Key Findings: New Method Designed to Detect the Type of Antibodies Linked to Inhibitor Development Among People with Hemophilia A and B
The Centers for Disease Control and Prevention (CDC), along with researchers from the Hemophilia Inhibitor Research Study (HIRS), have recently published two articles in The Journal of Thrombosis and Haemostasis. The articles describe important findings related to the formation of inhibitors (antibodies) in patients who have hemophilia. These research reports looked at people with hemophilia who enrolled in the HIRS from 2006-2015 at 29 US hemophilia treatment centers, and had their blood tested for inhibitors that interfered with their ability to clot blood. The study showed that people with hemophilia A and hemophilia B who develop inhibitors are likely to have a specific type of antibody (called immunoglobulin G subclass 4, or IgG4). When traditional inhibitor tests do not give clear results, tests for these antibodies may help clarify whether an inhibitor is present or even just starting to develop. You can read the scientific summary of each article online (hemophilia AExternal and for hemophilia BExternal).
What is Hemophilia?
Hemophilia is an inherited bleeding disorder in which the blood does not clot properly. This can lead to spontaneous bleeding as well as bleeding following injuries or surgery. There are several different types of hemophilia. The following two are the most common:
- Hemophilia A (Classic Hemophilia): This type is caused by a lack or decrease of a blood clotting protein called factor VIII (“factor eight”).
- Hemophilia B (Christmas Disease): This type is caused by a lack or decrease of a blood clotting protein called factor IX (“factor nine”).
- As many as one third of people with hemophilia will develop an inhibitor to the product used to treat or prevent bleeding.
- Developing an inhibitor is one of the most serious and costly health problems for people with hemophilia.
- People with hemophilia who develop an inhibitor are twice as likely to be hospitalized for a bleeding complication.
How is Hemophilia Treated?
The best way to treat hemophilia is to replace the missing blood clotting factor so that the blood can clot properly. This is done by infusing (injecting through a needle into a vein) commercial factor treatment products. People with hemophilia can learn how to perform these infusions themselves, which enables them to stop bleeding episodes on their own. In addition, by performing these infusions on a regular basis, patients can prevent most bleeding episodes from happening in the future.
What are Inhibitors?
Antibodies are proteins in the blood that are made by a person’s immune system to attack intruders and substances that aren’t recognized as being normal parts of the body, such as bacteria and viruses. Inhibitors are types of antibodies that develop against clotting factor products used to treat bleeding in people who have hemophilia. Inhibitors develop when the immune system in a person with hemophilia identifies the clotting factor product as a foreign substance because the person’s immune system has had little or no exposure to normal clotting factor. The inhibitors stop the infused factor from working, which makes it more difficult to stop a bleeding episode.
How are Inhibitors Diagnosed?
A blood test called the Nijmegen-Bethesda Assay (NBA) is used to diagnose inhibitors. The NBA measures inhibitor levels in the blood based on how much inhibitors interfere with blood clotting in a test tube. In some cases, the NBA does not produce a convincing positive or negative result, and it is unclear if the patient’s sample has an inhibitor or not. In order to address the problem of unclear results, CDC researchers developed a new inhibitor detection method to complement the NBA. This new method, which is called a fluorescence immunoassay (FLI), was developed as a part of the HIRS using blood samples from people who have hemophilia A to detect antibodies to factor VIII and blood samples from people who have hemophilia B to detect antibodies to factor IX.
Main Findings from the Studies
- In people with hemophilia A or hemophilia B who have inhibitors, IgG4 antibodies to the missing or defective clotting factor were consistently found. Although other types of antibodies were sometimes also found, the presence of IgG4 antibodies appears to be the best indicator that a person has an inhibitor to the clotting factor, even when traditional inhibitor tests do not give clear results.
- IgG1 antibodies to factor VIII were found in the blood of people with hemophilia A before they developed inhibitors. This might be an early sign of future development of inhibitors.
- Taken together, the findings from these studies will help laboratories and healthcare providers identify inhibitors in patients with hemophilia A and hemophilia B when traditional testing methods fail to give clear results.
About the Hemophilia Inhibitor Research Study (HIRS)
The Hemophilia Inhibitor Research Study was supported by the CDC Foundation through grants from Pfizer Pharmaceuticals and Baxter Healthcare.
Key Findings Reference
Boylan B, Rice AS, Dunn AL, Tarantino MD, Brettler DB, Barrett JC, Miller CH, for 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. J Thromb Haemost 2015;13:47-53.
Boylan B, Rice AS, Neff AT, Manco-Johnson MJ, Kempton CL, Miller CH, for the Hemophilia Inhibitor Research Study Investigators. Survey of the anti-factor IX immunoglobulin profiles in patients with hemophilia B using a fluorescence-based immunoassay. J Thromb Haemost 2016;14:1931-1940.