martes, 3 de marzo de 2020

Inhibitors and Hemophilia | CDC

Inhibitors and Hemophilia | CDC



Inhibitors and Hemophilia

Some people with hemophilia and von Willebrand disease (VWD) 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, it is important to be tested for inhibitors once a year. You can receive free inhibitor testing at federally funded hemophilia treatment centers (HTCs) by participating in 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 treatment product (medicine) used to treat or prevent their bleeding episodes. People with 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 it becomes more difficult to treat bleeds.

About Inhibitors

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 their 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 The excess cost of care for each person with hemophilia and an inhibitor is over $800,000 per year6 and, based on CDC surveillance data, there are nearly 1,500 people living with an inhibitor in the United States.

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 mutations7 are more likely to develop an inhibitor.
Genes are inside all cells in 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 include the following:8
  • Number of times one has used clotting factor concentrates in their lifetime,
  • Increased frequency and dose of treatment,
  • Black race or Hispanic ethnicity, and
  • Family history of inhibitors (other family members who have had inhibitors).

Diagnosis

Inhibitors are diagnosed with a blood test. The blood test measures if an inhibitor is present and the amount of inhibitor present (called an inhibitor titer) in the blood. Inhibitor titers are measured in Nijmegen-Bethesda units (NBU) if the lab test used was the Nijmegen-Bethesda assay (NBA), or Bethesda units (BU) if the lab test used was the Bethesda assay. A person with a high inhibitor titer has more inhibitor present in the blood compared to a person with a low inhibitor titer. 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.9 For these reasons, it is important that all people with hemophilia or VWD type 3 who use clotting factor concentrates get 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.

Treatment

Treatment for people who have an inhibitor is complex, and it remains one of the biggest challenges 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 consider seeking care at an HTC. HTCs are specialized healthcare centers that bring together a team of doctors (hematologists or blood specialists), nurses, and other health professionals experienced in treating people with bleeding disorders.
Inhibitor Treatment Fact Sheet
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. Close monitoring of people taking bypassing agents is important to make sure that their blood is not clotting too much or clotting in the wrong places in the body.
  • Products that mimic Factor VIII: This type of product works by replacing the function of factor VIII (8) without being affected by inhibitors, and can be used to treat and prevent bleeding episodes in people with hemophilia A. This treatment product can be given by injection under the skin.
  • 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 »external icon
All inhibitor treatment options require specialized medical expertise. Treatment can be costly, particularly bypassing agents and ITI. It is important that people who are being treated for inhibitors have their blood tested often to measure their inhibitor titers to be sure that the treatment is working. HTCs can serve a vital role in supporting patients who undergo intensive treatment regimens, such as ITI, for inhibitors.

CDC Research

CDC is learning more about why some people, but not others, develop inhibitors and how inhibitors can be prevented. The Hemophilia Inhibitor Research Study (HIRS) began in 2006 and ended patient data collection in 2016. During the 10 year study period, 37 federally funded HTCs across the United States enrolled approximately 1900 persons with hemophilia. Key findings and accomplishments from the HIRS study include the following:
  • Confirmed that certain hemophilia A and hemophilia B gene mutations (changes in the genes) are linked to inhibitor development. 7
  • Developed an inhibitor test method that can successfully test people for inhibitors while they receive clotting factor treatment, even treatment product usage the day of testing. 8 With traditional inhibitor tests, patients had to stop using treatment products for a few days before the test could accurately measure if an inhibitor was present. This new test method is now used as the centralized inhibitor testing for all federally funded HTCs in the CDC bleeding disorders monitoring program, Community Counts. 11 With everyone receiving the same test method, test results for patients in Community Counts can be compared.
  • Demonstrated the accuracy of several inhibitor test methods (chromogenic & fluorescence immunoassay) that can be used to confirm the test results of the standard NBA test method. 121314
  • 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(https://www.cdc.gov/ncbddd/hemophilia/champs.html), respectively) that have been reported worldwide.15,16
  • Demonstrated that all persons with hemophilia were at risk for inhibitor development, regardless of age, disease severity, or the number of times treatment product(s) was used,.17
Through additional studies, 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. CDC’s goal is to reduce the number of people who develop inhibitors, decrease healthcare costs, and ensure that all treatment products are safe and work well for people with bleeding disorders.

Did You Know?

There are many places people with inhibitors and their families can seek support.

References

  1. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003; 9(4):418-435.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Zheng-Yi Zhou, Marion A. Koerper, Kathleen A. Johnson, Brenda Riske, Judith R. Baker, Megan Ullman, Randall G. Curtis, Jiat-Ling Poon, Mimi Lou & Michael B. Nichol. Burden of illness: direct and indirect costs among persons with hemophilia A in the United States. Journal of Medical Economics 2015;18:457-465.
  7. 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.
  8. Witmer C, Young G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Therapeutic Advances in Hematology. 2013; 4(1):59-72.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Boylan B, Rice AS, Neff AT, Manco-Johnson MJ, Kempton CL, Miller CH; Hemophilia Inhibitor Research Study Investigators.  Survey of the anti-factor IX immunoglobulin profiles in patients with hemophilia B using a fluorescence-based immunoassay.  Journal of Thrombosis and Haemostasis. 2016; 14:1931-1940.
  15. 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.
  16. 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.
  17. 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.

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