Search

Because of successful thalassaemia prevention programmes in resource-rich countries and it's huge population China now has the greatest number of new cases of thalassaemia globally as well as more people with thalassaemia than any other country. 30 million Chinese have thalassaemia-associated mutations and about 300,000 have thalassaemia major or intermedia requiring medical intervention. Over the past 2 decades there has been tremendous economic growth in China including per capita spending on health care. There is now nation-wide availability and partial or full insurance for prenatal genetic testing, RBC-transfusions, iron-chelating drugs and haematopoietic cell transplants. Prenatal screening and educational programmes have reduced the incidence of new cases. However, substantial challenges remain. For example, regional differences in access to medical care and unequal economic development require innovations to reduce the medical, financial and psychological burdens of Chinese with thalassaemia and their families. In this review we discuss success in preventing and treating thalassaemia in China highlighting remaining challenges. Our discussion has important implications for resource-poor geospaces challenged with preventing and treating thalassaemia., Competing Interests: Declaration of Competing Interest RPG is a consultant to NexImmune Inc. and Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: To investigate the prevalence rate of hypothyroidism in children with β-thalassemia major (β-TM) and its risk factors., Methods: A total of 86 children with β-TM treated and followed up in the Department of Pediatrics of the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai Municipal Maternal and Child Health Care Hospital from August 2018 to August 2020 were enrolled. The clinical data of the children were analyzed to investigate the prevalence rate of hypothyroidism in children with β-thalassemia major (β-TM) and its risk factors., Results: The prevalence rate of hypothyroidism in children with β-TM in Zhuhai area was 17.4%. The level of serum ferritin(SF) (4948.27±1225.33 μg/L) in hypothyroidism children was significantly increased(t=10.273，P<0.05). The prevalence rate of hypothyroidism was significantly higher in β-TM children(age ≥10 years old, SF ≥2 500 μg/L and irregular iron removal) (P<0.05). Logistic regression result showed that age ≥10 years old was the independent risk factor affecting the increasing of hypothyroidism rate in the children. The levels of SF(3880.60±1269.17 μg/L), TSH(4.43±1.52 mIU/L) and the prevalence rate of hypothyroidism(37.14%)(P<0.05) were higher for the children in irregular iron removal group., Conclusion: The prevalence rate of hypothyroidism in children with β-TM in Zhuhai area is high, and it is related to the age ≥10 years old, SF ≥2 500 μg/L and irregular iron removal of the children.

β-thalassemia is a monogenetic inherited hemolytic anemia, which results in a series of pathophysiological changes due to partial or complete inhibition of the synthesis of β-globin chain. The curative therapy for this disease is to reconstitute hematopoiesis, and transplantation with genetically modified autologous hematopoietic stem cells can avoid the major difficulties of traditional allogeneic hematopoietic stem cell transplantation，such as HLA matching and immune rejection. β-thalassemia gene therapy strategies mainly include gene integration and genome editing. The former relies on the development of lentiviral vectors and adds a fully functional HBB gene to the chromosome; the latter rapidly develops with the research of specific nuclease which can repair the HBB gene in situ. In this review, the latest progress of the two strategies in gene therapy of β-thalassemia is summarized.

Background: Posterior reversible encephalopathy syndrome (PRES) is an increasingly recognized serious complication of cyclosporine A (CSA) and tacrolimus (TAC) use in hematopoietic cell transplantation (HCT) recipients., Procedure: A retrospective study was carried out, including 84 cases of HCT for TM from January 2012 to January 2017. Eleven cases were diagnosed with PRES., Results: The cumulative incidence of PRES was 13.4% (95% confidence interval (CI) 9.7%-17.2%). The median onset time of the symptoms was 63 [20, 143] days after transplantation. Lumber puncture found that CSF was normal. Univariate analysis showed that patients who received methylprednisolone (MP) (OR = 10.629 95% CI, 1.360-83.071, P = 0.024), female patients (OR = 4.275, 95% CI, 1.154-15.843, P = 0.032), patients who had severe hypertension (OR = 5.162, 95% CI, 1.042 to 25.559, P = 0.029) had significantly higher risks of PRES. Multivariate analysis showed that severe hypertension (hazard ratio [HR], 12.793; 95% CI, 1.477 to 110.813; P  = 0.021), and Pesaro class 3 (HR, 3.367; 95% CI, 1.210 to 9.368; P  =  0.020) were associated with PRES., Conclusions: The severe hypertension is an independent risk factor for PRES post-HCT in children with thalassemia major. Patients of Pesaro class 3 may benefit from optimum control of blood pressure post-HCT for prophylaxis of PRES., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The objective of this study was to evaluate the feasibility of a modified conditioning regimen for the treatment of patients with β-thalassaemia major (TM), using unrelated donor peripheral blood stem cell transplantation (UD-PBSCT)., Methods: A modified conditioning regimen based on intravenous busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin was performed in 50 consecutive childhood patients with β-TM and a median age of 4.6 years (range, 2-12 years). According to Pesaro's classification, three classes of risk are identified using the criteria of degree of hepatomegaly, portal fibrosis, and quality of the chelation treatment. Patients with three adverse criteria constituted class III, none of the adverse criteria constituted class I, and one or two of the adverse criteria formed class II. Ten patients were class I, 36 class II, and four class III. All patients were transplanted with UDs containing 37 of 10/10 human leukocyte antigen (HLA)-matched pairs, 11 of 9/10 matched pairs, and two of 8/10 matched pairs. The median follow-up was 36 months (range, 9-96 months)., Results: All patients successfully achieved engraftment, two of whom developed persistent thrombocytopaenia. The incidence of acute graft-versus-host disease (aGVHD) grade III-IV and chronic graft-versus-host disease (cGVHD) were 12% and 8%, respectively. However, 8.3% of HLA-matched and 15.4% of HLA-mismatched patients developed aGVHD. The incidence of severe bacterial infections and fungal pneumonia was 12% and 20%, respectively. The 3-year overall survival, disease-free survival, graft rejection, and transplant-related mortality were 94%, 92%, 2%, and 6%, respectively., Conclusion: This modified conditioning protocol effectively improved outcomes of UD-PBSCT for patients with β-TM., (© 2018 Wiley Periodicals, Inc.)

Background: β-Thalassemia major (β-TM) has become a public health problem in mainland China. Hematopoietic stem cell transplantation (HSCT) has remained the only cure for β-TM in mainland China since 1998., Methods: This multicenter retrospective study provides a comprehensive review of the outcomes of 50 pediatric patients with β-TM who received HSCT between 1998 and 2009 at five centers in mainland China. Both related (n = 35) and unrelated donors (n = 15) with complete human leukocyte antigen matches were included. The stem cell sources included bone marrow (BM), peripheral blood stem cells, umbilical cord blood (UCB) and a combination of BM and UCB or a combination of BM and peripheral blood stem cells from a single sibling donor., Results: The probabilities of 5-year overall survival (OS) and thalassemia-free survival (TFS) after the first HSCT were 83.1 and 67.3%, respectively. Graft failure (GF) occurred in 17 patients. Univariate analyses showed that umbilical cord blood transplantation (UCBT) was one of the potential risk factors for decreased OS (P = 0.051), and that UCBT (P = 0.002) was potentially related to TFS. GF incidence was distinct between the UCBT and non-UCBT groups (P = 0.004). Four cases of UCB-BM combined transplantation led to decreased risks of mortality and recurrence. In the UCBT group, related donor transplantation produced more favorable results than unrelated donor transplantation in OS (P = 0.009) but not in TFS (P = 0.217)., Conclusions: GF was the primary cause of UCBT failure. Though UCBT from related donors was not favorable, the combined transplantation of UCB and BM could improve the prognosis of UCBT.

Southern China has one of the world's largest population of patients needing transfusions. Transfusion and chelation are not uniformly available and no magnetic resonance imaging (MRI) assessment data exists to date. A total of 153 young β-thalassemia major (β-TM) patients were assessed using a validated 1.5T scanner in Hong Kong, People's Republic of China (PRC). Their median age was 13 (range 7 to 30), and most patients were young (22.0% age <10, 73.0% age <15, 88.0% age <18). Erratic health care made estimation of total transfusion and chelation exposure impossible. Despite their early age, 24.0% had severe cardiac hemosiderosis [T2*<10 milliseconds (ms)], at ages as early as 8 years old. Median heart iron was 1.68 mg/g dry weight (range 0.19-7.66) and increased with age (p = 0.017), while liver iron was 22.2 mg/g dry weight (range 3.15 to 39.2). Serum ferritin levels were poor predictors of heart and liver, or pancreatic R* and pituitary R* values. Magnetic resonance imaging scans are needed to screen very young β-TM patients with immediate risk of premature cardiac death in developing nations and triage them to more intensive treatment. This is particularly important in countries with a large number of patients and limited resources. Our data suggests that in developing countries, there is no lower limit for thalassemia MRI scanning programs.

β-Thalassemia (β-thal) is caused by a decrease in the production of β-globin chains that is a genetic disorder worldwide. The diagnosis of β-thal major (β-TM) depends on clinical manifestations, laboratory investigations, family history and genetic analysis. Patients with β-TM require long-term blood transfusion and chelation therapy. Hematopoietic stem cell transplantation is the only strategy for curing this disease. Many patients with β-TM cannot get regular diagnosis and treatment in developing countries. With economic improvement and medical technology development, a great progress has been made in Mainland China. In this study, we describe the current status of diagnosis and treatment of β-thal in Mainland China.

Hemolysis is a common feature in patients with β-thalassemia major. As a result, autoimmune hemolytic anemia complicating β-thalassemia is easily overlooked. Here, the authors described the clinical features and management of 7 patients with β-thalassemia major and autoimmune hemolytic anemia. These patients had fever, cough, and tea-colored urine on admission. The laboratory investigations showed a significant drop in hemoglobin and increased serum bilirubin. Coombs' tests revealed that anti-immunoglobulin G (IgG) and anti-C3 was positive in 7 and 5 cases, respectively, whereas anti-Rh E alloantibody was positive in 3 cases. All the patients received corticosteroids treatments and blood transfusions. Patients with anti-Rh E alloantibodies also received immunoglobulin treatments. Six of the patients responded well to the management, but 1 patient developed recurrent autoimmune hemolytic anemia that required cyclosporin A treatment. All the patients remained well by following up for more than 6 months.

The study was purposed to explore the effect of panel reactive antibody (PRA) serum from patients with β-thalassemia on proliferation and apoptosis of the CD34(+)cells from cord blood and its mechanism. CD34(+) cells of umbilical cord blood were incubated with different sera and complement respectively. After incubation, the samples were centrifuged and the supernatants were collected for lactate dehydrogenase (LDH) detection, and the CD34(+) cells were harvested and measured for the apoptosis by flow cytometry with Annexin V/PI. The intracellular DNA synthesis were also quantified by [(3)H]TdR incorporation using liquid scintillation counter. The results showed that concentration of LDH in PRA positive groups was higher as compared with control group, and the DNA synthesis of CD34(+) cells in PRA positive groups were inhibited. There were no differences in the percentage of cell apoptosis and necrosis among different groups. It is concluded that thalassemic serum PRA impairs the cell membrane, inhibits the DNA synthesis, which can be increased by addition of the complement, but PRA had no significant effect on apoptosis of CD34(+) cells.

Patients with β-thalassemia major require long-term blood transfusions, resulting in hepatic iron overload. Thirty-five Chinese children with β-thalassemia major were recruited in the present studies. Hepatic iron overload was evaluated by histological grading. The relationships between hepatic iron overload and both serum biochemical markers and magnetic resonance imaging (MRI) examination were studied. The majority of the patients showed high degrees of hepatic iron overload by histological study. The degree of hepatic iron overload was correlated with serum ferritin (r = .70, P < .01), hyaluronic acid (r = .58, P = .011), and type III precollagen (r = .55, P = .035). Moreover, hepatic iron overload showed a negative correlation with liver to muscle signal intensity ratio (r = -.44, P = .012), and a positive correlation with red marrow area percentage (r = .52, P < .01). These results indicated that hepatic iron overload might be assessed by serum biochemical markers and MRI examination.

Thalassemia is the most common single-gene disorder worldwide that is considered a major public health issue. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for thalassemia major, the form of the disease reflecting homozygosity for a mutant allele. In China, many patients with thalassemia major cannot financially afford life-long regular supportive care with blood transfusions and iron chelation. Although HSCT is expensive, it is a one-time treatment that is possible in some patients. Disease-free survival rates have been 52-82% after HSCT in China. Graft rejection is the main cause of failure following HSCT. Humoral immune activity may play an important role in engraftment of donor cells. This article reviews the current status of HSCT for children with thalassemia major in China.

Thalassemic children are at a high risk of graft rejection in cord blood transplantation. To investigate this possible mechanism, the authors evaluated the effect of panel reactive antibody on the growth of CD34(+) cells in vitro. On semisolid medium, CD34(+) cells derived from cord blood were incubated with thalassemic serum, and colony-forming units were counted after 10 days of culture. After incubation with serum-specific panel reactive antibody, profound decreases were found in the numbers of CFU-GM, CFU-GEMM and BFU-E compared with controls. The results indicated that serum-specific panel reactive antibody might have an apparent inhibition effect on proliferation and differentiation of cord blood CD34(+) cells.

Objective: The low rate of engraftment in children with beta-thalassemia has seriously restricted the popularity of the hematopoietic stem cell transplantation (HSCT). Panel reactive antibody (PRA) has been regarded as one of the important factors for the success of kidney transplantation. Poly-transfusion before transplantation is associated with the production of PRA. Also PRA is produced in the children with beta-thalassemia major who need poly-transfusion for life. PRA might be one of factors inducing the low rate of engraftment in children with beta-thalassemia. This study focused on observing the effect of PRA on the proliferation, differentiation, apoptosis and necrosis of cord blood CD34(+) cells in vitro by incubating the cord blood CD34(+) cells with serum containing PRA., Method: Seven samples of cord blood were collected and the HLA typing for every sample was done. Seven sera positive for PRA and seven negative sera were selected respectively. Mononuclear cells (MNCs) were obtained by Ficoll-Hypaque density gradient centrifugation. CD34(+) cells were isolated from MNCs by positive selection using an immunomagnetic separation (CD34(+) progenitor cell isolation kit and auto-MACS). The CD34(+) cells of umbilical cord blood were incubated with the serum and complement in the following groups: A (absence of serum), B (presence of PRA positive serum), C (presence of PRA positive serum and complement), D (presence of complement), and E (presence of PRA negative serum). After incubation the samples were centrifuged and the supernatant was collected for LDH detection. At the same time the CD34(+) cells were harvested for assessing the expression of Annexin V and CD95 of the CD34(+) cells by flow cytometry and also for the detection of the DNA synthesis by (3)H-TaR incorporation. Meanwhile the cells were inoculated into the methylcellulose cultural system. The proliferation and hematopoietic potential of the CD34(+) cell of cord blood by the colony formation assay were detected on the day 10., Result: The concentration of LDH in group A was (20.71 +/- 2.81) U/L, which was significantly lower than that in group B (64.28 +/- 5.12) U/L and group C (84.29 +/- 4.99) U/L. The concentration of LDH in group B was significantly lower than that in group C, while there were no significant differences in the concentration of LDH among groups A, D and E (P > 0.05). The cpm in group A was (22 629 +/- 3288), which was significantly higher than that in group B (4598 +/- 2178) and group C (1626 +/- 1192). And the cpm in group B was significantly higher than that in group C. There were no significant differences in the cpm among groups A, D and E (P > 0.05). On day 10 of culture, the total colonies, granulocyte-macrophage colony forming unit (CFU-GM), mixed colony forming unit (CFU-GEMM) and erythroid burst colony forming unit (BFU-E) in group A were significantly higher than that in group B and C. The total colonies, CFU-GM and CFU-GEMM in group B were significantly higher than those in group C. No significant differences were found in the total colonies, CFU-GM, CFU-GEMM and BFU-E among groups A, D and E (P > 0.05). There were no statistically significant differences in the CD95 and Annexin V expression among all the groups (P > 0.05)., Conclusion: PRA could impair the membrane, decrease the DNA synthesis, and inhibit the colony formation of CD34(+) cord blood cells, which could be strengthened by the presence of the complement at the given concentration in our study. PRA had no significant influence on the apoptosis of CD34(+) cells in vitro.

Objective: The presence of liver fibrosis in patients with beta-thalassemia major has been demonstrated to be an important negative prognostic factor. Identification of liver fibrosis in early stage would be of great value. Hyaluronic acid (HA), type III pre-collagen (PC III), collagen IV (C IV) and laminin (LN) as serum markers were widely used in the diagnosis of liver fibrosis in patients with chronic viral infections or alcoholic liver diseases. However, their values in thalassemic liver fibrosis have not been studied. This work was to determine the serum HA, PC III, C IV and LN levels in children with beta-thalassemia major and evaluate the diagnostic utility., Method: Serum HA, PC III, C IV and LN in 49 hospitalized children with beta-thalassemia major (aged 1 - 15 years with the media age of 6.27 years) and 41 healthy children served as controls (aged 1 - 13 years with media age of 6.40 years) were detected by radioimmunoassay (RIA). Forty-five of 49 cases were performed percutaneous liver biopsies, and the histopathological fibrosis was compared with the four serum markers. The correlation and discriminate analysis were used., Results: All the serum levels of HA, PC III, C IV and LN in beta-thalassemia were significantly higher than those in controls (P < 0.01). In 36 of 45 cases, the histopathology showed liver fibrosis including stage I and stage II by biopsies with a positive rate of 80%. The serum levels of four markers increased successively with the aggravation of liver fibrosis from stage 0 to stage II, and significant correlation was observed between the level of HA or PC III and the stage of fibrosis (HA, r = 0.379, P = 0.017; PC III, r = 0.455, P = 0.04). While there was no difference between the level of C IV or LN and fibrosis (C IV, r = 0.312, P = 0.053; LN, r = 0.310, P = 0.055). Using discriminate analysis, the discriminate function of co-detection of the four markers for the diagnosis of fibrosis was 0.002 HA + 0.003 PC III + 0.002 C IV + 0.006 LN-1.859, which had a sensitivity of 93.88%, specificity of 68.29%, predictive value of positive test and negative test of 77.97% and 90.32%, respectively. Moreover, there was a significant correlation between the serum level of HA or PC III and the liver iron concentration (HA, r = 0.318, P = 0.035; PC III, r = 0.305, P = 0.044)., Conclusion: The results suggest that, in beta-thalassemia major with chronic liver disease, HA and PC III showed more practical value in diagnosing liver fibrosis than the levels of C IV and LN. The combination of the four serum markers could improve the accuracy and reliability of the diagnosis. A validation study is necessary before introducing into the prediction function during the clinical practice.

To investigate the relationship between HLA-DQB1* alleles and major beta-thalassemia, the HLA-DQB1* loci typing was performed with polymerase chain reaction-sequence specific primer (PCR-SSP) in 42 unrelated (unconsanguineous) patients with major beta-thalassemia and 45 normal control individuals in Guangdong Province. Results showed that the frequency of HLA-DQB1*06 allele in patient group (19.0%) was higher than that in the control group (4.4%) kappa(2) = 8.961, p < 0.01). Our data suggests that HLA-DQB1*06 allele is associated with pathogenesis of the major beta-thalassemia in Guangdong area.