Hyperhaemolytic transfusion reaction in two ß-thalassaemia major patients: The role of eculizumab.

WHAT IS KNOWN AND OBJECTIVE: Hyperhaemolytic transfusion reactions are rare life-threatening events predominantly affecting patients with haemoglobinopathies. We report two cases in ß-thalassaemia major patients on chronic transfusion therapy and highlight the role of eculizumab in its management. CASE SUMMARY: Patient 1 presented with intravascular haemolysis on day 7 (D7) post-transfusion and responded to treatment with corticosteroids and intravenous immunoglobulin. However, patient 2 presented with severe symptomatic anaemia (D4 post-transfusion) unresponsive to the aforementioned measures. Eculizumab administration led to resolution of the hyperhaemolysis. WHAT IS NEW AND CONCLUSION: We report the successful management of hyperhaemolysis with eculizumab in a ß-thalassemia major patient.

Combined chelation therapy with deferoxamine and deferiprone in ß-thalassemia major: compliance and opinions of young thalassemic patients.

Treatment of ß-thalassemia major (ß-TM) includes regular blood transfusions and iron chelation with subcutaneous injection of deferoxamine (DFO). During the last decade, a new chelation agent, deferiprone (L1), was introduced. The purpose of our study was to determine the level of awareness/education regarding chelation therapy, the degree of compliance to this therapy and their views of L1 in patients with ß-TM. A relevant questionnaire was administered to 36 patients (12-26 years old) who were on combination chelation therapy with both DFO and L1. The majority of patients was well aware/educated about chelation therapy (76.6%), was compliant with this therapy (74.4%) and had a positive view towards oral chelation (86.0%). In conclusion, most patients with ß-TM who were on combination chelation therapy with DFO and L1 were satisfied with this treatment and this results in high compliance rates.

Poor correlations between measurements of bone quality by quantitative ultrasound sonography and dual energy X-ray absorptiometry in patients with beta-thalassaemia major.

OBJECTIVES: Osteopenia/osteoporosis is a major component of morbidity even in young patients with beta-thalassaemia major. Dual energy X-ray absorptiometry (DXA) is the reference method for determining bone mineral density (BMD). Quantitative ultrasound sonography (QUS) for bone measurement is a relatively new, inexpensive and radiation-free method that could serve as an alternative to DXA. Our aim was to assess bone status in thalassaemic patients both with QUS and DXA and, consequently, to investigate the degree of correlation between the two methods. METHODS: Thirty-three patients (15 male and 18 female) with beta-thalassaemia major, regularly transfused and systematically iron-chelated, participated in the study. Mean age was 22.0 +/- 8.0 yr (range: 6.5-41.0 yr). All patients were evaluated with QUS at radius and tibia and had DXA scan at lumbar spine vertebrae (L2-L4), whereas 20 patients were additionally assessed with DXA at the left hip (femoral neck, trochanter region and Ward's triangle). RESULTS: Results were expressed as Z-scores compared with sex- and age-matched population. Lowest mean Z-scores measured with DXA were recorded at lumbar spine and Ward's triangle (-1.1 +/- 1.13 and -0.95 +/- 1.07, respectively). Lowest mean QUS-derived Z-scores were measured at radius, statistically significant compared with Z-scores measured at tibia (-0.6 +/- 1.1 vs. 0.4 +/- 1.1, P < 0.001). QUS measurements at radius were significantly correlated to QUS measurements at tibia (r = 0.51, P = 0.002). The latter were correlated to BMD measured at lumbar spine (r = 0.516, P = 0.002) and at trochanter region (r = 0.646, P = 0.003). All BMD measurements at hip were significantly correlated to each other. Lumbar spine BMD was correlated to BMD at femoral neck (r = 0.607, P = 0.003) and to BMD at Ward's triangle (r = 0.438, P = 0.027). Finally, no agreement was recorded between the two methods in identifying thalassaemic patients at risk for osteoporosis (kappa = 0.203, P = 0.04). CONCLUSION: Quantitative ultrasound sonography could not serve as an alternate to DXA.

MRI assessment of liver iron content in thalassamic patients with three different protocols: comparisons and correlations.

Our aim was to assess liver iron content, in thalassaemic patients, by using three different MR protocols and compare their data. Ninety-four thalassaemic patients (44 M and 50 F, mean age 25.82 +/- 8.3 yrs), were enrolled in the study. In each patient, three measurements of the liver iron content were performed, with the use of a single imager, equipped with a 1.5 Tesla magnet. Liver R2* was measured on gradient-echo sequence. Calculation of MR-HIC values was based on an algorithm using liver to muscle (L/M) ratios in five axial gradient-echo sequences. Finally, determination of liver R2 employed a 16-echo, spin-echo pulse sequence. Additionally, myocardial R2* value was determined for each patient. Results showed that all three magnetic resonance imaging (MRI) methods were highly correlated to each other and significantly correlated to serum ferritin concentrations. Liver R2 method showed an increased sensitivity in detecting liver iron contents in the upper range. No correlation occurred between each liver MRI parameter and myocardial R2* values. Finally, we managed to provide formulae for equating values obtaining with any of these three MRI methods.

Beta-thalassemia: renal complications and mechanisms: a narrative review.

OBJECTIVES: Beta-thalassemias are a group of recessively autosomal inherited disorders of hemoglobin synthesis, which, due to mutations of the beta-globin gene, lead to various degrees of defective beta-chain production, an imbalance in alpha/beta-globin chain synthesis, ineffective erythropoiesis, and anemia. Improved survival in thalassemic patients has led to the emergence of previously unrecognized complications, such as renal disease. METHODS: A comprehensive literature review through PubMed was undertaken to summarize the published evidence on the epidemiology and pathophysiology of renal disease in thalassemia. Literature sources published in English since 1990 were searched, using the terms beta-thalassemia, renal disease. RESULTS: Renal disease is considered to be the 4th cause of morbidity among patients with transfusion dependent thalassemia. Chronic anemia, hypoxia and iron overload are the main mechanisms implicated in development of renal injury, whereas several studies also suggested a contributive role of iron chelators. DISCUSSION AND CONCLUSION: Kidney disease may develop through progressive renal tubular and glomerular damage; thus, its early recognition is important in order to prevent and/or reverse deterioration. This review will provide an insight on the involved mechanisms implicated in kidney disease in thalassemic patients and will discuss the updates on diagnosis and prevention of renal complications in thalassemia.

Effect of zoledronic acid on markers of bone turnover and mineral density in osteoporotic patients with beta-thalassaemia.

Osteoporosis has emerged as an important cause of morbidity in patients with thalassemia major. Studies regarding the efficacy of bisphosphonates in thalassemia-induced osteoporosis have yielded conflicting results. We performed this prospective study to evaluate the efficacy of zoledronic acid in osteoporotic patients with thalassemia major. Patients, 29, were given 1 mg zoledronic acid intravenously every 3 months for a total of four doses. Twenty age- and sex-matched healthy blood donors served as controls. Before each infusion and 3 months after the last infusion, we determined serum levels of osteoprotegerin (OPG), N-terminal cross-linking telopeptide of type I collagen (NTX), osteocalcin (OC) and insulin-like growth factor 1 (IGF-1). Bone mineral density (BMD) of the lumbar spine was measured at baseline and after the treatment's completion. At baseline, OPG did not differ significantly between patients and controls (p=0.2), NTX were higher in patients although not significantly (p=0.139), whereas, OC levels were significantly higher and IGF-1 levels significantly lower in patients than in controls (p<0.001 and p<0.006, respectively). Zoledronic acid administration resulted in a significant decrease in NTX, OC and IGF-1 (p<0.05, p<0.001 and p<0.05, respectively) and in a significant increase in OPG and BMD (p<0.05 for both comparisons). The change in NTX, osteocalcin and IGF-1 became significant as early as 3 months after the first administration of zoledronic acid, while the change in OPG reached significance only after three infusions. Our study supports the effectiveness of bisphosphonates in the treatment of thalassemia-induced osteoporosis.

comparison of effects of different long-term iron-chelation regimens on myocardial and hepatic iron concentrations assessed with T2* magnetic resonance imaging in patients with beta-thalassemia major.

The aim of this study was to compare the effect of different long-term chelation regimens on heart and liver iron stores with the use of T2* magnetic resonance imaging (MRI) in patients with transfusion-dependent beta-thalassemia major. Sixty-four patients (28 men, 36 women; mean age, 26.49 +/- 5.8 years) were enrolled in the study. The 3 groups were based on the chelation therapy received. The first group (19 patients) received deferiprone (DFP) (75 mg/kg per day orally), the second group (23 patients) received deferoxamine (DFO) (30-50 mg/kg per day subcutaneously at least 5 times/week), and the third group (22 patients) received a combination of DFO (30-50 mg/kg per day, 2-3 days/week) and DFP (75 mg/kg per day, 7 days/week). MRI scans were acquired with an imager equipped with a 1.5 T magnet, and the data included myocardial and hepatic iron measurements obtained by means of T2*, and ventricular volumes and ejection fractions obtained with standard cardiovascular MRI techniques. The results revealed that the DFP and the combined groups had significantly less myocardial iron than the DFO group (mean myocardial T2*, 35.77 +/- 18.3 milliseconds and 38.05 +/- 15.3 milliseconds versus 23.77 +/- 13 milliseconds [P = .02, and P = .001], respectively). On the contrary, the DFP group had a significantly higher hepatic iron content than the DFO and combined groups (mean hepatic T2*, 3.29 +/- 2.5 milliseconds versus 8.16 +/- 8.4 milliseconds and 11.3 +/- 10.9 milliseconds [P = .014, and P = .003], respectively). No correlation was observed between myocardial T2* and hepatic T2* values (r = -0.043; P = .37). Myocardial T2* values were inversely correlated with age (r = -0.249; P = .024) and positively correlated with both left and right ventricular ejection fractions (r = 0.33 [P = .004], and r = 0.279 [P = .014], respectively). Finally, liver T2* was strongly and inversely correlated with serum ferritin concentration (r = -0.465; P = .001). In conclusion, combined chelation therapy seems to sum the beneficial effects of DFO and DFP with respect to hepatic and myocardial iron. Because myocardial iron is not related to measurements of serum ferritin or hepatic T2*, important decisions on clinical management relating to cardiac risk should not rely on these conventional parameters. Thus, the use of MRI for assessing myocardial iron should be adopted in the routine clinical management of patients with beta-thalassemia major.

Evolution of OGTT in patients with beta-thalassaemia major in relation to chelation therapy.

Glucose metabolism disturbances are frequently reported among patients with beta-thalassaemia major on conventional treatment consisted of regular blood transfusions and adequate chelation treatment. Aim of this study was to evaluate the evolution of oral glucose tolerance test (OGTT) in thalassaemic patients in relation to their chelation treatment. Data from two OGTTs performed with an interval of 2 years were studied retrospectively. Patients considered eligible for this study were those who maintained unchanged chelation treatment and did not receive any anti-diabetic agent during the last 2 years. Thirty-one patients (16 M and 15 F) were enrolled with a mean age of 23.73+/-4.23 years at the end of the study. Patients were divided into three groups concerning chelation treatment. First group was receiving deferoxamine (DFO) by an 8-hourly subcutaneous infusion five-six times a week, second group was chelated with deferiprone (DFP) at a daily dose of 75 mg/kg orally and the third group was receiving combined therapy with DFO (3 days/week) and DFP (daily). At the time of the first OGTT, 26 patients (84%) were found to have normal OGTT; three of them showed an impaired glucose tolerance during second test (one was chelated with DFP and two were receiving combined therapy). None of the five patients with impaired glucose metabolism during the first test became diabetic. On contrary, one patient receiving combined therapy managed to normalize his second OGTT. In contrast with the overall trend of a deteriorating glucose tolerance in the whole patient series, the group receiving combined therapy managed to increased beta-cell function index and decreased insulin resistance index, although not statistically significant when compared to other groups. Further studies are needed to support these preliminary results.

MRI for the determination of pituitary iron overload in children and young adults with beta-thalassaemia major.

Hypogonadism, resulting from iron-induced pituitary dysfunction, is the most frequently reported complication in patients with beta-thalassaemia major. The aim of this study was to evaluate pituitary Magnetic Resonance Imaging (MRI) signal intensity reduction, on T2*-weighted images, as a marker of pituitary iron overload. Thirty patients (13 females and 17 males, mean age: 16.6+/-4.1) with beta-thalassaemia major on conventional treatment and 13 healthy volunteers (7 females and 6 males, mean age: 11+/-4.51 years) were studied with T2*-weighted images of the anterior pituitary using a 1.5T unit. Four thalassaemic patients (2 females and 2 males) had clinical hypogonadism and required hormonal replacement treatment. Results revealed a statistically significant reduction of pituitary signal intensity in the thalassaemia group compared to controls (p<0.001). Moreover, hypogonadal patients had significantly decreased MRI values compared to thalassaemic patients without hypogonadism (p=0.017). Relatively decreased adeno-hypophyseal MRI signal intensity was recorded in pubertal thalassaemic patients. A significant negative correlation was observed between pituitary MRI values and age (r=-0.67, r(2)=0.443, p=0.001), whereas ferritin levels and pituitary MRI values were moderately correlated (r=-0.56, r(2)=0.32, p=0.08) in adult thalassaemic patients. In conclusion, pituitary MRI indices as measured on T2*-weighted images seem to reflect pituitary iron overload and could, therefore, be used for a preclinical detection of patients who are in greater danger of developing hypogonadism.

A case of successful management with splenectomy of intractable ascites due to congenital dyserythropoietic anemia type II-induced cirrhosis.

The congenital dyserythropoietic anemias comprise a group of rare hereditary disorders of erythropoiesis, characterized by ineffective erythropoiesis as the predominant mechanism of anemia and by characteristic morphological aberrations of the majority of erythroblasts in the bone marrow. Congenital dyserythropoietic anemia type II is the most frequent type. All types of congenital dyserythropoietic anemias distinctly share a high incidence of iron loading. Iron accumulation occurs even in untransfused patients and can result in heart failure and liver cirrhosis. We have reported about a patient who presented with liver cirrhosis and intractable ascites caused by congenital dyserythropoietic anemia type II. Her clinical course was further complicated by the development of autoimmune hemolytic anemia. Splenectomy was eventually performed which achieved complete resolution of ascites, increase of hemoglobin concentration and abrogation of transfusion requirements.

Prevalence and severity of liver disease in patients with b thalassemia major. A single-institution fifteen-year experience.

During the last years, liver disease has emerged as a major cause of mortality in patients with b thalassemia major (TM). In spite of its clinical relevance, TM-associated liver damage has been insufficiently characterized. We therefore retrospectively analyzed all TM patients of our Department who underwent liver biopsy since 1990.

Acute large bowel pseudo-obstruction due to multiple myeloma.

Involvement of the gastrointestinal (GI) tract by multiple myeloma (MM) is extremely rare. The small intestine and stomach are the most frequent sites of spread. We report 1 case of a 61-year-old woman who presented with clinical and radiographic features of an acute large bowel pseudo-obstruction. An abdominal computerized tomography (CT) showed a large tumor of the rectum. On morphological and immunohistochemical examination the tumor fulfilled the criteria of MM. The patient received combined chemotherapy and radiotherapy which led to the disappearance of the tumor. A review of the literature revealed that this is the first reported case of MM presented as acute large bowel pseudo-obstruction due to a rectal myeloma tumor.

Fok-I gene polymorphism of vitamin D receptor in patients with beta-thalassemia major and its effect on vitamin D status.

Most of the biological actions of vitamin D are mediated by an intracellular receptor (VDR) in which several single nucleotide gene polymorphisms have been identified. Vitamin D deficiency is increasingly identified among thalassemic patients and recent evidence links it with myocardial iron accumulation. The aim of this work was to assess the distribution of the Fok-I polymorphism of the VDR gene among Greek children and young adults with beta-thalassemia major and to investigate its association with 25(OH)D(3) and 1,25(OH)(2)D(3) serum levels. Sixty-nine thalassemic patients (35 females and 34 males), with a mean age of 23·05±6·07 years, participated in the study. Genotype frequencies of Fok-I were similar to those previously reported for other populations; 44·9% of the patients were homozygotes for F allele, 43·5% were heterozygotes and 11·6% were homozygotes for the f allele. Low levels of serum 25(OH)D(3) were recorded, as 41 patients (59·4%) were below the cut-off limit of 50 nmol/l that determines deficiency, whereas, levels of 1,25(OH)(2)D(3) showed wide variability ranging from deficiency (≤50 pmol/l) in 34 patients (49·3%) to excess (≥125 pmol/l) in 13 patients (18·8%). When stratifying patients according to serum 1,25(OH)(2) D(3) concentrations, a higher prevalence of the f allele was observed in the deficiency group (P = 0·03). A comparison of the serum concentrations of the two vitamin D metabolites produced a trend towards a negative correlation (r = -0·204, P = 0·09). Further studies are required to assess the genetic contribution to the regulation of vitamin D metabolites in the serum of patients with beta-thalassemia major.

Liver iron content determination by magnetic resonance imaging.

Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients with hemochromatosis or transfusion-dependent anemia, therefore, liver iron concentration (LIC) accurately reflects total body iron stores. In the past 20 years, magnetic resonance imaging (MRI) has emerged as a promising method for measuring LIC in a variety of diseases. We review the potential role of MRI in LIC determination in the most important disorders that are characterized by iron overload, that is, thalassemia major, other hemoglobinopathies, acquired anemia, and hemochromatosis. Most studies have been performed in thalassemia major and MRI is currently a widely accepted method for guiding chelation treatment in these patients. However, the lack of correlation between liver and cardiac iron stores suggests that both organs should be evaluated with MRI, since cardiac disease is the leading cause of death in this population. It is also unclear which MRI method is the most accurate since there are no large studies that have directly compared the different available techniques. The role of MRI in the era of genetic diagnosis of hemochromatosis is also debated, whereas data on the accuracy of the method in other hematological and liver diseases are rather limited. However, MRI is a fast, non-invasive and relatively accurate diagnostic tool for assessing LIC, and its use is expected to increase as the role of iron in the pathogenesis of liver disease becomes clearer.

Treatment of congenital fibrinogen deficiency: overview and recent findings.

Afibrinogenemia is a rare bleeding disorder with an estimated prevalence of 1:1,000,000. It is an autosomal recessive disease resulting from mutations in any of the 3 genes that encode the 3 polypeptide chains of fibrinogen and are located on the long arm of chromosome 4. Spontaneous bleeding, bleeding after minor trauma and excessive bleeding during interventional procedures are the principal manifestations. We review the management of afibrinogenemia. Replacement therapy is the mainstay of treatment of bleeding episodes in these patients and plasma-derived fibrinogen concentrate is the agent of choice. Cryoprecipitate and fresh frozen plasma are alternative treatments that should be used only when fibrinogen concentrate is not available. Secondary prophylactic treatment may be considered after life-threatening bleeding whereas primary prophylactic treatment is not currently recommended. We also discuss alternative treatment options and the management of surgery, pregnancy and thrombosis in these patients. The development of new tests to identify higher risk patients and of safer replacement therapy will improve the management of afibrinogenemia in the future.

Immune and neural status of thalassemic patients receiving deferiprone or combined deferiprone and deferoxamine chelation treatment.

Deferiprone (L1), has previously been reported to be associated with immunological abnormalities in iron loaded thalassemia patients. However, other factors may also have similar effects such as the level of iron overload, chronic immuno-stimulation due to transfusions, splenectomy and deferoxamine (DFO). During chelation therapy with DFO, several complications have been reported, which were due to pharmacological activity and high dose toxicity with regard to both acoustic and visual effects, as well as peripheral nerve disorders that were measured by nerve conduction velocities. The immune and neural status of 44 beta-thalassemic patients, aged 10-30 years (mean 19.4 +/- 4.9), receiving L1 as a monotherapy (n = 21), or in combination with DFO (n = 23), has been followed for 2 years by monitoring the level of immunoglobulins (IgG, IgM, IgA), the level of T and B lymphocytes (CD4/CD8), the auto antibodies: anti nuclear (ANA), anti-double-stranded (anti-ds DNA), anti reticulin (anti-R1), anti-extra nuclear (anti-ENA), anti histone (anti-AHA), anti liver-kidney-muscle (anti-LKM), anti-smooth muscle (anti-SMA), anti-thyroid (anti-ATA), anti-mitochondrial (anti-AMA) antibodies and the C-reactive protein. The percentage of patients with disorders of the immune and nervous system concerned very few cases. None of our patients with pathological findings in their immunological or neurophysiological examinations presented any signs or symptoms of involvement of the immune or nervous system. Further advantages have been identified for the oral use of L1 and its combination with DFO, including synergistic efficacy and lower dosing with limited toxicity.

Evaluation of serum tumour markers concentrations in patients with homozygous beta-thalassaemia in relation to demographical, clinical and biochemical parameters.

Increased life expectancy in patients with homozygous beta-thalassaemia consequently increases the risk for neoplastic diseases. This study was conducted to assess the levels of five common tumour markers in thalassaemic patients and to investigate possible correlations to demographical, clinical and laboratory data. Eighty-five patients (44 female and 41 male) with homozygous beta-thalassaemia (mean age = 27.92 +/- 12.5), on regular blood transfusions and adequate chelation treatment, and 60 sex and age- matched healthy controls were enrolled in the study. Blood samples for the determination of carcinoma antigen (CA) 15.3, CA 125, CA 19.9, carcinoembryonic antigen (CEA) and alpha-fetoprotein (a-FP) were collected from every subject. Results showed that 69% of the thalassaemic patients had abnormal levels of CA 15.3, whereas only sporadic cases had increased levels of CA 125 and CA 19.9. On the contrary, all controls had normal levels of CA 15.3, CA 19.9 and CA 125. CEA and a-FP were within reference ranges both in the thalassaemic and in the control group. Levels of CA 15.3 were significantly lower in patients aged less than 20 years compared to older patients. Male patients had significantly increased levels of CA 15.3 compared to female patients. Relatively recent studies show an increased expression of CA 15.3 on progenitor cells of the erythroid lineage and increased amounts of circulating progenitor cells even in well-transfused thalassaemic patients. However, it seems that there are also other factors contributing to this phenomenon. In conclusion, our results indicate that CA 15.3 seems to be an unreliable marker of occult malignancy in patients with beta-thalassaemia. However, more studies are needed to support these preliminary results.