Perceived well-being and mental health in haemophilia.

The investigation of mental health among persons with haemophilia is mostly focused on negative and disease-related indicators. Literature however shows that psychosocial resources and optimal daily functioning can co-exist with chronic disease. The Dual Continua Model operationalizes positive mental health as 'flourishing', a condition comprising emotional, psychological, and social well-being dimensions. In the present study physical and mental health were comparatively assessed through positive and negative indicators in adults with haemophilia and a control group. Participants included 84 Italian persons with severe haemophilia (Mage = 43.44; SDage = 13.04) and 164 adults without history of chronic illness (Mage = 40.98; SDage = 12.26), who completed the Short Form Health Survey, the Positive and Negative Affect Schedule, and the Mental Health Continuum Short Form. MANOVA and post-hoc t-tests provided evidence of worse general health, lower negative affect and higher psychological well-being among participants with haemophilia compared with the control group. Moreover, the percentage of flourishing individuals was higher among participants with haemophilia. Results support previous evidence suggesting that a chronic disease does not prevent mental well-being attainment. The identification of assets and strengths allowing people with haemophilia to flourish can be fruitfully used to design resource-centered interventions.

Usefulness of bone microarchitectural and geometric DXA-derived parameters in haemophilic patients.

INTRODUCTION: Haemophilia is a recessive X-linked inherited bleeding disorder, whose typical symptom is spontaneous intra-articular haemorrhage leading to joint damage, which can be quantified by the Haemophilia Joint Health Score (HJHS). Arthropathy and other characteristics of haemophilic patients may reduce bone mineral density (BMD), increasing the risk for fragility fractures, which also may occur due to bone quality impairment. AIM: To evaluate bone quantity by BMD and bone quality by Trabecular Bone Score (TBS), bone strain (BS) and hip structural analysis (HSA) in a haemophilic population, and to relate these parameters to general and specific risk factors for osteoporosis and to HJHS. METHODS: Seventy haemophilic patients ≥18 years were enrolled. Densitometric derived lumbar spine and femoral BMD with TBS, BS and HSA were performed. Data regarding risk factors for osteoporosis, presence of arthroprosthesis or arthrodesis were collected, and HJHS was calculated. A Z-score ≤-2.0 defined a low bone mass. RESULTS: Overall, a reduced bone mass was present in 52 patients at the femur and in 38 at the lumbar spine. Lumbar spine BMD, TBS and BS did not correlate with HJHS. HSA bone geometric parameters correlated negatively with HJHS. BMD and HSA correlated with some risk factors for osteoporosis, namely HIV and its therapy, hepatitis C and smoking. CONCLUSIONS: Haemophilic patients showed a reduced BMD at lumbar spine and/or femur. Femoral bone density and geometry correlated with HJHS. The microarchitecture of the trabecular vertebral bone seemed to be not influenced by the haemophilic joint damage.

Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients.

The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is the most problematic and costly complication of FVIII replacement therapy that affects up to 30% of previously untreated patients with severe hemophilia A. The development of inhibitors is a multifactorial complication involving environmental and genetic factors. Among the latter, F8 gene mutations, ethnicity, family history of inhibitors, and polymorphisms affecting genes involved in the immune response have been previously investigated. To identify novel genetic elements underling the risk of inhibitor development in patients with severe hemophilia A, we applied whole-exome sequencing (WES) and data analysis in a selected group of 26 Italian patients with (n = 17) and without (n = 9) inhibitors. WES revealed several rare, damaging variants in immunoregulatory genes as novel candidate mutations. A case-control association analysis using Cochran-Armitage and Fisher's exact statistical tests identified 1364 statistically significant variants. Hierarchical clustering of these genetic variants showed 2 distinct patterns of homozygous variants with a protective or harmful role in inhibitor development. When looking solely at coding variants, a total of 28 nonsynonymous variants were identified and replicated in 53 inhibitor-positive and 174 inhibitor-negative Italian severe hemophilia A patients using a TaqMan genotyping assay. The genotyping results revealed 10 variants showing estimated odds ratios in the same direction as in the discovery phase and confirmed the association of the rs3754689 missense variant (OR 0.58; 95% CI 0.36-0.94; P = .028) in a highly conserved haplotype region surrounding the LCT locus on chromosome 2q21 with inhibitor development.

A recurrent F8 mutation (c.6046C>T) causing hemophilia A in 8% of northern Italian patients: evidence for a founder effect.

Hemophilia A is a heterogeneous hemorrhagic disorder caused by a large number of mutations. Recurrent mutations are rare, except intron 22 and intron 1 inversions. The substitution of a cytosine to a thymine at nucleotide 6046 in F8 gene was identified in a group of Italian patients affected by hemophilia A from a specific region of Northern Italy with a prevalence of 7.6%. This F8 variant was the second most frequent mutation in our cohort, after the intron 22 inversion. The identification of the same mutation in a restricted population gets to suppose the existence of a founder effect. Intragenic and extragenic polymorphic markers were tested to assess this assumption. A peculiar haplotype in linkage disequilibrium with this recurrent mutation (c.6046C>T) was identified in 71% of patients, supporting a founder effect. This distinctive haplotype was not identified in a control group (Fisher's exact test, P < 0.0001), coming from the same geographic region. These data strongly suggested the presence of a founder effect, supporting the existence of a single mutation event. Using DMLE+2.3 software and the mathematical approach described by Bengtsson and Thomson, the inferred age of this mutation is supposed to be about 2325 years (95% CI: 904-5081) ago.

Thrombin Generation Assay as a Laboratory Monitoring Tool during Bypassing Therapy in Patients with Hemophilia and Inhibitors.

Hemophilia treatment relies upon replacement of the deficient factor to restore physiological levels in plasma. The development of inhibitors is the main complication of replacement therapy, which renders replacement therapy ineffective and requires the use of alternative hemostatic drugs known as bypassing agents. The hemostatic response to bypassing agents is different from patient to patient and even in the same patient during different bleeding episodes. Up to now, no routine laboratory test has been found suitable to monitor efficacy and safety of these drugs. The unpredictable clinical response to bypassing therapy and the lack of a monitoring laboratory tool renders surgery in inhibitor patients a big challenge for the risk of both bleeding and thromboembolic complications. The thrombin generation assay (TGA) has been proposed as a monitoring tool in this patient population on the basis of the results obtained both in vitro and ex vivo. This review aims to summarize the current published evidence on the use of TGA as a laboratory monitoring tool in patients with hemophilia complicated by inhibitors.

Interferon lambda 3 rs12979860 polymorphism in patients with haemophilia and HCV infection: a predictor of spontaneous viral clearance and sustained virological response.

Chronic hepatitis C is the main cause of morbidity and mortality in adult haemophilic patients who received non-virally inactivated plasma-derived clotting factor concentrates. Overall, spontaneous viral clearance rate is 10-25% and the only approach that can halt disease progression is hepatitis C virus (HCV) eradication by means of antiviral therapy. In non-haemophilic patients a single nucleotide polymorphism located upstream the gene of interferon lambda 3 (IFNλ3) has been associated with both spontaneous viral clearance and sustained virological response after antiviral treatment. The aim of this study was to assess whether the rs12979860 polymorphism was a predictor of spontaneous viral clearance and of sustained virological response after antiviral therapy in a large cohort of haemophilic patients with HCV infection. The rs12979860 polymorphism, defined as CC genotype or T allele, was tested in a cohort of 342 haemophilic patients and evaluated as predictor of spontaneous clearance or response to antiviral therapy. By multivariate regression analysis the IFNλ3 CC genotype was an independent predictor of spontaneous viral clearance (odds ratio: 3.7, 95% confidence interval: 2.0-6.8). Sustained virological response rates were doubled in patients with the CC genotype than in those with the T allele (78% vs 44%; p<0.001), especially in patients with HCV type 1 (67% vs 32%; p<0.001) and higher sustained response rates were observed in patients with the CC genotype who did not achieve rapid virological response (61% vs 30% in T allele patients; p=0.006).

Hemophilia a and hemophilia B: different types of diseases?

Hemophilia A and B are traditionally considered clinically indistinguishable; however, differences in bleeding frequency, clinical scores, use of prophylaxis, and need for orthopedic surgery have been reported, suggesting that the bleeding tendency associated with factor IX deficiency may be less severe with consequent better outcomes in the long term.Hemophilia A and B show their own peculiar aspects, not only in terms of epidemiological and clinical features, including inhibitor incidence and associated symptoms, but also with respect to molecular defects. The type of factor VIII/IX mutation is a major determinant of the bleeding tendency as well as of the risk of inhibitor formation; thus, there is a biological plausibility behind the different clinical expression of these two forms of congenital hemophilia. The distinction of various bleeding phenotypes in hemophilia has considerable therapeutic implications; therefore, further research in this field is required to optimize treatment regimens.

Absence of cardiac siderosis despite hepatic iron overload in Italian patients with thalassemia intermedia: an MRI T2* study.

Cardiac involvement in patients with thalassemia intermedia (TI) is characterized by a high-output state and pulmonary hypertension, with systolic left ventricle function usually being preserved. Myocardial iron overload in patients with TI has not been extensively studied. We conducted a cross-sectional study of 49 Italian patients with TI. Patient charts were reviewed and data collected for transfusion and iron chelation history, status of the spleen, and comorbid illnesses or infections. Blood samples were obtained for assessment of hemoglobin, serum ferritin, and liver enzyme levels. Doppler echocardiography was done for all patients. Cardiac and hepatic iron levels were measured by magnetic resonance imaging T2*. The mean age was 40.5 +/- 8.3 years, with a male to female ratio of 29:20. A total of 34 (69.4%) patients were splenectomized, and four patients had evidence of hepatitis C infection. Around 45% of patients were transfusion naïve while the rest received infrequent (47%) or regular (8%) transfusions. A total of 31 (63.3%) patients were maintained on iron chelation therapy. None of the patients had evidence of heart failure. Mean serum ferritin and liver iron concentration were 1,060.2 ng/ml and 8.2 mg Fe per gram dry weight, respectively. None of the patients had evidence of cardiac iron overload (mean cardiac T2* = 38.7 +/- 11.0 ms). There were no statistically significant correlation between cardiac T2* values and liver iron concentration, serum ferritin, or any patient, disease, or treatment-related parameters. Patients with TI show absence of cardiac iron overload even if hepatic iron accumulation is significant.

Hypercoagulability in splenectomized thalassemic patients detected by whole-blood thromboelastometry, but not by thrombin generation in platelet-poor plasma.

BACKGROUND: The mechanisms responsible for the increased thrombotic risk associated with thalassemia are still unclear. They might be related to the effects of red blood cell or endothelial cell derangements, increased numbers of platelets as well as abnormal plasma coagulation. DESIGN AND METHODS: To evaluate the relative role played by cells and plasma we investigated 169 patients with thalassemia by means of thromboelastometry and thrombin generation tests. Thromboelastometry measures indices of the viscoelastic properties of whole blood after activation of coagulation and is characterized by the clotting time, which may be considered as a conventional coagulation time, clot formation time, defined as the time needed for the clot to reach a fixed firmness, and the maximum clot firmness, defined as the maximal amplitude of the tracing. RESULTS: All the thromboelastometry parameters determined in whole blood (including shortened clotting time and clot formation time, and increased maximum clot firmness), were consistent with hypercoagulability, especially in splenectomized patients. Conversely, thrombin generation as determined in platelet-poor plasma was not. CONCLUSIONS: These findings point to blood cells and/or platelets rather than to plasma abnormalities as the most important determinants of the thrombotic risk observed in thalassemic patients who had been splenectomized. These results might have important diagnostic and therapeutic implications.