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PubMed1996

Increased levels of redox-active iron in follicular fluid: a possible cause of free radical-mediated infertility in beta-thalassemia major.

OBJECTIVE: Our purpose was to investigate the follicular fluid parameters associated with redox activity and the consequent production of the deleterious hydroxyl radical in beta-thalassemia major. STUDY DESIGN: The levels of ferritin, total iron, total copper, and redox-active iron were measured in follicular fluid aspirated from three follicles during three consecutive ovum pickups from a patient with beta-thalassemia major and were compared with the levels in nine follicles aspirates from nine healthy control patients. The redox activity in the follicular fluid samples was monitored by the extent of follicular fluid-mediated deoxyribonucleic acid degradation and salicylate hydroxylation. RESULTS: Total iron and ferritin concentrations were elevated in thalassemic follicular fluid samples compared with control samples (6.7 fold, and 53.3-fold, respectively), whereas the total copper concentration was similar. Thalassemic follicular fluid samples exhibited a marked increase of redox activity, indicating a higher potential of free radical production leading to deoxyribonucleic acid degradation. Likewise, free radical-induced conversion of salicylate to dihydroxybenzoic acid derivatives was enhanced in the thalassemic follicular fluid samples compared with controls (2,3-dihydroxybenzoic acid: 67.7 +/- 22 vs 20.3 +/- 12.9 ng/mg protein; 2,5-dihydroxybenzoic acid: 101.6 +/- 25.9 vs 4.42 +/- 2.7 ng/mg protein). CONCLUSIONS: The increased level of redox activity found in the follicular fluid from a patient with beta-thalassemia major focuses the attention on the small fraction of redox-active iron ions as mediators of free radical production, inducing tissue injury and possibly contributing to impairment of reproduction in these patients.

Adult↗
PubMed1979

Laboratory diagnosis of HB CC-alpha-thalassemia.

Routine laboratory investigations of hemoglobinopathies include Hb electrophoresis for abnormal hemoglobins, determination of Hb A2 (alpha 2 delta 2) for beta-thalassemia traits, staining for Hb H (beta 4) inclusions for alpha-thalassemia traits and estimation of Hb F (alpha 2 lambda 2) for the presence of hereditary persistence of fetal hemoglobin genes (HPFH). Frequently, analytical column chromatography and alpha/beta hemoglobin chain synthesis are used in the studies of more complicated hemoglobinopathies. This communication outlines the procedures used in this laboratory for the diagnosis of a case of Hb CC-alpha-thalassemia.

Adult↗
PubMed1997

Plasma lipoprotein composition, apolipoprotein(a) concentration and isoforms in beta-thalassemia.

Patients with homozygous beta-thalassemia show an abnormal lipoprotein profile. In asymptomatic heterozygotes the lipid pattern is less markedly affected but interestingly related to a diminished cardiovascular risk. The extent and significance of these findings are still a matter of debate and no data are available on lipoprotein(a) plasma levels. Seventy patients with homozygous beta-thalassemia (HT-P), 70 beta-thalassemia trait carriers (TT-C) and 70 sex and age-matched controls were investigated and their plasma lipoprotein profile and apo(a) phenotypes determined. In a subgroup of these same subjects (12 HT-P, 12 TT-C and 24 controls) and in 12 bone marrow-transplanted homozygous beta-thalassemic patients (BMT-P) plasma lipoprotein composition was assessed. HT-P disclosed significantly lower total-cholesterol, LDL-cholesterol, HDL-cholesterol, apo A-I, apo B plasma levels and higher triglyceride concentration than TT-C (-7, -11, -8, -8, -13 and +11%, respectively) or controls (-39, -50, -46, -32, -30 and + 35%, respectively). All lipoprotein subclasses were triglyceride-enriched, while LDLs were also protein-enriched and HDLs protein-depleted. TT-C disclosed a small but significant reduction in apo A-I and apo B plasma levels but only minor lipoprotein abnormalities with respect to the controls. BMT-P lipoprotein composition was intermediate between HT-P and normal subjects. Apo(a) plasma levels did not differ among the groups. A higher prevalence of 'small' apo(a) isoforms was present in HT-P. Within the same 'isoform group', apo(a) plasma levels were significantly lower in HT-P than in TT-C or controls. Since liver cirrhosis is almost always present in HT-P, it is conceivable that an altered hepatic apo(a) synthesis or catabolism due perhaps to diminished apolipoprotein glycation may be involved. In TT-C a partially improved cardiovascular risk profile was apparent (low hematocrit, low LDL-cholesterol and apo B), thus justifying the claim for a low prevalence of ischemic heart disease, but no Lp(a) plasma level modification could be detected.

Adolescent↗
PubMed1992

Differentiation of homozygous hemoglobin E from compound heterozygous hemoglobin E-beta O-thalassemia by hemoglobin E mutation analysis.

OBJECTIVES: To facilitate the differential diagnosis of hemoglobin FE in newborn infants (homozygous hemoglobin E vs hemoglobin E-beta O-thalassemia). METHODS: The beta-globin gene in DNA from infants found to have hemoglobin FE in the California newborn screening program was amplified by the polymerase chain reaction, and the product was digested with Mnl I, which fails to cut the product when the hemoglobin E mutation is present. When both amplified alleles fail to be cut, homozygous EE is diagnosed. If only one allele is cut, a beta-globin allele without the E mutation is present (non-E), which is most likely a gene with a beta O-thalassemia mutation. RESULTS: Samples from 18 infants revealed an EE genotype, and from two samples a non-E/E genotype was determined. Clinical examination of these two patients confirmed a diagnosis of hemoglobin E-beta O-thalassemia. An independent clinical diagnosis agreed with DNA analysis for all 17 of the 20 infants for whom follow-up and family studies were available. The DNA results were obtained within a week, but the clinical diagnoses often could not be resolved unequivocally for months. CONCLUSIONS: The direct analysis of patient DNA samples for the hemoglobin E mutation allowed rapid and accurate diagnosis in this sample of infants with hemoglobin FE on the newborn screen. This rapid discriminatory test should reduce cost and simplify the diagnostic approach for these patients, which currently consists of expensive and lengthy follow-up until clinical data and family studies result in a diagnosis.

Asian↗
PubMed1975

The micromeasurement of free erythrocyte protoporphyrin as a means of differentiating alpha thalassemia trait from iron deficiency anemia.

Free erythrocyte protoporphyrin levels were measured in 29 individuals with alpha thalassemia trait, 19 with proved iron deficiency anemia, and 25 normal control subjects. Individuals with alpha thalassemia trait and normal iron studies had FEP levels in the normal range despite marked degrees of microcytosis. In contrast, individuals with iron deficiency anemia had marked elevation of FEP levels with similar degrees of microcytosis. Measurement of FEP levels appears to be a useful tool in differentiating alpha thalassemia trait from iron deficiency anemia.

Anemia, Hypochromic↗
PubMed1976

Complex alpha-thalassemia-like syndrome: a cause of neonatal normoblastemia.

A previously unrecognized hypochromic anemia associated with marked normoblastemia during the newborn period is reported. One male and two female siblings and a first cousin had a hypochromic anemia and marked normoblastemia (300 to 900 normoblast index per 100 white blood cells) at birth. Globin chain synthesis studies on peripheral blood of the proband at birth indicated the presence of alpha-thalassemia trait with possible reduced gamma chain synthesis. Studies of globin chain synthesis on the father, two older affected siblings of the proband, and the proband at 1.5 years of age revealed alpha-thalassemia trait. The data suggest this complex alpha-thalassemia-like condition as a new syndrome associated with marked neonatal normoblastemia.

Adolescent↗
PubMed1978

Sickle cell syndromes. II. The sickle cell anemia-alpha-thalassemia syndrome.

Five American black patients, ages 1 to 16 years, with the sickle cell anemia-alpha-thalassemia syndrome are described. Each patient had persistent microcytosis not explained by iron deficiency, and in each family the presence of alpha-thalassemia in combination with sickle cell trait was demonstrated in one of the parents. In one patient, in whom the diagnosis of sickle cell anemia was established at birth, an elevated level of Barts (gamma4) hemoglobin was also found. In these patients levels of alkali-resistant hemoglobin and reticulocyte counts were similar to those of sickle cell anemia patients of comparable age; however, stained smears of their peripheral blood rarely showed the presence of irreversibly sickled cells. No major ameliorative effect of the alpha-thalassemia on the clinical expression of the sickle cell disease of these patients was evident.

Adolescent↗
PubMed2001

Pharmacological induction of fetal hemoglobin in sickle cell disease and beta-thalassemia.

A number of pharmacological agents are currently available for the induction of fetal hemoglobin (HbF) in patients with sickle cell disease and beta-thalassemia. Here we review the development of this new class of therapeutics and summarize the clinical trials that investigate their efficacy in patients with hemoglobin disorders. Hydroxyurea is the first of these drugs to be approved by the Food and Drug Administration for the treatment of sickle cell disease. Currently, the major focus is the development of safer agents and combinations of drugs that can increase HbF to levels high enough to prevent all complications of the disease. Progress in adapting the same strategy to the treatment of thalassemic disorders has been much slower. Although all the agents that are effective in sickle cell disease have similar HbF-inducing activity in beta-thalassemia, their use has rarely resulted in significant amelioration of the anemia. More research and more effective agents will be needed to make a significant impact on thalassemia. Nonetheless, success in this relatively young field has been very gratifying; before the end of this decade, clinically meaningful induction of HbF may become an achievable goal in most patients with hemoglobin disorders.

Anemia, Sickle Cell↗
PubMed1998

Spinal cord compression due to extramedullary hematopoiesis in beta-thalassemia intermedia.

BACKGROUND: Extramedullary hematopoiesis (EMH) occurs in many disorders, including thalassemias and other hemoglobinopathies, and commonly presents in the spleen and liver. We present a case of spinal cord compression in a patient with beta-thalassemia intermedia, and review the literature and available treatment options. PATIENT AND METHODS: A 35-year-old black female with beta-thalassemia intermedia presented with a 3-week history of back pain and lower extremity weakness. Neurologic examination was consistent with spinal cord compression, and gadolinium enhanced magnetic resonance imaging (MRI) confirmed this diagnosis. She was given intravenous steroids and radiotherapy was begun in 200 cGy fractions to a total dose of 2000 cGy. RESULTS: At the completion of radiotherapy the patient was ambulatory with mild residual weakness. MRI scans 16 months later showed smaller, but persistent masses, and she remains asymptomatic 5 years from her diagnosis. CONCLUSION: Recognition of spinal cord EMH requires prompt physical examination and MRI for accurate diagnosis. EMH can be managed with radiation, surgery, transfusions, or a combination of these therapies. Radiation in conservative doses of (750-3500 cGy) is non-invasive, avoids the surgical risks of potentially severe hemorrhage and incomplete resection, and has a high complete remission rate in the majority of patients. Relapse rates are moderate (37.5%), but retreatment provides excellent chance for second remission.

Adult↗
PubMed1997

Microchromatographic quantitation of hemoglobin A levels in phenotypes of sickle cell-beta(+) thalassemia.

The inheritance of the sickle cell gene in combination with a gene for beta(+) thalassemia results in a spectrum of sickle cell-beta(+) thalassemia syndromes with varying levels of hemoglobin A (HbA). Some severe sickle cell-beta(+) thalassemia syndromes have small amounts of HbA, which may be difficult to quantitate in the presence of fetal hemoglobin. A microcolumn chromatographic method, using 0.5 M Tris-acetic acid developers with varying pH values from 9.0 to 6.0, appears to adequately quantitate small amounts of HbA. This method is relatively simple and cheaper than high-performance liquid chromatography, a major consideration in developing countries.

Chromatography↗
PubMed1987

Thalassemia diagnosed through facial distortion.

Thalassemia is an inherited genetic disorder of hemoglobin synthesis characterized by a reduction of either alpha or beta chains of globin. Typical features of patients with thalassemia are skeletal modifications, particularly in the skull and in the malar bone. This report describes a patient who was originally found to have an oro-facial deformity and subsequently demonstrated clinical and laboratory findings consistent with those recorded for thalassemia intermedia.

Child↗
PubMed1998

Preimplantation diagnosis of thalassemias.

PURPOSE: Preimplantation genetic diagnosis (PGD) is an important option for couples at risk of having children with beta-globin mutations to avoid selective abortions of affected fetuses following prenatal diagnosis. METHODS: We performed PGD for thalassemia in 12 clinical cycles (IVS1-110, and IVS-745 mutations) using biopsy of the first and second polar bodies (PBs) extruded from oocytes during maturation and fertilization, coupled with nested polymerase chain reaction analysis and restriction digestion. RESULTS: A total of 118 oocytes was obtained, of which 78 had results for both the first and the second PBs. This resulted in the selection and transfer of 30 unaffected embryos (2.5 embryos per cycle). To avoid a possible misdiagnosis due to allele dropout (ADO), we have also introduced simultaneous detection of two highly polymorphic linked markers, a short tandem repeat immediately at the 5' end of the globin gene and HUMTH01 which is a syntenic short tandem repeat. The application of multiplex polymerase chain reaction of the beta-globin gene and linked polymorphic markers enabled detection of ADO in five first PBs, thus avoiding the transfer of potentially affected embryos resulting from their corresponding oocytes. CONCLUSIONS: Confirmation studies of the embryos resulting from the oocytes predicted to contain an affected gene confirmed the diagnosis in 98% of the cases, thus demonstrating the accuracy and reliability of PB PGD of thalassemia mutations. The application of PB analysis in six patients resulted in two ongoing pregnancies with a thalassemia-free fetus already confirmed in both of them by prenatal diagnosis.

Alleles↗
PubMed2001

Real-time quantitative PCR analysis for alpha-thalassemia-1 of Southeast Asian type deletion in Taiwan.

Since homozygosity of the alpha-thalassemia-1 of Southeast Asian (SEA) type deletion results in hydrops fetalis, a novel protocol based on the real-time quantitating polymerase chain reaction (PCR) technique has been developed to quantify the intact and aberrant alpha-globin genes in adults. The ratio of the normal/SEA-bearing alpha-globin genes was expressed in cycle threshold (C(T)) values. Theoretically, a relative ratio of one to one was anticipated in individuals carrying the SEA type deletion. Twenty-five heterozygous and 20 normal cases were analyzed retrospectively with this protocol. Data showed that the CT values for the intact alpha-globin gene allele and the allele bearing the SEA type deletion in carriers were 28.74+/-1.49 and 26.46+/-2.05, respectively. Therefore, the ratio of normal/SEA type deletion-bearing alpha-globin genes in the carriers was 1.09+/-0.043. No ambiguous results were observed from other less common genotypes associated with alpha-thalassemia, such as the Philippine type deletion. Based on the results, we concluded that this protocol could provide a rapid method to mass screen carriers with alpha-thalassemia-1 of SEA type deletion in this region.

Alleles↗
PubMed2005

Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait.

The hemoglobinopathies, disorders of hemoglobin structure and production, protect against death from malaria. In sub-Saharan Africa, two such conditions occur at particularly high frequencies: presence of the structural variant hemoglobin S and alpha(+)-thalassemia, a condition characterized by reduced production of the normal alpha-globin component of hemoglobin. Individually, each is protective against severe Plasmodium falciparum malaria, but little is known about their malaria-protective effects when inherited in combination. We investigated this question by studying a population on the coast of Kenya and found that the protection afforded by each condition inherited alone was lost when the two conditions were inherited together, to such a degree that the incidence of both uncomplicated and severe P. falciparum malaria was close to baseline in children heterozygous with respect to the mutation underlying the hemoglobin S variant and homozygous with respect to the mutation underlying alpha(+)-thalassemia. Negative epistasis could explain the failure of alpha(+)-thalassemia to reach fixation in any population in sub-Saharan Africa.

Africa South of the Sahara↗
PubMed1998

Prognostic factors in bone marrow transplantation for beta thalassemia major: experiences from Iran.

This study concerns the effects of several pre-transplant features on outcome for patients with beta thalassemia major who underwent bone marrow transplantation (BMT). Seventy patients with beta thalassemia major underwent bone marrow transplantation during the period 1991-1997 in Shariati Hospital in Tehran, Iran. The survival and rejection curves levelled off at 8 and 18 months after transplantation at 82.6% and 11.4%, respectively. Pre-transplant clinical features (age, serum ferritin, portal fibrosis, hepatomegaly and quality of chelation therapy) were examined for their effects on survival and recurrence of thalassemia in this group of patients who were less than 16 years old. Increasing age, presence of portal fibrosis and increasing serum ferritin were significantly associated with reduced probability of survival (P = 0.0047, P = 0.016 and P = 0.024, respectively). Hepatomegaly and inadequate pre-transplant chelation therapy which were documented as poor prognostic factors in previous studies, were not evaluable in this study. We also showed the benefits of transplanting more than 5.5 x 10(8)/kg cells in this group of patients with no increase in complications.

Adolescent↗
PubMed2001

Peripheral blood stem cell transplantation in children with beta-thalassemia.

Fifteen patients with beta-thalassemia received an allogeneic peripheral blood stem cell transplant. Median age was 3.5 years (1-15 years). Six were class I, four class II and five class III according to the Pesaro criteria. All of the donors were HLA-phenotypically identical (13 siblings and two parents). Nine patients were given BU + CY and six BU + CY plus ATG as conditioning. All patients received MTX (+1, +3, +6) and CsA (9-12 months) post transplant for GVHD prophylaxis. The median neutrophil and platelet engraftment times were day 12 and day 16, respectively. cGVHD was observed in three patients. Two patients died. Thirteen patients are well, and transfusion-independent 2-30 months after PSCT. No recurrences of thalassemia have been seen. Overall and event-free survival were 86.6%. In conclusion, we suggest that PSCT can be considered a safe and effective treatment for children with beta- thalassemia.

Adolescent↗
PubMed2006

Financial burden of national health insurance for treating patients with transfusion-dependent thalassemia in Taiwan.

The thalassemias are a heterogeneous group of inherited hypochromic anemias of varying severity. The mainstay of supportive treatment is regular blood transfusion accompanied by iron-chelating therapy. Hematopoietic stem cell transplantation (HSCT) provides an alternative option when curative therapy is considered. More than 400 patients in Taiwan have beta-thalassemia major or other transfusion-dependent thalassemias, and their treatment costs account for a considerable percentage of the National Health Insurance expenditure. In this report, we estimated the treatment costs of conventional therapy (regular blood transfusion accompanied by iron-chelating agents) and HSCT. The undiscounted medical cost of 20 years of follow-up (20 years from diagnosis) and the undiscounted total lifetime cost were NT$ 4 739 888 (NT$ means New Taiwan Dollars)/US$ 149 288 and NT$ 11 529 990/US$ 363 149, respectively, for patients undergoing conventional therapy, and NT$ 2 639 982/US$ 83 149 and NT$ 3 511 172/US$ 110 588, respectively, for those undergoing successful HSCT. Comparisons of treatment costs and other parameters between these two modalities can add to the information base on which policy is made by health authorities or clinicians.

Blood Transfusion↗
PubMed1999

Improvement of mouse beta-thalassemia upon erythropoietin delivery by encapsulated myoblasts.

The goal of the present study was to analyze if sustained delivery of elevated doses of recombinant erythropoietin (Epo), by genetically modified and immunoprotected allogenic cells, was able to correct the chronic anemia, characteristic of a spontaneous mouse model of beta-thalassemia (Hbb thal 1). Mouse C2C12 myoblast cells were transfected with a plasmid containing the mouse Epo cDNA and a mutated dihydrofolate reductase (DHFR) gene for gene amplification upon administration of increasing doses of methotrexate. In order to immunoprotect the transplanted cells, the stably modified cells were loaded into polyethersulfone microporus hollow fibers which were implanted subcutaneously into Hbb thal 1 mice. An increase in hematocrit starting 2 weeks after implantation was associated with elevated blood levels of Epo and an improved red blood cell phenotype. The latter indicated an improvement of cell morphology and membrane defects, in particular a reduced amount of free alpha hemoglobin chain, the hallmark of globin chain imbalance in beta-thalassemia. A reduction of reticulocyte count contrasting with the increase in hematocrit was also observed suggesting an improved erythrocyte survival. We conclude that the phenotype can be durably improved in some beta-thalassemic mice upon in vivo delivery of recombinant Epo by polymer encapsulated cells. Sustained elevated delivery of recombinant Epo holds promise for the treatment of beta-thalassemia-associated chronic anemia.

Animals↗