The European Principles of Inhibitor Management
By Paul Giangrande, EHC Medical Advisory Board Chair and lead author of the European Principles of Inhibitor Management

The European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD) have collaborated on the development of a document, which sets out the basic principle of care for the management of people with haemophilia and inhibitory antibodies. They were presented for the first time at the recent joint EHC and EAHAD World Haemophilia Day event in Brussels on April 19th and have since been published in an academic journal1. These guidelines follow on from a number of previous initiatives, most notably the original European ‘Principles of Care’ document, which was published a decade ago, as well as the recommendations which have emerged from the various meetings hosted by the Council of Europe’s European Directorate for the Quality of Medicines and Healthcare (EDQM), in which the EHC played a key role.
The process involved a thorough review and evaluation of published literature and clinical guidelines on the topic, as well as a series of face-to-face meetings in Brussels. In all, it took around 18 months to formulate the final text. A total of 21 people from 13 countries contributed to the development of these guidelines. This international working group was also very much a multidisciplinary one and included people with inhibitors.
Recent surveys conducted by the EHC have highlighted that, despite recent major advances in the understanding and treatment of inhibitor development in patients with haemophilia, management of many of these patients remains suboptimal and highly heterogenous across Europe. It is hoped that publication of this document will set a benchmark to improve standards of care.

The ten principles are set out in headline form in the table below:

Table 1: Ten European Principles of Inhibitor Management
1. Awareness of the incidence of inhibitors and risk factors throughout life
2. Early recognition and accurate diagnosis
3. Optimal organisation of care and communication between all stakeholders
4. Haemostatic treatment with bypassing agents in inhibitor patients
5. Inhibitor eradication by immune tolerance induction (ITI) therapy
6. Access to, and optimal preparation for, surgery and other invasive procedures
7. Provision of specialist nursing care
8. Provision of tailored physiotherapy care and monitoring
9. Access to psychosocial support
10. Involvement in research and innovation

The following is a brief summary of individual points. Please consult the published manuscript for full details.

1. Awareness of the incidence of inhibitors and risk factors across the life-span
The incidence of inhibitor development is approximately 30% amongst patients with severe haemophilia. Genotype constitutes the principal risk factor, whilst environmental risk factors are less clearly understood. The first 50 exposure days (EDs) constitute the highest risk period for the development of inhibitors in severe haemophilia. Discussions on treatment options should take place with the parents of previously untreated patients (PUPs) before starting treatment.

2. Early recognition and accurate diagnosis
Early recognition and accurate diagnosis are essential for successful management. All PUPs should be closely monitored and regularly screened for inhibitors. Screening should also be performed prior to surgery or other invasive procedures and whenever the clinical response to conventional treatment is deemed inadequate.

3. Organisation of care and communication between all stakeholders
The coordination and organisation of multidisciplinary inhibitor management, and regular communication between the multidisciplinary care providers, are the key elements of effective management. Once diagnosed, every patient who has developed inhibitors should be followed up in one of the certified European Haemophilia Comprehensive Care Centres (EHCCCs) or European Haemophilia Treatment Centres (EHTCs).

4. Haemostatic treatment with bypassing agents
There are currently only two licensed by-passing agents: both products have been demonstrated to be similarly effective in treating patients with inhibitors. It is advisable for haemophilia treatment centres to have both products readily available, as some patients seem to respond to one agent better than the other.

5. Inhibitor eradication by immune tolerance induction (ITI) therapy
Currently, the only way to eradicate an inhibitor is through prolonged exposure to Factor VIII (or Factor IX) by frequent administration of these concentrates at high dosage. Breakthrough bleeds should be treated with bypassing agents, given on demand or prophylactically in selected patients. ITI is a demanding and resource-heavy treatment, and the patient (or parents) should receive detailed information before initiation of ITI. A plan should be in place for the management of those patients who fail to respond to ITI.

6. Access to, and optimal preparation for, surgery and other invasive procedures
Patients with inhibitors are often denied surgery or any invasive procedures, as these entail high cost and are also perceived to carry a significant risk of bleeding. However, there is now an extensive body of evidence proving that surgery may be carried out safely and effectively under cover of by-passing agents. This may also prove cost-saving in the long term. Regular dental reviews are strongly recommended along with effective methods of preventative home care.

7. Provision of specialist nursing care
Provision of high quality specialist nursing care for haemophilia patients with inhibitors is of the utmost importance. A key nursing responsibility is the administration of replacement factor and bypassing agents through both peripheral venous access and central venous access device. The development of an inhibitor affects the whole family, especially when diagnosed in a young child. The nurse offers support throughout the inhibitor management process.

8. Provision of tailored physiotherapy care and monitoring
Provision of physiotherapy is focused on maintaining optimal musculoskeletal function. Assessment and management of bleeds requires a careful balance of rest and activity; often with slower progress than with inhibitor-free patients. If optimal functional recovery after every bleed is not achieved, both in joint and muscle bleeds, the long-term consequences will be significant.

9. Access to psychosocial support
Inhibitors are a major burden for the patient, as well as for the family and caregivers, and the immediate social network. Members of the multidisciplinary care team should be proactive and refer patients to a social worker and/or psychologist when any needs are identified. Local and national patient organisations are also a very good source of advice and support.

10. Involvement in research and innovation
Improvements in clinical outcomes for inhibitor patients will increasingly depend on future research and innovation. It is highly desirable that patients with inhibitors are registered with treatment centres where innovations and contribution to research are accessible. National patient registers can help to identify eligible patients for relevant clinical trials.

This document has been published in the Orphanet Journal of Rare Diseases. This journal has an established track record of publications in the field of haemophilia and has a very similar ‘impact factor’ (an independent scoring system used to measure scientific merit of a journal) to the journal Haemophilia. A major advantage of publication in this journal is that it offers unrestricted access to anyone via the internet, by contrast with most other journals, which limit access only to subscribers or people with institutional access. EAHAD and EHC intend to develop more joint publications in other areas relating to haemophilia and other bleeding disorders.

You can access the published article here.

1. Giangrande, P.L.F., Hermans, C., O’Mahony, B., de Kleijn, P., Bedford, M., Batorova, A., Blatný, J. and Jansone, K., 2018. European principles of inhibitor management in patients with haemophilia. Orphanet Journal of Rare Diseases, 13(1), p.66.

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