Haemophilia and Inhibitors

What is an inhibitor

The basis of haemophilia A treatment is the administration of the missing coagulation factor VIII (hereinafter referred to as "FVIII"), and for haemophilia B, coagulation factor IX (hereinafter referred to as "FIX"). In some people with haemophilia, particularly those with the severe form of the disease, antibodies against FVIII or FIX develop during treatment. This is a reaction of the patient's immune system to the foreign FVIII or FIX administered during treatment or prophylaxis of bleeding. The antibody binds to FVIII or FIX and prevents it from performing its function in the blood clotting process — it inhibits it. Such an antibody is therefore referred to as an inhibitor. As a result, the administered coagulation factor VIII or IX becomes completely ineffective in treating bleeding.

Risk of inhibitor development

The risk of inhibitor development is highest in severe haemophilia A, affecting approximately 10–40% of patients, while in severe haemophilia B it does not exceed 3%. Inhibitor development occurs only rarely in moderate and mild haemophilia B, whereas in the same severity of haemophilia A it occurs in 3–10% of patients. Inhibitor development usually occurs during the first 50 days of coagulation factor concentrate administration, most commonly between days 10 and 20 of treatment, which for severe haemophilia patients is typically during preschool age.

Factors influencing inhibitor development

Factors that demonstrably influence inhibitor development:

• type of genetic defect in FVIII (mutations associated with complete absence of FVIII increase the risk)
• other genetic changes outside the FVIII gene (affecting the body's immune responses)
• family history of inhibitor (increases the risk of inhibitor development)
• higher risk in individuals of African descent

Bethesda units and classification

The amount of inhibitor is described using so-called Bethesda Units (BU). One BU is defined as the amount of inhibitor in the blood plasma that, when mixed with healthy blood plasma in a 1:1 ratio, reduces the FVIII or FIX content in the healthy plasma by exactly half. If, despite repeated administration of FVIII or FIX, the inhibitor does not rise above 5 BU/ml, the patient is classified as a so-called low responder. If the inhibitor rises above 5 BU/ml after factor administration, the patient is a so-called high responder, which has fundamental implications for further treatment.

Treatment for low responders

In the case of a low responder, the missing coagulation factor concentrate targeted by the inhibitor can still be used to treat bleeding. A high dose of the administered factor can temporarily eliminate the inhibitor. In this case, all of the patient's inhibitor binds to the administered factor, and the factor administered in excess then ensures a therapeutic level in the patient's blood, thereby stopping the bleeding or providing prophylaxis, for example during surgery.

Treatment for high responders

However, this cannot be achieved in a high responder. In these patients, we are unable to ensure blood clotting through the normal natural pathway (by simply increasing the missing FVIII or FIX), which has two serious consequences: 1. Bleeding treatment may not always be fully effective. 2. For bleeding treatment, we must use medications other than FVIII or FIX, such as NovoSeven® or FEIBA®.

The efficacy of both products in treating uncomplicated bleeding is comparable, although there are opinions that NovoSeven® is more effective; however, there is no direct evidence for this — no studies on patients comparing the efficacy of both products.

Individual patient response to one product or the other may vary. If bleeding does not stop with one product, it must be replaced with the other (only with NovoSeven® can doses also be increased). In exceptional cases, when standalone administration fails, alternating administration of FEIBA® and NovoSeven® to patients during a single day, at intervals of 4–8 hours, has been described.

Immune tolerance induction

The greatest benefit for a person with haemophilia and an inhibitor is if the inhibitor can be eradicated (eliminated), after which FVIII or FIX substitution becomes effective again for treating bleeding, and FVIII or FIX concentrate can also be administered prophylactically. This is achieved through so-called immune tolerance induction (ITI), which involves repeated administration of FVIII or FIX concentrate over a period of up to several years (daily or just 3 times a week), which can induce tolerance of the immune system to FVIII or FIX while the inhibitor disappears. As a rough estimate, immune tolerance induction is successful in approximately 80% of haemophilia patients.

In practice, immune tolerance induction is performed in children in the Czech Republic, and rarely in adult patients. If it fails, immunosuppression can be used — medications that weaken the body's immune response and thus inhibitor production, including rituximab, which is used as an adjunctive treatment in selected patients.

Emicizumab in haemophilia A with inhibitors

Since 2018, emicizumab (Hemlibra) has been approved in Europe for bleeding prophylaxis in haemophilia A patients with inhibitors. Emicizumab is a bispecific antibody that replaces the function of factor VIII and is administered subcutaneously. According to the CNHP registry, 10 out of 12 patients with active inhibitors in the Czech Republic were treated with emicizumab in 2024. Emicizumab is now the standard of care for prophylaxis in haemophilia A patients with inhibitors and has significantly reduced the frequency of bleeding episodes.

Further information

• What is haemophilia
• Haemophilia treatment
• Von Willebrand disease treatment