The challenge of inhibitors

While treatment for haemophilia using clotting factor replacement therapy is extremely effective, some people may develop what are known as ‘inhibitors’ or ‘antibodies’. Inhibitor development is usually a serious medical problem that can occur when a person with haemophilia has an immune response to clotting factor replacement therapy.

Inhibitors are produced by the body’s natural defense system if it starts to recognise that the replacement clotting factor is a foreign substance introduced to the body, and tries to destroy it. If this happens, the inhibitors stop the replacement clotting factor from working. Bleeds become harder to control as they may no longer respond adequately to the clotting factor replacement therapy.

How common are inhibitors?

Approximately 30% of people with severe haemophilia A develop inhibitors, usually during the first 20–50 days of exposure to clotting factor replacement therapy. In contrast, only around 5% of people with severe haemophilia B develop inhibitors.

In a minority of people, inhibitors are detected temporarily, and are no longer found during clotting factor replacement treatment. These are known as ‘transient inhibitors’.

Risk factors for inhibitors

It is not known exactly what causes inhibitors to develop. However, risk factors that have been shown in some studies to play a possible role include:

  • Age
  • Race/ethnicity
  • Type of haemophilia gene defect
  • Family history of inhibitors
  • Frequency and amount of treatment (inhibitors typically occur within the first 50 times clotting factor is used)
  • Type of clotting factor treatment product
  • Presence of other immune disorders.


High- and low-titre inhibitors

The presence of inhibitors can be confirmed with a simple blood test. The strength of the inhibitor is known as its ‘titre’. Low-titre inhibitors usually only require treatment with a larger dose of clotting factor. However, this does not tend to work for people with high-titre inhibitors. In these cases, treatment with different clotting factors is usually required. These are known as bypassing agents. 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.

Immune tolerance induction therapy

Immune tolerance induction therapy aims to stop the inhibitor reaction from happening in the blood. Frequent high doses of clotting factor replacement therapy are administered every day for many weeks or months so that the body gets used to the replacement therapy and doesn’t attack it.

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