Research progress on differential diagnosis of thalassemia trait and iron deficiency anemia by blood erythrocyte parameters / 中华预防医学杂志

Thalassemia trait is an autosomal recessive genetic disease, which is a hemolytic anemia caused by disturbance of erythrocyte hemoglobin production caused by gene mutation or deletion. Iron deficiency anemia is caused by a lack of iron in the body due to an imbalance between the demand and supply of iron. The laboratory manifestations of both are microcytic hypochromic anemia, but the treatment schemes are completely different, and it is difficult to distinguish them from the results of blood count. Erythrocyte parameters can be used to establish a formula or model to differentiate them, which can achieve the purpose of early screening, early diagnosis and early treatment,preventing the occurrence of severe anemia and providing a scientific basis for the thalassemia and iron deficiency anemia prevention. This article will review the research progress of using erythrocyte parameters to distinguish thalassemia trait with iron deficiency anemia.

Research progress on differential diagnosis of thalassemia trait and iron deficiency anemia by blood erythrocyte parameters / 中华预防医学杂志

Thalassemia trait is an autosomal recessive genetic disease, which is a hemolytic anemia caused by disturbance of erythrocyte hemoglobin production caused by gene mutation or deletion. Iron deficiency anemia is caused by a lack of iron in the body due to an imbalance between the demand and supply of iron. The laboratory manifestations of both are microcytic hypochromic anemia, but the treatment schemes are completely different, and it is difficult to distinguish them from the results of blood count. Erythrocyte parameters can be used to establish a formula or model to differentiate them, which can achieve the purpose of early screening, early diagnosis and early treatment,preventing the occurrence of severe anemia and providing a scientific basis for the thalassemia and iron deficiency anemia prevention. This article will review the research progress of using erythrocyte parameters to distinguish thalassemia trait with iron deficiency anemia.

Molecular genetic characteristics of a family which coinheritance of rare-88 C>G (HBB:c.-138 C>G) β-thalassemia mutation with α-thalassemia and review of the literature / 中华预防医学杂志

The molecular genetic characteristics of a family with rare -88 C>G (HBB: c.-138 C>G) β-thalassemia gene mutation were studied using cohort study. The cohort study was conducted from June to August 2022 by Prenatal Diagnosis Center of Sanya Women and Children's Hospital Managed by Shanghai Children's Medical Center. The phenotype and genotype were analyzed by hematological cytoanalyzer, automatic electrophoretic analysis system, and next-generation sequencing (NGS). And then, Sanger sequencing was used to verify the rare gene results. The results showed that the proband, her father, her uncle and her younger male cousin had discrete microcytosis (MCV 70.1 fl, 71.9 fl, 73.1 fl and 76.6 fl, respectively) and hypochromia (MCH 21.5 pg,22.0 pg,22.6 pg and 23.5 pg, respectively), elevated hemoglobin A2 level (5.3%, 5.4%, 5.4% and 5.5%, respectively), slightly elevated or normal fetal hemoglobin (Hb F), but no anemia. The proband was identified to have co-inherited ɑ-thalassemia (Hb Westmead gene heterozygous mutation, ɑwsɑ/ɑɑ) and β-thalassemia with a rare -88 C>G (HBB: c.-138 C>G) heterozygous mutation (β-88 C>G/βN). Her mother had the same α-thalassemia as the proband. Her father, her uncle and her younger male cousin had the same rare -88 C>G heterozygous mutations as the proband. While her grandmother and younger brother were not carrier of thalassemia. In conclusion, 4 cases of rare -88 C>G(HBB:c.-138 C>G) heterozygous mutation had been detected in a Chinese family. Carriers of this beta-thalassemia are clinically asymptomatic. This study enriches the knowledge of the thalassemia mutation spectrum in Chinese people and provides valuable information for genetic counseling, prenatal diagnosis, and prevention of thalassemia, providing a scientific basis for improving the quality of birth population and preventing birth defects.

Epidemiological Survey of Hemoglobinopathies Based on Next-Generation Sequencing Platform in Hunan Province, China / 生物医学与环境科学（英文）

OBJECTIVE@#This study was aimed at investigating the carrier rate of, and molecular variation in, α- and β-globin gene mutations in Hunan Province.@*METHODS@#We recruited 25,946 individuals attending premarital screening from 42 districts and counties in all 14 cities of Hunan Province. Hematological screening was performed, and molecular parameters were assessed.@*RESULTS@#The overall carrier rate of thalassemia was 7.1%, including 4.83% for α-thalassemia, 2.15% for β-thalassemia, and 0.12% for both α- and β-thalassemia. The highest carrier rate of thalassemia was in Yongzhou (14.57%). The most abundant genotype of α-thalassemia and β-thalassemia was -α 3.7/αα (50.23%) and β IVS-II-654/β N (28.23%), respectively. Four α-globin mutations [CD108 (ACC>AAC), CAP +29 (G>C), Hb Agrinio and Hb Cervantes] and six β-globin mutations [CAP +8 (C>T), IVS-II-848 (C>T), -56 (G>C), beta nt-77 (G>C), codon 20/21 (-TGGA) and Hb Knossos] had not previously been identified in China. Furthermore, this study provides the first report of the carrier rates of abnormal hemoglobin variants and α-globin triplication in Hunan Province, which were 0.49% and 1.99%, respectively.@*CONCLUSION@#Our study demonstrates the high complexity and diversity of thalassemia gene mutations in the Hunan population. The results should facilitate genetic counselling and the prevention of severe thalassemia in this region.

Genotype and Phenotype of α-Thalassemia Fusion Gene in Huadu District of Guangzhou, Guangdong Province of China / 中国实验血液学杂志

OBJECTIVE@#To explore the carrier rate, genotype and phenotype of α-thalassemia fusion gene in Huadu district of Guangzhou, Guangdong province of China, and provide data reference for the prevention and control of thalassemia.@*METHODS@#A total of 10 769 samples who were screened for thalassemia in Maternal and Child Health Hospital of Huadu District from July 2019 to November 2020 were analyzed retrospectively. Blood cell analysis and hemoglobin (Hb) electrophoresis were performed. Thalassemia genes were analyzed by gap-PCR and PCR-reverse dot blot hybridization (PCR-RDB).@*RESULTS@#A total of 9 cases with α-thalassemia fusion gene were detected in 10 769 samples (0.08%). There were 7 cases with fusion gene heterozygote, 1 case with compound of α-thalassemia fusion gene and Hb G-Honolulu, 1 case with compound of α-thalassemia fusion gene and Hb QS. The MCV results of 4 samples of blood cell analysis were within the reference range, the Hb A2 value of 1 case was decreased, and there were no other abnormalities found.@*CONCLUSION@#The α-thalassemia fusion gene is common in Huadu district of Guangzhou, and heterozygotes are more common, and current screening methods easily lead to misdiagnosis.

Gene Mutation Types of Thalassemia in Chongzuo Childbearing-age Population of Guangxi Zhuang Autonomous Region of China / 中国实验血液学杂志

OBJECTIVE@#To investigate the gene mutation and genotype distribution of thalassemia in the population of childbearing age in Chongzuo area of Guangxi.@*METHODS@#Six α-thalassemia and 17 β-thalassemia gene mutations common in Chinese were detected by gap-polymerase chain reaction (gap-PCR) combined with agarose gel eletrophoresis and reserve dot bolt hybridization in 29 266 cases of child-bearing age suspected of thalassemia.@*RESULTS@#A total of 19 128 (65.36%) cases were identified with thalassemia. The detection rate of α-thalassemia, β-thalassemia and α-combining β-thalassemia was 45.25% (13 242/29 266), 15.47% (4 526/29 266) and 4.65% (1 360/29 266), respectively. A total carrying rate of 8 kinds of α-thalassemia gene mutations was 26.74% (15 649/58 532), including 12.51% for --SEA, followed by 5.70% for -α3.7, and 0.24% for --Thai. Among 32 α-thalassemia genotypes, the most common five were --SEA/αα, -α3.7/αα, αCSα/αα, -α4.2/αα and αWSα/αα, accounting for 47.27%, 18.31%, 8.56%, 8.52% and 7.91%, respectively, as well as 0.97% for --Thai/αα. A total carrying rate of 13 kinds of β-thalassemia gene mutations was 10.07% (5 897/58 532), including 3.63% for CD41-42, followed by 2.55% for CD17, and 0.003% for -50 (G>A). Among 17 β-thalassemia genotypes, the most common six were CD41-42/N, CD17/N, CD71-72/N, CD26/N, 28/N and IVSI-1/N, accounting for 36.15%, 25.81%, 9.43%, 8.18%, 8.09% and 7.75%. The homozygous genotype CD26/CD26 [hemoglobin (Hb): 121 g/L] and -28/-28 (Hb: 56 g/L) were respectively detected in one case, and double heterozygous genotype were detected in 5 cases, including 3 cases of CD41-42/CD26 (Hb: 41 g/L, 51 g/L, 63 g/L, respectively), 1 case of -28/IVSI-1 (Hb: 53 g/L), and 1 case of CD71-72/CD26 (Hb: 89 g/L), in which patients with moderate or severe anemia had a history of blood transfusion. Among 104 α-combining β-thalassemia genotypes, the most common were --SEA/αα, -α3.7/αα combining CD41-42/N and --SEA/αα combining CD17/N, accounting for 12.13%, 9.63% and 9.26%, respectively. In addition, 1 case of --SEA/-α3.7 combining -28/IVSI-1 (Hb: 83 g/L) and 1 case of -α3.7/αα combining CD41-42/ CD41-42 (Hb: 110 g/L) were detected without history of blood transfusion, while 1 case of αWSα/αα combining CD41-42/CD17 (Hb: 79 g/L) and 1 case of --SEA/αα combining CD17/-28 (Hb: 46 g/L) were detected with history.@*CONCLUSIONS@#The detection rate of thalassemia genes is high and the mutations are diverse in the population of childbearing age in Chongzuo area of Guangxi. The common deletion genotype is --SEA/αα in α-thalassemia and CD41-42/N in β-thalassemia, and deletion genotype --Thai is not rare. There is a certain incidence of intermediate and severe β-thalassemia, and most patients require transfusion therapy. The results are beneficial for genetic consultation and intervention of thalassemia.

Characteristics of Silent Alpha Thalassemia Gene in Child-Bearing Adults in Guangdong / 中国实验血液学杂志

OBJECTIVE@#To investigate characteristics of silent alpha thalassemia genes in child-bearing adults in Guangdong, in order to provide data for the prevention and control of hemoglobin H disease.@*METHODS@#A total of 8 752 cases were collected from January 2016 to December 2020. Gap-PCR was used to detect the deletional of α-thalassemia mutations (-α3.7, -α4.2), while PCR reverse dot blot hybridization assay (RDB) was used to detect the non-deletional α-thalassemia mutations (Hb CS, Hb QS and Hb Westmead).@*RESULTS@#Among 8 752 subjects, 717 cases of silent α-thalassemia were detected, the detection rate was 8.19%, including 555 cases of deletional α-thalassemia (77.41%) and 162 cases of non-deletional α-thalassemia 22.59%. The mean corpuscular volume (MCV) of deletional silent α-thalassemia was (82.09±4.10) fl, and mean corpuscular hemoglobin (MCH) was (27.03±1.37) pg, which both were over the diagnostic cut-off value for thalassemia. The MCV of non-deletional silent α-thalassemia was (81.07±4.93) fl, and MCH was (26.77±2.20) pg. According to the diagnostic criteria, if using MCV<82 fl or (and) MCH<27 pg as a positive criteria for screening thalassemia in the childbearing age, the screening sensitivity was 53.14% and different in different genotype, among which ααQS/αα was 100%, -α3.7/αα, -α4.2/αα, ααCS/αα and ααWS/αα was 62.15%, 63.41%, 44.83% and 39.62%, respectively. Namely, nearly half the carriers of such mutations might have escaped detection as a result of their screening strategy.@*CONCLUSION@#When a couple is preparing for pregnancy, if one of them has been determined to be mild α-thalassemia or hemoglobin H disease, other half is necessary to carry out silent α thalassemia detection to prevent the birth of children with hemoglobin H disease even if MCV>82 fl and MCH>27 pg.

Analysis of HKαα Genotype and Hematological Characteristics in South Guangxi / 中国实验血液学杂志

OBJECTIVE@#To investigate the detection rate and hematologic phenotype of HKαα thalassemia in south Guangxi, in order to provide reference for the prevention and control of thalassemia and prenatal and postnatal care consultation in this region.@*METHODS@#Gene testing was performed on pre-marital medical examinations, pre-pregnancy eugenic health examinations, prenatal examinations and hospitalized thalassemia-positive persons in south of Guangxi, and the results were analyzed.@*RESULTS@#A total of 183 190 thalassemia patients were included in this study, the age was mainly concentrated in 26-35 years old (101 709 cases, accounting for 55.521%), and 40 HKαα mutations were detected, detection rate was 0.022%, including 5 cases in Nanning, 22 cases in Qinzhou, 2 cases in Fangchenggang, 11 cases in Beihai. A total of 29 ethnic groups were included in the survey, but HKαα gene was observed only in Han nationality (0.0380%) and Zhuang nationality (0.0068%). A total of 8 genotypes carrying HKαα mutations were detected in this study ( HKαα/--SEA, βN/ βN, HKαα/αα, β-28/ βN, HKαα/αα, β-50/ βN, HKαα/αα, βCD17/ βN, HKαα/αα, βCD27/28/β N, HKαα/αα, βCD41-42/ βN, HKαα/αα, βCD71-72/ βN, and HKαα/αα, βN/ βN). Except for most cases with HKαα/αα, βN/ βN genotypes with no significant changes in the hematological indexes, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) of other genotypes were decreased, showing microcytic hypochromic performance, mild anemia or no anemia.@*CONCLUSION@#HKαα carrier is often misdiagnosed as -α3.7 carrier, which easily leads to missed diagnosis or misdiagnosis. Therefore, it is necessary to continuously improve the diagnostic level of laboratory testing personnels and genetic counselors to avoid unnecessary interventional puncture operations and birth of children with moderate and severe thalassemia.

Causes of Abnormal Hemoglobin Electrophoresis / 中国实验血液学杂志

OBJECTIVE@#To investigate the possible causes of abnormal hemoglobin electrophoresis results.@*METHODS@#The hemoglobin electrophoresis results of 5 696 patients in the First Affiliated Hospital of Chengdu Medical College from September 2018 to July 2021 were collected, and the abnormal results and clinical significance were analyzed.@*RESULTS@#The results of 486 patients (accounting for 8.53%) were abnormal, of which 300 cases had increased HbA2, 135 cases had decreased HbA2, 44 cases had increased F alone, and 7 cases had abnormal hemoglobin bands. Among the 486 patients, 246 patients were thalassemia gene positive (the positive rate was 50.62%), including 29 cases of α thalassemia, 208 cases of β thalassemia and 9 cases of αβ thalassemia. Among the patients with elevated HbA2, 68.67% were detected β thalassemia, 3.00% αβ thalassemia, 9.33% were suspected to be caused by macrocytosis, 6.33% by thyroid dysfunction, and 12.67% by uncertainty of the method. Among the patients with reduced HbA2, 21.48% were detected α thalassemia, 60.00% iron deficiency anemia, 8.15% were suspected to be caused by thyroid dysfunction, and 10.37% by uncertainty of the method. Among the patients with elevated F alone, the results of thalassemia gene detection were negative, 40.91% of them were suspected to be caused by macrocytosis, 27.27% by hereditary persistence of fetal hemoglobin, 29.55% by special physiological condition of pregnant women, and 2.27% by hyperthyroidism. Abnormal hemoglobin bands were detected in 7 patients, including 4 cases of hemoglobin D, 2 cases of hemoglobin E, and 1 case of hemoglobin J.@*CONCLUSION@#Thalassemia, iron deficiency anemia, macrocytosis such as megaloblastic anemia and non-severe aplastic anemia, thyroid dysfunction, hereditary persistence of fetal hemoglobin, abnormal hemoglobin diseases, the uncertainty of the method are all important causes of abnormal hemoglobin electrophoresis results. In clinical work, the patient's indicators should be comprehensively analyzed to determine the possible cause.

Risk factors for hemorrhagic cystitis in children with β-thalassemia major after allogeneic hematopoietic stem cell transplantation / 中国当代儿科杂志

OBJECTIVES@#To explore the risk factors for hemorrhagic cystitis (HC) in children with β-thalassemia major (TM) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT).@*METHODS@#A retrospective analysis was conducted on clinical data of 247 children with TM who underwent allo-HSCT at Shenzhen Children's Hospital from January 2021 to November 2022. The children were divided into an HC group (91 cases) and a non-HC group (156 cases) based on whether HC occurred after operation. Multivariable logistic regression analysis was used to explore the risk factors for HC, and the receiver operating characteristic curve was used to analyze the predictive efficacy of related factors for HC.@*RESULTS@#Among the 247 TM patients who underwent allo-HSCT, the incidence of HC was 36.8% (91/247). Univariate analysis showed age, incompatible blood types between donors and recipients, occurrence of acute graft-versus-host disease (aGVHD), positive urine BK virus deoxyribonucleic acid (BKV-DNA), and ≥2 viral infections were associated with the development of HC after allo-HSCT (P<0.05). Multivariable analysis revealed that incompatible blood types between donors and recipients (OR=3.171, 95%CI: 1.538-6.539), occurrence of aGVHD (OR=2.581, 95%CI: 1.125-5.918), and positive urine BKV-DNA (OR=21.878, 95%CI: 9.633-49.687) were independent risk factors for HC in children with TM who underwent allo-HSCT. The receiver operating characteristic curve analysis showed that positive urine BKV-DNA alone or in combination with two other risk factors (occurrence of aGVHD, incompatible blood types between donors and recipients) had a certain accuracy in predicting the development of HC after allo-HSCT (area under the curve >0.8, P<0.05).@*CONCLUSIONS@#Incompatible blood types between donors and recipients, occurrence of aGVHD, and positive urine BKV-DNA are risk factors for HC after allo-HSCT in children with TM. Regular monitoring of urine BKV-DNA has a positive significance for early diagnosis and treatment of HC.

Association Analysis between Genotype and Phenotype of α,β-Thalassaemia Carriers in Huizhou Area of Guangdong Province / 中国实验血液学杂志

OBJECTIVE@#To analyze the prevalence, genotype distribution and hematological characteristics of α,β-thalassaemia carriers in Huizhou area of Guangdong Province.@*METHODS@#10 809 carriers of simple β-thalassaemia and 1 757 carriers of α,β-thalassaemia were enrolled as our study cohort. The hematological parameters were detected by automated blood cell counters and automatic capillary electrophoresis. Suspension array technology, gap-polymerase chain reaction (gap-PCR) and PCR-reverse dot blot were used for the genotyping of thalassaemia carriers.@*RESULTS@#The prevalence of α,β-thalassaemia in Huizhou area of Guangdong Province was 1.99%. A total of 62 genotypes were detected, and the most prevalent genotype was --SEA/ αα, βCD41-42/ βN (19.29%), the next was --SEA/ αα, βIVS-II-654/ βN (16.73%). Significant differences in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were found between different genotype groups for simple β-thalassaemia and α,β-thalassaemia. Violin plots showed that carriers with co-inheritance of β-thalassaemia and mild α-thalassaemia expressed the lightest anemia, and carriers with co-inheritance of β-thalassaemia and hemoglobin H (Hb H) disease expressed the most severe anemia.@*CONCLUSION@#There is a high prevalence of α,β-thalassaemia in Huizhou area of Guangdong Province. Because of the lack of specific hematological makers for diagnosis of α,β-thalassaemia, it is necessary to distinguish it from simple β-thalassaemia by genotyping of α- and β-thalassaemia in order to correctly guide genetic counseling and prenatal disgnosis.

Thalassemia, a human blood disorder / Talassemia, uma doença do sangue humano

Abstract A group of inherited blood defects is known as Thalassemia is among the world's most prevalent hemoglobinopathies. Thalassemias are of two types such as Alpha and Beta Thalassemia. The cause of these defects is gene mutations leading to low levels and/or malfunctioning α and β globin proteins, respectively. In some cases, one of these proteins may be completely absent. α and β globin chains form a globin fold or pocket for heme (Fe++) attachment to carry oxygen. Genes for alpha and beta-globin proteins are present in the form of a cluster on chromosome 16 and 11, respectively. Different globin genes are used at different stages in the life course. During embryonic and fetal developmental stages, γ globin proteins partner with α globin and are later replaced by β globin protein. Globin chain imbalances result in hemolysis and impede erythropoiesis. Individuals showing mild symptoms include carriers of alpha thalassemia or the people bearing alpha or beta-thalassemia trait. Alpha thalassemia causes conditions like hemolytic anemia or fatal hydrops fetalis depending upon the severity of the disease. Beta thalassemia major results in hemolytic anemia, growth retardation, and skeletal aberrations in early childhood. Children affected by this disorder need regular blood transfusions throughout their lives. Patients that depend on blood transfusion usually develop iron overload that causes other complications in the body systems like renal or hepatic impairment therefore, thalassemias are now categorized as a syndrome. The only cure for Thalassemias would be a bone marrow transplant, or gene therapy with currently no significant success rate. A thorough understanding of the molecular basis of this syndrome may provide novel insights and ideas for its treatment, as scientists have still been unable to find a permanent cure for this deadly disease after more than 87 years since it is first described in 1925.

Resumo Um grupo de defeitos sanguíneos hereditários é conhecido como talassemia e está entre as hemoglobinopatias mais prevalentes do mundo. As talassemias são de dois tipos, como talassemia alfa e beta. As causas desses defeitos são as mutações genéticas que levam a níveis baixos e/ou proteínas de globina com mau funcionamento, respectivamente. Em alguns casos, uma dessas proteínas pode estar completamente ausente. As cadeias de globina α e β formam uma dobra ou bolsa de globina para a fixação de heme (Fe ++) para transportar oxigênio. Os genes das proteínas alfa e beta globina estão presentes na forma de um cluster nos cromossomos 16 e 11, respectivamente. Diferentes genes de globina são usados ​​em diferentes estágios do curso de vida. Durante os estágios de desenvolvimento embrionário e fetal, as proteínas γ globina se associam à α globina e, posteriormente, são substituídas pela proteína β globina. Os desequilíbrios da cadeia de globina resultam em hemólise e impedem a eritropoiese. Indivíduos que apresentam sintomas leves incluem portadores de talassemia alfa ou as pessoas com traços de talassemia alfa ou beta. A talassemia alfa causa condições como anemia hemolítica ou hidropsia fetal fatal, dependendo da gravidade da doença. A beta talassemia principal resulta em anemia hemolítica, retardo de crescimento e aberrações esqueléticas na primeira infância. As crianças afetadas por esse distúrbio precisam de transfusões de sangue regulares ao longo da vida. Os pacientes que dependem de transfusão de sangue geralmente desenvolvem sobrecarga de ferro que causa outras complicações nos sistemas do corpo, como insuficiência renal ou hepática, portanto as talassemias agora são classificadas como uma síndrome. A única cura para as talassemias seria um transplante de medula óssea ou terapia genética sem atualmente uma taxa de sucesso significativa. Uma compreensão completa da base molecular dessa síndrome pode fornecer novos insights e ideias para seu tratamento, já que os cientistas ainda não conseguiram encontrar uma cura permanente para essa doença mortal depois de mais de 87 anos desde que foi descrita pela primeira vez em 1925.

Thalassemia, a human blood disorder / Talassemia, uma doença do sangue humano

A group of inherited blood defects is known as Thalassemia is among the world's most prevalent hemoglobinopathies. Thalassemias are of two types such as Alpha and Beta Thalassemia. The cause of these defects is gene mutations leading to low levels and/or malfunctioning α and β globin proteins, respectively. In some cases, one of these proteins may be completely absent. α and β globin chains form a globin fold or pocket for heme (Fe++) attachment to carry oxygen. Genes for alpha and beta-globin proteins are present in the form of a cluster on chromosome 16 and 11, respectively. Different globin genes are used at different stages in the life course. During embryonic and fetal developmental stages, γ globin proteins partner with α globin and are later replaced by β globin protein. Globin chain imbalances result in hemolysis and impede erythropoiesis. Individuals showing mild symptoms include carriers of alpha thalassemia or the people bearing alpha or beta-thalassemia trait. Alpha thalassemia causes conditions like hemolytic anemia or fatal hydrops fetalis depending upon the severity of the disease. Beta thalassemia major results in hemolytic anemia, growth retardation, and skeletal aberrations in early childhood. Children affected by this disorder need regular blood transfusions throughout their lives. Patients that depend on blood transfusion usually develop iron overload that causes other complications in the body systems like renal or hepatic impairment therefore, thalassemias are now categorized as a syndrome. The only cure for Thalassemias would be a bone marrow transplant, or gene therapy with currently no significant success rate. A thorough understanding of the molecular basis of this syndrome may provide novel insights and ideas for its treatment, as scientists have still been unable to find a permanent cure for this deadly disease after more than 87 years since it is first described in 1925.

Um grupo de defeitos sanguíneos hereditários é conhecido como talassemia e está entre as hemoglobinopatias mais prevalentes do mundo. As talassemias são de dois tipos, como talassemia alfa e beta. As causas desses defeitos são as mutações genéticas que levam a níveis baixos e/ou proteínas de globina com mau funcionamento, respectivamente. Em alguns casos, uma dessas proteínas pode estar completamente ausente. As cadeias de globina α e β formam uma dobra ou bolsa de globina para a fixação de heme (Fe ++) para transportar oxigênio. Os genes das proteínas alfa e beta globina estão presentes na forma de um cluster nos cromossomos 16 e 11, respectivamente. Diferentes genes de globina são usados em diferentes estágios do curso de vida. Durante os estágios de desenvolvimento embrionário e fetal, as proteínas γ globina se associam à α globina e, posteriormente, são substituídas pela proteína β globina. Os desequilíbrios da cadeia de globina resultam em hemólise e impedem a eritropoiese. Indivíduos que apresentam sintomas leves incluem portadores de talassemia alfa ou as pessoas com traços de talassemia alfa ou beta. A talassemia alfa causa condições como anemia hemolítica ou hidropsia fetal fatal, dependendo da gravidade da doença. A beta talassemia principal resulta em anemia hemolítica, retardo de crescimento e aberrações esqueléticas na primeira infância. As crianças afetadas por esse distúrbio precisam de transfusões de sangue regulares ao longo da vida. Os pacientes que dependem de transfusão de sangue geralmente desenvolvem sobrecarga de ferro que causa outras complicações nos sistemas do corpo, como insuficiência renal ou hepática, portanto as talassemias agora são classificadas como uma síndrome. A única cura para as talassemias seria um transplante de medula óssea ou terapia genética sem atualmente uma taxa de sucesso significativa. Uma compreensão completa da base molecular dessa síndrome pode fornecer novos insights e ideias para seu tratamento, [...].

La doble heterocigosis por la mutación común en el codón 39 (C>T) (ß0) y la deleción siciliana (δß0) 13.4 kb causa una beta-talasemia transfusión dependiente en dos pacientes costarricenses / (Double heterozygosity for the common mutation at codon 39 (C>T) (ß0) and the Sicilian (δß0) 13.4 kb deletion, causes transfusiondependent beta-thalassemia in two Costa Rican patients)

Las talasemias son desórdenes autosómicos recesivos de las cadenas de hemoglobina que poseen expresión clínica variable según el tipo de mutación o deleción. Presentamos el caso de dos jóvenes mujeres costarricenses no relacionadas entre sí y ambas diagnosticadas con la mutación común en el codón 39 (C>T) (β0) en combinación con la deleción siciliana (δβ0) 13.4 kb. La caracterización de doble heterocigota no había sido descrita antes en la literatura médica, y discutimos el significado de este genotipo que causa un defecto tipo β0 talasemia transfusión dependiente.

Thalassemia are autosomal recessive disorders of hemoglobin chains with variable clinical expression depending on the type of mutation or deletion present. We present the common codon 39(C>T) (β0) in combination with the δβ0 13.4 kb Sicilian deletion in two non-related young women from Costa Rica. We report the characterization of the compound heterozygous not previously described phenotype, and discuss the significance of this genotype combination with a transfusion dependent β0 defect Thalassemia.

The inverse correlation between serum levels of anti-pneumococcal and ferritin after pneumococcal vaccination in splenectomised beta thalassemia major

Splenectomy is necessary in beta thalassemia major patients when the spleen becomes hyperactive, leading to extreme destruction of erythrocytes. This study assessed the ferritin effect on serum pneumococcal antibody response following pneumococcal vaccination, in patients with beta thalassemia major after splenectomy. In this case series study, convenience sampling was used to recruit 347 splenectomised beta thalassemia patients under the auspices of Jahrom University of Medical Sciences. Demographic data such as age, sex, and time after splenectomy were recorded by a questionnaire. All participants had been splenectomised and received a dose of Pneumovax1 23 vaccine 14 days before surgery. The IgG antibody responses to pneumococcal vaccine and levels of serum specific ferritin were determine by commercial enzyme immunoassay kits. For the analysis, SPSS software version 16 was used. A p-value less than 0.05 was considered statistically significant. Most of the participants (63.4 percent) were hypo-responders to pneumococcal vaccine. Also, serum anti-pneumococcal IgG antibody was related to post splenectomy duration and serum ferritin (p 0.05). An important result was a relation of serum anti-pneumococcal IgG antibody to serum ferritin according to post splenectomy duration groups. Therefore, in three groups of post splenectomy duration, the serum ferritin was higher in hypo-responder than in good responder subjects. Our results indicate that serum anti-pneumococcal IgG antibody decreased with increment of serum ferritin and post splenectomy duration. Thus, there is a need to re-address the approach towards revaccination in this immune-compromised group of patients by administering a booster pneumococcal vaccination in an attempt to recover immunity and reduce morbidity(AU)

La esplenectomía es necesaria en pacientes con beta talasemia mayor cuando el bazo se vuelve hiperactivo, lo que lleva a una destrucción extrema de los eritrocitos. Este estudio evaluó el efecto de la ferritina sobre la respuesta de anticuerpos antineumocócicos en suero después de la vacunación antineumocócica, en pacientes con talasemia beta mayor a los que se les realizó esplenectomía. En este estudio de serie de casos, se utilizó un muestreo de conveniencia para reclutar a 347 pacientes con beta talasemia esplenectomizados bajo los auspicios de la Universidad de Ciencias Médicas de Jahrom. Los datos demográficos como la edad, el sexo y el tiempo después de la esplenectomía se registraron mediante un cuestionario. Todos los participantes fueron esplenectomizados y recibieron una dosis de la vacuna Pneumovax® 23, 14 días antes de la cirugía. Las respuestas de anticuerpos IgG a la vacuna neumocócica y los niveles de ferritina sérica específica se determinaron mediante estuches comerciales de inmunoensayo enzimático. Para el análisis se utilizó el programa SPSS versión 16. Un valor de p inferior a 0,05 se consideró estadísticamente significativo. La mayoría de los participantes (63,4 por ciento) resultaron hiporrespondedores a la vacuna antineumocócica. Además, el anticuerpo sérico antineumocócico IgG se relacionó con la duración de la esplenectomía y la ferritina sérica (p0,05). Un resultado importante fue la relación del anticuerpo sérico IgG antineumocócico con la ferritina sérica según los grupos de duración postesplenectomía. Por lo tanto, en tres grupos de duración posterior a la esplenectomía, la ferritina sérica fue mayor en los sujetos con hiporrespuesta que en los sujetos con buena respuesta. Nuestros resultados indican que el anticuerpo sérico IgG antineumocócico disminuyó con el incremento de la ferritina sérica y la duración posterior a la esplenectomía. Por lo tanto, existe la necesidad de volver a abordar el enfoque hacia la revacunación en este grupo de pacientes inmunocomprometidos mediante la administración de una vacunación antineumocócica de refuerzo en un intento por recuperar la inmunidad y reducir la morbilidad(AU)

Association of FOXO3 polymorphism (rs3800231) and clinical subphenotypes of beta thalassemic individuals

Abstract Introduction Studies have shown that the loss of the FOXO3 transcriptional function is involved in the pathophysiology of some chronic erythroid disorders, including beta-thalassemia (β-thal). Therefore, the single nucleotide polymorphism (SNP) rs3800231 (35-2764A > G) could contribute to alterations in its transcriptional activity, acting as a modifier of β-thal phenotypic manifestations. Objective and method In order to better understand the genotypic and/or allelic distributions among β-thal patients, we evaluated 83 β-thal heterozygous and 20 homozygous, compared to 117 individuals without hemoglobinopathies (control group). Additionally, we verified any influence of the FOXO3 polymorphism on clinical manifestations among β-thal homozygotes. Results We obtained higher frequencies of the wild-type homozygous (AA) and the wild-type allele (A) in the β-thal group (p< 0.0001 and p= 0.00014, respectively). The most common clinical manifestations found among β-thal homozygotes were iron overload (90%), splenomegaly (65%) and bone complications (35%), e.g., osteopenia/osteoporosis. We observed that close to 80% of the patients presenting such manifestations had the genotype AA. However, we did not find any significant involvement of the FOXO3 polymorphism in clinical manifestation occurrences. Conclusion Thus, we concluded that the SNP rs3800231 did not play a significant role as a modifier of the clinical manifestations observed in the β-thal homozygotes studied.

Assessment of serum endocan levels in patients with beta-thalassemia minor

SUMMARY OBJECTIVE: Beta-thalassemia minor is a blood disease caused by a hereditary decrease in beta-globin synthesis, frequently leading to hypochromic microcytic anemia. Formerly called endothelial cell-specific molecule 1, endocan is a proteoglycan released by vascular endothelial cells in many organs. Our aim was to investigate the relationship between the beta-thalassemia minor patients and the healthy control group in terms of serum endocan level. METHODS: The study was performed in a total of 80 subjects. They were divided into two groups, the beta-thalassemia minor group (n=40) and the healthy control group (n=40). Serum endocan levels, age, sex, body mass index value, and tobacco use data of these groups were compared. RESULTS: No statistically significant difference was detected between the two groups in terms of age, sex, and body mass index values (p>0.05). Endocan levels were measured to be 206.85±88.1 pg/mL in the beta-thalassemia minor group and 236.1±162.8 pg/mL in the control group with no significant difference between the groups in terms of serum endocan levels (p>0.05). CONCLUSIONS: In our study, there was no change in endocan level in beta-thalassemia minor. This might be because serum endocan levels are affected by multi-factorial reasons. Serum endocan levels may be altered secondarily to decreased beta-globin chain, increased sympathetic activity due to anemia, or platelet dysfunction induced by oxidative stress in beta-thalassemia minor. Further multicenter studies involving more patients are necessary to demonstrate this.

Clinical characteristics and risk factors of pericardial effusion after hematopoietic stem cell transplantation in children with thalassemia major / 中华儿科杂志

Objective: To investigate the characteristics, risk factors and outcomes of thalassemia major (TM) children with pericardial effusion (PE) after allo-geneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Clinical data of 446 TM children received allo-HSCT at Shenzhen Children's Hospital between January 2012 and December 2020 were analyzed retrospectively. Patients were divided into PE and non-PE group according to the occurrence of PE. Chi-square tests were used to investigate the risk factors that were associated with the development of PE. Kaplan-Meier method was used for survival analysis of the 2 groups. Results: Twenty-five out of 446 patients (5.6%) developed PE at a time of 75.0 (66.5, 112.5) days after allo-HSCT. Among these patients, 22 cases (88.0%) had PE within 6 months after allo-HSCT and 19 patients (76.0%) had PE within 100 days after allo-HSCT. The diagnoses of PE were confirmed using echocardiography. Pericardial tamponade was observed in only 1 patient, who later undergone emergency pericardiocentesis. The rest of patients received conservative managements alone. PE disappeared in all patients after treatment. Risk factors that were associated with the development of PE after allo-HSCT included the gender of patients, the type of transplantation, the number of mononuclear cells (MNC) infuse, pulmonary infection after HSCT and transplantation associated thrombotic microangiopathy (TA-TMA) (χ²=3.99, 10.20, 14.18, 36.24, 15.03, all P<0.05). In 239 patients that received haploidentical HSCT, the development of PE was associated with the gender of patients, pulmonary infection after HSCT and TA-TMA (χ²=4.48, 20.89, 12.70, all P<0.05). The overall survival rates of PE and non-PE groups were 96.0% (24/25) and 98.6% (415/421). The development of PE was not associated with the overall survival of TM children after allo-HSCT (χ²=1.73, P=0.188). Conclusions: PE mainly develop within 100 days after allo-HSCT in pediatric TM recipients. Haploidentical grafts, female gender, pulmonary infection after HSCT and TA-TMA are the main risk factors associated with PE development after transplant. However, the presence of PE don't have a significant impact on the outcomes of pediatric TM patients after allo-HSCT.

Optimization of β-globin Stable Expression Using the Third Generation Lentiviral Vector for β-thalassemia Therapy / 中国实验血液学杂志

OBJECTIVE@#To provide a research basis for a safe and effective cell therapy for β-thalassemia through optimization of HS4 region of the third generation lentiviral vector for stable expression of β-globin.@*METHODS@#The human β-globin HS4 region in the third generation lentiviral expression vector was optimized to construct the lenti-HBB, and the transcription and translation of β-globin gene were analyzed by RT-PCR and Western blot after the transduction of lenti-HBB in MEL cell line. Furthermore, the erythroid differentiation of CD34+ cells which were transduced lentiviral virus carrying human β-globin from normal human umbilical cord blood cells and peripheral blood cells of patients with β-thalassemia major were confirmed by colony formation assay, cell smear assay and flow cytometry. The safety and effectiveness of the optimized lenti-HBB were verified by NSG mouse in vivo test.@*RESULTS@#The human β-globin was expressed stably in the MEL cells, and CD34+ cells from health umbilical cord blood as well as PBMC from patient with β-thalassemia major transduced with lenti-HBB could be differentiated to mature red blood cells. The β-globin expression and differentiation in CD34+ cells were demonstrated successfully in the NSG mouse for about 35 months after post-transplant.@*CONCLUSION@#Stable β-globin expression through the optimization of HS4 from CD34+ in the third generation lentiviral vector is safe and effective for patients with severe β-thalassemia and other β-globin abnormal diseases.

The value of combined detection of HbA2 and HbF for the screening of thalassemia among individuals of childbearing ages / 中华医学遗传学杂志

OBJECTIVE@#To assess the application value of combined detection of HbA2 and HbF for the screening of thalassemia among a population of childbearing age in Quanzhou, Fujian, and determine the optimal cut-off values for the region.@*METHODS@#Capillary hemoglobin electrophoresis and genetic testing for α and β globin gene mutations were simultaneously carried out on 11 428 patients with suspected thalassemia. Statistical methods were used to analyze the distribution of various types of thalassemia and compare the performance of HbA2 and HbF measurement for the screening of various types of thalassemia. The optimal cut-off values for HbA2 and HbF were determined with the ROC curves.@*RESULTS@#4591 patients with α, β, and αβ compound thalassemia were identified by genetic testing. The most common genotypes for α and β thalassemia included --SEA/αα and β654/βN, β41-42/βN, and β17/βN. The ROC curves were drawn to compare the performance of HbA2 screening for α-, β-, αβ-compound, static α-, mild α-, and intermediate α-thalassemia, and the maximum area under the curves was 0.674, 0.984, 0.936, 0.499, 0.731, 0.956, and the optimal cut-off values for HbA2 were 2.45%, 3.25%, 3.65%, 2.95%, 2.55%, 1.75%, respectively.@*CONCLUSION@#HbA2 is an efficient indicator for identifying intermediate types of α-, β-, and αβ compound thalassemia. The combination of HbA2 and HbF measurement can effectively detect carriers for β-thalassemia mutations.