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The Medical Directors of nine Italian Hemophilia Centers reviewed and discussed the key issues concerning the replacement therapy of hemophilia patients during a one-day consensus conference held in Rome one year ago. Particular attention was paid to the replacement therapy needed for surgery using continuous infusion (CI) versus bolus injection (BI) of standard and extended half-life Factor VIII (FVIII) concentrates in severe hemophilia A patients. Among the side effects, the risk of development of neutralizing antibodies (inhibitors) and thromboembolic complications was addressed. The specific needs of mild hemophilia A patients were described, as well as the usage of bypassing agents to treat patients with high-responding inhibitors. Young hemophilia A patients may take significant advantages from primary prophylaxis three times or twice weekly, even with standard half-life (SHL) rFVIII concentrates. Patients affected by severe hemophilia B probably have a less severe clinical phenotype than severe hemophilia A patients, and in about 30% of cases may undergo weekly prophylaxis with an rFIX SHL concentrate. The prevalence of missense mutations in 55% of severe hemophilia B patients allows the synthesis of a partially changed FIX molecule that can play some hemostatic role at the level of endothelial cells or the subendothelial matrix. The flow back of infused rFIX from the extravascular to the plasma compartment allows a very long half-life of about 30 h in some hemophilia B patients. Once weekly, prophylaxis can assure a superior quality of life in a large severe or moderate hemophilia B population. According to the Italian registry of surgery, hemophilia B patients undergo joint replacement by arthroplasty less frequently than hemophilia A patients. Finally, the relationships between FVIII/IX genotypes and the pharmacokinetics of clotting factor concentrates have been investigated.

About 5000 people in Italy suffer from hemophilia, the most common coagulation disorder. As for other chronic diseases, even in the case of hemophilia, the engagement of the patient is essential: the patients, in fact, must be empowered and helped to become strong partners of the care team and sensitized with respect to their rights and duties for the successful achievement of the goals set by their healthcare path. Hence the initiative to start a new research-intervention project in the field of hemophilia. The study had different phases of research: a first moment inspired by the principles of narrative medicine, aimed at collecting stories and narratives of patients with hemophilia related to the experience of the disease and therapy and expectations of active involvement in the relationship with the clinician. At the same time, among hematologists and patients has been surveyed the experience of therapeutical relationship and communication, to capture the aspects in which they feel effective and the areas of improvement and unmet needs. Subsequently, a workshop dedicated to patients and hematologists was organized to foster mutual awareness between these two targets and the formation of a better communication and relational skills of clinicians. The results of the project formed the basis for a policy brief document, aimed at disseminating recommendations to support better relationship and empathic communication between clinicians and patients.

This study aimed to identify the characteristics of patients with hemophilia B eligible for once-weekly treatment with Nonacog alfa. Methods: A survey was conducted in 14 Hemophilia (HCs) of Italy. These centers were given a questionnaire consisting of ten closed multiple-choice questions. The centers were asked: (a) the percentages of their hemophilia B (HB) patients undergoing replacement therapy, “On-demand”, or weekly prophylaxis, (b) the criteria guiding the monitoring of patients, the advantages according to the age of patients, and (c) the obstacles to prophylaxis. The percentage of patients receiving “On-demand” (OD) treatment or continuous prophylaxis (prophy) differed depending on patient age and the severity of the disease. Only 57% of HCs provided “On-demand” therapy to the mild HB patients, about 93% to moderate ones, of whom 43% on prophylaxis. About 78% of patients 65 years old. Many centers assigned a medium-high score to the baseline concentration of FIX level at diagnosis in all age groups. Most HCs attributed a medium-high score to type of genetic mutation in the younger age groups. As for socio-cultural barriers and quality of life, the majority of respondents gave a medium-high score in all age groups. For periodic monitoring of patients receiving continuous prophylaxis, 59% of the centers reported using clinical assessment. With regard to prophylaxis administration method, the majority of hemophiliacs were given infusions twice weekly, while as regards to the dose of FIX concentrate delivered, 50% of the centers reported administering prophylaxis once-weekly at a dose ranging from 5−100 IU/kg in 10−50% of HB patients. Thus, 93% of the centers reported using a dose of 25−50 IU/kg for twice-weekly prophylaxis in 6−100% of the patients. The majority of centers (86%) believe that, in a program of early primary prevention, once-weekly treatment with nonacog alfa may represent an alternative strategy to dose escalation. The results show that patients with mild hemophilia, with functional musculoskeletal status and difficulties with venous access, are candidates for once-weekly prophylaxis with nonacog alfa. For such patients, this regimen can improve treatment compliance and quality of life.

Background The high mutational heterogeneity of hemophilia A is a challenge for the provision of genetic services. We plan to identify the mutation in patients with hemophilia A in order to create a confidential national database of mutations for the optimization of genetic services in Italy.Design and Methods The factor VIII gene (F8) was analyzed in 1296 unrelated patients with hemophilia A using screening methods for intron 22 and 1 inversions and rare mutations (denaturing high performance liquid chromatography, conformation sensitive gel electrophoresis) and/or direct sequencing.Results F8 mutations were identified in 874 (89%), 146 (89%), and 133 (94%) families with severe, moderate, or mild hemophilia A, respectively. Mutations predicting a null allele were responsible for 80%, 15%, and less than 1% of cases of severe, moderate, or mild hemophilia A, respectively. About 40% of missense and nonsense mutations occurred at a CpG site, arginines being most frequently affected. Of the small deletions or insertions, 29% occurred at one of two stretches of adenines, codons 1191–1194 (8As) and 1439–1441 (9As). Overall, these “hotspots” accounted for 31% of the point mutations in the patients with hemophilia A. Inhibitors developed in 22% of the patients with severe hemophilia A, 8% of those with moderate disease and in 4% of patients with mild hemophilia A. Patients who had severe hemophilia A and mutations predicting a null allele developed inhibitors more frequently (22 to 67%) than patients with missense mutations (5%).Conclusions We report a wide spectrum of mutations in a large national database. The type of mutation was a strong predictor of the clinical phenotype. This database is expected to considerably improve the genetic counselling and medical care of families with hemophilia A in Italy.