The appearance of factor VIII inhibitors is a problem that affects about 20-30% of patients with haemophilia and can seriously endanger their health.

In order to counteract inhibitors effectively, it is of paramount importance to detect their presence as soon as possible and to determine the concentrations at which they are produced by the body.

Indeed, depending on their concentration, inhibitors can counteract the efficacy of replacement therapy to varying degrees, and must be treated using different strategies.

The Bethesda test is a valuable weapon in the battle against inhibitors, as it makes it possible both to reliably identify the presence of inhibitors in the blood and to determine their concentration, which is expressed in Bethesda Units (BU).

Depending on their concentration, inhibitors can be classified into two categories:

  • Low-Titre Inhibitors (LTI),e. inhibitors that give a result of below 5 BU (Bethesda Units) on the Bethesda test;
  • High-Titre Inhibitors (HTI), which give a Bethesda test result that is greater than or equal to 5 BU.

Low-titre inhibitors (LTIs) are often produced by the body only for a limited period of time and then disappear spontaneously within 6 months of their appearance. Therefore, in the case of LTI, physicians may decide not to intervene immediately and to simply monitor the situation, subjecting the patient to the Bethesda test at regular intervals, usually every 2-4 weeks. If the inhibitors persist for a prolonged period of time, or if the patient begins to bleed frequently, it is possible to use the Immunotolerance Induction (ITI) protocol, a special treatment based on high doses of factor VIII that forces the immune system to tolerate the presence of factor VIII, which therefore reacquires its effectiveness. A patient with LTI can still benefit from the protection provided by replacement therapy, although factor VIII will need to be administered in significantly higher doses in order to maintain its effectiveness. As soon as the inhibitors have disappeared, it will be possible to revert to normal doses.

Unlike LTIs, high-titre inhibitors (HTIs) tend to persist once they appear, meaning that the only way to stop the body from producing them is to use the ITI protocol. In order for ITI therapy to have maximum efficacy, it is necessary to allow a period between the time the inhibitors are detected and the start of therapy during which each factor VIII infusion is discontinued. During this period, because the body does not come into contact with factor VIII, the immune system is not stimulated to produce inhibitors, and their concentration in the blood therefore decreases. At this point, the ITI protocol can be applied with the greatest effectiveness. HTIs tend to completely neutralise the efficacy of replacement therapy, therefore, until immunotolerance is restored, bleeding will have to be kept at bay by resorting to alternative solutions that will be chosen by the physician on a case-by-case basis, to suit the patient’s characteristics.

Therefore, although inhibitors undeniably pose a serious threat to the health of patients with haemophilia, scientific progress has provided us with important tools for tackling the problem effectively.



  • Carcao M. et al. Inhibitors in hemophilia: a primer. Fifth edition, 2018. World Federation of Hemophilia (WFH)
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Learn more about the meaning of the words you read on this page and learn about the entire glossary on hemophilia.

Antibodies produced by the immune system of patients with haemophilia, following an infusion of replacement factor VIII.

The inhibitors recognise the infused factor VIII and bind with it in a specific manner, thereby neutralising its effect.