Inhibitors Are the Main Treatment Challenge Today1

Inhibitors are a serious complication of hemophilia treatment in which the body's immune system develops antibodies (inhibitors) to the infused factor used to treat bleeding episodes. Inhibitors greatly reduce—or inhibit—the ability of the factor to stop bleeding, making it very hard to control or prevent bleeding episodes.

Inhibitors can develop in up to 35% of people with severe hemophilia A who receive factor VIII (FVIII) replacement therapy. Inhibitors attach to FVIII and diminish its ability to stop bleeding. Inhibitors are the most serious and challenging complication of hemophilia A management.1,2

PREVALENCE AND RISK

The risk of inhibitor development in hemophilia A is significant.

~35%

of people with hemophilia A may develop an inhibitor2

~25%

of people with hemophilia A who develop an inhibitor will deal with that inhibitor for life3

~60%

of people, as well as their treatment centers, were not aware they had an inhibitor, according to a recent study4

ALL

patients with hemophilia A are at risk of inhibitors, regardless of age and disease severity4,5

PREVALENCE AND RISK OF INHIBITORS

The risk of inhibitor development in hemophilia A is significant.

~35% of people with severe hemophilia A may develop an inhibitor2

~25% of people with hemophilia A who develop an inhibitor will deal with that inhibitor for life3

~60% of people, as well as their treatment centers, were not aware they had an inhibitor, according to a recent study4

ALL patients with hemophilia A are at risk of inhibitors, regardless of age and disease severity4,5

 

WHAT RAISES YOUR RISK OF INHIBITORS?

Some genetic and environmental risk factors are linked to the development of inhibitors.

Risk factors include:

Genetic

  • Severity of hemophilia A6
  • Large mutation of the FVIII gene6,7
  • Family history of inhibitors6,7
  • Ethnicity6,7

Environmental

  • Intensive FVIII treatment at peak treatment moments6
  • Early intensive exposure to FVIII treatment6,7
  • Immunologic/inflammatory/infectious events (eg, vaccination, surgery, illness)7
  • FVIII product type8

IMPACT AND HEALTH RISKS

Death due to bleeding-related causes is significantly higher with an inhibitor than without.9
Inhibitors also increase the risk of bleeding and joint damage as well as the costs of care.10

2X MORE LIKELY TO BE HOSPITALIZED

People with inhibitors are twice as likely to be hospitalized for a bleeding complication as people who have not developed them.4

 

HIGHER TREATMENT COSTS

Treatment costs for a person with an inhibitor are on average 2 to 10 times higher than costs for a person without inhibitors, and can exceed $1,000,000 annually.4,11

 

What are the signs that a person may have an inhibitor?

Anyone who responds poorly to treatment for hemophilia A should be tested for inhibitors.6 Although it is common that people with inhibitors may not have any signs or symptoms, any of the following can be a sign that it's time to see a healthcare professional about being tested6:

  • Not responding to factor concentrate
  • Not healing after experiencing an injury
What are the signs that a person may have an inhibitor?

Is it possible to have an inhibitor without realizing it?

Yes. It is not always obvious that someone has developed an inhibitor, so regular testing and continuous care from a healthcare professional is recommended.

It is common practice to test for inhibitors when people with hemophilia are not responding to their therapy.

Research has suggested that testing for inhibitors be considered for people with mild and moderate hemophilia as well as for people who have had more than 150 treatments.4,6

~60% of people, as well as their treatment centers, were not aware they had an inhibitor, according to a recent study.4

Is it possible to have an inhibitor without realizing it?

How are inhibitors diagnosed?

When someone has the signs of an inhibitor, 2 tests are usually done to see if an inhibitor is present.

The first test, a factor level test, determines how much factor there is. If the number is lower than expected, a second test, called Bethesda assay, is performed to confirm the diagnosis and to determine the level of inhibitor that the person has developed.6,12

Inhibitor testing should be initiated if a person is responding poorly to treatment. Some hemophilia treatment centers test frequently in the early days of treatment, before every surgery, and at annual comprehensive clinic visits.6

How are inhibitors diagnosed?

How are inhibitors classified?

Inhibitors can be classified by titer. The amount of inhibitor titer is measured in Bethesda units (BU)—higher BU indicates more inhibitor presence; lower BU indicates less inhibitor presence.

High-titer inhibitors are considered to be 5 BU or greater and low-titer inhibitors are considered to be less than 5 BU. Once an inhibitor is detected, the strength with which the body reacts to factor concentrate (also known as anamnestic response), can further classify the inhibitor type.6

How are inhibitors classified?

How does an inhibitor affect someone's health?

A person with inhibitors will likely face more difficulty controlling bleeding and pain because treatment with factor concentrates may be ineffective.

If bleeding into the joints is not controlled, permanent joint damage is likely. This joint damage can impair mobility. More people with an inhibitor are hospitalized for orthopedic procedures than those without.13

The risk of complications in a surgical procedure, like a knee replacement, is significantly higher.14

Death due to bleeding-related causes is significantly higher with an inhibitor than without.9

How does an inhibitor affect someone's health?

What are the treatment options for people with inhibitors?

Treating and managing hemophilia for people with inhibitors is more challenging. Healthcare professionals have many considerations when choosing a treatment regimen in an effort to avoid inhibitor development. However, it is not completely understood why inhibitors develop in some people, which is why it cannot always be prevented. For those people who do develop inhibitors, there are treatment options. When choosing treatment options, a healthcare professional considers inhibitor titer, strength with which the body reacts to factor, site/severity of bleed, and other possible influences. People with low-titer inhibitors can sometimes continue to use factor concentrates but may need more. It is also possible that some inhibitors will resolve on their own. For cases in which the inhibitors do not resolve on their own or for high-titer inhibitors, other treatment options must be considered.15,16

Be sure to consult a healthcare professional before making any treatment decisions and continue to remain informed to help facilitate care.

What are the treatment options for people with inhibitors?

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REFERENCES

  1. World Federation of Hemophilia. What are inhibitors? http://www1.wfh.org/publication/files/pdf-1343.pdf. Published 2009. Accessed May 10, 2016.
  2. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016;374(21):2054-2064.
  3. Valentino LA, Kempton CL, Kruse-Jarres R, Mathew P, Meeks SL, Reiss UM. US guidelines for immune tolerance induction in patients with haemophilia A and inhibitors. Haemophilia. 2015:1-9. doi: 10.1111/hae.12730.
  4. Soucie JM, Miller CH, Kelly FM, et al. A study of prospective surveillance for inhibitors among persons with haemophilia in the United States. Haemophilia. 2014;20(2):230-237.
  5. Hay CRM, Palmer B, Chalmers E, et al. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood. 2011;117(23):6367-6370.
  6. Hemophilia Federation of America. Inhibitors. Hemophilia Federation of America website. http://www.hemophiliafed.org/bleeding-disorders/inhibitors/. Accessed May 10, 2016.
  7. Carcao M, Re W, Ewenstein B. The role of previously untreated patient studies in understanding the development of FVIII inhibitors. Haemophilia. 2015;22(1):22-31.
  8. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003;9:418-435.
  9. Walsh CE, Soucie JM, Miller CH and the United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol. 2015;90(5):400-405.
  10. Medical and Scientific Advisory Council. MASAC Recommendations on Standardized Testing and Surveillance for Inhibitors in Patients with Hemophilia A and B. New York, NY: National Hemophilia Foundation; August 15, 2015. MASAC Document #236.
  11. Ullman M, Hoots WK. Assessing the costs for clinical care of patients with high-responding factor VIII and IX inhibitors. Haemophilia. 2006;12(Suppl 6):74-80.
  12. Kaspar CK. Diagnosis and Management of Inhibitors to Factors VIII and IX. Montreal, Canada: World Federation of Hemophilia; 2004.
  13. Morfini M, Haya S, Tagariello G, et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia. 2007;13:606-612.
  14. Solimeno L, Mancuso M, Pasta G, Santagostino E, Perfetto S, Mannucci PM. Factors influencing the long-term outcome of primary total knee replacement in haemophiliacs: a review of 116 procedures at a single institution. Br J Hematol. 2009;145:227-234.
  15. National Hemophilia Foundation. Inhibitors. National Hemophilia Foundation website. http://www.hemophilia.org/Bleeding-Disorders/Inhibitors-Other-Complications/. Accessed May 10, 2016.
  16. DiMichele DM. Inhibitors in Hemophilia: A Primer. 4th ed. Montreal, Canada: World Federation of Hemophilia; 2008.