G. Pizzarelli

Thromboembolic Events in Beta Thalassemia Major: An Italian Multicenter Study

Thromboembolic (TE) events have been frequently reported in β-thalassemic patients in association with known risk factors such as diabetes, complex cardiopulmonary abnormalities, hypothyroidism, liver function anomalies, and postsplenectomy thrombocytosis. In a recent survey involving 9 Italian thalassemic centers, we identified 32 patients with TE episodes in a total of 735 subjects, of whom 683 had thalassemia major and 52 thalassemia intermedia, corresponding to 3.95 and 9.61%, respectively. There was a great variation in localization: the main one (16/32) was CNS, with a clinical picture of headache, seizures and hemiparesis. Other localizations were the pulmonary (3 patients), mesenteric (1 patient) and portal (2 patients) sites. There were 6 cases of deep venous thrombosis (2 in the upper limbs, 4 in the lower ones). Intracardiac thrombosis was found in 2 subjects and clinical and laboratory signs of DIC were observed in 2 others during pregnancy. Since our patients with TE events present a statistically significantly higher incidence of associated dysfunction (cardiomyopathy, diabetes, liver function anomalies, hypothyroidism) than those without TE events (50 vs. 13.8%), we suggest close monitoring of those patients who are at higher risk of developing TE events because of the presence of one or more of these predisposing factors.

Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis

Osteoporosis in Β-thalassemia major has emerged as a topic of interest since optimized transfusion regimens have increased life expectancy and quality in these patients. Although the pathogenesis of thalassemic osteopathy is multifactorial, the evidence of an increased resorption phase suggests that the use of antiresorptive drugs such as bisphosphonates can be considered a valuable therapeutic strategy to reduce bone turnover and the risk of fragility fractures. We compared the effects of long-term cyclical clodronate therapy (300 mg intravenous infusion every 3 weeks for 2 years) and of an active placebo (calcium 1 vitamin D) on bone mass and bone turnover in 30 male patients with Β-thalassemia major. We also tested the possibility of using quantitative ultrasound (QUS) for assessing bone involvement in thalassemic osteopenia and in monitoring the response to antiresorptive therapy. Broadband ultrasound attenuation (BUA) was significantly reduced in patients with Β-thalassemia major as compared to healthy controls. In calcium and vitamin D-treated patients, a significant decline in spine, femoral, and total body areal bone density was observed. In the patients given intravenous clodronate we measured a substantial stability of bone mass, which was not significantly changed at the end of the study. The urinary excretion of deoxypyridinoline (a marker of bone resorption) showed a progressive significant decline throughout the study period in clodronate-treated patients. No significant change was observed in BUA values in both groups of patients. These results indicate that intermittent intravenous clodronate administration was not able to increase areal bone density in our thalassemic patients. Moreover, this is the first study to have assessed the usefulness of broadband ultrasound measurements in Β-thalassemia major.

Immune status and the immune response to hepatitis B virus vaccine in thalassemic patients after allogeneic bone marrow transplantation

We evaluated the immune status with respect to HBV and the immune response to readministration of HBV vaccine in a series of 20 patients with homozygous β-thalassemia, aged 6–23 years (mean age: 13.0 ± 4.2) who had undergone allogeneic bone marrow transplantation (BMT). Thirteen of them (group A), had received three doses of plasma-derived HBV vaccine from 7 to 5 years before BMT and 4–5 weeks after the last dose of vaccine, they had had high serum levels of HBV antibodies (anti-HBs). The remaining seven patients (group B) had had clinical symptoms and laboratory evidence of HBV infection in childhood with markedly elevated serum of anti-HBs. Before revaccination, a significantly lower percentage of patients (P < 0.005) with seropositive levels of anti-hbs was observed in group a than in group b. after administration of the second dose of hbv vaccine the percentage of subjects with protective levels of anti-hbs rose to 100% in both groups of patients even if the geometric mean of titers of anti-hbs increased more significantly in group b patients than in group a. we conclude that the serum levels of anti-hbs afforded by hbv vaccine administered from 7 to 5 years previously are very low and probably non-protective in most β-thalassemic patients after allogeneic BMT, and that at least two doses of HBV vaccine should be readministered from 18 to 24 months after BMT to achieve adequate and long-term protection from HBV.

An alternative to continuous subcutaneous infusion of desferrioxamine in thalassaemic patients

Sixteen patients with thalassaemia major were treated with subcutaneous desferrioxamine (DF) 50 mg/kg/d, 5 consecutive days a week, for 8 weeks. Every other week the total dose was administered by 12 h infusion pump or by rapid injection of the same dose (25 × 2 mg/kg) twice a day. The two methods of DF administration produced no significant differences in urinary iron excretion. No significant changes in serum ferritin levels were observed at the end of the study. Compared with continuous infusion, rapid injection is equally efficacious, does not induce serious side‐effects, is better accepted by the patients, and can improve their compliance to the iron‐chelating therapy.

Leukocyte function and characterization of leukocyte glucose-6-phosphate dehydrogenase in Sicilian mutants.

Extract: Nine Sicilian children known to be deficient in glucose-6-phosphate dehydrogenase (G6PD) were studied to see if there were anomalies of bactericidal activity in peripheral blood phagocytes. The type of deficiency was established. The G6PD levels in the leukocyte were found to be 26% of the controls (0.094 ± 0.03, normal controls 0.360 ± 0.12). The Michaelis constant for NADP and glucose-6-phosphate (G6P) was lower than the control. Conversely, the utilization of the analogous 2-deoxyglucose-6-phosphate (2dG6P) and galactose-6-phosphate (Ga16P) was higher. The thermostability of the enzyme in the deficient subjects was lower and the pH optima (8 and 9.5) were different from the controls. An identical electrophoretic pattern was found in both normal and deficient subjects. The bactericidal activity in the deficient subjects was normal. There was no difference in the results of nitroblue tetrazolium (NBT) tests in either group.Speculation: Although leukocyte G6PD was only one-quarter of the normal level, the phagocytic activity and the NBT test were normal in all subjects studied. It is not clear how such low levels of enzyme allow normal function. Perhaps further investigation under simulated intracellular conditions could give more reliable information about the enzyme activity.

Interferon-α Therapy in Sicilian and Sardinian Polytransfused Thalassaemic Patients with Chronic Hepatitis C

AbstractObjective: Our study was designed to evaluate the effects of 2 dosage schedules of recombinant interferon (IFN)-α (IFNα-2a and IFNα-2b) in reducing serum ALT and eradicating serum hepatitis C virus (HCV) RNA in β-thalassaemic patients with chronic hepatitis C. Design: 38 Sicilian β-thalassaemic patients (22 males and 16 females) received intramuscular IFNα-2a (Roferon-A®; Roche) 5 MU/m2 3 times weekly for 6 months, followed by 3 MU/m2 3 times weekly for a further 6 months. 13 Sardinian β-thalassaemic patients (7 males and 6 females) received intramuscular IFNα-2b (Intron®; Schering-Plough) 3 MU/m2 3 times weekly for 12 months. Parallel control groups (n = 20 and n = 8, respectively) did not receive IFNα. All patients received continuous subcutaneous desferoxamine infusion. Results: 24 (63%) Sicilian patients had a positive clinical response to IFNα-2a therapy. Two different patterns of response were apparent: (i) early and progressive decrease in ALT values until stable normalisation; and (ii) slower reduction of ALT values, which fluctuated on the way to normalisation. Five (21%) patients relapsed during the 12-month follow-up period. ALT levels decreased early in 5 (38%) Sardinian patients and one patient (20%) relapsed during the 12-month follow-up period. In the control groups, ALT values spontaneously normalised in 3 (10%) untreated patients. None of the patients treated with IFNα developed anti-IFNα antibodies. Viral clearance was demonstrated in 19 (50%) of 38 patients in the Sicilian group and 4 of 13 patients (31%) in the Sardinian group. Conclusion: Treatment with intramuscular recombinant IFNα-2a 5 MU/m2 3 times weekly for 6 months, followed by 3 MU/m2 3 times weekly for 6 months, appeared to be more effective than intramuscular IFNα-2b 3 MU/m2 3 times weekly for 12 months.

Clinical and biochemical reactivation of HBV infection in a thalassemic patient after bone marrow transplantation

SummaryThe case of a young man effected by homozygous beta-thalassemia is reported who had serologic findings of a prior HBV infection and who presented with clinical and biochemical acute HBV infection probably caused by HBV reactivation after allogeneic bone marrow transplantation. The patients clinical history suggests that HBV can persist without serological findings of HBsAg and HBV-DNA in persons previously infected by HBV and that HBV reactivation can occur 2 years after allogeneic bone marrow transplantation, as a result of immunosuppressive therapy or an HCV activation.

β-Thalassemia in Sicily

The degree of imbalance in β °-Th and β +-Th as well as the frequency of the two forms in Sicilian β -thalassemic subjects have been st

Alpha Thalassaemia in Sicily: Haematological and Biosynthetic Studies

Summary. Eight Sicilian patients with Hb H disease and their families have been studied. The standard haematological tests and the α/β chain synthesis ratios showed significantly different results in the patients with Hb H disease as compared with α thalassaemia carriers, except for Hb A2 values. There was no significant difference in the mean RBC, MCV, Hb A2, Hb A1 and Hb F of α thalassaemia carriers compared with normal controls. On the contrary significant difference was found between the mean α/β chain synthesis ratio of a thalassaemia carriers and that of the normal controls; however, the extensive overlapping of α/β values between these two conditions make this parameter insufficiently discriminant. No correlation was found between MCV, MCH, RBC and α/β chain synthesis ratio in patients with α thalassaemia trait, suggesting that the ratio cannot be used to distinguish between carriers of a mild gene (‘silent’carrier) and carriers of the more severe α thalassaemia gene. A possible genetic model for α thalassaemia in Sicily is presented.

50 HEMOGLOBIN LEPORE IN SICILY: HEMATOLOGICAL AND BIOSYNTHETIC STUDIES

The results of hematological and biosynthetic studies in 15 subjects carriers of Hb Lepore and in 5 double heterozygotes for Hb Lepore and thalassemia are presented.In the carriers the hematological and biosynthetic data are compared with carriers of thal., while the five double heterozygous patients were compared with ° and + thal. major subjects. In the carriers of Hb Lepore no synthesis of chains was observed in the peripheral blood cells, on the contrary we found a peak in the bone marrow. Double heterozygous subject with circulating nucleated red cells showed in the peripheral blood chains synthesis.