Ashokrao Mane College of Pharmacy, Peth Vadgaon Maharashtra, India
Thalassemia comprises a spectrum of genetic hemoglobin disorders due to impaired or complete loss of the synthesize one or more globin chains, thus leading to chronic hemolytic anemia with different degrees of clinical severity. Here, thalassemia is reviewed fully from its inception in history up to the modern world's overall epidemiology of thalassemia specifically within areas such as the Middle East, the Mediterranean, and South Asia. The molecular pathogenesis and genetic basis of alpha and beta thalassemia are reviewed, with particular attention to the effect of individual mutations on presentation. Classification systems, such as the separation between thalassemia trait, intermedia, and major, are discussed in relation to both laboratory and symptomatology. The book also describes the key complications of thalassemia, including iron overload, organ dysfunction, and growth retardation, and reviews new diagnostic techniques, including hemoglobin electrophoresis and genetic analysis. Options for management from chronic transfusions and chelation with iron to cure by bone marrow transplantation and current gene therapies under investigation are assessed. Lastly, prevention via genetic counseling, premarital testing, and prenatal diagnosis is highlighted as important, especially in high-risk groups. This report is intended to be a reference for healthcare providers, researchers, and public health planners who are engaged in the prevention and care of thalassemia.
The thalassaemias are a class of recessive autosomal hereditary illnesses. [1] It is characterized by a reduction in red cell hemoglobin due to the absence or reduced production of one of the two polypeptide chains (beta/alpha) that comprise the typical adult human hemoglobin molecule (haemoglobin A, alpha2/beta2). [2] The term "thalassaemia," which comes from the Greek words "thalassa" (sea) and "haima" (blood), refers to the various thalassaemia syndromes that are named after the abnormal hemoglobin. β thalassaemia can be caused by defects in the β globin gene, whereas α thalassaemia can be caused by abnormalities in the α globin gene. [3]
There are more than Two hundred deletions or point mutations that affect the transcription, processing, or translation of α- or β-globin m RNA. [4] The clinical characteristics range from lack of symptoms to severe life-threatening anemias in womb or in early childhood if left untreated.[5] By the early 1900s, physicians in Europe had identified a splenomegaly-associated anemia condition in infants.[6] How this nomenclature came to be is unclear, though it is stated that the initial patients were typically of Mediterranean descent.[7]The first clinical report of thalassemia in American literature is credited to the pediatricians Thomas B. Cooley and Pearl Lee of Detroit. George Whipple is the one who originally named the disease thalassemia. [8] As suggested in the 1960s, where they were associated with the unbalanced globin chain synthesis. The platform was laid for further advances. [9] An easier methodology was worked out by which ordinary laboratories could measure amount of hemoglobin A2 and establish the diagnosis of thalassemia [10]. Additional noticeable changes about hemoglobin patterns in thalassemia patients resulted in the identification of HbH (β4) and Hb Barts (γ4), that is subsequently proved to be specific markers of alpha-thalassemia. [11] Reticulocytes from thalassemic individuals treated in vitro with radiological amino acids,David Weatherall and associates at Johns Hopkins University demonstrated that alpha or beta chain synthesis was impaired in both alpha and beta thalassemic patients as a result of an imbalance in globin chain synthesis. [12] [13] Determining if protein formation was aberrant at the structural gene or globin chain synthesis level was now necessary. [14] The majority of thalassemia syndromes were found to have a shortage of specific messenger RNA, as well as problems in messenger RNA translation to protein, according to a series of investigations. [15] Ribosomal units that can start, lengthen, and stop the globin chain are involved in this later step. [16] Thus, a better understanding of genetic control of human hemoglobins had become apparent. It was now understood that several loci of structural genes, i.e., alpha, beta, gamma, and delta, regulated synthesis of their respective globin chains. [17] People from the Mediterranean, Middle East, Transcaucasus, Central Asia, Indian subcontinent, and Far East have thalassemia, one of the most prevalent autosomal recessive illnesses in the world. However, populations in Africa also have a substantial amount of them. [18] Thalassemias are currently common in Australia, North Central and South America, and Northern Europe as a result of population migration [19].56,000 pregnancies worldwide result in a severe thalassemic condition, of which approximately 30,000 have BTM and 3500 pass away during pregnancy due to hydrops fetalis syndrome. [20]
CLASSIFICATION OF THALASSEMIA
2.1 Alpha Thalassemia [AT]
Among the most common genetic abnormalities of hemoglobin is AT [21] The main flaw is the decreased or nonexistent synthesis of alpha globin chains, which make up the moieties of various hemoglobins (Hb), including the minor component HbA2 (alpha2 delta2), the fetal HbF (alpha2 gamma2), and the adult HbA (alpha2 beta2). [22] AT is prevalent in tropical and subtropical regions of the world, where malaria was and is still endemic, much like other common globin gene diseases. Carriers of hemoglobinopathy are believed to be comparatively protected in a malarial environment. [23] Despite a great deal of investigation, the nature of this protection has not yet been determined. Note that the prevalence of the numerous genetic abnormalities that cause alpha-thalassemia varies throughout populations, and that the prevalence of the clinically relevant types, such as HbH illness and Hb Bart hydrops fetalis syndrome, also varies. [24] Alpha-thalassemia is now a fairly frequent clinical condition in North America, North Europe, and Australia due to recent significant population shifts. [25] The overproduction of beta globin chains due to decreased or missing alpha globin chain production is the cause of alpha thalassemia. Two genes on each chromosome 16 regulate the expression of the alpha globin chain. [26] Usually, the deletion of one or more of these genes results in the decreased output. The alpha thalassemia silent carrier state, which is asymptomatic and has typical clinical and hematologic findings, is caused by the mutation of a single gene. [21] Alpha thalassemia trait (minor) with microcytosis and typically minimal anemia is caused by the loss of two genes. Hemoglobin H (HbH), a beta4-structured hemoglobin that functions poorly, is produced symptomatically when three genes are deleted.[26].Hemolysis, splenomegaly, and microcytic anemia are the outcomes of alpha thalassemia intermedia, often known as HbH sickness. When four genes are deleted, hemoglobin Bart's (Hb Bart's), which has a gamma structure, is produced symptomatically. Because of hydrops fetalis, alpha thalassemia major (Hb Bart's) typically causes fetal mortality.[27]
Clinical classification of Alpha Thalassemia [28]
1.Silent Carrier State
2. Alpha Thalassemia Trait
3. Hemoglobin H Disease
4. Hydrops Fetalis
2.2 Beta Thalassemia
Excess alpha chain is the result of reduced or nonexistent beta globin chain production, which causes beta thalassemia. One gene, found on both chromosomes 11, controls the production of beta globin. [13] Patients may create different amounts of alpha globin chain in comparison to beta globin chain synthesis, depending on the amount of beta globin chain produced (from almost normal to none). [30] A gene mutation might result in beta thalassemia trait (minor), which is symptomless and manifests as microcytosis and very less anemia. [29] A patient has BTM (Cooley anemia) if their beta globin chain synthesis is either completely absent or drastically diminished. [13] Due to HbF, patients with BTM are nearly always asymptomatic during birth however, symptoms begin to appear at 6 months of age, when the beta globin chains are required. [31] The patient has beta thalassemia intermedia if the reduction in beta chain synthesis is less severe [29]. These patients may not need lifetime transfusions to survive past the age of 20, and their symptoms are less severe. [32]
Beta-thalassemias is classified as: [29]
• Thalassemia major [BTM]
• Thalassemia intermedia [BTI]
• Thalassemia minor
The signs of thalassemia major will first arise between 6 and 24 months of age; during this time, affected infants will exhibit poor growth.[33] Feeding difficulties, diarrhea, irritability, recurring acting febrile conditions, and growing abdominal distension due to splenomegaly and hepatomegaly may occur.[34] The symptoms of thalassemia major include poor growth, jaundice, generally poor musculature, genu valgum, a liver condition, ulcers in the legs, due to extramedullary hematopoiesis, and skeletal deformities due to bone marrow expansion. Thalassemia major is often poorly treated and transfused in developing countries where resources are scarce. [35] Long bone abnormalities in the legs and common craniofacial modifications (head bossing, nasal bridge depression, eye mongoloid slant, and maxillae hypertrophy, exposing the maxillary teeth) are among the skeletal changes. Growth and development will typically proceed normally for ten to twelve years if a planned transfusion program is initiated that aims for an acceptable Hb concentration should be 9.5 to 10.5 g/dL. [36] Patients who have received transfusions may experience iron overload-related problems [37]. Growth latency (failure to attain predicted heights) and/or failing or delay of sexual development are among the issues that children who are iron overloaded may have [38]. Subsequent iron overload complications may include hepatic (cirrhosis and fibrosis), cardiac (dilated myocardiopathy or occasionally arrhythmias), and endocrine (diabetes mellitus, hypogonadism (inability to develop secondary sexual characteristics), as well as deficiencies in the parathyroid, thyroid, anterior pituitary, and, adrenal glands). [39,40] Additional contraindications involve HIV infection, venous thrombosis, osteoporosis, hypersplenism, and persistent hepatitis brought on by the hepatitis B and/or C viruses. [41] Patients with iron excess and a viral infection of the liver are at a greater risk of getting malignant hepatoma. [42] The frequency and severity of iron overload-related problems are mostly determined by adherence to iron chelation therapy (described later). [43] People who don't get transfusions often die prior to they reach their second or third decade of life. [44] Patients can live past the age of 40 if they receive regular transfusions and the right chelation to cure iron excess. [45] Heart illness brought on by myocardial siderosis (iron buildup in the heart) is the most severe and clinically significant sign of iron overloading from beta-thalassemia. [46] 71% of individuals with BTM die from heart problems brought on by iron excess. [47]
Patients with thalassemia intermedia will show up after those with BTM and may have less complications of anemia, from which they need blood transfusion or other therapy either not at all or just periodically [48]. Patients with thalassemia live on the severe end of the clinical spectrum, with symptoms presenting between the ages of 2 and 6 years, and although they can survive without regular blood transfusion, they would be expected to demonstrate stunt growth and development.[29] The other extreme of the clinical spectrum would be individuals who have no symptoms and may only have mild anemia throughout maturity.[49]In the bone marrow uses extramedullary erythropoiesis, a compensatory strategy to get around the persistent anemic state of thalassemia, when patients with the condition exhibit hypertrophy of the erythroid marrow[29] This leads to characteristic features of bone and facial deformities, osteoporosis, and formation of erythropoietic masses that primarily affect spleen, liver, chest, and spine.[50] Splenomegaly develops due to the role of the spleen in removing abnormal red cells from circulation.[51] In the case of extramedullary erythropoiesis, patients may experience neurologic problems, for example, spinal cord compression leading to paraplegia or the presence of intrathoracic masses.[52] Due to dysfunctional erythropoiesis and peripheral hemolysis, gallstones may form in patients with BTI, and this occurs more frequently than in patients with BTM.[53] Patients with BTI often experience leg ulcers and are likelihood of acquiring thromboses compared to BTM patients, especially in the case of splenectomy.[54] Thrombotic events include deep vein thrombosis, portal vein thrombosis, stroke, and pulmonary embolism. Patients with BTI are exposed to higher concentatation of iron as a result of intestinal iron overload.[55] In patients with thalassemia intermedia, hypogonadism, hypothyroidism, and diabetes are not common.[56] However, in the event blood transfusion are given while pregnant, patients who have never or minimal amounts transfused may develop iso alloantibodies against the transfused blood and erythrocyte auto antibodies.[57] Retardation of growth within the womb has been reported even with an adequate transfusion schedule.[58] Cardiac involvement in thalassemia intermedia is primarily due to a elevated output condition with hypertension in the lungs, and the systolic function of the typically, the left ventricle remains intact.[59] Patients with BTI have been documented to get pseudoxanthoma elasticum, a diffuse connective tissues. condition that affects the arteries due to calcium accumulation and the deterioration of the artery wall's elastic lamina. [60]
Iron deficiency must be figure out to be able to recognize beta-thalassemia minor since it can alter the normally elevated values of HbA2. Regardless on the underlying modification, large levels of HbF may also be present.[61] The RBC of a carrier will be hypochromic and microcytic. The majority of patients with beta-thalassemia minor enjoy a reasonable quality of life, and the condition is frequently medically mild. [62] While carriers are sometimes found to have enlarged spleen, modest bone abnormalities, leg ulcers, or cholelithiasis, the most of carriers do not have clinically significant anemia and do not need special therapy. In [63] Pregnant women who suffer from anemia may need transfusion therapy and 1–5 mg of folic acid per day (Hb 7 and the third trimester). [64] Couples, particularly those with close family members, compulsorily screened for atypical or silent α and β mutations. If found, medical assistance should be provided. [29].
3. Etiology
Thalassemia results in unequal hemoglobin synthesis due to reduced levels of minimum one globin polypeptide chain (beta, alpha, gamma, and delta). [13] Hereditary sequence for thalassemia is autosomal recessive. Beta thalassemia is characterized by decreased beta-polypeptide chain production. Heterozygotes with low to modest microcytic anemia (thalassemia minor) show no clinical signs. [65] In homozygotes with beta-thalassemia major, commonly referred to as Cooley's anemia, severe anemia and bone marrow hyperactivity are the results. AT results from decreased sy nthesis of alpha globin. When a genetic deficiency is heterozygous, the consequence is silent alpha thalassemia. [66] In When abnormalities in three of the four genes more significantly affect the formation of alpha chains, tetramers of excess beta chains (HbH) or, in babyhood, gamma chains (Bart's Hb) are generated.[67] In Since hemoglobin E (Hb E) is not connected to hemoglobin lacking alpha chains, abnormalities in all four genes are lethal until they undergo therapy with transplanted blood while still in gestation.[68]In addition to changing structure, the mutation decreases the rate of beta globin synthesis. As a result, Hb E trait and disease usually exhibit a modest Beta thalassemia phenotype. [13] In Bangladesh, India, and Southeast Asia, co-inheritance of thalassemia and Hb E is common. [69] The signs of this Hb E/thalassemia compound heterozygote disease fluctuate between transfusion dependency to moderate anemia. The most important their genome, Hb E/Beta thalassemia, is responsible for half of all occurrences of severe beta thalassemia. [70] People who have Hb E/Beta thalassemia are prone to suffer from vitamin D deficiency or pulmonary hypertension. [71]
4. Pathophysiology
The pathology that underlies the various forms of thalassemia is similar, despite the fact that clinical spectra differ based on the co-inheritance of other genetic modifiers. [72] This disorder is defined by impaired preparation of Hb and survival of red blood cells (RBCs) because of an excess of undamaged globin chains that precipitate as inclusion bodies as unstable homotetramers. [73]. Due to their greater instability, the β homotetramers in β-thalassemia precipitate earlier in the RBC life span than those in α-thalassemia. This causes considerable RBC injury and severe bleeding associated with extramedullary hemolysis and inefficient erythropoiesis (IE). IE results in larger marrow cavities that press against good bone in severe thalassemia, causing the face, long bones, and skull to be deformed. Additionally, excessive erythroid activity in extramedullary hematopoietic locations can result in extramedullary malignancies, extensive lymphadenopathy, and hepatosplenomegaly. A lack of oxygen and chronic anemia also increase the uptake of iron in the gastrointestinal (GI) tract. [74,75] If transfusion support is not offered, over 86% of patients with severe homozygous thalassemia will die from severe anemia by the time they are five years old. [76] As serum transferrin saturation rises above 70%, free iron species, including labile plasma iron, have been found in the plasma and labile iron pool in the red blood cells. [77] Reactive oxygen species, which ultimately lead to tissue damage, organ dysfunction, and death, are mostly caused by these iron species. [78] To date, there have been unsuccessful attempts to use antioxidants to reduce thalassemic blood cells under oxidative stress. [79] Iron chelation treatment has been found to be the sole means of reducing morbidities and improving lifespan during the fourth and fifth decades of life. [80]
Figure no.1
Iron overload: Frequent transplants of blood can cause iron overload, one of the most common adverse effects of thalassemia that can damage the liver, heart, and endocrine system. [81] Infection: Person with thalassemia are an easy target for getting ill, which can harm their bodily systems. [82] Bone deformities: These disorders impact the body's development. Then, thalassemia patients may show it. Most of the time, the skull bone is visible. Also, the swelling of the skull and face bones leads to skeletal anomalies. [83] Spleen enlargement: Numerous bacterial, viral, and infectious causes might contribute to this illness. Additionally, it may happen unintentionally as a result of blood flow problems and liver failure. [84]
Offering prospective genetic counseling and informing carriers of the dangers of intra marriage are crucial in nations with high thalassemia incidence. [85] Attempts to use this strategy have so far been largely unsuccessful. As a result, programs for prenatal diagnosis have received a lot of attention. [86] Due to the easy identification of thalassemia carrier states, affected fetuses can be diagnosed. Recent efforts have concentrated on early diagnosis by using embryonic fluid cells for fetal genetic testing or chorionic villus collection. [87] Further, oligonucleotide probes to identify particular mutations have greatly improved the accuracy rate of prenatal diagnosis. Because of this, research is being done on removing fetal tissues from the blood supply of the mother. [88] Management during pregnancy: For everyone with thalassemia, preconception genetic counseling is highly recommended.One in four children born to two parents with β thalassemia trait will have β thalassemia major thus, three out of four will either have thalassemia trait or be normal.[89] The inheritance pattern of people with alpha thalassemia trait is more intricate. The result will change depending on whether both faulty genes are located on the same or separate chromosomes. [21] Babies with beta thalassemia can be identified by chorionic villus sampling that uses PCR technique. [90] Alpha thalassemia trait carriers should think about getting a pregnancy diagnosis due to Hb Bart's raises the risk of postpartum hemorrhage and toxemia. When combined with in vitro fertilization, pre-implantation genetic diagnosis is becoming accessible. [91]
TREATMENT
6.1 Blood transfusion
People with BTM need frequent blood transfusions throughout their lifetimes to sustain a normal development and hemoglobin concentrations higher than 9.5 g per dL (95 g per L). The need for blood transfusions may arise as early as six months of age. For those with BTI, the decision to transfuse is a more personalized clinical judgment. [92,93,94] An individual may require episodic transfusions if their hemoglobin levels are insufficient for a healthy life. [95] Alpha thalassemia intermedia, another name for HbH illness, is characterized by light to serious hemolysis. Sometimes transfusions are necessary, depending on how severe the clinical situation is. [96]
6.2 Chelation
Patients who are transfusion-dependent experience iron overload because their bodies are unable to eliminate excess iron from repeated transfusions. [97] Because of this, they need to be treated with an iron chelator from the age of five to eight.The preferred treatment is deferoxamine (Desferal), administered intravenously or subcutaneously.[98] This therapy is costly and time-consuming, despite being comparatively nontoxic. The alternative treatment oral deferasirox (Exjade) was recently approved by FDA. [99] There were no reported cases of agranulocytosis, and deferasirox's side effects were gastrointestinal in nature and temporary. [100]
6.3 Stem Cell Therapy (SCT) and Gene Therapy
Stem cell therapy is still the only treatment option for TM, despite advancements in treatment that have improved survival and quality of life.[101] Even though 80–90% of patients who receive SCT from a related donor who shares the same human leukocyte antigen are disease-free and over 90% of them survive, there are still questions about how the potentially fatal but curative procedure can be used for adults, and patients with a matched unrelated donor.[102] The main drawback of SCT is that most affected patients (70–75%) do not have an HLA-identical sibling donor.[103] All thalassemia patients may eventually be cured through gene therapy, which could solve the issue of donor availability.[104] Patients with beta-thalassemia are showing encouraging results from extensive clinical and molecular research on the treatment of thalassemia and the creation of targeted therapies (such as gene therapy, cell therapy, and reactivation of HbF production).[105] To manage this growing global health burden, however, efforts must continue to be made to establish universal health services that include screening, counseling, and prenatal diagnosis.[106]
Informatics channels can be used to implement thalassemia education. As DNA analysis becomes more affordable, it may potentially be utilized as the initial screening method. [107] By employing microchip technology, which is intended to detect all recognized alpha- and beta-thalassemias in addition to genetic variations that aid in phenotypic prediction, it is possible to circumvent the initial blood evaluation [108]. Technological developments in the methods of fetal DNA or fetal cell examination in mother's plasma may enable future clinical use of this important noninvasive approach. [109] The biggest difficulty for the coming years is the implementation of national prevention campaigns in areas like the Middle East, the Indian subcontinent, where thalassemias are prevalent. [110] Many of the aforementioned problems currently impede the execution of such programs. [111]
CONCLUSION
Millions of people around the world suffer from thalassemia, a dangerous hereditary blood condition. Even though therapies like iron chelation and blood transfusions have helped patients, genetic counseling and carrier screening are still necessary for prevention. Hope for a cure is offered by developments like gene therapy and bone marrow transplantation. To lessen the effects of thalassemia and enhance the lives of those who are impacted, research, early diagnosis, and ongoing awareness are crucial.To ensure comprehensive care and eventually move toward the eradication of this preventable genetic disorder, cooperation between clinicians, researchers, policymakers, and communities is essential
REFERENCE
Karande Samiksha*, Khot Seema, Kumbhar Saee, Dr. S. C. Burli, Thalassemia: An Extensive Analysis of Epidemiology, Diagnosis, and Treatment Approaches, Int. J. Sci. R. Tech., 2025, 2 (4), 449-460. https://doi.org/10.5281/zenodo.15249553
10.5281/zenodo.15249553
