Thalassemia: A lifelong battle with hemoglobin deficiency

 Corresponding author: Turdaliev samatbek Orozalievich. Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Thalassemia: A lifelong battle with hemoglobin deficiency Madhu Kushwaha, Turdaliev samatbek Orozalievich *, Ansy Abdul Rasheed, Gaurav kushwaha, Asraful alom, Mohammad ubaid ur rehman, Shahid afridi and Akshay parasram chautmal Department of Public health, Infectious disease favulty, Osh State University, Kyrgyzstan. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 Publication history: Received on 01 December 2024; revised on 08 January 2025; accepted on 10 January 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.21.1.0042 Abstract Thalassemia is a heterogeneous group of inherited disorders of haemoglobin caused by reduced or absent production of one or more of the globin chains. They are the commonest single gene disease worldwide. The disease was first described by Thomas Cooley (a paediatrician from Detroit, USA) in 1925. the two common types, majority of β thalassaemias are caused by point mutations, while most of the α thalassaemias result from gene deletions.The resulting imbalance in globin synthesis is responsible for the ineffective erythropoiesi sand hemolysis typically observed in the thalassemia syndromes.About 3.2 % of the world’s population (152 million people) carry β-thalassemia genes.The initial symptoms of the disease appear in the latter half of the first year of life, when the synthesis of γ-chains is not replaced by the synthesis of β-chains.The improved survival of patients with thalassemia major has been attributed to improvement in transfusion therapy, better understanding of mechanisms of organ damage from iron, more effective iron chelation, the availability of magnetic resonance for the evaluation of cardiac iron overload, and the referral of patients to centers of excellence. Keywords: Thalassemia; Hemoglobin; Alpha-thalassemia; Beta-thalassemia; Anemia; Genetic Disorders; Blood Transfusions; Iron Chelation; Bone Marrow Transplant; Prognosis; Genetic Screening 1. Introduction 1.1. Thalassemia Syndromes Thalassemia syndromes are a group of inherited hematological disorders characterized by reduced or absent synthesis of one or more globin subunits that constitute normal human hemoglobin (Hb). The most common forms include α-, β- , γ-, and δβ-thalassemia. According to the latest Bulletin of the World Health Organization, thalassemia mutations (2013) pose a significant public health burden, affecting 71% of 229 nations globally. It is estimated that approximately 1.5% of the global population carries genetic mutations that impair hemoglobin production. 1.2. Geographical Distribution Thalassemia gene mutations are predominantly found across a broad geographical region extending from the Mediterranean basin through the Middle East, the Indian subcontinent, Burma, Southeast Asia, Melanesia, and the Pacific Islands. Α-thalassemia is particularly prevalent in Southeast Asia (e.g., China, Thailand, Vietnam, Malaysia, and the Philippines), the eastern Mediterranean, and parts of the Middle East. In contrast, it is less common in Africa and India; however, α+ thalassemia is relatively more frequent in India. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 324 Figure 1 Prevalence of thalassemia major in different countries The high prevalence of thalassemias, alongside sickle-cell disease and glucose-6-phosphate dehydrogenase (G6PD) deficiency, in malaria-endemic regions is likely due to the protective advantage heterozygous carriers possess against Plasmodium falciparum malaria. Mutations affecting the αand β-globin genes are highly variable, with distinct frequencies across countries and regions. Even within specific countries, variations in migration patterns and the prevalence of consanguineous marriages have led to differences in the distribution of thalassemic mutations. 1.3. Pathophysiology of α-Thalassemia The underlying defect in α-thalassemia is an imbalance in globin chain synthesis, causing an excess of βand/or γ-globin chains. Unlike the unstable α-globin chains, excess γ-globin chains during fetal life and excess β-globin chains in postnatal life form soluble tetramers: γ4 (Hb Bart) and β4 (HbH), respectively. These tetramers, although soluble, impair red blood cell (RBC) function and stability, leading to hemolysis and, to a lesser extent, ineffective erythropoiesis. Despite the identification of over 100 α-thalassemia mutations, clinical manifestations are categorized into four phenotypes of increasing severity: silent carrier, α-thalassemia trait, HbH disease, and Hb Bart hydrops fetalis. • Four-Gene Deletion (Hb Bart Hydrops Fetalis): Involves the deletion of all four α-globin genes (both alleles on both chromosomes), resulting in complete absence of α-globin chain synthesis. Only γ4 tetramers (Hb Bart) are produced, which cannot transport oxygen effectively. The condition is incompatible with life, leading to intrauterine death (stillbirth at 28–40 weeks) or death shortly after birth. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 325 • Three-Gene Deletion (HbH Disease): Characterized by a severe reduction in α-globin chain synthesis. Results in the production of β4 tetramers (HbH) alongside reduced levels of HbA and Hb Bart. HbH is ineffective for oxygen transport and precipitates in erythrocytes and erythroblasts, leading to moderate anemia (hemoglobin levels 70–100 g/L) and splenomegaly, a presentation consistent with thalassemia intermedia. Most individuals are not transfusion-dependent. HbA2 levels are typically normal or reduced. • Two-Gene Deletion (α-Thalassemia Trait): Causes mild microcytosis with or without minimal anemia. HbH inclusion bodies may be observed in a peripheral blood smear stained with brilliant cresyl blue. • One-Gene Deletion (Silent Carrier): Typically, asymptomatic with a normal blood picture. Reference: The alpha Thalassaemia (Fessas P, Loukopoulos D, Kaltsoya A. Peptide analysis of the inclusions of erythroid cells in beta thalassemia. Biochim Biophys Acta. 1966; 124:430-432) Figure 2 The alpha Thalassaemias 1.4. Β-Thalassemia Β-Thalassemia refers to a group of inherited disorders characterized by reduced or absent synthesis of the β-globin chains of hemoglobin, leading to imbalanced globin chain production. The resulting accumulation of unpaired α-globin chains causes hemolysis, ineffective erythropoiesis, and varying degrees of anemia. Β-Thalassemia is classified into three clinical forms: β-thalassemia major, β-thalassemia intermedia, and β-thalassemia minor, depending on the severity of clinical presentation and transfusion requirements. 1.5. Β-Thalassemia Major Β-Thalassemia major, also known as Cooley’s anemia or Mediterranean anemia, represents the most severe form of the disorder. It results from homozygosity or compound heterozygosity for β-thalassemic mutations. Clinically, it is characterized by severe transfusion-dependent anemia requiring more than eight red blood cell transfusions annually. The major pathological features of β-thalassemia major include: • Severe Anemia: Reduced hemoglobin synthesis due to absent or markedly decreased β-globin chain production. • Shortened red cell lifespan caused by the precipitation of insoluble excess α-globin chains. • Ineffective erythropoiesis resulting from erythroid precursor apoptosis. • Relative folate deficiency. o Skeletal Abnormalities:Expansion of erythroid marrow leads to bone deformities, including distortion of the skull, facial bones, and long bones. o Splenomegaly:Significant spleen enlargement occurs due to extramedullary hematopoiesis and chronic hemolysis. o Red Cell Morphology:Peripheral blood smear shows marked microcytosis, hypochromia, target cells, and extensive anisopoikilocytosis (variations in size and shape). World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 326 o Hemoglobin F Persistence:Hemoglobin F (HbF, α₂γ₂) remains elevated throughout life, as β-globin synthesis is severely impaired. Symptoms typically appear around 6 months of age when HbF levels begin to decline. o Iron Overload (Hemosiderosis): Chronic hemolysis, ineffective erythropoiesis, and repeated blood transfusions cause generalized iron overload, leading to organ damage. 1.6. β-Thalassemia Intermedia β-Thalassemia intermedia describes a milder form of the disease, characterized by moderate anemia (hemoglobin levels between 70–100 g/L) that does not necessitate regular blood transfusions. Symptoms are less severe, and transfusions may only be required intermittently, such as during periods of physiological stress. The clinical presentation may result from: • Milder Genotypes:Homozygosity for mild β⁺ mutations that permit partial β-globin chain synthesis.Coinheritance of α-Thalassemia: • Reduced α-chain production mitigates α/β-globin chain imbalance, alleviating ineffective erythropoiesis and hemolysis.Hereditary Persistence of Fetal Hemoglobin (HPFH).Increased γ-globin chain synthesis (HbF) helps compensate for the β-globin deficiency, reducing the impact of α-chain excess. 1.7. β-Thalassemia Minor β-Thalassemia minor, or β-thalassemia trait, occurs in heterozygous individuals who inherit one mutated β-globin allele. It is typically asymptomatic or associated with mild clinical manifestations, including: • Minimal hypochromic microcytic anemia.Elevated levels of hemoglobin A₂ (HbA₂, α₂δ₂), a minor hemoglobin component that becomes more prominent in β-thalassemia minor. 1.7.1. Pathophysiology of β-Thalassemia The fundamental defect in β-thalassemia is the reduced or absent production of β-globin chains, leading to a relative excess of unpaired α-globin chains. The key pathological consequences include: • Decreased Hemoglobin Production:Reduced β-globin chain synthesis results in overall lower hemoglobin levels. • Α-Globin Chain Imbalance:Unpaired α-globin chains precipitate in erythroid precursors and mature red blood cells, disrupting erythroid maturation and membrane integrityThe extent of α-chain accumulation determines the severity of clinical manifestations. • Erythroid Damage:Excess α-globin chains lead to oxidative stress, apoptosis of erythroid precursors, and shortened red cell lifespan, resulting in hemolysis and ineffective erythropoiesis. In β⁺-thalassemia (partial β-globin synthesis), residual β-globin production helps reduce the severity of α-chain imbalance. Similarly, persistence of γ-globin chain synthesis in β-thalassemia intermedia partially compensates for the β-chain deficit, improving the clinical outcome.Overall, the degree of α/non-α globin chain imbalance determines the clinical severity of β-thalassemia, ranging from asymptomatic carriers to transfusion-dependent β-thalassemia major. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 327 Figure 3 Pathophysiology of β-thalassemia. Ig, immunoglobulin. (Fessas P, Loukopoulos D, Kaltsoya A. Peptide analysis of the inclusions of erythroid cells in beta thalassemia. Biochim Biophys Acta. 1966; 124:430-432) 1.8. Clinical Features of β-Thalassemia In β-thalassemia, the transition from fetal hemoglobin (HbF, α₂γ₂) to adult hemoglobin (HbA, α₂β₂) occurs postnatally. Consequently, the anemia develops gradually during infancy, typically around 6 months of age, and progressively worsens. 1.9. Key Clinical Manifestations 1.9.1. Severe Anemia Progressive anemia leads to symptoms such as pallor, fatigue, and failure to thrive in early childhood. Growth and Developmental Delays Retarded physical growth and failure to achieve developmental milestones are common. 1.9.2. Skeletal Abnormalities Expansion of erythroid marrow causes skeletal deformities, including: Frontal bossing of the skull. Maxillary overgrowth, resulting in the characteristic “chipmunk facies.” 1.9.3. Radiological Changes These include widening of the diploic space of the skull, “hair-on-end” appearance on X-rays, cortical thinning, and widening of the medullary cavities of long bones, with a predisposition to pathological fractures. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 328 Figure 4 (A) Child with thalassaemia, showing the typical facial features. (B) Skull Xray of a child with β-thalassaemia, showing the ‘hair-on-end’ appearance. (C) X-ray of a hand, showing expansion of the marrow and a thinned cortex. (Courtesy of Dr. Orzincolo C, Castaldi G, Scutellari PN, Franceschini F. The beta-thalassaemia.Skeletal Radiol. 1989; 18:373-376.) 1.9.4. Hepatosplenomegaly Enlargement of the liver and spleen occurs due to extramedullary hematopoiesis and chronic hemolysis. 1.9.5. Recurrent Infections Increased susceptibility to infections is associated with iron overload, as elevated serum iron levels promote bacterial growth. 1.9.6. Iron Overload Complications Chronic iron overload, resulting from repeated transfusions and hemolysis, can lead to systemic complications, including: Growth retardation, Skin hyperpigmentation., Hepatic damage progressing to cirrhosis, Endocrine dysfunction, such as insulin-dependent diabetes mellitus, delayed puberty, hypoparathyroidism, and hypothyroidism, Cardiac failure due to myocardial iron deposition. 1.9.7. Folate Deficiency The increased erythroid turnover in β-thalassemia often results in relative folate deficiency 1.10. Screening for Thalassemia Screening is an essential preventive strategy, particularly during antenatal care: • Maternal Screening: All pregnant women should be screened during their first antenatal visit. • Paternal Screening: If the mother is identified as a carrier, the father is screened to assess the risk of severe thalassemia in the fetus. • Prenatal Diagnosis: Chorionic Villus Sampling (CVS): Performed at ≥10 weeks of gestation, CVS provides fetal DNA for genetic analysis using advanced methods such as PCR, Southern blotting, or RFLP analysis. • Fetal Blood Sampling: Conducted at 18 weeks of gestation for analysis of globin chain synthesis. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 329 • Preimplantation Genetic Diagnosis: Embryonic biopsy allows for genetic analysis before implantation, reducing the risk of affected pregnancies. 1.11. Laboratory Features • Peripheral Blood Examination:Severe microcytic hypochromic anemia with hemoglobin levels ranging from 2 to 6 g/dL.Red blood cells exhibit marked anisopoikilocytosis, target cells, basophilic stippling, Howell-Jolly bodies, and nucleated red cells on blood smear examination. • Test for Inclusion Bodies:Aggregates of unpaired α-globin chains can be visualized in erythroblasts using supravital staining (e.g., methyl violet). Post-splenectomy, these inclusion bodies may also appear in peripheral blood. • Hemoglobin Electrophoresis:Elevated levels of HbF (ranging from 10% to 98%).HbA₂ may be normal or mildly elevated.In homozygous β⁰-thalassemia, HbA is absent; in β⁺/β⁺ or β⁰/β⁺ forms, reduced levels of HbA are detected. • Bone Marrow Examination:Shows marked erythroid hyperplasia, indicative of ineffective erythropoiesis. • Iron Studies:Increased serum iron and ferritin levels.Unconjugated bilirubin is elevated due to hemolysis. • Osmotic Fragility:Decreased red cell osmotic fragility is noted. Β-Thalassemia major represents a significant public health concern, particularly in regions surrounding the Mediterranean, the Middle East, and Southeast Asia. In resource-limited settings, inadequate transfusion support and iron chelation therapy result in poor survival rates and reduced quality of life. Β-Thalassemia Major: Without regular blood transfusions and iron chelation therapy, affected infants rarely survive beyond early childhood. Inadequate treatment leads to severe complications, including iron overload and organ dysfunction. Β-Thalassemia Intermedia: Represents a milder phenotype where regular transfusions are not required, but patients may experience anemia-related symptoms and growth retardation. 1.12. Principles of Therapy 1.12.1. Blood Transfusion Historically, transfusions were administered only when anemia became symptomatic. This “on-demand” approach resulted in skeletal deformities, hepatosplenomegaly, and poor survival.The hypertransfusion protocol was developed to maintain hemoglobin levels ≥9.5–10 g/dL. Regular transfusions help suppress ineffective erythropoiesis, prevent skeletal deformities, and improve quality of life. 1.12.2. Iron Chelation Therapy Chronic transfusions result in iron overload, which requires chelation therapy to prevent organ damage.Desferrioxamine (DFO): Administered subcutaneously via infusion pumps (25–60 mg/kg/day) for 12 hours, 5– 6 days per week, often combined with vitamin C to enhance iron excretion. 1.12.3. Bone Marrow Transplantation (BMT) BMT is the only curative option for β-thalassemia major, though it carries significant risks of morbidity and mortality. The decision to pursue BMT depends on a careful assessment of individual risk-benefit profiles. Reference: Properties of iron chelating drugs used in thalassaemia. (Cohen AR, Glimm E, Porter JB. Effect of transfusional iron intake on response to chelation therapy in beta-thalassemia major. Blood. 2008; 111:583-587.) World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 330 Table 1 Properties of iron chelating drugs 1.13. Prevention of Thalassemia: Strategies and Priorities Thalassemia prevention should be prioritized due to its significant health and economic burden. Effective strategies rely on public awareness, carrier screening, genetic counseling, and prenatal diagnosis. 1.13.1. Public Health Education Raising awareness through mass communication platforms, such as media campaigns, helps educate the population about the nature of thalassemia, its socioeconomic impact, and the importance of preventive measures. 1.13.2. Carrier Screening and Genetic Counseling Carrier screening involves identifying individuals who are heterozygous for thalassemia mutations through simple, cost-effective diagnostic tests.Genetic counseling plays a pivotal role in informing at-risk individuals about the genetic implications and risks of inheritance.It is strongly recommended that heterozygous carriers avoid marrying another carrier of the same thalassemia gene to reduce the likelihood of having offspring with severe disease. 1.13.3. Prenatal Diagnosis Prenatal diagnosis is a critical intervention for couples at risk of having a child with thalassemia. It can be divided into two approaches: • Retrospective Diagnosis: Performed in couples who already have an affected child. • Prospective Diagnosis: Conducted in couples identified as carriers through screening programs. • Advances in prenatal diagnostic techniques allow early detection of affected fetuses, enabling informed decisions, including the option of selective termination of pregnancy where permissible. • By integrating health education, carrier screening, genetic counseling, and prenatal diagnostics into public health initiatives, the incidence of thalassemia can be effectively reduced. 1.14. prognosis Thalassemia is a group of inherited blood disorders that impact hemoglobin production, resulting in anemia. The severity of the condition can vary widely based on the specific type of thalassemia, the mutations involved, and the age at which it is diagnosed. Prognosis for those with thalassemia is influenced by several factors, including the type of thalassemia, the availability of treatments, and how well complications are managed. Both alpha and beta thalassemia types often require regular blood transfusions, iron chelation therapy, and other medical interventions. If left untreated, thalassemia can lead to serious complications such as endocrine dysfunction (which may include growth retardation, hypothyroidism, and diabetes), splenomegaly (enlargement of the spleen), and hepatomegaly (enlargement of the liver). Additionally, bone deformities can occur due to increased erythropoiesis, which is the expansion of bone marrow.The outlook for individuals with thalassemia is contingent on various factors, including whether it is alpha or beta thalassemia, the severity of the condition, the age at which it is diagnosed, and the effectiveness of treatment. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 323-334 331 2. Results Thalassemias are inherited as autosomal recessive disorders. Hemoglobin A (HbA) is composed of two α-globin and two β-globin chains (α2β2). The synthesis of α-globin chains is regulated by two gene clusters located on chromosome 16, while β-globin chain production is controlled by genes on chromosome 11. Each globin gene contains three exons (coding sequences) and two introns (non-coding regions). The synthesis of both αand β-globin chains is mediated by RNA transcription. Studies have consistently demonstrated that regular blood transfusions, combined with iron chelation therapy, significantly improve the quality of life and survival rates in patients with thalassemia. However, long-term management remains challenging due to complications such as iron overload, which can cause irreversible organ damage. Figure 5 Kaplan-Meier survival curve after the first decade of life, subdivided by cohort of birth of patients from an Italian cooperative study. The survival data were collected in 2009. The role of the cohort of birth is evident Bone marrow transplantation has emerged as a curative approach for some patients, though its widespread use is limited by the availability of suitable donors and the risks associated with the procedure. A large cooperative Italian study reported improved survival rates for patients born in recent years, with females exhibiting better outcomes compared to males. Despite these advancements, mortality rates in thalassemia patients remain elevated compared to the general population. Data from 2010 indicated that 68% of patients survived beyond 35 years of age, with heart disease accounting for 67% of deaths. Iron-induced oxidative damage remains a major contributor to complications in thalassemia, emphasizing the need for ongoing surveillance, infection prophylaxis, and early intervention. Chronic hepatitis, which is often observed in transfusion-dependent patients, should be appropriately managed. As survival rates continue to improve, new complications are emerging, shifting the clinical landscape of thalassemia and necessitating novel therapeutic strategies to address these evolving challenges.