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Giorgia Gollo,1 Gaia Savioli,2 Manuela Balocco,2 Cristina Venturino,3 Elio Boeri,4 Massimo Costantini,1 Gian Luca Forni21Regional Palliative Care Network, IRCCS AOU San Martino-IST, Genoa; 2Hematology, Center for Thalassemia, Galliera Hospital, Genoa, 3Psychiatric Service, Galliera Hospital, Genoa, 4Department of Hematology and Oncology, Gaslini Institute, Genoa, Italy Background: The prolonged survival of patients with thalassemia major as a result of the novel therapeutic strategies introduced in the last decade makes patient quality of life an important issue. This study investigated the changes occurring in overall quality of life in patients with thalassemia in the last decade.Methods: This was a population-based cross-sectional survey of quality of life in the entire population with thalassemia major resident in the Liguria region of Italy from 2001 to 2009. The self-administered Short Form-36 (SF-36) questionnaire was used to measure quality of life in patients with thalassemia.Results: Forty-nine and 52 eligible patients were assessed in 2001 and 2009, respectively. A total of 43 patients were assessed in both 2001 and 2009. Almost 40% of these 43 patients received deferasirox in 2009, a drug which was not available in 2001. The distribution of ferritin levels was lower in 2009 (median 730) as compared with 2001 (median 1107). Analysis of the raw differences between the two years did not show a significant difference. An improvement was observed in most SF-36 scales in 2009 as compared with 2001, particularly in the Mental Health scale (mean difference in Z score +4.0; 95% confidence interval 0.4–7.5; P = 0.030) and in the Mental Component Summary scale (mean difference in Z score +3.2; 95% confidence interval 0.2–6.2; P = 0.039).Conclusion: The challenge associated with new therapies and improvement in mental quality of life dimensions indicates that implementation of effective interventions for screening and evaluation of quality of life is now urgent.Keywords: thalassemia major, quality of life, survey, Short Form-36

Summary. We describe 18 novel mutations, unreported in the Haemophilia A mutation Databases, that have been identified in a cohort of unrelated, Italian patients affected with haemophilia A (HA). Screening of the factor VIII gene (FVIII) was performed using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing. Eight mutations were characterized as non-missense alterations, and the remaining 10 were missense mutations. Heterozygosity for the identified mutations was observed in the female relatives of patients belonging to eight families with sporadic cases. In an attempt to understand better the causative effect of the mutations and the clinical variability of the patients, missense mutation consequences were investigated for: (1) the nature of the new amino acid; (2) the location of the substituted amino acid within crystallographic and theoretical models; and (3) the degree of conservation of the native residue in factor VIII (FVIII) protein and FVIII-related protein family aligned sequences. These research tools have provided evidence that the mutations we describe involve residues that were conserved, at least in FVIII proteins, in all the species we compared.

Plasma-derived concentrates containing von Willebrand factor and factor VIII (VWF/FVIII concentrates) are the mainstay of treatment of patients with inherited von Willebrand's disease (VWD) who are unresponsive or have a contraindication to desmopressin (DDAVP) therapy. Only a few clinical studies are available on the use of these VWF/FVIII concentrates in large numbers of cases and within the same country. The aim of our study was to collect retrospective data on the efficacy and safety of Haemate P (CSL Behring, Marburg, Germany) in a large cohort of well-characterized VWD patients after the introduction of the guidelines for VWD management in Italy.A retrospective survey of data records was organized among ten Italian Hemophilia Centers in order to retrieve information on the clinical use of Haemate P. Data on 100 VWD patients (44 males and 56 females, median age 41.5, range 2-87 years) were available relating to the period from January 2002 to December 2004. All patients were diagnosed according to the criteria proposed by the Italian guidelines for VWD management.Of the 100 VWD patients enrolled, 23 had type 1 VWD, 40 had type 2 (2A=7, 2B=11, 2M=9, 2M Vicenza=13) and 37 had type 3. Seventy-one percent were severely affected, as shown by VWF:RCo levels10 IU/dL. Fifty-nine patients were treated with Haemate P because of 280 spontaneous bleeding episodes. These patients required 1,003 infusions of Haemate P with a median daily dose of 72 (27-135) VWF:RCo IU/kg. In ninety-five per cent of patients, clinical responses were rated as excellent/good. Fifty-six patients underwent major surgery (n=17), minor surgery (n=28), invasive procedures (n=9) or dental procedures (n=19), with a total consumption of 1.97x10(6) IU of VWF:RCo through 366 infusions of Haemate P. The median daily dose was 80 (range, 27-146) VWF:RCo IU/kg, with clinical responses rated as excellent/good in 97% of patients. Twelve patients (type 1=1, type 2B=1, type 2M Vicenza=1, type 3=9, with a median age of 34.5, range 11-71 years) also underwent 17 long-term secondary prophylaxis regimens to prevent recurrent bleeding at the same site (47% in the gastrointestinal tract, 35% in joints). During the 4,358 days of prophylaxis, the patients received 1,424 infusions of Haemate P, given three times (53%) or twice (47%) a week, with clinical responses rated as excellent/good in 100%. No serious adverse events, including thrombosis, were reported in the 370 evaluated treatments.Based on this retrospective study conducted in a large cohort of Italian patients (n=100) and covering a long period of observation (36 months), Haemate P was shown to be effective and safe for the clinical management of patients with VWD, whether given on demand or as prophylaxis.

A basic tenet of the Lyon hypothesis is that X inactivation occurs randomly with respect to parental origin of the X chromosome. Yet, nonrandom patterns of X inactivation are common - often ascertained in women who manifest recessive X-linked disorders despite being heterozygous for the mutation. Usually, the cause of skewing is cell selection disfavouring one of the cell lineages created by random X inactivation. We have identified a three generation kindred, with three females who have haemophilia A because of extreme skewing of X inactivation. Although they have both normal and mutant factor VIII (FVIII) alleles, only the mutant one is transcribed; and, they share an XIST allele that is never transcribed. The skewing in this case seems to result from an abnormality in the initial choice process, which prevents the chromosome bearing the mutant FVIII allele from being an inactive X.

In a multicenter case-control study we investigated the impact of prenatal/perinatal events and early FVIII exposure on the inhibitor risk in hemophiliacs. Patients: 102 children (age:13–196 months) with hemophilia A (FVIII≤2%) exclusively treated with recombinant FVIII and evaluated for inhibitors every 3 months were included. Forty-seven patients who developed inhibitors at the median age of 26 months (4–80) after a median of 16 exposure days (ED, 5–150), 37 high-responders (6–500 BU/mL) and 10 low-responders (200 ED). Results: by univariate analysis, family history of inhibitors, intron 22 inversion and prophylaxis started after the first 20 ED were significantly associated with an increased risk of inhibitor development (OR 9.5, 95%CI 1.1–79.9; OR 2.7, 95%CI 1.1–6.6; OR 3.7, 95%CI 1.1–12.1, respectively). No statistically significant differences were found for variables such as villocentesis/amniocentesis, premature/caesarian birth, breast-feeding, surgery, central venous devices and FVIII infusions associated with infections/vaccinations. By multivariate analysis, the inhibitor risk was 2.8-folds (95%CI 1.1–7.3) in children with intron 22 inversion and 4.5-folds (95%CI 1.1–17.5) in patients who started prophylaxis after the first 20 ED. By univariate and multivariate analysis, there was not a linear trend in the inhibitor development according to the age at first FVIII exposure (≤6, 7–12, 13–18, 19–24, >24 months). Conclusions: this study showed that starting prophylaxis within the first 20 ED had a favourable impact on the inhibitor risk independently from the age at first FVIII exposure.

Protein C deficiency is one of the most important cause of thrombosis during early infancy and may have different ways of presentation. We have collected 11 patients, 10 with portal vein thrombosis, 1 with thrombosis of both right and left jugular vein after a Broviac catheter insertion. As far as the time and the trigger event are concerned, we suppose that the thrombosis took place in 9 patients during the neonatal period. Seven out of the nine patients with portal vein thrombosis had umbilical catheterization during neo-natal period (4 due to hyperbilirubinemia and 3 due to prematurity), one patient received surgery in the first day of life because anorectal malformation, whereas we have no information about the last patient. The early symptoms of thrombosis started within the first year of life in 5 patients and within the forth year in 4. In 9 patients the symptoms were, in sequence: splenomegaly, esophageal varices and hypersplenism. The diagnosis of protein c deficiency has been made from 6th month to 14th year after the trigger event. Protein c biological activity values was X = 47% ±9.03 (n.v. 65-128%) and Protein c antigen was X = 51% ±14 (n.v. 68-110%). Antithrombin III (ATIII) was slightly decreased in 7 patients, protein s in 2, factor v below the normal in 3, whereas FII was in the normal range. Four of these patients received Protein c concentrate (Immuno - Vienna), together with heparin treatment during vascular surgery (spleen, renal vein, shunt). In conclusion we can say that all our patients had a more or less marked first type Protein c congenital deficiency. From the pathogenetic point of view we can speculate that the mechanical and chemical action on the vessell wall due to the catheter and the fluid, associated with the prematurity related disorders, can trigger the thrombotic mechanism.