Principles of treatment and update of recommendations for the management of haemophilia and congenital bleeding disorders in Italy.

Abstract

Patients with congenital bleeding disorders (CBD) in Italy are regularly followed by 52 Haemophilia Treatment Centres (HTCs) distributed throughout the country1. The expertise gained from these HTCs is coordinated within the framework of the Italian Association of Haemophilia Centres (AICE, Associazione Italiana Centri Emofilia). This medical organisation promotes an uniform approach to the treatment of haemophilic syndromes, developing shared therapeutic strategies, conducting collaborative clinical research activities and handling the organisational aspects of the facilities providing care of CBD patients in Italy. AICE collaborates with the National Institute of Health (Istituto Superiore di Sanita, ISS) in the management and updating of the National Registry of Congenital Coagulopathies1. It also holds a database for the census and monitoring of patients with CBD, registries collecting data on specific aspects of treatment (e.g., AICE Registry of Immune Tolerance Induction [ITI] in severe haemophilia A patients with inhibitors; RENAWI, National Registry of von Willebrand disease) and databases of gene mutations in haemophilia A and B patients. Some HTCs members of AICE participate in the European Haemophilia Safety Surveillance (EUHASS). The management of patients with CBD is essentially based on home treatment2 which allows replacement therapy to be carried out as soon as possible and is associated with a higher therapeutic efficacy and a better quality of life3. Self-treatment at home does, however, imply that the patient (and/or his caregiver) is specifically trained to take decisions on the proper timing of administration of replacement therapy, to adhere strictly to the prescribed dosage, to recognise any side effects, and to keep accurate records of each infusion made. To this purpose, the HTCs periodically organise courses and training educational activities to grant qualification for home treatment to the patients or their family members. The HTCs are also responsible for a periodic review and assessment of skills for self-management of home treatment for each individual patient. All these procedures are governed by specific regional regulations4. In the last decade there have been significant advances in the therapy of haemophilia and related inherited bleeding disorders. The technological evolution of the processes of purification and viral inactivation has allowed the marketing of new plasma-derived concentrates5, while progress with the production of factor VIII (FVIII) and factor IX (FIX) in animal cells by recombinant DNA technology has enabled the progressive elimination of human and animal proteins from various stages of the manufacturing process. Some recombinant products have, therefore, been replaced by newer generation products and other innovative molecules are currently in an advanced experimental or registration stage6. Considering these important developments, the AICE working group has updated the Italian treatment guidelines7, taking into account the recommendations by the World Federation of Haemophilia (WFH)8, by the European Association of Haemophilia and Allied Disorders (EAHAD)9, and the recent approval of an agreement of the national State-Regions Conference, which defined care pathways to meet the specific needs of CBD patients and to ensure uniform levels of care throughout the country4. The AICE working group also carried out systematic reviews of the literature aimed to assess the quality of the available evidence on issues still controversial, in particular the risk of development of inhibitor in previously untreated patients (PUPs) with severe haemophilia A10. In addition, a survey among Directors of HTCs that are members of AICE, which was attended by 77% (40/52) of them, was carried out11. An ad hoc questionnaire (19 questions), was specifically designed to determine the opinion of clinicians about the most important aspects of the treatment of haemophilia, including the choice of products for replacement therapy in patients with different clinical characteristics, indications for prophylaxis and ITI treatments and the modality of implementation of these regimens. The reviews of the literature and the results of the survey were used to define cornerstone “principles” for the management and treatment of patients with CBD, which have been shared with the Italian Federation of Haemophilia Associations (FedEmo, Federazione delle Associazioni Emofilici) and were approved by AICE members on October 8, 2013.