.
- Page last reviewed: February 6, 2017
- Page last updated: December 7, 2016
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