The Hemophilia Registry of the Italian Association of Hemophilia centres

Introduction: National Hemophilia registries were found to be powerful instruments to support health care and research. A National Registry was mantained in Italy by the Ministry of Health (ISS) until 1999. In 2003 the Italian Association of Hemophilia Centres (AICE) started a new program aimed to build up a National Registry of congenital coagulation diseases. Methods: The AICE identified an expert panel to steer the registry program. A computer software to assist patient care management was developed, and all the AICE Hemophilia Centres were prompted to adopt it. Twice a year a predefined set of anonymized data is centralized and merged into a national database. Duplicated entries are managed through a confidentiality sparing mechanism. Draft of local and national reports are submitted to a validation step by all Hemophilia Centres Directors through a web-based procedure. The Registry covers sociodemographic, clinical, laboratoristic and treatment data. A subset of data is shared with the ISS. Results: Overall, data were collected six times by 45/51 Hemophilia Centres; 34 centres updated their patients' records up to June 2006. The database contains 6183 records (347 duplicates), 380 of which relating to dead patients. Database growth and missing data clearance showed a constantly positive trend over time. The database collects records of the following alive patients: Hemophilia A: 1368 severe (mean age = 31.25, range 0.75 \u2013 83.08), 385 moderate and 810 mild; Hemophilia B: 207 severe (mean age = 28.08 range 1.83 \u2013 74.83), 128 moderate and 169 mild; vWD: 1023 type 1, 315 type 2 and 92 type 3; Factor VII deficiency 187, other rare deficiencies 531. Median age at diagnosis was 2 year for severe and 16 year for mild hemophilia patients. Inhibitor patients were 213 (107 high responder, of which 34 undergoing immunotolerance treatment and 48 low responder, of which 40 transient). Conclusions: The AICE runs a National Registry intended to become a powerful tool for policy making and epidemiological research

Screening of mutations of hemophilia A in 40 italian patiens: a novel G-to-A mutation in intron 10 of F8 gene as putative cause of mild hemophilia A in southern Italy

Hemophilia A is an X-linked bleeding disorder caused by widespread mutations in the human coagulation factor 8 gene. We have searched for mutations in factor 8 gene DNAs from 40 unrelated Italian patients with hemophilia A. All patients came from the same region (Calabria) and were followed-up at the same hemophilia center. Of the 40 patients, 20 (50%) had severe hemophilia A, 19 (47.5%) had moderate hemophilia A, and one (2.5%) had mild hemophilia A. All patients were first screened for the common intron 22 and intron 1 inversions. Inversion-egative samples were screened for point mutations by direct sequencing of all coding regions and intron-exon boundaries of the factor 8 gene. Mutations previously reported as causative of hemophilia A were identified in 14 of the 40 patients. These included five (12.5%) intron 22 inversions, one (2.5%) small deletion, one (2.5%) small insertion and seven (17.5%) point mutations. In all patients with moderate and mild hemophilia A, a nucleotide change in the c.1538 -18G > A in intron 10, not reported in the HAMSTeRS factor 8 mutation database (http:// europium.csc.mrc.ac.uk/), was found. The G-to-A change predicts the appearance of a new acceptor splice site. We have also demonstrated that all patients share a common haplotype, suggesting that the mutation probably occurred in a single ancestor. In conclusion, we suggest that the c.1 538-1EIG > A transition can be the putative mutation, which probably occurred in a common ancestor and then spread in neighbours, in patients with moderate-mild hemophilia A investigated in the present study

Diagnosis and treatment of chronic synovitis in patients with haemophilia: consensus statements from the Italian Association of Haemophilia Centres

Although synovitis is recognized as a marker of joint disease activity, its periodic assessment is not included in routine clinical surveillance of patients with haemophilia (PwH). In order to evaluate the current knowledge and to identify controversial issues, a preliminary literature search by the Musculoskeletal Committee of the Italian Association of Haemophilia Centres (AICE) has been conducted. Statements have been established and sent to the Italian AICE members to collect their level of agreement or disagreement by a Delphi process. Thirty-seven consensus recommendations have been drafted. We found a general agreement on the indication to consider the presence of synovitis as a marker of joint disease activity in PwH. Accordingly, there was agreement on the indication to search for synovitis both in patients reporting joint pain and in asymptomatic ones, recognizing ultrasound as the most practical imaging technique to perform periodic joint screening. Interestingly, after detection of synovitis, there was agreement on the indication to modify the therapeutic approach, suggesting prophylaxis in patients treated on demand and tailoring treatment in patients already under prophylaxis. Whereas the need of an early consultation with a physiotherapist is recommended for PwH affected by chronic synovitis, the exact timing for an orthopaedic surgeon consultation is currently unknown

Differences between patients', physicians' and pharmacists' preferences for treatment products in haemophilia : a discrete choice experiment

The provision of health care to patients with haemophilia through replacement of the deficient coagulation factor is the result of a complex interaction between patients, physicians and policy makers, each carrying their individual sets of preferences. Preferences of patients, physicians and pharmacists towards perceived viral safety, risk of inhibitor development, infusion frequency during prophylaxis, pharmaceutical dosage form, distribution modes and price were evaluated by conjoint analysis, using a discrete choice experiment. Overall 178 patients', 69 physicians and 58 pharmacists completed the study. Patients, physicians and pharmacists displayed preferences: (i) similar in direction and strength for risk of inhibitors and frequency of prophylaxis, (ii) similar in direction, but not in strength for perceived viral safety and price, with patients showing lower strength compared with physicians and pharmacists, and (iii) dissimilar in direction and/or strength for: (i) dosage form, which tested important only for pharmacists and (ii) distribution mode, which tested important for patients and physicians only. Our study provides evidence of the differences between different stakeholders in the preferences towards haemophilia replacement therapy, indicating that different opinions should be taken into account when planning optimal care

Mortality and causes of death in Italian persons with haemophilia, 1990-2007

Although a number of studies have analysed so far the causes of death and the life expectancy in haemophilic populations, no investigations have been conducted among Italian haemophilia centres. Thus, the aim of this study was to investigate mortality, causes of deaths, life expectancy and co-morbidities in Italian persons with haemophilia (PWH). Data pertaining to a total of 443 PWH who died between 1980 and 2007 were retrospectively collected in the 30 centres who are members of the Italian Association of Haemophilia Centres that chose to participate. The mortality rate ratio standardized to the male Italian population (SMR) was reduced during the periods 1990-1999 and 2000-2007 such that during the latter, death rate overlapped that of the general population (SMR 1990-1999: 1.98 95% CI 1.54-2.51; SMR 2000-2007: 1.08 95% CI 0.83-1.40). Similarly, life expectancy in the whole haemophilic population increased in the same period (71.2 years in 2000-2007 vs. 64.0 in 1990-1999), approaching that of the general male population. While human immunodeficiency virus infection was the main cause of death (45%), 13% of deaths were caused by hepatitis C-associated complications. The results of this retrospective study show that in Italian PWH improvements in the quality of treatment and global medical care provided by specialized haemophilia centres resulted in a significantly increased life expectancy

Therapeutic management and costs of severe haemophilia A patients with inhibitors in Italy

Haemophilia A (HA) patients with high responding inhibitors require therapies with bypassing agents to control bleedings or Immune Tolerance Induction (ITI) to attempt inhibitor eradication and restore FVIII therapy. The aim of this study was to assess the therapeutic management and product consumption of HA inhibitor patients and the relative costs in Italy. A retrospective survey was performed utilizing data from the National Registry of Congenital Coagulopathies and from a specific questionnaire on product consumption of HA inhibitor patients over the year 2011. Among HA patients, 10% had currently detectable inhibitors; 24% of patients were undergoing ITI (mostly children) and 76% utilized bypassing agents. Patients on ITI consumed 45,000,000 IU of FVIII (median consumption/patient of 1,200,000 IU year(-1)). Patients receiving bypassing agents utilized 21,000,000 IU of aPCC (median consumption/patient of 360,000 IU year(-1)), and 38,000 mg of rFVIIa (median consumption/patient of 440 mg year(-1)). The annual cost/patient on ITI and on bypassing agents therapy was analysed. Recombinant products represented the product of choice for children therapies in >90% of the cases. FVIII prophylaxis of severe HA patients without inhibitor costs about half than therapy with bypassing agents and is three times less expensive than prophylaxis with such agents. Therefore, the possibility to restore FVIII prophylaxis, having eradicated the inhibitor through ITI, can justify the high costs of ITI treatment needed in the short term. Consistent with this notion, over the last years a 50% increase in the number of patients undergoing ITI in Italy was registered