What are inhibitors?
Inhibitors are antibodies that prevent factor treatment from working. Inhibitors develop when the body sees factor treatment as a foreign agent and wants to protect itself. When inhibitors develop, the factor treatment is immediately rejected, rendering the treatment ineffective at halting the bleeding episode.
In haemophilia, inhibitors occur more often in individuals with the severe form than those with moderate or mild haemophilia. For rare bleeding disorders, figures are unclear due to the limited patient population and the lack of treatment.
| Severe Haemophilia A | 25-30% affected |
| Moderate/mild haemophilia A | 0-15% affected |
| Severe Haemophilia B | 1-5% affected |
| Moderate/mild Haemophilia B | <1% affected |
Inhibitors are a very serious complication of haemophilia because factor concentrates are no longer effective. People with inhibitors are at risk for crippling bleeding into their joints. Thankfully, newer treatment options that have been licensed and are in clinical trials are changing these outcomes.
How are inhibitors diagnosed?
Inhibitors typically occur in the first 75 exposures to the treatment. This is why it is important that people with bleeding disorders receive their first treatment under medical supervision in a treatment centre, where the right medical facilities and expertise are available. This also ensures safety in case of an allergic reaction. In fact, allergic reactions may amplify when treatment is given over time. Ideally, children and adults who are newly diagnosed with haemophilia should be tested regularly for inhibitors between the 1st and 50th days of treatment. Even after the 50th day of treatment, they should be checked at least twice a year until they have received 150-200 doses and at least once a year after that. Testing for inhibitors should also be done before any major surgery. The risk of developing inhibitors decreases very significantly after the first 150 exposure days to factor concentrate. If the amount of inhibitory antibodies in the blood is high- these are known as high titre inhibitors. If they are low, these are known as low titre inhibitors. Low titre inhibitors may be transient and are easier to treat.
How are inhibitors treated?
New products for those with haemophilia A inhibitors do provide a prophylactic effect, but without the use of factor concentrate. These are called Non-(factor) Replacement Therapies (NRTs). Currently, there is only one product licenced. This is called a bi-specific anti-body which are often referred to as mimetics. The currently licenced product is know as Emicizumab (brand name Hemlibra)
Administering factor concentrates at higher doses and/or more frequent intervals is the preferred treatment for acute bleeding in those with low inhibitor levels.
Immune tolerance induction (ITI) therapy involves giving the person with inhibitors frequent doses of factor concentrates over several months, or sometimes years, to train the body to recognise the treatment product without reacting to it. This process is called tolerance induction. If a person plans to undergo immune tolerance induction therapy, but has not yet started, it is better not to use factor products to treat acute bleeding episodes because they are likely to provoke a rise in inhibitor titre (amount).
An antibody is a type of protein made in a laboratory that can bind to substances in the body. A bi-specific antibody is one that is made to bind specifically to two substances- in this case Factor IXa (9) and Factor X (10) This is not a factor protein. When you take FVIII, you are replacing the FVIII that is missing from the body. FVIII connects two other proteins activated FIX (FIXa) and FX protein. FVIII creates the bridge between these proteins so the clotting process continues to form a clot and stop bleeding. Instead of the FVIII protein bridging the other two proteins, it is the antibody that does this connection. The inhibitors to FVIII do not recognise bi-specific antibodies. The person will still have an inhibitor so there will need to be a plan for the management of trauma or surgery.
These have several benefits. Firstly, they provide a consistent level of protection without peaks or troughs. There is no actual clotting factor infused provided, so they are not affected by FVIII inhibitors. Secondly, they are given subcutaneously (under the skin). They have long half-life’s so how the number of injections per month is less. On the other hand, unlike factor concentrates they can not target the level of protection required for certain activities and they can not be used to treat a bleed. So conversations with a clinician are important to find which treatment is best to suit your lifestyle and activities and give you the best protection for your body short and long term.
For the treatment of bleeding , people with inhibitors can receive activated prothrombin complex concentrate (aPCC) or recombinant factor VIIa. These are called by-passing agents. They can be used to skip steps in the clotting process. Whilst these are good for the treatment of bleeding, they do not replace the missing factor and therefore are not quite as good in stopping bleeding. Also it is very difficult to give these as prophylaxis, to prevent bleeding and joint damage.
Tranexamic acid (also known as Cyklokapron) is an anti-fibrinolytic agent. This means that it slows the breakdown of blood clots. It is used to prevent or treat bleeding from mucous membranes such as the inside of the mouth, nose, gut or womb. It may be given before dental work, for nosebleeds. However, it should not be used in combination with aPCC’s.
Plasmapheresis is a procedure that removes inhibitors from the person’s bloodstream. It is usually done when the inhibitor titre needs to be brought down quickly (for example, before major surgery or in cases of severe bleeding that are not well controlled with bypassing agents).
Clinical Trials
Unfortunately, there are not alternative licensed products for those with Haemophilia B with inhibitors that have the same prophylactic effect. There are however, many in clinical trials a which currently look promising, such as rebalancing agents. The same also applies for von Willebrands with inhibitors. Some reports have been published on the use of licenced non replacement therapies being successfully used and broader research is now taking place.
European Principles of Inhibitor Management
The European Principles of Inhibitor Management in Patients with Haemophilia were developed through a collaboration between the European Haemophilia doctors organisation (EAHAD) and the European Haemophilia patients organisation – European Haemophilia Consortium (EHC). Their purpose is to serve as a benchmark for improving the multidisciplinary and practical management of inhibitors in haemophilia.
The 10 principles put forth were defined by a multidisciplinary group of health professionals and patients and emphasise the importance and benefits of a centralised, multidisciplinary, expert, and holistic approach in addressing this most serious complication in haemophilia.
The 10 Principles of comprehensive inhibitor management are:
- Awareness of the incidence of inhibitors and risk factors throughout life
- Early recognition and accurate diagnosis
- Optimal organization of care and communication between all stakeholders
- Haemostatic treatment with bypassing agents in inhibitor patients
- Inhibitor eradication by immune tolerance induction (ITI) therapy
- Access to, and optimal preparation for, surgery and other invasive procedures
- Provision of specialist nursing care
- Provision of tailored physiotherapy care and monitoring
- Access to psychosocial support
- Involvement in research and innovation
For more information, see the paper, European Principles of Inhibitor Management in Patients with Haemophilia: Implications of New Treatment Options.