Beta-globin Chain Research Articles

Delta beta thalassemia, a rare hemoglobin variant

CONTEXT: Fetal hemoglobin (HbF) reduces to <1% few months after birth. However, it can persist beyond infancy into adult life in rare conditions such as delta-beta (δβ) thalassemia and hereditary persistence of HbF. δβ thalassemia is a relatively rare type of thalassemia due to decrease in both beta and delta globin chain production. AIMS: This study aims to assess the hematological and high-performance liquid chromatography (HPLC) findings in δβ thalassemia. SETTINGS AND DESIGN: Cross-sectional observational study. SUBJECTS AND METHODS: The study was conducted in department of Clinical Pathology, PGIMS, Rohtak. On screening of 1197 patients over a period of around 1 year, a total of 13 cases of δβ thalassemia were detected by HPLC. STATISTICAL ANALYSIS USED: Not done. RESULTS: The age of presentation ranged from 1 to 42 years with a mean age of 22.8 years. Eleven cases were diagnosed as heterozygous δβ thalassemia and two as homozygous δβ thalassemia. CONCLUSIONS: δβ thalassemia is an uncommon cause of elevated HbF. Clinical and hematological parameters should be carefully analyzed for accurate diagnosis.

The Effect of Curcumin on Iron Overload in Patients with Beta-Thalassemia Intermedia.

β-thalassemia is an inherited disorder that stems from a defect in beta-globin chain synthesis. Iron overload toxicity is one of the major clinical complications in β-thalassemia that may be due to a reduction in the hepcidin level. As a result, intestinal iron absorption increases and finally iron overload occurs. The current study aimed to investigate the effect of curcumin on serum iron status, ferritin, and transferrin in patients with β-thalas-semia intermedia. This study was a randomized, controlled, double-blind clinical trial. Before and after the intervention period with curcumin, 5 ml blood was taken for the measurement of the entire index related to iron status. Our results demonstrated the levels of serum iron (p-value < 0.001), ferritin (p-value = 0.002), and transferrin saturation (p-value < 0.001) significantly decreased in the curcumin group compared to placebo. The data presented in this article show that curcumin supplementation would be effective in alleviating iron overload in patients with β-thalassemia intermedia.

Assessment of the Effectiveness of Self-Instructional Module on Knowledge Regarding Home Care Management of Thalassemia Children among the Parents in A.V.B.R. Hospital, Wardha

Background of Study: Thalassemia is a genetic condition in which the production of globin chains is reduced or non-existent. Beta-thalassemia is caused by mutations in the beta-globin gene, which impede the formation of beta-globin chains. Based on clinical severity, beta thalassemia is categorised as follows.&#x0D; The most severe form of beta thalassemia is characterised by severe anaemia and the requirement for blood transfusions. Anaemia caused by beta thalassemia intermedia can be treated with medication or transfusions. Beta thalassemia minima- Also known as beta thalassemia trait, this type is typically asymptomatic.&#x0D; Children with beta-thalassemia major require regular blood transfusions, which can result in issues such as iron overload and the transfer of illnesses such as HIV, HCV, and HBsAg, all of which can shorten their life. Inadequate transfusions, on the other hand, result in severe anaemia as well as fatigue and debility.&#x0D; Objectives: To measure parents' existing knowledge of thalassemia children's home care management.&#x0D; To analyses the efficiency of a self-instructional module on thalassemia children's home care management expertise.&#x0D; To link the post-test knowledge score to the demographic factors chosen.&#x0D; Materials and Methods: A descriptive research design study was conducted to evaluate the efficiency of a self-instructional module on parental understanding of thalassemia children's home care management. The total number of samples in this study was 30. All of them were parents of thalassemia children from A.V.B.R. Hospital in Sawangi (Meghe), Wardha. The study employed a non-probability convenient sampling strategy, with the instrument being designed questionnaires on parental understanding of their children's medical conditions and knowledge of home care management of thalassemia. Based on the aims and hypothesis, the data was statistically analysed using various tests such as descriptive statistics and inferential statistics.&#x0D; Results: The purpose of this study was to determine the efficiency of a self-instructional module on parental understanding of thalassemia children's home care management. Following the installation of the seif-instructional module, 63.33 percent of Thalassemia parents had a poor level of knowledge and 36.67 percent had an average level of knowledge prior to the exam, according to analysis. The lowest knowledge score on the pre-test was 2 and the highest knowledge score was 7. The pre-test mean percentage of knowledge score was 33.559.17, and the pre-test mean knowledge score was 5.031.37. Post-test knowledge scores were average for 23.33 percent of Thalassemia parents and excellent for 76.67 percent of Thalassemia parents. The minimum post-test knowledge score was 8 and the maximum post-test knowledge score was 14. The mean post-test knowledge score was 11.901.84, and the mean percentage of knowledge score was 79.3312.29.&#x0D; Conclusion: The current study's pre-test results reveal that parents of thalassemia children had insufficient information about thalassemia home care management. Following the self-instructional module, it was a modest attempt to develop understanding of thalassemia home care management. Based on their pre-test scores, 19% of subjects had low knowledge, 11% had moderate knowledge, and 0% had strong knowledge, according to the findings. However, according to post-test results, 0% of subjects had low knowledge, 7% of subjects had average knowledge, and 23% of subjects had strong knowledge. As a result, the post-test knowledge score was statistically interpreted to be greater than the pre-test knowledge score.

Serum Preptin Level in Iraqi Beta Major Thalassemic Patients

Background Beta thalassemia syndromes are a set of hereditary blood disorders marked by a deficiency of beta-globin chain synthesis, result in decrease hemoglobin in red blood cells, anemia, and a reduced RBC production. Iron overload is a common finding in chronically transfused beta thalassemia major patients with possible effect on beta cell function and secretion. This study aimed to assess preptin level in the serum in beta major thalassemic patients, in order to indicate the effect of oxidative stress on preptin secretion. And explain preptin effect on bone cells. Subject and methods; A case-control study that was performed in the Ibn Albaladi Hospital (during the period from 1st of September 2020 to the end of January 2021. It included 48 beta major thalassemic patients and 36 subject as healthy control. Information was taken from each subject including age, diseases. Subjects with any cardiovascular diseases, hyperemesis gravidram, liver diseases, kidney diseases, bone disease, diabetes mellitus, and patients take corticosteroid as well as patients in childhood were excluded in this study. The biomarkers studied were: fasting serum preptin, insulin were assessed. Serum preptin and insulin were measured by ELISA technique. Results; The mean values of (Preptin, Insulin) in patients group were less than control group. There was a moderate direct significant correlation P&lt;0.01 between preptin and insulin. Conclusion; The mean value of serum preptin was less in thalassemic major group than control group. And direct correlated with insulin level which is also reduced in thalassemic patients.

Preclinical Development of EDIT301, an Autologous Cell Therapy Comprising AsCas12a-RNP Modified Mobilized Peripheral Blood-CD34 + Cells for the Potential Treatment of Transfusion Dependent Beta Thalassemia

Beta thalassemia is one of the most common recessive hematological disorders in the world with more than 200 mutations identified to date. These mutations reduce or completely abrogate beta globin expression. As beta globin pairs with alpha globin to form adult hemoglobin (HbA, α2β2), reduced or absent beta globin results in excessive alpha globin chains, which form toxic aggregates. These aggregates cause maturation blockade and premature death of erythroid precursors, and hemolysis of red blood cells (RBC), leading to varying degrees of anemia. Patients with the most severe form of beta thalassemia, namely beta thalassemia major, are transfusion-dependent, i.e., requiring life-long RBC transfusions accompanied by the burden of iron chelation therapy.EDIT-301 is an experimental autologous cell therapy in which CD34 + cells are genetically modified to promote gamma globin expression. EDIT-301 is currently in clinical development for sickle cell disease, and IND enabling stage for transfusion-dependent beta thalassemia (TDT). Gamma globin decreases the alpha to beta globin chain imbalance in beta thalassemia by pairing with the over-abundant alpha globin chains to form fetal hemoglobin (HbF, α2γ2). Gamma globin induction, and consequently HbF induction, for EDIT-301 is achieved through AsCas12a ribonucleoprotein (RNP)-mediated editing of the distal CCAAT box region of the HBG1 and HBG2 promoters, where naturally occurring hereditary persistence of fetal hemoglobin (HFPH) mutations exist. We chose this target over BCL11A based on previous preclinical data demonstrating that BCL11A editing reduces erythroid output in NBSGW mice. An engineered AsCas12a RNP edits the HBG1 and HBG2 promoter distal CCAAT box with high efficiency and specificity. We have previously shown that on-target editing of >80% was achieved in mobilized peripheral blood (mPB) CD34 + cells from normal donors with no detectable off-target editing both at research scale and at clinical manufacturing scale. Edited normal donor CD34 + cells led to long-term, polyclonal, multilineage engraftment without lineage skewing in immunocompromised mice and sustained robust HbF production in their erythroid progeny.To test whether EDIT-301 may be an efficacious therapy for TDT, mPB CD34 + cells from individuals with TDT were electroporated with the engineered AsCas12a RNP targeting the HBG1 and HBG2 promoters. AsCas12a RNP edited mPB CD34 + cells from individuals with TDT as efficiently as CD34 + cells from normal donors. Importantly, EDIT-301 has the potential to address the underlying pathophysiology of TDT, i.e., the maturation blockade and premature death of erythroid precursors. Erythroid differentiation of edited beta thalassemia CD34 + cells showed significant improvement in erythroid maturation and health. Specifically, ~70% edited erythroblasts reached late erythroblast stage compared to ~53% unedited erythroblasts; ~56% edited erythroid cells underwent terminal maturation and enucleated compared to ~28% of unedited erythroid cells; and non-viable erythroblasts decreased from ~33% to ~22% after editing. The improved erythropoiesis was accompanied by significantly increased total hemoglobin content per cell. These data strongly support that editing of the HBG1 and HBG2 promoter CCAAT box using engineered AsCas12a RNP can reverse the dyserythropoiesis associated with beta thalassemia and increase the hemoglobin production.In summary, we have provided strong preclinical data supporting the development of EDIT-301 for the treatment of TDT. Edited mPB CD34 + cells retained their ability to engraft without lineage skewing, resulted in robust HbF induction long-term, improved erythropoiesis, and increased hemoglobin content in TDT erythroid cells. These data support that a single administration of EDIT-301 may have the potential to safely and effectively reverse dyserythropoiesis and ameliorate anemia in individuals with TDT long-term. Clinical studies to demonstrate the safety and efficacy of EDIT-301 in the treatment of TDT are currently being planned. DisclosuresSousa: Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Janoudi: Editas Medicine: Current Employment, Current equity holder in publicly-traded company. deDreuzy: Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Shearman: Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Zhang: Editas Medicine: Current Employment, Current equity holder in publicly-traded company. Chang: Editas Medicine: Current Employment, Current equity holder in publicly-traded company.

Safety and Efficacy of Mitapivat (AG-348), an Oral Activator of Pyruvate Kinase R, in Subjects with Sickle Cell Disease: A Phase 2, Open-Label Study (ESTIMATE)

BackgroundSickle cell disease (SCD) is one of the most common and devastating inherited blood disorders characterized by a single nucleotide mutation in the beta-globin chain leading to the production of mutant hemoglobin S (HbS). HbS polymerizes upon deoxygenation causing red blood cells (RBC) to sickle which results in extremely painful episodes of vaso-occlusive crisis (VOC), severe hemolytic anemia, chronic multiorgan failure and a reduced life span. An important metabolic feature directly associated with RBC sickling is increased intracellular levels of the glycolytic intermediate 2,3-diphosphyglycerate (2,3-DPG) which promotes deoxygenation by lowering the oxygen affinity of hemoglobin (Hb). Pyruvate kinase R (PKR) is a key enzyme in RBC metabolism, generating adenosine triphosphate (ATP) to maintain energy homeostasis, membrane integrity and deformability, and modulates 2,3-DPG levels. Mitapivat (AG-348) is an oral, small molecule allosteric activator of PKR and shows promise as an anti-sickling agent in addition to its effect in PK deficiency and thalassemia. The safety and efficacy of mitapivat in subjects with SCD was evaluated in the dose finding period of this ongoing phase 2 study.MethodsThe ESTIMATE study is a phase 2, open-label study in which subjects ≥16 years with SCD (HbSS, HbS/β0, HbS/β+) with a baseline hemoglobin >6.1 g/dL and ≤11.1 g/dL, no chronic transfusion and adequate organ function were eligible. In the 8-week Dose Finding Period, initial dosing of mitapivat was 20 mg twice daily (BID). Subjects received a maximum of two sequential dose escalations of mitapivat (i.e. from 20 mg BID to 50 mg BID and 100 mg BID) depending on safety. The primary endpoints were safety, evaluated by frequency and severity of adverse events (AEs), and efficacy of mitapivat on RBC sickling. RBC sickling was evaluated by change in Point of Sickling (PoS), the pO2 at which sickling occurs as measured by oxygen gradient ektacytrometry on the Lorrca (RR Mechatronics). Secondary endpoints included changes in hematological parameters, levels of 2,3-DPG and ATP, Hb-oxygen affinity (p50) and surrogate markers of organ damage and mortality. Subjects who safely tolerated mitapivat and showed evidence of clinical improvement, were eligible to continue a 52-week follow-up period (Fixed Dose Extension Period).ResultsSix subjects have been enrolled as of September 2020 and completed the Dose Finding Period. All had homozygous HbSS except one patient who had HbS/β0-thalassemia. Baseline characteristics were: median age of 36 years (range 20-59 years), 4 (66.7%) were female and 5 (83.3%) were on stable-dose hydroxyurea. All subjects received dose escalation to a maximum dose of 100 mg BID. No serious adverse events (SAEs) occurred. Adverse events (AEs) were mild and often transient, with the most common treatment emergent AEs: transaminase increase (n=3 [50.0%], Grade 1), gastrointestinal disorders including dyspepsia, diarrhea and abdominal discomfort (n=3 [50.0%], Grade 1) and headache (n=2 [33.3%], Grade 1). One VOC occurred without hospital admission and did not require dose reduction or discontinuation. Table 1 summarizes the anti-sickling effect as well as the hematological and biochemical response to mitapivat treatment. Sickling occurred at lower pO2 levels in all 6 patients during the Dose Finding Period reflected by a significant decrease in treatment week 8 mean PoS compared to baseline. 5/6 subjects (83.3%) achieved a Hb increase of ≥1 g/dL during this period, which was accompanied by a decrease in hemolytic markers. Consistent with activation of PKR, 2,3-DPG levels decreased and ATP levels increased. Additional results including biomarker data will be presented.ConclusionMitapivat demonstrated an adequate safety profile during the 8-week Dose Finding Period in patients with SCD. The data show promising efficacy in terms of a decrease in the pO2 at which RBCs start to sickle, as well as increase in Hb from baseline and a concomitant decrease in markers reflecting hemolysis. The observed changes in 2,3-DPG and ATP levels are consistent with the proposed mechanism of the drug. The study is ongoing and further data including follow-up data, patient-reported outcomes, PKR activity and thermostability will be reported at a later stage. [Display omitted] Disclosuresvan Dijk: Agios Pharmaceuticals: Research Funding; Axcella Health: Research Funding. Rab: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Rijneveld: Servier: Research Funding; Amgen: Research Funding. Nur: Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Roche: Speakers Bureau. Schutgens: CSL Behring: Research Funding; Novo Nordisk: Research Funding; OctaPharma: Research Funding; Pfizer: Research Funding; Shire/Takeda: Research Funding; Bayer: Research Funding. Wijk: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Beers: Pfizer: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding.

Current status of beta-thalassemia and its treatment strategies.

BackgroundThalassemia is an inherited hematological disorder categorized by a decrease or absence of one or more of the globin chains synthesis. Beta‐thalassemia is caused by one or more mutations in the beta‐globin gene. The absence or reduced amount of beta‐globin chains causes ineffective erythropoiesis which leads to anemia.MethodsBeta‐thalassemia has been further divided into three main forms: thalassemia major, intermedia, and minor/silent carrier. A more severe form among these is thalassemia major in which individuals depend upon blood transfusion for survival. The high level of iron deposition occurs due to regular blood transfusion therapy.ResultsOverloaded iron raises the synthesis of reactive oxygen species (ROS) that are noxious and prompting the injury to the hepatic, endocrine, and vascular system. Thalassemia can be analyzed and diagnosed via prenatal testing (genetic testing of amniotic fluid), blood smear, complete blood count, and DNA analysis (genetic testing). Treatment of thalassemia intermediate is symptomatic; however; it can also be accomplished by folic supplementation and splenectomy.ConclusionThalassemia major can be cured through regular transfusion of blood, transplantation of bone marrow, iron chelation management, hematopoietic stem cell transplantation, stimulation of fetal hemoglobin production, and gene therapy.

Comprehensive Review: Extramedullary Hematopoiesis in Patients with Beta Thalassemia Major (transfusion dependent thalassemia)

AbstractIntroduction:Thalassemia is one of the most common hemoglobinopathies, with around 5% of world's population expected to have some degree and type of thalassemia. Beta thalassemia (BT) occurs due to a deficient production of the beta-globin chain of hemoglobin. BT is classified into minor, intermedia, and major, defined by their clinical and laboratory findings. Extramedullary hematopoiesis is one of the complications of BT, primarily seen in minor/intermedia subtypes. EMH is the production of blood cells outside the marrow as a compensatory response to longstanding hypoxia. Due to chronic transfusions, it is not expected in patients with beta thalassemia major (BTM). However, there are multiple case reports of EMH in BTM. The incidence of EMH in BTM is thought to be <1%. However, given the increasing cases, it seems that the true incidence is much higher than expected. This systematic review aims to pool the available data and provide cumulative evidence on the occurrence of EMH in BTM patients.Methods:This is a systematic review of case reports, series, and retrospective studies that presented data on the occurrence of EMH in BTM patients. Data were recorded and analyzed in Microsoft Excel 2016 and SPSS 26. The protocol has been registered in PROSPERO: CRD42021242943.Results:Data from 253 cases of EMH in BTM patients were extracted from 2 retrospective studies and 71 case reports (some of the descriptive data from case reports and most of the descriptive data from retrospective studies was missing). The mean age at presentation was 35.3 +/- 0.5 years. Males constituted 57.7% of the total population. Mean hemoglobin at presentation with EMH was 8.2 +/- 2.1 mg/dL. Lower limb weakness was the most common presenting feature (N=23). Other features included localized pain, urinary incontinence, and an incidental finding of EMH. Magnetic resonance imaging (MRI) was the most widely used diagnostic modality (N=226). However, computed tomography scans, positron emission tomography scans, tissue biopsy, myelograms, and X-rays were also used to diagnose EMH. Various treatments were reported either alone or in combination. Overall, blood transfusion was the commonest reported treatment (N=30), followed by radiotherapy (N=20), surgery (N=15), hydroxyurea (N=12), steroids (N=6), and exchange transfusion (N=2). An outcome was reported in 20% of patients, all recovered, with no reported mortality.Conclusion:EMH is considered a rare phenomenon in BTM patients. However, there are many cases reported in which EMH occurred in BTM despite chronic blood transfusions. EMH can occur in any organ system and can present with a varied clinical feature. MRI can effectively diagnose EMH, and conservative management is reported to have similar results compared to invasive treatments. More extensive studies, focusing especially on outcomes, are required to enhance the guidelines on managing EMH in patients with BTM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

EXTRAMEDULLARY HEMATOPOIESIS IN PATIENTS WITH TRANSFUSION DEPENDENT β-THALASSEMIA (TDT): A SYSTEMATIC REVIEW

Thalassemia is one of the most common hemoglobinopathies, with around 5% of the world's population expected to have some degree and type of thalassemia. Beta thalassemia (BT) occurs due to a deficient production of the beta-globin chain of hemoglobin. Extramedullary hematopoiesis (EMH) is one of the complications of BT, mainly observed in minor/intermedia subtypes. EMH is the production of blood cells outside the marrow as a compensatory response to longstanding hypoxia. Due to chronic transfusions, it is not expected in patients with beta-thalassemia major (BTM). However, there are increasingly reported cases of EMH in BTM. The incidence of EMH in BTM is thought to be &lt;1%. However, it seems that the true incidence is much higher than expected. This review aims to pool the available data and provide cumulative evidence on the occurrence of EMH in BTM patients. We aim to conduct a systematic review via searching multiple electronic databases (PubMed, Scopus, Google Scholar) to identify eligible articles from any date up to December 2020. Eligible studies should report extramedullary hematopoiesis in beta-thalassemia major. Case reports, case series, observational studies with cross-sectional or prospective research design, case-control studies, and experimental studies will be included if found relevant. Two reviewers (FA and ES) will individually analyze the study quality using the statistical methodology and categories guided by the Cochrane Collaboration Handbook, PRISMA guidelines, and Joanna Briggs Institute checklist for case reports and series. Data from 253 cases of EMH in BTM patients were extracted with mean age of 35.3 +/- 0.5 years. Mean hemoglobin at presentation with EMH was 8.2 +/- 2.1 mg/dL. Lower limb weakness was the most common presenting feature (N=23) (paraspinal EMH). Magnetic resonance imaging (MRI) was the most widely used diagnostic modality (N=226). Overall, blood transfusion was the commonest reported treatment (N=30), followed by radiotherapy (N=20), surgery (N=15), hydroxyurea (N=12), steroids (N=6), and exchange transfusion (N=2). An outcome was reported in 20% of patients, all recovered, with no reported mortality. EMH is considered a rare phenomenon in BTM patients. It can occur in any organ system with varied clinical features. MRI can effectively diagnose EMH, and conservative management has similar results compared to invasive treatments. Larger studies, focusing on outcomes may enhance guidelines on preventive and therapeutic strategies for managing EMH in BTM.

Improving Ineffective Erythropoiesis in Thalassemia: A Hope on the Horizon.

Beta-thalassemia is an inherited hemoglobinopathy characterized by the impaired synthesis of beta-globin chains of hemoglobin leading to chronic hemolytic anemia. The mainstay of treatment for most patients remains regular blood transfusions and iron chelation. This conventional therapy has many limitations and challenges. Allogeneic hematopoietic stem cell transplant (HSCT) is the only available curative treatment but the availability of a suitable donor, financial constraints, and a need for specialist physicians can be limiting factors. Gene therapy is an upcoming curative therapeutic modality. An increased understanding of the underlying pathophysiology and molecular mechanisms of thalassemia has paved the way for novel pharmacological agents targeting ineffective erythropoiesis. These drugs act by decreasing transfusion requirements and hence decrease transfusion-related complications. The present review intends to provide an insight into the recent advances in pharmacological agents targeting ineffective erythropoiesis. Literature was searched and relevant articles evaluating newer drugs in thalassemia were collected from databases, including Pubmed, Scopus, Prospero, Clinicaltrials.gov, Google Scholar, and the Google search engine. We used the following keywords: thalassemia, novel, treatment, drugs, and ineffective erythropoiesis during the initial search. Relevant titles and abstracts were screened to choose relevant articles. Further, the full-text articles were retrieved and relevant cross-references were scanned to collect information for the present review.

Hypogonadotropic Hypogonadism in a Female Patient with Thalassemia Major

Thalassemia refers to a group of inherited diseases characterized by decreased or absent synthesis of normal globin chains. The direct consequence is an imbalance of the alpha and beta globin chain synthesis that results in anemia from ineffective erythropoiesis and hemolysis. The term thalassemia major refers to the severe form that is often associated with life-long transfusion dependent anemia. Hypogonadism is the most frequently reported endocrine complication, affecting 70-80% of thalassemia major patients.

STUDY OF SERUM LIPID PROFILE IN BETA-THALASSEMIA MAJOR PATIENTS

Background: Beta-thalassemia is the commonest single-gene disorder in the Indian population. Beta thalassemia major is caused by complete absence of beta globin chain production resulting from reduced synthesis of one or more globin chains which can be caused by different globin gene mutation resulting in ineffective hematopoiesis, increased hemolysis and early onset anemia.&#x0D; Methods: A cross-sectional; case control study was done on 50 diagnosed Cases of beta-thalassemia major in the age group of 1 year to 18 years receiving regular blood transfusions; not suffering from any ailment or any other disease leading to deranged lipid profile were included. In controls; 50 normal healthy children were included.&#x0D; Results: Lipid analyses of controls and thalassemic children. It is clear from the results that beta thalassemia major patients had significantly lower total cholesterol (TC), high-density lipoprotein cholesterol (HDL) and low-density lipoprsotein cholesterol (LDL) compared with controls (p&lt;0.001).&#x0D; Conclusion: Lipid profile in Beta thalassmia patients show significantly low levels of total cholesterol, LDLC and HDL-C.&#x0D; Keywords: Beta Thalassemia Major, Lipid Profile, Hypocholesterolemia.

A Case Report: Infertility Treatment of a Female with Beta-thalassemia Major

Beta-thalassemia is caused by a genetically mediated deletion of beta-globin chain of hemoglobin. It is an autosomal recessive disease, which causes a severe medical condition that requires longterm blood transfusions. An impaired hypothalamic-pituitary-ovarian axis mainly causes infertility in such patients. This case report presents a 26-year-old female, a known case of beta-thalassemia major, that received monthly blood transfusions before conceiving. The patient sought consultation for the treatment of primary infertility at Bahrain Defence Force Royal Medical Services (BDF-RMS) Hospital. The patient underwent two trials of intrauterine insemination (IUI). The goal was to build up endometrial thickness by gonadotrophins administration for embryo implantation. To conclude, IUI combined with gonadotrophins for ovarian stimulation has shown success. Keywords: Artificial Insemination, Beta-Thalassemia, Hypogonadism, Infertility, Pregnancy

Scheduled Outpatient Red Blood Cell Exchange Program Reduces Admission and Complications in Sickle Cell Disease

Background:Sickle cell disease (SCD) is one of the most common inherited genetic disorders. It is caused by a mutation in the beta globin chain that allows for polymerization, which causes the phenotypic sickle shape of the red blood cells (RBCs). SCD causes patients (patients) to suffer a number of complications such as pain crises, anemia, pulmonary hypertension, chronic kidney disease (CKD) and stroke. This leads to significant mortality, hospital admissions and lengthy stays. Many patients suffer from chronic pain and require significant amounts of opioids. Hydroxyurea works well for some patients but is not a cure. Many patients do not adhere to it well. For patients with persistent severe disease, our institution has offered scheduled outpatient red cell exchange (RBCX) to reduce complications from SCD.MethodsAfter obtaining IRB approval, we queried the procedure logs in our apheresis center to identify patients on the RBCX program from 1/1/2000 to 1/15/2016. We are doing a retrospective chart review of identified patients. Baseline demographics, indication for enrolling into RBCX, daily pain medication requirements (standardized to oral morphine equivalents (OME), history of DVT/PE, iron overload, CKD and pulmonary HTN. We are also evaluating compliance with RBCX, number of hospital admissions and length of stay (LOS) one year before and after enrolling in RBCX.ResultsSo far, we have analyzed data from 104 patients on our RBCX program with median age of 24 (15-62). 42% are male and 86% were HbSS. 35 patients were enrolled for pain and 54 for strokes. 66% patients had been on hydroxyurea prior to enrolling but only 13% continued on it while on RBCX. 86% used intermittent central venous catheters (CVC) as access for exchange. 54% of patients had documented iron overload with 87% of those on an iron chelator. Excellent compliance with SCRX was seen (92%).In the pain group, 18 (51%) were on hydroxyurea prior to enrolling to RBCX; only 7(20%) continued the drug while on the program. Median age in pain group was 27 (19-56), 17(49%) were males and 29(83%) HbSS. Mean HbA levels on enrolling in pain group was 45.8. The year prior to enrolling, median no of admits was 5, which dropped to 2 during first year on RBCX (decrease of 60%). Median total LOS at 1 yr prior was 16 days and 1 yr after was 2 days for the year post starting RBCX (decrease of 87.5%). In the pain group, OME(mg/day) decreased by 21.5% from 370 to 290. There were no cases of VTE associated with periodic CVC placement.Median ferritin level prior to RBCX in the stroke group was 2988 (56-11877) with 63% of patients receiving concurrent chelator therapy.DiscussionSCD is a morbid condition with pain being a major reason for hospital admission and stays. We describe a single center experience with RBCX. In the patients enrolled for pain, we demonstrated a decrease in opioid use (21.6% in daily OME use), in hospital admits, and length of stay. In the stroke group, there was no recurrent stroke. Interestingly, there were no admissions for pain crisis or ACS in stroke group; indicating RBCX is effective in preventing complications. Compliance was excellent in our program and complications, such as line associated VTE and infections, were not found in this initial group. Additional analyses of the rest of our population are underway. While this is a small sample, we believe RBCX is a viable treatment option in a patient population with a complicated disease and limited therapies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Zinc levels in Beta-Thalassemia Major: A Review of the Literature

Objective: Zinc is an essential trace element for the body that is involved in various significant body functions such as protein synthesis, DNA synthesis, and cellular growth. It is found in almost every cell and plays an important role in the immune system, affecting both innate and acquired immunity. Patients with beta-thalassemia major are at risk of zinc deficiency. Beta-thalassemia major is an inherited disease caused by a reduction or complete absence of beta-globin chains and the affected patients need repeated blood transfusions to survive. Accordingly, it causes oxidative stress and tissue damage, alteration of antioxidant enzymes, and changes in other essential trace element levels due to iron overload. Zinc levels in beta-thalassemia major patients were reported to be significantly reduced in most of the studies. Serum zinc levels of the patients with beta-thalassemia major should be monitored regularly and zinc supplementation should be provided to these patients.

English

Thalassemia, derived from Thalassa [Greek: Sea] refers to a cluster of hereditary haemoglobinopathies initially reported in areas of Sub-Saharan Africa, the Indian subcontinent, Southeast Asia, and the Mediterranean where malaria was (or is) endemic. Currently, it is the most frequently recognized haemoglobinopathy, and has been correlated with a plethora of immune system changes such as neutropenia, natural killer cell dysfunctions, increased activity of CD8 suppressor cells, along with disturbances in macrophage function, chemotaxis, phagocytosis, and interferons INFγ production.1 The reduction in the alpha or beta chain that leads to the production of haemoglobin is the key pathophysiology behind thalassemia. Therefore, weakened red blood cells can contribute to inadequate erythropoiesis and haemolytic anaemia. Thalassemia diseases are known as transfusion-dependent or non-dependent according to either their beta-globin chain genotype or their clinical path. The most serious type of thalassemia is beta-thalassemia major, and it is transfusiondependent, presenting in early infancy.2 A diagnosis of β-thalassemia major (BTM) means lifelong, regular transfusions, supplemented with adequate iron chelation therapy for the patient.3 This also means that unless adequate blood screening and hygiene procedures are in place, patients with BTM are at a risk of transfusion transmitted infections (TTI).4 Many countries have been prompted by the spread of Covid-19 infection to shutter routine outpatient coronary health care units before the pandemic is over, which also extends to people with thalassemia, who require regular follow-ups. While Covid-19 infection rates remain high, patients with thalassemia with planned cardiovascular examinations are advised to delay their medical appointments for a minimum of 3 months.1 In addition, according to the statement published by the Thalassemia International Foundation on the 13th of July, 2020, patients with hemoglobinopathies are at a greater risk in acquiring the Covid-19 infection, posing an additional challenge to the patients, families, and medical staff managing these disorders.5 Thalassaemic patients have reduced levels of protein S and protein C; elevated aggregation of platelets; and recruitment of monocytes, granulocytes, and endothelial cells. Patients of thalassemia also show elevated markers of platelet and coagulation activation, even in the absence of major thromboembolic events. An increase in D-Dimer levels is also seen in most Covid-19 patients who are hospitalised, attributable to the underlying inflammatory process.1 A variety of questions have been raised during the ongoing Covid-19 pandemic with respect to diagnostic and clinical approaches towards this particular population. The precise path of infection with Covid-19 in those patients has yet to be elucidated.2 The progression of Covid-19 infection in patients with hemoglobinopathy in general and thalassemia in particular is not fully known and is still an area of discussion and under review. We report a case of a 30-year-old male patient, a known case of beta thalassemia major on maintenance transfusion and iron chelation therapy who acquired Covid-19 infection.

Investigation of Some Trace Elements levels Antioxidants in Patients with Thalassemia Major and Sickle Cell AnemiaThalassemia in South of Iraq

Back ground: Thalassemia major) THM( is the most common single gene disorder. It is a hereditary blooddisease characterized by reduced or absent production of beta globin chains. For the patients with SCA-Thal,they have two mutations (sickle cell anemia and thalassemia). The ratio of minerals and trace elements in thepatients’ blood played an important role in many biological processes. This study aims to measure the levelof seven elements, Fe, Mn, Ca+2, Mg, P, Cr, Co and three another antioxidant element (Zn, Cu &amp;Se) in theblood of THM and SAC-thal patients.Results: In THM and SCA-Thal patients, antioxidant elements (Cu, Zn &amp; Se), showed highly significantbehaviour when compared to each other and with the control group as total patient population, and as (total,male and female) numbers. In thalassemia patients, Fe, P &amp; Co also showed highly significant behaviour,while Ca + 2 behaviour was not significant for male numbers only. Elemental Mg &amp; Cr, demonstratedinsignificant behaviours. In SCA-Thal patients, Mn &amp; Ca + 2 showed highly significant behaviour, while,Fe showed a non-significant behaviour relative to male numbers only, and Mg, P, Cr &amp; Co showed nonsignificant behaviour.Conclusion: The study revealed the similarity of antioxidant elements behaviour in both diseases, as well asthe statistical behaviour of all elements when compared with the control group for these diseases.

Design and Development of Reverse Slot Blot for the Simultaneous Detection of Rare and Regional Specific Mutations in the Beta Globin Gene in Khuzestan Province of Iran.

Beta-thalassemia is the most frequent hemoglobin disorder in Iran resulting from disrupting mutations in the beta globin (HBB) gene that causes decreased or complete absent of beta-globin chains. The screening of beta-thalassemia minor and major individuals and prenatal diagnosis is important for familial planning. Therefore, it is essential, depending on the ethnicity and local frequency of changes, to develop a rapid and accurate method for molecular diagnosis of beta-thalassemia. Here, we developed reverse slot blot (RSB) assay for the simultaneous detection of six common pathogenic changes in the HBB gene (-88, -28, IVSII-745, IVSII-848, Codon 6 [G → A] for HbC, Codon 6 [A → T] for HbS) in the Khuzestan Province of Iran. We designed normal and mutant oligonucleotide probes for each selected mutation and fixed them on positively charged nylon membrane. In the next step, a multiplex-polymerase chain reaction (PCR) performed for the amplification of the entire HBB gene using labelled 5'-biotinylated primers. The PCR products were hybridized to immobilized oligonucleotide probes on the membrane at the appropriate temperature. Finally, we developed the membrane by chemically colorimetric reaction using nitro-blue tetrazolium-5-Bromo-4-chloro-3-indolyl phosphate. For the best probe concentration, we made a serial dilution of probe pairs for each mutation. The optimal probe concentration for each mutation varied from 25 to 50pmol. In the next step, DNA samples from homozygous affecting individuals were subjected for multiple PCR. Hybridization of each PCR products on the nylon membrane with probe pairs revealed specific bands with expected signal intensity without any background. Our designed RSB test is a rapid, sensitive and cost-effective method for screening of regional specific beta-thalassemia mutations in the Khuzestan population of Iran, which might be extended for the detection of any desired pathogenic changes.

Voxelotor for the treatment of sickle cell disease

ABSTRACT Introduction: The clinical manifestations of sickle cell disease (SCD) result from an inherited mutation in the beta-globin chain of hemoglobin (Hb) that causes Hb tetramers to polymerize when deoxygenated. The resulting erythrocyte deformation causes mechanical obstruction of blood flow by sickled cells, hemolysis, anemia and end-organ injury. While pain is the hallmark symptom of SCD, chronic organ injury as a result of anemia, inflammation and progressive vasculopathy play a major role in morbidity and mortality. Due to the complex pathophysiology of SCD, the need for an individualized, multi-modal pharmacologic approach is apparent. Until 2018, hydroxyurea was the only disease-modifying pharmacologic therapy approved for use in SCD. Since then, three new agents have been approved including voxelotor, the subject of this review.Areas covered: Published pre-clinical and clinical data are reviewed. Voxelotor is a first-in-class small-molecule agent that binds to Hb and increases oxygen affinity, preventing polymerization. Recent clinical trials have shown that it increases Hb concentration and reduces hemolysis in patients with SCD. This increase in Hb concentration may significantly impact morbidity and mortality from chronic organ injury.Expert opinion: The mechanism of action, published studies and current opinions on the clinical use of voxelotor in SCD are presented.

Musculoskeletal imaging manifestations of beta-thalassemia

Beta-thalassemia is a heterogeneous group of anemic disorders caused by the absence or defective production of beta-globin chains. Their clinical manifestations vary from asymptomatic to severe symptoms leading to a transfusion-dependent anemic state. The genes that cause thalassemia are prevalent in Asian and African populations, particularly concentrated in the Middle East, Mediterranean region, parts of India, and South East Asia. Over time, the disease causes various musculoskeletal abnormalities with complex pathophysiology secondary to chronic anemia. The compensatory mechanisms result in diffuse marrow hyperplasia, yellow to red marrow reconversion, osteopenia, and pathologic fractures. Inability to remove excess iron and inevitable iron overload as a result of multiple blood transfusions in patients with thalassemia major and intermedia is another face of the disease. Musculoskeletal manifestations include osteopenia, coarse trabeculae, bone expansion, synovitis, joint effusion, and metaphyseal dysplasia. These complications have long-lasting effects on the skeletal growth pattern resulting in bone deformity, short stature, premature closure of physes, and predisposition to infection. Additionally, there are radiologic features of iron-chelator therapy, which are unique and unrelated to the disease process itself. Familiarity of radiologists with the imaging features of beta-thalassemia is crucial in both diagnosis and timely management of the disease and its complications.