In this section we will provide more information on:

People with bleeding disorders are treated with what is called replacement therapy. This means that the missing clotting factor is infused in their body on a regular basis so that the clotting process can occur normally. Unfortunately, some people develop antibodies, called inhibitors, that neutralise the replacement clotting factor. This means that the body induces an immune response to the treatment and therefore prevents the infused clotting factor from functioning normally. In this case, bleeds become very hard to control and can lead to permanent joint or muscle damage, making people with inhibitors disabled.

Treatment of inhibitors is the biggest challenge in haemophilia care today. It is possible to get rid of inhibitors using a technique called immune tolerance induction (ITT). However, this type of treatment requires specialised medical expertise, is expensive and takes a long time. Drugs called bypassing agents can be used to work around inhibitors and help blood clot.

In haemophilia, inhibitors occur more often in individuals with the severe form than those with moderate or mild haemophilia. It is estimated that approximately 30% of patients with haemophilia A and 1.5% to 3% of patients with haemophilia B develop inhibitors to factor VIII and factor IX concentrates, respectively. For rare bleeding disorders, figures are unclear due to the limited patient population and the lack of treatment.

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 in case of inhibitor development or other allergic reactions. 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.

Some studies have shown that people who receive regular treatments with factor concentrates to prevent bleeds (prophylaxis or prophylactic treatment) have a lower chance of developing inhibitors in their lifetimes. Little is known about whether the type of factor concentrates (recombinant or plasma-derived) that is used plays a role, but there are ongoing studies to shed light on this matter.

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Treatment options for people with inhibitors:

Immune tolerance induction therapy

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 titer.

Bypassing agents

Bypassing agents, such as activated prothrombin complex concentrates (APCC) and recombinant factor VIIa (rFVIIa), are used to treat acute bleeding in people with high titer inhibitors. However, these treatment products are expensive and not always available in every country.

Tranexamic acid

Tranexamic acid is an antifibrinolytic drug that can be given as an additional therapy in pill form or by injection to help stop blood clots from breaking down. It is particularly useful for bleeding that involves mucous membranes such as those in the nose or mouth. However, it should not be used in combination with APCCs.

Plasmapheresis

Plasmapheresis is a procedure that removes inhibitors from the person’s bloodstream. It is usually done when the inhibitor titer 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).

High-dose factor concentrates

Administering factor concentrates at higher doses and/or more frequent intervals is the preferred treatment for acute bleeding in low responders. The person’s factor level should be measured right after each infusion to make sure that target levels are reached. Continuous infusion may be useful. High-dose factor concentrate is also the preferred treatment option for acute bleeding in previous high responders with current low titer inhibitors — however, it is vital to take into account that the anamnestic response will get stronger within five to seven days, at which time treatment should be switched to bypassing agents.

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Resources:

You will find more information on inhibitors and their treatment through the following websites and documents:

Collins PW et al. (2013). Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia

World Federation of Hemophilia

The EHC organised in June 2014 a Round Table looking at the role of von Willebrand Factor in inhibitor formation in haemophilia. You can find all the documents from this event here.

The EHC will be organising in March 2015 a Round Table on: ‘Factor concentrate-related inhibitor risk in haemophilia A.’ Find out more about this event here.

Adapted from the World Federation of Hemophilia website

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ein_logo

The European Inhibitor Network is a project of the European Haemophilia Consortium (EHC), which seeks to address the variety of needs of people who have haemophilia with inhibitors.
The number of people with inhibitors in a given country is often very small. Therefore it can be difficult to meet the specific needs of this sub-group of the haemophilia community and address the personal and systemic challenges they face, such as lack of information, insufficient treatment, mobility constraints, social and financial barriers, psychosocial impact, etc.

This situation can be changed by acting on a European level – just as the European Inhibitor Network seeks to do! The programme aims to understand the needs of people with inhibitors and look at ways to meet those needs; build a community of people with inhibitors and their families and caregivers, allow mutual support, education and empowerment through online and face-to-face exchanges. It also seeks to provide them with education and advocacy training to engage with decision-makers. Finally, it is the objective of the EHC to work closely with medical experts towards a framework for treatment and care that could possibly bridge the gaps of inhibitor treatment in Europe.

Programme elements
The European Inhibitor Network programme consists of a variety of activities designed to achieve the above-mentioned goals. To develop a programme that fits the needs of people with inhibitors, their families and caretakers, concrete programme elements are being developed in close cooperation with the EHC’s National Member Organisations (NMOs) and based on a needs assessment carried out through specific surveys. Those surveys have been completed by various stakeholders involved in the optimal management of inhibitors – patients, healthcare professionals and representatives of the NMOs.

Meaningful engagement with healthcare professionals
Developments in haemophilia treatment over the years, such as safe clotting factor concentrates, and validation and promotion of prophylaxis as the standard of care, have significantly improved the situation of persons with haemophilia. However this cannot be said about people with haemophilia who develop inhibitors. Today inhibitors are the most serious complication in haemophilia, inhibitor management is complex and expensive, and treatment is still inaccessible for many.
Within the framework of the European Inhibitor Network, the EHC seeks to engage in a meaningful way with healthcare professionals and to partner with the relevant organisations, such as the European Association for Haemophilia and Allied Disorders (EAHAD), in order to work on quality and standards of inhibitor management in Europe.
Even without a needs assessment it is clear that such European standards do not currently exist and that people with haemophilia who have inhibitors receive a wide range of treatment and care depending on their geography. Agreeing on European principles for inhibitor management could be a step to help people with inhibitors receive optimum treatment and care in Europe.
Online community
Although the needs assessment shows that there are existing formal and informal structures to socially connect people with inhibitors within European countries, no such exchange platforms exist on the European level. However, the needs assessment shows that this kind of platform would be needed.
The EHC is currently working on development of an online community platform for people with inhibitors and their caregivers. This platform will contain sections for people with inhibitors, caregivers and NMOs, and will provide a variety of information in different formats, as well as a discussion forum.
Advocacy tools
Although people with inhibitors are included generally in overarching haemophilia advocacy, very few specialised materials and data exist to represent their specific needs with payers, policymakers and other authorities. In the framework of the European Inhibitor Network, the EHC is looking to collect data and develop such materials.
Inhibitor Summit
The first EHC Inhibitor Summit will take place from 1-4 December 2016 at Barretstown in Ireland – a facility founded by the american actor Paul Newman as a place designed for children living with a serious illness and their families.
The objective of this event is to offer a special time and space for people with haemophilia who have inhibitors, as well as their family members and caregivers, to build a community, educate and empower themselves and improve the quality of their lives.
The programme of the Inhibitor Summit will be built in a way that all the age groups present will benefit greatly from the informative and practical elements offered in the programme. However, the most important part will be dedicated to peer-to-peer sessions and exchange between the participants. This will help to build lasting friendships and find people in similar situation to talk to!

Inhibitor Working Group
The European Inhibitor Network is coordinated by the Inhibitor Working Group (IWG), a group of volunteers, consisting of patients, healthcare professionals and patient organisation representatives. The IWG is in charge of planning and implementing the programme of the EIN. However, to make it more complete and fill it with content that will be useful and interesting for people with inhibitors and their caregivers across Europe, it is essential to collaborate closely with the EHC NMOs, enabling better exchange of information and experiences.

Inhibitor Ambassadors
To facilitate this process, the EHC is looking for NMO Inhibitor Ambassadors. The role of the NMO Inhibitor Ambassadors will be to support the work of the IWG in the following ways:
• Report to the NMO about the work of the IWG;
• Promote the EIN activities within the NMO;
• Share information with the IWG about relevant initiatives/publications on the national/ regional level.

It will be essential that the persons nominated are committed to improving the situation for people with inhibitors and are prepared to actively engage in the realisation of the EIN programme on the local level. In addition, it could be helpful to involve people with inhibitors living in different regions of the country to be as inclusive as possible!

Contacts
If you want to get involved, please contact your NMO or EHC Inhibitor Programme manager, Ms Kristine Jansone at kristine.jansone@ehc.eu

Sponsor
The European Inhibitor Network is made possible thanks to an educational grant from Baxalta (now part of Shire).

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