Thalassemia is a hereditary blood disorder that disrupts the body’s ability to produce healthy hemoglobin, leading to chronic anemia and various complications. This comprehensive guide explores the causes, types, and symptoms of thalassemia, while offering in-depth insights into diagnosis, treatment options like blood transfusions and gene therapy, and crucial management strategies for affected individuals. We also cover the genetic factors, pregnancy considerations, and ongoing research efforts aimed at improving quality of life and patient outcomes.
1. Introduction to Thalassemia
Thalassemia is a hereditary hematologic disorder characterized by defects in the production of one or more of the globin chains that make up the normal adult hemoglobin (Hb A) molecule, thus resulting in anemia. Hemoglobin synthesis requires the normal production of 2 α globin chains and 2 β globin chains. β-thalassemia is characterized by a defect of the β globin gene cluster located on chromosome 11, whereas α-thalassemia is due to defects of the α globin gene cluster located on chromosome 16. The thalassemias are the most common monogenic disorders in man and are now global in distribution owing to historical migration of populations from high prevalence areas [1]. The thalassemias are inherited diseases that require life-long care and follow-up. The understanding of their natural history or epidemiology is useful for designing targeted prevention strategies. The introduction and effective dissemination of safe effective treatments for both thalassemias in the late 1950s to early 1960s changed their natural history from lethal forms of anemia in childhood, to chronic diseases defined by their treatment. Chronic blood transfusion therapy, however, has its own problems such as iron overload and a number of complications usually requiring referral to specialty centers.
Thalassemia is caused by a genetic alteration that reduces the synthesis of a type of globin chain, a component of hemoglobin, and is a common, complex group of iron-related diseases [2]. Humans are genetically predisposed to thalassemia, and it is most common in certain geographic regions. Thalassemia is classified as β‐, α‐, δ γ, δβ, and γδβ within a spectrum, and α‐ thalassemia and β‐thalassemia are major subcategories. β‐thalassemia was first reported in 1925 and is a hereditary disorder of abnormal hemoglobin production due to defects in the β-globin gene cluster located on chromosome 11.
1.1. Definition and Types of Thalassemia
Thalassemia is a common hereditary autosomal recessive blood disorder caused by a genetic mutation that leads to reduced production of normal hemoglobin. It is characterized by abnormality in the globin synthesis of hemoglobin, resulting in continuous destruction of red blood cells (RBCs). By WHO (World Health Organization) definition, β-thalassemias are a group of genetically determined disorders in which there is a decreased or absent synthesis of the β-globin chains of hemoglobin. In North India, thalassemia major is a disease of unbridled iron overload which leads primarily to cardiac, hepatic and endocrine dysfunction. It carries the enormous burden of socio-economic disability and a significant toll on utilization of health care resources. Abnormalities in the structure or synthesis of either the α- or the β-globin chains of the hemoglobin molecule characterise the hereditary disorder known as thalassemia [2]. The genes responsible for making β-globin are positioned on chromosome 11 while the α-globin genes are found on chromosome 16. Hb is a spherical protein, a conglomeration of globin (chained polypeptide) and a porphyrin ring, and is present in the red blood cells. In adults, Hb A (α2β2) is responsible for carrying oxygen from alveolus to tissues. Thalassemia is categorized as β, α, δ γ, δβ, as well as γδβ, depending upon which globin chain is affected [3]. The α- and β-thalassemia are two major categories and their occurrence depends on four and two genes, respectively. It is produced by alterations in the DNA segment. The unpaired globin chains are not stable. They lead to immature destruction of precursors of RBC and shortening of life span of mature RBCs in the blood. Globin tetramers thus formed precipitate, leading to membrane damage and ineffective erythropoiesis. Hb breakdown (direct action of heme on the membrane lipid bilayer) culminates in generation of free iron, which catalyze chemical reactions (Fenton reaction) in which free radicals or reactive oxygen species (ROS) are produced.
1.2. Epidemiology and Global Burden
Thalassemia syndromes are a group of single gene disorders, which lead to the impaired synthesis of the globin part of hemoglobin (Hb), the oxygen carrier through the blood. With this definition, one might wonder why they are presented here as common hereditary disorders of the Mediterranean area; after all, a number of other globin disorders belong to the same family of diseases, for instance those due to structural alterations of globin chains [4]. The question could be answered if one takes the liberty to use a wider view and enlarge the vision from Mediterranean Sea to the coasts of the almost enclosed Red Sea and Persian Gulf, then to the other side of the world, the beaches of Indian, Andaman and South China Seas. Keeping this wider vision, it will be easy to include Southern Russia, Iran, Turkey, the Middle East, Central and Southern India, Southern China, and finally all the archipelagos of the Far East. All these lands carry the same name: “Thalassemia belt” [5]. People living in these areas are believed to have the same background in terms of cross-island migration from the sea in ancient times and similar persecution of an endemic malarial environment. At each coast wore high, forests covered mountains where malaria never existed, but were the by-pass geography of the sea migrations. It is in these continents’ core that the safe haven of the Sea People wanted by the Pharaon has to be sought. The Quaternary ices and the Pleistocene glacial periods saw this haven becoming accidentally an entitlement by finding a refuge from the deadly jungle. The consequent vicissitude can only be speculated, with the Mediterranean and Indian Ocean rivers becoming the natural exit of a massive exodus. This and the following migrations along the coasts to Eastern Europe and the pro-western Atlantic countries explain the absence of thalassemic genes in the same coasts.
2. Genetics of Thalassemia
The genetic basis of α-thalassemia and β-thalassemia and molecular techniques applicable in a clinical laboratory for the diagnosis of thalassemia have been described. Understanding the genetic basis of thalassemia and these molecular techniques will have a strong impact on the accurate molecular diagnosis of thalassemia. So, this article focuses on explaining the genetics of thalassemia in detail.
Thalassemia is one of the most commonly inherited Hb disorders. It is a genetically heterogeneous disorder having different forms which are classified based on which globin chain is affected. The mechanism of the β-thalassemia mutation is described in detail. The structure of the β-globin gene cluster on chromosome 11 and the mutations occurring in β-thalassemia were described by 7 deletional and other point gene mutations [2]. Furthermore, there is a classification of point mutations into five groups. Factors affecting the severity of β-thalassemia are also described focusing on complex β-thalassemia. The structure of α-globin gene cluster on chromosome 16, the mechanism of α-thalassemia, and for 30 deletional forms and 21 point mutations are described including non-deletional mechanism. Complications of thalassemia including endocrine complication, bone complications, liver complications, cardiomyopathy, and infectious complications are also described [3].
2.1. Inheritance Patterns
As thalassemia is an inherited disorder, the discussion of genetic taint constitutes a major consideration of any discussion of thalassemia. At the moment of fertilization, the genetic make-up of an individual is determined. The sex of a person is based on either an X or Y chromosome from the father and an X chromosome from their mother. Females possess an X/X chromosome arrangement whilst males are X/Y. Each chromosome has thousands of genes, the fundamental units of heredity. A gene may exist in different forms, known as alleles. For example, the beta globin gene can have many alleles, all of which are considered mutations of the normal/non-thalassemia beta globin gene. A normal individual could have a pair of normal beta globin (B) genes (BB genotype). Should that individual give rise to an egg or sperm that possessed one of the defective mutant forms (for example, a gene that causes beta-thalassemia (B0)), a subsequent child would therefore have a genotype of (BB0). This arrangement is known as being an unaffected beta-thalassemia carrier (beta+-thalassemia carrier) or heterozygotes. Should that child meet someone who also gave rise to an egg/sperm with an equal chance of having a defective beta globin gene (the same heterozygote arrangement), the subsequent child would have a genotype of (B0B0). Such a child would be homozygous for the beta-thalassemia gene arrangement and would therefore be affected by the disorder. It is said to possess an identical gene arrangement in both copies of the beta globin gene and hence would produce no functional beta globin.Thus, the Autosomal Recessive pattern, typical example in inheritance pattern of the non-HbE gene of G6PD deficiency can explain the basic mechanism of how abnormal genes appear in a population over generations [5].
2.2. Molecular Basis of Thalassemia
The abnormal production or reduction in the rate of formation of normal α-or β-globin subunits of hemoglobin (Hb) A is called thalassemia. Recipients of thalassemia either totally lack gene/output or produce abnormal quantity of globin chain subunits, which leads to excess production of one subunit (globin). The genes responsible for making β-globin are positioned on chromosome 11 while α-globin genes are found on chromosome 16. The β-globin subunit genes are therefore responsible for β-gene mutation or deletion leading to β-thalassemia. There are more than 600 different types of known mutations/deletions leading to β-thalassemia [2]. According to the pattern of inheritance, genetic errors can result in loss of function or depletion of gene copies. Thalassemia is of two types: α and β thalassemia depend on which globin chain is affected. Thalassemia is categorized as β, α, δ γ, δβ, as well as γδβ, depending upon which globin chain is affected. Other minor types of thalassemia are tx‐thalassemia, dux gene thalassemia (with absence of function of γ‐gene), epsilon thalassemia with absence of epsilon globin chain), and fugu thalassemia being found in an aquatic species. The α‐ and β‐thalassemia are two major categories. With different types of mutations in α and β thalassemia, there are numerous minor classifications within α‐thalassemia, imbal, with genes located within the same chromosome. The excess globin chains can then form unstable tetramers, and chain aggregated binding to thalassemia can occur [3].
3. Clinical Presentation and Symptoms
Thalassemias are a group of genetically inherited disorders characterized by partial or complete absence of one or more of the globin chains of hemoglobin (Hb). Individuals with thalassemia may be asymptomatic carriers of abnormal hemoglobin or may develop symptomatic microcytic anemia of varying severity and complications. Almost all individuals matter of race, religion, culture, and even levels of economic development are at risk of thalassemia. The prevalence of thalassemia major (TM) and/or thalassemia intermedia (TI) is one in 700 in Mediterranean countries [5]. The permanent transfusion requirement of TM and TI patients—transfusions of red blood cells every two to three weeks after they developed anemia—is responsible for a number of complications, which appear after the 10 years of age in patients with TM receiving adequate medical care. The most severe complications of thalassemia are hematological: iron overload due to transfusions and, in some cases, due to increased intestinal iron absorption. Life-expectancy of well-treated thalassemia patients nowadays can exceed 50 years. Patients with genetically controlled reduction in the activity of one globin chain producing genes—particularly those of the β-globin family—can have different forms of β-thalassemias. Heterozygous forms are asymptomatic conditions called “thalassemia minor”. Homozygous or double heterozygous genotype is thalassemia major. There are subtypes of thalassemia major like IVS1-110 (G>A), IVS1-6 (T>C) and codon 39 (C>T).
Thalassemia is among the earliest manifestation of chronic diseases that are recognized to have a range of impact on the physical, psycho-social, emotional, financial state, and quality of life negatively in the affected individuals however, it still remains an inadequately explored theme [6]. In pediatric age-group patients with chronic diseases, quality of life is an important aspect after health status which further includes socio-economic status but is often overlooked. There are growing advancements in treatment options and opportunities to improve the health and longevity of patients with hemoglobinopathies i.e. thalassemia, however, a more holistic perspective encompassing such complications which involves the quality of life is warranted. Increasing awareness and knowledge on the quality of life in thalassemia and other chronic infectious and non-infectious diseases is vital for designing and implementing those effective modalities and intervention strategies to improve their health and wellbeing.
3.1. Anemia and Hemoglobin Levels
The hematological picture is characterized by a hypochromic-microcytic anemia with an increase of red-cell production and a low reticulocyte count. The diagnosis is confirmed by the demonstration of an imbalance in the aerobic chain α/non-α globin in the presence of normal iron stores [2]. The laboratory work-up should include the following:
* 1. Anemia is determined by hemoglobin levels adjusted for age and gender. Also, measurements of blood indices help delineate the etiology of the anemia. Anemia is classified as either microcytic (< 80 fl) or macrocytic (> 100 fl) based on the mean corpuscular volume (MCV) [5]. * 2. Observed blood film is interpreted to calculate the red blood cell (RBC) count, white blood cell (WBC) count, and basic information on platelets, shape, size, maturity, and conditions of the cells.
The following observations are of relevance in the hematological analysis of thalassemia:
Microcytic Hypochromic Anemia
In cases of thalassemia, there is defective synthesis of one or more globin chains. Consequently, the α/β equilibrium is disturbed and the excess β-chains precipitate. Precipitation of excess globin chains is harmful for the red cell progenitors as well as the mature red blood cells engendering oligoblastia in the marrow and short-lived red cells, respectively. The final result is severe anemia contrived mainly due to the damaged precursors that are phagocytosed by macrophages in the marrow. As a consequence of the drastic drop in the hemoglobin level, the hematopoietic system undergoes hyperplastic changes stimulating hematopoiesis outside the marrow. These initiate reparative mechanisms and the influx of reticulocytes from the marrow into the peripheral blood.
Low/Normal Reticulocyte Count
In cases of thalassemia, there is an increase in red cell production caused by erythropoietic activity inducible by tissue hypoxia. However, the reticulocyte count remains low or only marginally increased. This low reticulocyte count in view of the severely lowered hemoglobin concentration is a unique aspect of this disease.
3.2. Complications and Organ Involvement
Thalassemia is a blood disorder characterized by reduced production of hemoglobin. It is inherited by autosomal recessive, and the affected individuals may have a variety of presentations from asymptomatic forms to severe anemias which require blood transfusions. Chronic hemolysis, ineffective erythropoiesis, and multi-organ micro and macro iron overload due to regular blood transfusions are the major pathophysiological processes related to thalassemia. Chronic anemia can lead to developmental impairment, skeletal changes, cardiac, endocrine, and hepatic complications. Iron overload causes damage to multiple organs including the heart, liver, pancreas, and kidneys, and endocrine glands. It is correlated with serious complications like heart failure, liver cirrhosis, diabetes mellitus, growth retardation, and infertility [7]. Cardiac, liver, and endocrine complications remain among the major causes of mortality and morbidity. Salient features of complications and organ involvement are listed below, according to the organ systems involved.
Heart: Iron accumulation in the heart muscle causes grave clinical manifestations. Cardiomyopathy along with arrhythmias is the major cause of death. Arrhythmias are due to congestion of septum and wall, altered conduction, and fibrosis [8]. Sudden unexplained deaths, usually during sleep or rest, are not always preceded by clinical symptoms. It may also lead to tachyarrhythmias, atrio-ventricular blocks, and acute heart failure on transfusing massive blood transfusions. Most patients develop heart failure by the 3rd-4th decade due to cardiac iron overload protruding EF < 55%.
Liver: With the advent of chelation therapy, the incidence of hepatic iron overload has come down, but still, moderate liver iron concentration is encountered in 57.4%, and severe overload in 14.5% of patients with good chelation therapy. Most patients develop fibrosis by the age of 10. Cirrhosis usually develops in girls after puberty along with overt diabetes. Iron overload is related to the severity of fibrosis. Hepatitis B virus infection, a history of hemotransfusions may cardio fertilize liver cirrhosis besides iron overload.
Endocrine: Endocrinopathy is a multisystem disorder affecting the growth, metabolism, and sexual functions of various organs. It is due to iron deposition in the anterior pituitary, ovaries, pancreas, adrenal glands, etc., leading to infertility, growth retardation, delayed puberty, diabetes mellitus, etc. It is found in 55.0% by 30 years and 91.7% incidence by 30 ̀s involving the growth hormone, thyroid hormone, sex hormones, cortisol, etc.
4. Diagnostic Approaches
Patients suspected of having thalassemia should have a CBC (complete blood count), blood smear for cell morphology, reticulocyte count assessed. If the MCV (mean corpuscular volume) measured by CBC is ≤ 80 fL, thalassemia is considered a possible diagnosis. Results are considered normal if MCV > 80 fL or if MCV is between 80 and 95 fL and the RDW (red cell distribution width) is > 17%. After the initial laboratory testing, it has to be determined as to which thalassemia screening tests should be done on the sample. Screening tests may include an iron study, hemoglobin electrophoresis, or a combination of tests. Beta thalassemia is present in most patients with an RBC count greater than 6.0 x 10^12/L and an MCV of less than 70 fL. The use of a family history of thalassemia is important in the approach to screening for thalassemia. If both parents are heterozygous for the same type of thalassemia, the population risks and the type of studies available must be explained to the couple [9].
Iron deficiency is usually suspected because of microcytic hypochromic anemia. Initial screening tests usually include a complete blood count and an examination of the peripheral blood smear. The common laboratory screening tests for thalassemia are as follows: packed cell volume, MCV, MCH, MCHC, RDW, and age. Among them, MCV is the most important index in the diagnosis of thalassemia. MCV is less than 80 fL in beta-thalassemia and less than 78 fL in alpha-thalassemia. The second most important index is RDW. RDW is greater than 14% in iron deficiency anemia, greater than 20% in blood loss anemia, and lower than 14% in thalassemia [3].
4.1. Laboratory Tests and Imaging Techniques
Thalassemia is an inherited blood disorder that affects hemoglobin synthesis [9]. Genetic mutations lead to decreased production of either alpha (α) or beta (β) globin chains, resulting in thalassemia syndromes. There is a wide range of clinical severity, from asymptomatic if fully compensated, through mild, moderate and severe symptomatic forms. The most severe forms require regular blood transfusions from early childhood for survival. However, this may lead to accumulation of iron due to the transfusions and excessive absorption of iron from the diet, which must be treated to prevent iron-overload damage to vital organs. New therapies for thalassemia are being intensively researched.
Thalassemia is classified into two main types based on the affected globin chains: α- and β-thalassemia. Each type has several clinically significant mutations known as the α (involved in α-thalassemia) or β (involved in β-thalassemia) globin gene. Clinically, thalassemia can be classified by its severity into the following types: Thalassemia major: It is the most severe form of thalassemia, presenting at about 6 months of age when HbF levels drop. It is characterized by severe anemia, growth retardation, hepatosplenomegaly, and skeletal abnormalities. Thalassemia intermedia: It is best described as patients who are not severe enough to require regular blood transfusions, but who have a higher degree of anemia than thalassemia minor.
4.2. Genetic Testing and Counseling
Thalassemia is a group of hereditary blood disorders that affect the body’s ability to produce hemoglobin, leading to severe anemia. Affected individuals require lifelong red blood cell transfusions, which can result in serious complications such as damage to the heart, liver, and other organs due to iron overload. Genetic testing and counseling play a key role in the diagnostic process, estimating the risk to prenatal children, understanding prognosis, and exploring prenatal diagnosis and in vitro fertilization with pre-implantation genetic diagnosis considerations. Various techniques are available to molecularly characterize mutations resulting in thalassemia. Individuals are counseled on mode of inheritance and clinical features of thalassemia within their family and on the risk that partner is a carrier. Genetic testing is available for most common mutations, and couples are informed of their potential reproductive options [10].
Thalassemia is an autosomal recessive disorder caused by a variety of genetic changes in the beta-globin locus. Common deletions are found in non-Indian ethnic groups, although rare non-coding deletions have been reported in the Indian population. A comprehensive strategy for identifying base-pair substitutions has been developed. Knowledge of population changes at the beta-globin locus can help explain some of the complex genotype-phenotype correlations in thalassemia [11]. Understanding mutations present in a community can assist in implementing the most cost-effective screening procedures.
5. Management Strategies
Anemia is a condition that arises as a result of a deficiency in hemoglobin (Hb) and the red blood cell mass in the blood. With the deficiency of hemoglobin, the oxygen-carrying capacity of the red blood cells ineffective to circulate the oxygen in the body. In doing so, the thalassemia blood transfusion is carried out at a frequency of 2-4 weeks interval. As the result of these repeated transfusion, iron becomes excessive in the blood to be over than the rate of iron excretion from the body. This iron overload substance is toxic resulting different organ damage among which the heart dysfunction is a major cause of morbidity and mortality [2].
Patients with thalassemia require specialized, lifelong multidisciplinary care. As detailed in the TIF Guidelines for the Management of Transfusion-dependent Thalassemia, a comprehensive approach for the management of thalassemia incorporates the following: 1) Regular blood transfusions and the use of iron chelation therapy. 2) Comprehensive care that includes medical, therapeutic and supportive management. 3) A holistic approach that encompasses the social and psychological development of the child, education, and family welfare. 4) A multidisciplinary team including: hematologists, clinical and laboratory experts in transfusion medicine, hematopathology, iron metabolism and chelation therapy, computer/IT specialists, psychologists, pediatricians, social workers and other ancillary staff [1].
5.1. Blood Transfusions and Iron Chelation Therapy
Blood transfusions in thalassemics are recommended at the age of six months every two to three weeks, depending on the rising of the level of Hb. Continuous transfusion is needed for patients with high reticulocyte counts. Transfusion therapy is needed to maintain Hb levels more than 9.5mg%, in order to avoid compulsory erythropoiesis [2].
Individual differences in the absorption of dietary iron determine rates of iron overload. Generally, patients with thalassemia can ingest 4-15 mg of elemental iron daily. Due to the genetically-acquired non-exportable and non-excretory iron, patients with thalassemia major suffer chronic iron overdose and consequent organ failure if iron is not chelated continuously [8].
The body iron load is best assessed using S.Ferritin. Because needles and syringes of metal sterile sets are used in transfusion centers, an exposure to steel needles must be considered. The necessity of estimating S.Ferritin before each transfusion and three days after is suggested. Intensive chelation treatment (Deferoxamine continuous infusion) is recommended before S.Ferritin levels reached 100 ng/ml in patients with a low starting level.
5.2. Bone Marrow Transplantation
The most promising “curative” intervention is bone marrow transplantation, which aims to permanently correct the hematologic defect of the disease. The success of bone marrow transplantation is dependent on multiple factors, with “conventional” treatment as the most important and the greatest determinant. It is now considered standard treatment for thalassemia patients with an HLA-matched sibling [2]. In centers with expertise, the safest window for successful transplantation appears to be children under five years of age and without a history of severe graft versus host disease (GVHD). Attempts should be made to use HLA-matched unrelated donors and boycot infant donor transplantation, due to potentially serious consequences and high complications. Active efforts must continue to improve techniques and explore alternative transplantation sources, since some patients without siblings and non-matched donors are intended for “traditional” treatment. The probability of survival is predicted by various pretransplantation parameters. Bone marrow transplantation offers the best hope for a cure in thalassemia patients, but it is important to emphasize that it is currently performed only in selected pediatric patients [12].
6. Emerging Therapies and Research
Gene therapy is a promising approach that has recently achieved remarkable success in treating hemoglobinopathies [13]. Gene therapy for β-thalassemia is based on: (i) the addition of a functional β-globin gene to the genome of β-thalassemic hematopoietic stem cells (HSCs) using β-globin gene transfer and globin gene editing approaches, (ii) the correct modulation of the expression of different genes involved in gene globin gene regulation using the pharmaceutical modulation of γ-globin gene (HbF induction). Significant milestones on gene therapy for β-thalassemia have been achieved in the last decade, including the optimization of preclinical models, the establishment of suitable vectors, the discovery of new potent γ-globin gene regulators, and the generation of encouraging results from clinical trials [14]. Despite these remarkable progress, the research on gene therapy strategies against β-thalassemia is still at its infancy and several hurdles have to be overcome in order to guarantee the successful translation of these promising therapeutic approaches from laboratories to clinical practice.
6.1. Gene Therapy and Genome Editing
Gene therapy and genome editing offer new avenues for thalassemia, given the Mendelian nature of the disease. Approaches are being developed to correct the primary mutation, insert a normal β-globin gene (using lentivirus, a retrovirus, or AAV) in place of a faulty gene, or target disorders in a rather precise manner via CRISPR/Cas9. There have been recent encouraging results with such approaches, with 2 gene therapy products approved or in widely used clinical trials [14]. After treatment with the β-globin gene therapy LentiGlobin, treated patients with severe β-thalassemia became transfusion-independent, exhibited durable high levels of T2β+, normal β-chain tetramer-containing hemoglobin, and 70-100 normalized expression of β-type globin [15]. These studies provide proof-of-principle of the efficacy of gene therapy for β-thalassemia. Progress has been made with these clinical trials. Several other products are in clinical trials, including lentiviral juvenile β-thalassemia, AAV vectors covering the β-globin locus (with or without CAS9), and CRISPR/Cas9 (with or without AAV vectors).
6.2. Stem Cell Research
Stem cell research is a rapidly evolving area of research that has implications for the treatment and care of thalassemia. Hematopoietic stem cell transplantation (HSCT) remains the only curative approach to thalassemia, but it is restricted by limited donor availability and the rigorous conditioning regimens required in the setting of non-malignant diseases. Cell-based therapies using either genetically-modified hematopoietic stem and progenitor cells (HSPC) or iPSCs are warranted. Recent advances in gene-editing technologies, such as CRISPR/Cas9, allow for efficient knockout of target genes in a wide range of cell types. This breakthrough technology, coupled with lentiviral vector-based gene transfer, has formed the basis for the rapid development of alternative strategies for HSCT and their application in thalassemia [15]. HSPCs with knockout of the Transferrin receptor 1 (TFR1) were generated using CRISPR/Cas9 technology, transduced with a lentiviral vector expressing the therapeutic β-globin and transplanted in β-thalassemic mice. Correction of thalassemia was observed, indicating that blockade of transferrin uptake at the level of the stem/progenitor cells effectively reduces iron overload. Unfortunately, mutations in HSCs may have been introduced by the editing procedures utilized and these mutations did not remain clonal. Another exciting area of research is the use of hemangioblasts or embryonic stem (ES) cell-derived hematopoietic stem cells. Cell populations expressing both vascular and hematopoietic markers are capable of generating mesodermal structures in vivo, including hematopoietic cells. However, there are still safety, ethical, and regulatory hurdles associated with their use that need to be addressed. An alternative approach would involve the use of induced pluripotent stem cells (iPSCs), which have emerged as potentially unlimited sources of HSPCs for a myriad of regenerative treatments. iPSCs can be derived from all somatic cell types, including adult fibroblasts, and hESCs. Importantly, HSCs derived from iPSCs circumvent the HLA-matching barriers of conventional HSCT. However, the major hurdle with this therapy in the setting of thalassemia is the need to correct mutations in the β-globin locus before differentiation into HSPCs. Like HSCs, mutations may have been introduced in both β-thalassemic alleles as a result of the editing procedures and these mutations did not remain clonal [13].
7. Psychosocial Impact and Patient Support
Focusing purely on psychosocial aspects of thalassemia, particularly for patients with TDT, this environment holds a plethora of experiences that encompass the emotional, social, and psychological dimensions of living with thalassemia. There is a lack of balance between the treatment that keeps TDT patients alive and the need for comprehensive, holistic patient support. While pill boxes, pen needles, and infusion pumps are the tools of medication management, some attention also must be given to the emotional tools that support focus, organization, and adherence. The psychosocial complexity of the continuous management of a chronic genetic condition, such as TDT, requires multilevel exploration. Highlighting experiences emerging from the exploration of the psychosocial impact of thalassemia on patients and their families adds understanding to a sensitive and important aspect of life with chronic disease [6].
The psychosocial complexity can be understood through understanding the emotional, social, and psychological experiences of the patients. Although the approaches to different aspects of multifaceted psychosocial impact of disease are delineated further below, such aspects are interlaced and cannot strictly be separated. Each experience influences others and collections of experiences contribute to overall psychosocial impact with varying degrees of intensity. Many of the emotional experiences emerge in different contexts but impact on the patients in similar emotional ways. Knowledge of thalassemia, perception of health, financial and work related issues, relationships with family and friends, and the importance of thalassemia treatment create a social context that shapes the psychosocial impact and gives rise to different social experiences [16].
7.1. Quality of Life and Mental Health
Beside the physical and biological aspect of the disease, the psychosocial aspect should be deemed equally important. Illness is one of the most challenging life events for everyone since it minimises the control of their lives, which is one of the primary causes of anxiety. Specially chronic diseases that require lifelong medical care and long-time follow-up lead to difficulty in daily life, social life, work life, and high expenses. Children and adolescents are mostly affected by some chronic diseases negatively by affecting both their quality of life and their developmental stages. Thalassemia, which is the most common monogenic disease in the world and requires blood transfusion from infancy, is a chronic disease with high medical complexity and life-long care requirements [6].
In the present study, the issues of work-life, marital life, family life, change in daily life, and worry about independence after parents’ death were asked as the quality of life of adults with thalassemia considering their young adulthood. It was found that other quality-of-life issues were around 3 and aggravated after the disease was treated; no study was found in the literature on this subject. Therefore, the data obtained as a result of this study might provide insight into the planning of psychosocial services in this area in the future. It was recommended that psychoeducation be arranged to raise awareness of patients and families about these issues. It was also determined that their mothers were more worried than fathers. Therefore, it was suggested that on-going psychosocial services at the centre be provided in a father-inclusive manner [16].
7.2. Support Groups and Resources
Patient support organizations and related resources are widely available. These organizations not only provide opportunities for patients and families to interact with each other and share experiences but also provide a strong community and network for individuals with thalassemia. All national thalassemia organizations should become members of the Thalassemia International Federation (TIF) and utilize its services. These services include education for healthcare professionals, materials with up-to-date international standards of care, the organization of international scientific conferences, and the dissemination of knowledge and prevention programs to at-risk populations [1]. Medical professionals can contact the TIF Secretariat for assistance in establishing a national thalassemia organization and the availability of educational programs.
Thalassemia is a common hereditary chronic disease that affects millions of individuals worldwide. In countries with limited resources, thalassemia maxima can result in severe disruptions of a family’s economic and social status, and ultimately affect their quality of life [5].
8. Pregnancy and Thalassemia
The pregnancy and thalassemia nexus encompasses a spectrum of considerations, traversing the perspectives of both the mother-to-be and the infant. For mothers, in addition to the expected physiological changes during pregnancy, thalassemia-associated complications, response to treatment, and accompanying morbidities influence the determination on whether to continue with the pregnancy or not. In addition to maternal considerations, fetal considerations may include fetal viability, fetal prognosis based on detected anomalies, and the associated risks and timeliness of different management options [17].
It is crucial at the outset to explore the mother’s perspective, including her awareness and concerns prior to pregnancy, emotional response to the pregnancy state and the knowledge of thalassemia carrier status, pregnancy desires, expectations for the pregnancy outcome vis-à-vis personal or cultural views, and willingness to engage in fetal anatomy assessment, genetic testing, and to act on the information obtained [18].
8.1. Preconception Counseling and Pregnancy Management
Preconception counseling is critical for women with thalassemia, as it helps them understand the genetic implications and health risks associated with pregnancy. Prior to conception, genetic counseling is recommended to assess the risk of passing on thalassemia to offspring. Testing both partners for carrier status enables couples to make informed decisions regarding reproductive options, such as in vitro fertilization with pre-implantation genetic diagnosis (PGD), which can prevent the transmission of the disorder [1].
During pregnancy, women with thalassemia require specialized care to manage the complications associated with their condition. This includes regular monitoring of hemoglobin levels, iron chelation management, and close surveillance of organ functions, particularly the heart and liver. Transfusion needs may increase during pregnancy, and maintaining optimal hemoglobin levels is essential to support both maternal and fetal health. Additionally, iron overload must be carefully monitored, as it can exacerbate pregnancy complications.
For women with beta-thalassemia major or intermedia, a multidisciplinary approach involving hematologists, obstetricians, and other specialists is crucial to optimize pregnancy outcomes. Fetal monitoring, early detection of complications, and individualized delivery plans are vital components of pregnancy management in women with thalassemia.
Proper counseling and medical support before and during pregnancy can significantly reduce the risks to both mother and child, ensuring a healthier pregnancy and delivery [19].
9. Ethical and Legal Considerations
Life with thalassemia sometimes covering the main points with words made more familiar through everyday use. Surveying and developing, organizing and reviewing, drafting and production, visualizing and reviewing. The important points, such as where, when and how a thalassemia event occurred, fails to outline discrimination and harm. A note in the text about the kind of supportive measures that have been used might be helpful. This might include things like medical assistance, emotional support, educational assistance, access to legal, communication, transport, interpreting, or employment services and accommodation about genetically related conditions along with basic details.
There may be issues surrounding the reproduction rights of couples with the same genetic condition. These include couples who are both healthy but who carry the same gene mutation. Such cases may be reported as discrimination, disadvantage or harm, often unqualified with respect to whether the genetic relatedness is known to stakeholders. Consideration should also be given to genetic discrimination and objections on ethical grounds to the use of reproductive technology that seeks to avoid not just disease but disability or difference more broadly [20]. Such objections may be based on notions of social justice or equity, on concerns that wider societal attitudes toward disability may be negative, and on the view that societal perception of a genetic condition may change even if the underlying reproduction technology remains the same.
9.1. Reproductive Rights and Genetic Discrimination
Focusing specifically on reproductive rights and genetic discrimination, Boardman et al. (2020) examine a particularly pressing case where genome science and technology come together. Thalassemia is an autosomal recessive condition resulting in severe disability and early mortality; it is most prevalent in communities of South Asian, Mediterranean, Middle Eastern, and Asian origin. The race in the UK, representing a growing number of newborns with beta-thalassemia major and stillbirths due to hydrops fetalis, is mostly restricted to 5% of families from specific backgrounds. Foetal screening adopts a “family test” approach, screening both mothers and fathers of foetuses found to be at risk. Debate exists within the community regarding parental implication in the event of an affected child being born, given understanding that thalassemic parents “knowingly” risk having affected children and that families that choose to remain “screen naive” are choosing to be ignorant about the disease. Community concerns regarding screening highlight ethical, governance, and health inequities, seeing interventions in the community as episodic, peaks into the lives of these reprogenetic families, potentially stigmatizing, and yet life changing [20]. Stepping into the constellation of genes, fears, hopes, imperfections, and responsibility that come to shape the configurations of new reproductive technologies and genetic knowledge in the practice of screening, reproductive rights and genetic discrimination define the big ethical picture of the genome age, thickening early debates around the commercialization and patenting of life.
The potential opportunities and challenges genome science offers are manifold and, in an expanding academic literature, are explored in nuanced details. Enabling extended kinship relations is one such prominent opportunity, explored through the lens of reproductive technologies and genome science employed to screen family and kin. Thalassemia is an ancient condition with roots in malaria-endemic regions and extensive migration histories as populations still feel socio-political and environmental impacts. Community-levels of the condition are de-stabilizing as it propagates communities’ resources while leaving in-tact those separating communities through nativity, status, wealth, or ability. Facing a sea of big choices that reshuffle the conditions of being human through kin, questions surrounding kinship re-configure both blood and genome, recalibrating being human [15].
10. Public Health Strategies and Screening Programs
In accordance with WHO recommendations, a total population under 20 years of age (usually from 3 to 10 years) of a region is screened for thalassemia and other hemoglobin disorders as health care delivery cascades used in HMIS. Community screening programs are recommended for thalassemia and are cascaded through health care providers or a village health volunteer supported by an ASHA worker (Indian Government). Various models of screening in India have operated with education initiatives led by NGOs, state departments, schools, colleges, and universities [9]. Screening can be confidential, that is the screened are informed of their status and there is follow-up care planned or anonymous screening, that is only the high-risk women are identified for counseling and testing. Broadly in public health, there are two types of screening activity: voluntary screening by virtue of socioeconomic status, religion, caste, and similar factors, and population screening which is irrespective of the above factors.
A pilot population screening project on thalassemia was initiated in the year 2000 with village populations in Nagapattinam district, Tamil Nadu, India. For screening, the village population was sub-grouped into homogenous social strata with respect to caste, religion, neighbouring villages, and family trees. A total of about 7500 individuals in the age group of 3-17 years were screened for thalassemia in 65 villages and very few were found to have thalassemia (1.7%) with no transfusion-dependant cases. About 230 cardiac cases were screened in the age group and on corroborating the birth records/reports, no new cases were found. Further studies were undertaken on a nomination and voluntary basis in the general non-cardiac population and all the thalassemics were detected to be 3-4 years of age. The hospital-based voluntary screening model where public health recommendations of screening are followed by health education and health delivery cascades produced a thalassemia load of 3.2%. Following the above pilot projects, ‘thalassemia prevention’ was included in the Tamil Nadu government’s National Programme for Prevention and Control of Birth Defects and Neurological Disorders (BNDCP) in 2006.
10.1. Newborn Screening and Carrier Detection
Newborn screening and carrier detection programs are essential components of public health strategies for the control and prevention of inherited disorders such as thalassemia [21]. These public health screening programs aim to identify affected individuals for appropriate intervention as early as possible, to prevent harmful effects on their health and quality of life [20]. Parents or offspring of positive newborn screening results are also screened to determine their genetic status regarding the disorder. In thalassemia, they are provided with information, education, and counseling on the implications of the positive screening result. Commonly used tests for screening and confirmation include hemoglobin electrophoresis or high-performance liquid chromatography. In thalassemia screening programs, in addition to parental screening with standard tests, the use of DNA-based genotyping tests to screen parents for the presence of mutations in a given population is also recommended. This enhances screening efficiency and reduces the number of tests performed on “at risk” couples. Genetic counseling on reproductive options presently available to these couples is then provided.
In populations where sickle cell disease and/or β-thalassaemia are common, screening of pregnant women and newborns for these disorders should be implemented whenever possible, regardless of the socioeconomic standing of the population. It is nearly impossible to eliminate these disorders from a population. Therefore, wherever applicable, newborn screening and, in its absence, carrier detection programs should also be implemented in even the lowest resource settings to reduce the burden of these diseases among affected individuals and their families.
11. Global Collaborations and Advocacy Efforts
In July 2021, the Thalassaemia International Federation (TIF), with the support of the European Union’s Health Programme, launched the 2021 Thalassemia and Sickle Cell Disease World Patient Advocacy Day Grants Programme (TGDG). This initiative invites organizations of patients affected by thalassemia and sickle cell disease to submit proposals for projects aimed at raising awareness about their disease at the global, regional, or national level. Such projects could comprise various activities, including campaigns featuring informational, educational, or scientific publications and audiovisual materials, exhibitions, workshops or meetings, articles in the media, conferences, etc. The deadline for proposal submission was set for early January 2022 [1].
TIF and the Genomics Policy Unit of the World Health Organization (WHO) jointly organized a webinar on Novel Genetic Technologies & Societal Implications, which was held on September 30, 2021. This was the fifth in a series of webinars on Genomics and Global Policy Issues of Interest to Low- and Middle-Income Countries. An overview of WHO’s role in global health policy and its implementation, together with an explanation of wider developments in the field of genomics, was provided. There was a focused discussion on the challenges of the equitable application and social acceptability of new technologies [4].
11.1. International Partnerships and Funding Initiatives
Focusing on international partnerships and funding initiatives, this section delves into the concerted global efforts to address thalassemia. It highlights the importance of collaborative partnerships and financial support in driving research, advocacy, and healthcare interventions for thalassemia.
Reducing the global burden of thalassemia is an imperative however, current funding efforts are limited. With a focus on research, advocacy, and other healthcare proposed interventions, the need for collaborative partnerships and funded call projects is presented. Three partnership models have been explored and implemented leading to successful funded interventions in breast cancer, cervical cancer and epilepsy. Thalassemia partnership proposals have been developed using existing networks of the Thalassaemia International Federation (TIF), health ministries, non-governmental organizations, universities and the pharmaceutical industry. These proposals offer a large number of projects focusing on fourteen countries and concern thalassemia prevention, control and treatment as well as patient organization capacity building. Through such partnerships, it is hoped that innovative projects for the reduction of the thalassemia burden will be funded bringing benefit to affected families and whole communities [1].
12. Conclusion and Future Directions
The comprehensive analysis of thalassemia presented in this guide highlights the multifaceted nature of this condition, encompassing its genetics, pathophysiology, clinical manifestations, diagnosis, management strategies, psychosocial and economic implications, and ongoing research and advocacy efforts. While the scientific understanding and clinical management options for thalassemia have advanced significantly in recent decades, important gaps remain, particularly in terms of awareness, resource allocation, appropriate management, and access to health care and preventive education in many parts of the world [13]. The importance of thalassemia as a global public health issue and the need for increased awareness, research funding, and establishment of appropriate disease management and prevention programs throughout the world are emphasized. Such initiatives will increase the likelihood of providing safe and effective health care and preventive programs in the future for those at risk. It is hoped that this guide will serve as a foundation for further discussion and analysis regarding thalassemia and consider the possibilities for its improved management. There is an increasing need for global attention to and action regarding public health issues such as thalassemia [1].
Surveillance and need assessments in affected regions could delineate the gap between the current and the desired state of management and prevention of thalassemia. Costs associated with both the illness and the failure to manage its transmission would clarify the economic burden of the disease on individuals and affected communities. In high-prevalence countries, adequate disease management would dramatically reduce mortality and greatly improve the quality of life of patients with thalassemia. Infection control and improvements in the blood supply and transfusion services are equally relevant to other diseases whose incidence is affected by thalassemia.
12.1. Challenges and Opportunities in Thalassemia Research
As the thalassemia research community gathers to celebrate recent achievements, share best practices, and address challenges and opportunities, there is much to celebrate, much to be proud of, and much to ask why. Three compelling and related questions regarding future directions of thalassemia research are as follows: What should be the key priorities for thalassemia research in the next 10 and/or 25 years? Are we doing enough as a community to realize these priorities? Are resources being well used? There is no single right answer to these questions, just as different people in different circumstances have different challenges and opportunities; but this personal reflection concerns some of the challenges to be tackled and opportunities to be grasped and how these could be tackled collaboratively at both the local and global levels [13].
There are opportunities to harness ‘big data’ to accelerate the pace of research and improve organizations’ ability to deliver successful candidate drugs. In recent years, it has become clear that thalassemia is a relatively straightforward monogenic disorder, and new technologies may soon emerge to enable genome-wide, high-throughput, in vivo screens of chemical libraries and potentially rapid identification of new patients’ drugs [2]. For thorough exploration of the genome, however, the starting point would need to be a deep understanding of the thalassemia phenotype, and the screening systems would need to be capable of reproducing that phenotype. This would be facilitated by thalassemia features that appear to involve both loss of function and gain of function (for mutations affecting the hemoglobin tetramer), as well as phenotypes that are primarily erythroid anomalies like a severe excess of proerythroblasts in the marrow. There are opportunities to erase beta thalassemia at the genomic level in patients but equally importantly at the population level through gene-restrictive surgery or target deletion of variants protective against malaria. There is a major opportunity to intervene at the genetic level as nearly all thalassemic syndromes are preventable with precision medicine. Current opportunities in prevention range from the cheap and effective to the more expensive but potentially more effective and accurate.
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