Beta Thalasemia Overview

#### **Chapter 1**

## Overview of Beta-Thalassemia

*Kenneth Oshiokhayamhe Iyevhobu, Lucky E. Omolumen, Tobechukwu Joseph Okobi, Edidiong Raphael Usoro, A. Airefetalor Ivie, Benedicta A. Ken-Iyevhobu and O. Omokpo Victoria*

#### **Abstract**

Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. Three main forms have been described: thalassemia major, thalassemia intermedia, and thalassemia minor. Individuals with thalassemia major usually present within the first 2 years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Thalassemia minor is clinically asymptomatic, but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta-globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive; however, dominant mutations have also been reported. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. Laboratory tests that are conventionally performed to diagnose the β-thalassemia and HbE are classified into two groups, based on the purposes, including the screening tests and confirmatory tests.

**Keywords:** beta, thalassemia, hemoglobin, anemia, globin

#### **1. Introduction**

The term thalassemia is deduced from the Greek, namely thalassa (ocean) and haima (blood). Thalassemia is among the most common heritable diseases in the world [1–3]. The thalassemias are conditions caused by dropped expression of one of the two globin chains of the hemoglobin patch, namely α (HBA) and β (HBB). Inherited through an autosomal sheepish pathway, point mutations and elisions on the genes that decode for the globin chains beget dropped hemoglobin (Hb) product, leading to severe anemia [4]. Thalassemia cases depend on lifelong medical care, entering routine blood transfusions and supplemental curatives [5]. Thus, timely opinion and forestallment is essential, especially in regions with high frequency of this complaint [6–8]. Beta-thalassemia characterized by reduced or absent β-globin chain conflation is one of the most common inherited blood diseases in the world and hence a major interference to public health. Beta-thalassemia is a blood complaint

that reduces the product of hemoglobin [9]. The protein in red blood cells called hemoglobin, which contains iron, transports oxygen to every cell in the body. Low hemoglobin levels in beta-thalassemia patients cause an oxygen shortage in a number of bodily passageways [10]. A lack of red blood cells in affected people (anemia) can result in pale skin, weakness, weariness, and more severe problems. Beta-thalassemia patients are more likely to get irregular blood clots [11]. Beta-thalassemia runs are a group of heritable blood diseases characterized by reduced or absent beta-globin chain conflation, performing in reduced Hb in red blood cells (RBC), dropped RBC product and anemia. Beta-thalassemia major was first described in the medical literature in 1925 by an American croaker-Thomas Cooley. Beta-thalassemia includes three main forms, namely thalassemia major, perfectly appertained to as "Cooley's Anemia" and "Mediterranean Anemia", thalassemia intermedia, and thalassemia minor also called "beta-thalassemia carrier", "beta-thalassemia particularity", or "heterozygous beta-thalassemia" [10, 11]. Piecemeal from the rare dominant forms, subjects with thalassemia major are homozygotes or emulsion heterozygotes for beta0 or beta genes, subjects with thalassemia intermedia are substantially homozygotes or emulsion heterozygotes, and subjects with thalassemia minor are substantially heterozygotes. Although wide, the major at- threat populations are substantially from Mediterranean, Middle East, and Southeast Asian countries [12, 13]. The thalassemia category of hemoglobin conflation illnesses differs from the others in that there is either little or no-globin chain conflation. The main forms of β-thalassemia are two. The two types of thalassemia are βO-thalassemia, in which no-globin chain is made, and -thalassemia, in which some globin is produced but at a lower level than usual [14]. Microcytosis, often known as thalassemia minor clinically, affects heterozygotes for either type of allele. A more severe phenotype known as β-thalassemia intermedia, which involves anemia, hemolysis, iron loading, and the sporadic need for transfusion, is present in homozygous heterozygotes for two thalassemia alleles or one and one β<sup>0</sup> allele. The most severe form of the condition, known asthalassemia major, is present in people who have two β<sup>0</sup> -thalassemia alleles and results in transfusiondependent anemia, severe transfusional iron overload, reduced life expectancy, and chelation therapy. A severe form of thalassemia with no globin chain product is called β0 -thalassemia. Point mutations in the rendering region (exon) or exon-intron junction of the β-globin gene, which result in an unseasonable stop codon or the production of aberrant β-globin mRNA, are the primary cause. Absence of the β-globin chain product is the result of these anomalies [14]. The frequency of thalassemia is growing mainly in non-indigenous regions, similar as Northern Europe, North America, and Australia, due to increased mobility and migration overflows of populations in recent decades [12, 15–18]. The global burden of hemoglobinopathies necessitates perpetration of public health interventions, similar as webbing programs and antenatal opinion, indeed in non-indigenous countries with high rates of immigration [15]. The genes that render for globin proteins are located on β-and α-globin gene clusters on chromosome 11 and 16, independently [4]. Expression of each globin gene varies throughout the embryonic and fetal development, which is why the Hb patterns of babe and grown-ups differ from each other [19, 20].

#### **2. Epidemiology of beta-thalassemia**

Beta-thalassemia is an in actuality normal blood inconvenience round the field. A huge amount of babies are considered with beta-thalassemia consistently.

#### *Overview of Beta-Thalassemia DOI: http://dx.doi.org/10.5772/intechopen.111682*

Beta-thalassemia happens limit of the time in people from Mediterranean nations, North Africa, the Center East, Central Asia, Southeast Asia, India, southern China, and the Far East, notwithstanding nations close by the northern coast of Africa and within side the South America. The most extreme exceptional carrier repeat is situated in Cyprus (14%), Sardinia (10.3%), and Southeast Asia [21]. High-incredible repeat of beta-thalassemia in those districts might be extremely probably to be perceived with the special strain of wilderness fever Plasmodium falciparum [21]. Populace resettlement and intermarriage among unique ethnic congregations have incited thalassemia in virtually all nations of the field, along with northern Europe, wherein thalassemia in the past did now presently do not exist. It has been normal that round 1.5% of the field's general population (80 to 90 million people) are organizations of beta-thalassemia, with cycle 60,000 characteristic individuals transforming into pregnant every year, the especially gigantic a piece of the scene. Without a doubt the yearly cost of interesting people is normal at 1 out of 100,000 worldwide and 1 out of 10,000 within side the European Affiliation [10]. Regardless, there might be a deficiency of explicit records on delivery costs in several people gatherings, for the most part in areas of the field which can be perceived or anticipated to be emphatically impacted [12, 21]. As indicated by the Thalassemia Overall Association, around 200,000 victims stay with thalassemia dominating and are enrolled for standard cure worldwide [21]. The excellent perceived total of beta-thalassemia with phenomenal Hb or number one Hb form with thalassemic homes is HbE/beta-thalassemia, that is typically huge in Southeast Asia, wherein carrier.

#### **2.1 Types and clinical description of beta-thalassemia**

The aggregates of homozygous or hereditary heterozygous compound betathalassemias incorporate Cooley's frailty and thalassemia intermedia [10]. People with Cooley's frailty ordinarily come to clinical consideration inside the essential 2 years of life and need standard RBC bondings to endure. Those introducing later do not need bonding and get an analysis of thalassemia intermedia [22]. Thalassemia intermedia incorporates patients who present later and do not need customary bonding. Besides inside the uncommon predominant structures, heterozygous beta-thalassemia prompts the clinically quiet transporter state. HbE/beta-thalassemia and HbC/beta-thalassemia display a superb home as far as variety of aggregates and range of seriousness [11].

#### *2.1.1 Beta-thalassemia major (Cooley's anemia)*

Beta-thalassemia significant alludes to a serious clinical aggregate that happens when patients are homozygous or compound heterozygous for more extreme beta chain transformations (for example serious B+/B+ changes, B+/B0, B0/B0) [10, 11].

Clinical show of thalassemia major happens somewhere in the range of 6 and 2 years. Youngsters foster dangerous weakness. They do not put on weight and develop at the normal rate (inability to flourish) and may create yellowing of the skin and whites of the eyes (jaundice) and become logically pale. Influenced people might have an amplified spleen, liver, and heart, and their bones might be distorted. Taking care of issues, looseness of the bowels, peevishness, repetitive episodes of fever, and reformist amplification of the midsection brought about by spleen and liver augmentation might happen. The clinical picture of thalassemia major is described by development impediment, paleness, jaundice, helpless musculature, genu valgum, hepatosplenomegaly, leg ulcers, improvement of masses from extramedullary hematopoiesis, and

skeletal changes brought on by extension of the bone marrow in some developing nations where patients are untreated or ineffectively bonded due to a lack of resources. Skeletal modifications include frequent craniofacial changes and deformations of the long bones of the legs (bossing of the skull, conspicuous malar greatness, gloom of the extension of the nose, inclination to a mongoloid inclination of the eye, and hypertrophy of the maxillae, which will in general uncover the upper teeth). A few youths with thalassemia significant experience deferred adolescence. Many individuals with thalassemia major have such extreme manifestations that they need incessant blood bondings to recharge their red platelet supply. Over the long haul, a convergence of iron-containing hemoglobin from ongoing blood bondings can prompt a development of iron in the body, bringing about liver, heart, and chemical issues.

On the off chance that a customary bonding program that keeps a base Hb centralization of 9.5 to 10.5 g/dL is started, development and advancement will in general be ordinary up to 10 to 12 years [15]. Bonded patients might foster difficulties identified with iron over-burden. Entanglements of iron over-burden in youngsters incorporate development hindrance and disappointment or postponement of sexual development. Later iron over-burden-related inconveniences incorporate inclusion of the heart (widened myocardiopathy or once in a while arrythmias), liver (fibrosis and cirrhosis), and endocrine organs (diabetes mellitus, hypogonadism, and inadequacy of the parathyroid, thyroid, pituitary, and, less regularly, adrenal organs) [23]. Consistence with iron chelation treatment essentially impacts recurrence and seriousness of the iron over-burden-related complexities [24].

#### *2.1.2 Beta-thalassemia intermedia*

Beta-thalassemia intermedia is in the middle of clinical aggregate with heterogeneous hereditary changes that actually consider some beta chain creation (e.g., B+/B0, B+/B+). Some uncommon cases likewise exist in which both beta and alpha transformations exist together [11, 12].

Individuals with thalassemia intermedia present later than thalassemia major, have milder anemia and by definition do not require or only occasionally require transfusion. At the severe end of the clinical spectrum, patients present between the ages of 2 and 6 years and although they are capable of surviving without regular blood transfusion, growth and development are retarded. At the opposite finish of the range are patients who are totally asymptomatic until grown-up existence with just gentle frailty. The signs and side effects of thalassemia intermedia show up in youth or sometime down the road. Influenced people are gentle to direct sickliness and may likewise have slow development and bone anomalies. Hypertrophy of erythroid marrow with the chance of extramedullary erythropoiesis, a compensatory system of bone marrow to beat ongoing iron deficiency, is normal. It leads to common facial and bone deformities, osteoporosis with pathologic breaks in long bones, and the growth of erythropoietic masses that have a significant impact on the spleen, liver, lymph nodes, chest, and spine. The spleen's important role in clearing damaged red blood cells from the circulatory system contributes to its growth. Extramedullary erythropoiesis may result in neurological problems, such as intrathoracic masses and spinal rope pressure with paraplegia. Gallstones may develop in thalassemia intermedia individuals more frequently than in thalassemia major because to ineffective erythropoiesis and fringe hemolysis [25]. Patients with thalassemia intermedia often foster leg ulcers and have an expanded inclination to apoplexy when contrasted with

#### *Overview of Beta-Thalassemia DOI: http://dx.doi.org/10.5772/intechopen.111682*

thalassemia major, particularly if splenectomised. Such occasions incorporate profound vein apoplexy, entrance vein apoplexy, stroke, and aspiratory embolism [26].

In spite of the fact that people with thalassemia intermedia are in danger of iron over-burden optional to expanded digestive iron retention, hypogonadism, hypothyroidism, and diabetes are not normal [27]. Ladies might have effective unconstrained pregnancies. Nonetheless, if blood bondings are fundamental during pregnancy, those never or negligibly bonded are in danger of creating hemolytic alloantibodies and erythrocyte autoantibodies. Intrauterine development hindrance, in spite of a customary bonding routine, has been accounted for [28]. Cardiovascular inclusion in thalassemia intermedia results chiefly from a high-yield state and aspiratory hypertension, while systolic left ventricle work is generally protected [29]. Pseudoxantoma elasticum, a diffuse connective tissue issue with vascular indication brought about by degeneration of the versatile lamina of the blood vessel divider and calcium statement, has been portrayed in such patients [30].

#### *2.1.3 Beta-thalassemia minor (Beta-thalassemia carrier/trait)*

Beta-thalassemia minor is a gentle clinical aggregate when one typical duplicate of the beta globulin quality is available (e.g., B+/B, B0/B). Transporters of thalassemia minor are normally clinically asymptomatic, however, here, and there have a gentle weakness. At the point when the two guardians are transporters, there is a 25% danger at every pregnancy of having kids with homozygous thalassemia [10, 11].

#### *2.1.4 Dominant beta-thalassemia*

Conversely, with the old style latent types of beta-thalassemia, which lead to a diminished creation of ordinary beta-globin chains, some uncommon transformations bring about the union of incredibly unsteady beta-globin variations which hasten in erythroid forerunners causing insufficient erythropoiesis [11]. These transformations are related with a clinically perceptible thalassemia aggregate in the heterozygote and are in this way alluded to as prevailing beta-thalassemias. The presence of hyper-temperamental Hb ought to be suspected in any person with thalassemia intermedia when the two guardians are hematologically ordinary, or in families with an example of autosomal prevailing transmission of the thalassemia intermedia aggregate. Beta-globin quality sequencing sets up the conclusion [6].

Most people who are heterozygous for a beta-thalassemia change have clinicopathological highlights depicted as "thalassemia minor"; for example, the blood count and film are strange yet there are no unusual actual discoveries or indications. Notwithstanding, a few transformations produce clinically obvious anomalies in heterozygotes, mostly splenomegaly, frailty, jaundice, and an expanded occurrence of gallstones. This is alluded to as predominant beta-thalassemia [6]. Predominant beta-thalassemia is uncommon; however, cases are found dissipated all through the world. The clinicopathological highlights are those of thalassemia intermedia. Red cell endurance is not exactly in run of the mill beta-thalassemia attribute and the reticulocyte count is expanded. Patients might require incidental blood bondings. There is extramedullary hematopoiesis, and iron over-burden might happen. The blood film is typically exceptionally unusual with conspicuous basophilic texturing and circling nucleated red cells. The bone marrow shows erythroid hyperplasia and dyserythropoiesis [6].

#### *2.1.5 Beta-thalassemia associated with other Hb anomalies*

The participation of HbE and beta-thalassemia achieves thalassemia totals going from a condition unclear from thalassemia major to a delicate sort of thalassemia intermedia. Dependent upon the earnestness of signs, three characterizations may be perceived [31]:


Patients with HbC/beta-thalassemia may live freed from signs and be examined during routine tests. Exactly when present, clinical appearances are iron lack and improvement of the spleen. Blood bondings are just every so often required. Microcytosis and hypochromia are found for every circumstance. The blood film shows specific Hb C valuable stones with straight equivalent edges, target cells, and irregularly contracted cells with components of thalassemia like microcytosis [11]. The relationship of acquired ingenuity of fetal Hb (HPFH) with beta-thalassemia mitigates the clinical appearances which change from normal to thalassemia intermedia. Individuals with HbS/beta-thalassemia have a clinical course like that of Hb SS [10].

#### *2.1.6 Beta-thalassemia associated with other features*

Rarely, the beta-globin quality group does not contain the beta-thalassemia defect. The sub-atomic damage has been discovered in the quality encoding the record factor TFIIH (beta-thalassemia attribute related with tricothiodystrophy) or in the X-connected record factor GATA-1 (X-connected thrombocytopenia with thalassemia) in cases where the beta-thalassemia characteristic is related with different elements [32–34].

#### **2.2 Signs and symptoms of beta-thalassemia**

The majority of people with beta-thalassemia quality do not show any symptoms. Depending on the type of disorientation gained, different people will experience different side effects. Children with beta-thalassemia intermedia or major may not display any symptoms at all, although they usually develop them during the first 2 years of life. Beginning with one person and progressing to the next, the symptoms and severity of beta-thalassemia vary dramatically [10].

The most serious kind of beta-thalassemia is beta-thalassemia major. Children that are born with this type of personality will show signs early on in life, such as

*Overview of Beta-Thalassemia DOI: http://dx.doi.org/10.5772/intechopen.111682*


Over time more symptoms will appear, including:


Individuals with beta-thalassemia or intermedia typically have a development of iron within the body, either from the particular illness or from the rehashed blood bondings. Abundance iron will hurt the center, liver, and endocrine framework. While not treatment, the spleen, liver, and heart become broadened. Bones will likewise end up to be meager, weak, and twisted. People with this condition would force continuous blood bondings and will not stick with it with a typical lifespan. Iron develops within the heart and totally different organs from blood bondings. This may cause vast breakdown as right time because the teenagers or middle 20s people with beta-thalassemia might need different real medical problems, including:

**Thalassemia minima:** this type often causes no symptoms but may have a mild anemia. Many individuals with beta thalassemia minor go through life never knowing they carry an altered gene for the disorder.

**Thalassemia intermedia:** folks determined to own beta monogenic disorder intermedia have a typically shifted articulation of the difficulty. Creditably extreme weakness is traditional, and influenced folks may need intermittent blood bondings. Each individual case is one among a form. This type will create aspect effects of moderate serious sickliness including:


**Predominant Beta-Thalassemia:** Prevailing beta-thalassemia is a very uncommon structure where people who have one changed HBB quality foster specific manifestations related with beta-thalassemia. Influenced people might create gentle to direct sickliness, jaundice, and a strangely broadened spleen (splenomegaly).

#### **2.3 Etiology of beta-thalassemia**

Hemoglobin is made of two alpha proteins and two beta proteins. A quality change (transformation) in the alpha proteins causes alpha thalassemia. A quality change in the beta proteins causes beta-thalassemia. Most beta-thalassemia cases are brought about by a transformation in the HBB quality. In incredibly uncommon cases, a deficiency of hereditary material (erasure) that incorporates the HBB quality causes the issue [11]. In beta-thalassemia, the quality change causes an irregularity of hemoglobin proteins. The irregularity causes sickliness in light of the fact that [10]:


The awkwardness additionally prompts clinical issues during the bones, bone marrow, and different organs. In excess of 200 changes have been so far announced; the larger part is point transformations in practically significant districts of the beta-globin quality [35]. Erasures of the beta-globin quality are remarkable. The betaglobin quality transformations cause a diminished or missing creation of beta-globin chains. Transformations in the HBB quality reason beta-thalassemia. The HBB quality gives guidelines to making a protein called beta-globin. Beta-globin is a part (subunit) of hemoglobin. Hemoglobin comprises four protein subunits, ordinarily two subunits of beta-globin and two subunits of another protein called alpha-globin [35].

The development of any beta-globin is prevented by a few modifications to the HBB quality. The term beta-zero (β<sup>0</sup> ) thalassemia refers to a lack of beta-globin. Additional HBB quality alterations allow for the creation of some beta-globin, but in smaller amounts. Beta in addition to (β<sup>+</sup> ) thalassemia is characterized by a decreased level of beta-globin. Possessing either a β<sup>0</sup> or β<sup>+</sup> thalassemia does not necessarily indicate how bad your condition will be; people with these two types have been found to have thalassemia major and thalassemia intermedia, respectively.

An absence of beta-globin prompts a diminished measure of practical hemoglobin. Without adequate hemoglobin, red platelets do not grow regularly, causing a deficiency of mature red platelets. People with beta-thalassemia have pallor and other *Overview of Beta-Thalassemia DOI: http://dx.doi.org/10.5772/intechopen.111682*

related medical problems due to the low quantity of developed red platelets. Betathalassemia is the result of damaged or absent components. There are two distinct traits present. There are various varieties of this problem:

Cooley's weakness (beta-thalassemia major). There are two damaged characteristics. The most severe form of this issue is this. Those with this ailment will need further blood bondings. They might not live out a typical lifespan.

Beta-thalassemia minor or thalassemia attribute. Just a single quality is harmed. This causes less extreme pallor. Individuals with this kind have a half shot at passing the quality to their kids. On the off chance that the other parent is not influenced, their kids will likewise have this type of the problem. This sort is additionally isolated into


Many individuals with this problem are given iron substitution unintentionally. This happens when an absence of iron is accepted to cause their pallor. An excessive amount of iron can be hurtful. So, get the right determination.

#### *2.3.1 Genetic modifiers*

The modifying qualities are characterized by being hereditary variations that give rise to contrasts in the aggregate of the infection. In homozygous beta-thalassemia, the essential inherited modifiers that affect the clinical severity of the infection contain inherited variations that are ready to reduce the irregularity of the globin chain, creating a milder form of thalassemia [11]. These elements are the presence of quiet or mild beta-thalassemia alleles associated with a high residual yield of beta-globin, the co-inheritance of alpha-thalassemia, and, in addition, hereditary determinants ready for the incessant production of gamma-globin chains of support (HbF) in adult life [36]. Some beta-thalassemia transformations (e.g., deleting and not canceling delta-beta-thalassemia, local 5′ deletions of beta-globin quality) "essentially" increase the performance of gamma-globin quality [10]. Several transformations that extend HbF production are associated with deletional and non-deletional HPFH associated with the beta-globin quality package. Recently, the genome-wide affiliation approach, which specifically focuses on quantitative quality loci (QTL) that cause elevated HbF levels, has inherited components (e.g., changing the severity of homozygous betazero thalassemia [37].

The clinical aggregate of homozygous beta-thalassemia may also be altered by the interaction of other planned heritable variations outside the globin groups. These additional heritable modifiers have a profound effect in confounding the aggregate of thalassemia [11]. Some additional heritable modifiers have been recognized in recent years. The appearance of polymorphism (TA) 7 in the uridine diphosphate glucuronosyltransferase quality-reporting site, which in the homozygous state is associated with Gilbert's disease, is a risk factor for the progression of cholelithiasis in patients with thalassemia major and intermedia [38]. Other competing qualities to alter the aggregate of thalassemia are the apolipoprotein E 4 allele and some HLA haplotypes, which appear to be inherited risk factors for left ventricular disappointment in homozygous beta-thalassemia [10, 39, 40]. For qualities related to iron digestion (e.g., C282Y and H63D-HFE quality transformations), less stable information was considered, probably since its effects on iron deposition are obscured by

treatment (e.g., B. iron deposits auxiliary to the binding of red blood cells and iron chelation) and for qualities related to bone digestion [41–43]. Recently, a polymorphism in the quality of glutathione transferase M1 has been associated with an increased risk of heart iron overload in thalassemia major [44].

In certain cases, heterozygous beta-thalassemia could trigger the intermediate aggregation of thalassemia instead of the asymptomatic transporter state [10]. Most of these patients have an abundance of practical alpha globin qualities (triple or quadruple alpha quality), which increases the asymmetry in the ratio of the combination of alpha/non-alpha globin chains [36, 45].

#### *2.3.2 Pathophysiology*

A general oversupply of unbound alpha globin chains that speed in erythroid precursors in the bone marrow cause their unexpected passing and consequently lead to insufficient erythropoiesis. This is caused by a decreased amount (beta+) or nonexistence (beta0) of beta-globin chains. The concept of the transformation at the beta-globin quality located on chromosome 11 controls the degree of globin chain decline. As opposed to thalassemia intermedia, fringe hemolysis, which exacerbates illness, occurs when insoluble alpha globin attaches rapid layer damage to the fringe erythrocytes. Paleness animates the creation of erythropoietin with resulting concentrated yet inadequate development of the bone marrow (up 25 to multiple times ordinary), which thusly causes the regular recently portrayed bone disfigurements. Delayed and serious paleness and expanded erythropoietic drive additionally result in hepatosplenomegaly and extramedullary erythropoiesis [31].

#### *2.3.3 Hereditary transmission*

The beta-thalassemias square measures nonheritable in AN chromosome latent approach. The guardians of AN influenced juvenile square measure commit heterozygotes and convey a solitary duplicate of illness inflicting beta simple protein quality amendment. Mediterranean anemia intermedia square measures non-heritable in an chromosome passive example, which means the 2 duplicates of the HBB quality in each cell have changes. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition [11]. At times, in any case, people with just one HBB quality amendment in each cell foster light paleness. These somewhat influenced people square measure same to own Mediterranean anemia minor. At origination, each offspring of heterozygotes guardians has 25th shot at being influenced, shot at being AN symptomless transporter, and 25th shot at being unaffected and not transporter. The guardians of the proband have 25% hazard of getting to boot influenced youngsters in every gestation [31].

Predominant varieties of beta-thalassemia, connected with transformations that outcome within the creation of deeply unsound transferrin variations and prompting a clinically showing combination of beta-thalassemia in heterozygotes, are talked regarding on top of within the clinical portrayal section. In an exceedingly very little level of families, the HBB quality transformation is nonheritable in AN chromosome predominant approach. In these cases, one duplicate of the changed quality in each cell is up to cause the signs and manifestations of beta Mediterranean anemia [10].

#### **3. Diagnosis beta-thalassemia**

Beta-thalassemia is regularly found in individuals who are from Greek, Italian, African, or Asian beginning. The determination is frequently made somewhere in the range of 6 and 12 years of age. Thalassemia major is normally suspected in a newborn child more youthful than 2 years old with extreme microcytic frailty, gentle jaundice, and hepatosplenomegaly. Thalassemia intermedia presents at a later age with comparative yet milder clinical discoveries. Transporters are typically asymptomatic, however, at times might have gentle paleness. People with thalassemias have more modest measured red platelets than unaffected individuals just as low red platelet counts (pallor). Thalassemia major and thalassemia minor would now be able to be analyzed (and recognized from each other) by ordinary clinical and blood testing, yet additionally by atomic and hereditary tests. These tests license exact finding to be made whenever, even before birth (indeed, a long time before the beta chains are even incorporated) [33].

#### **3.1 Hematologic diagnosis**

RBC lists show microcytic iron deficiency. Thalassemia major is portrayed by diminished Hb level (50 < 70 fl and mean corpuscolar Hb (MCH) > 12 < 20 pg. Thalassemia intermedia is portrayed by Hb level somewhere in the range of 7 and 10 g/dl, MCV somewhere in the range of 50 and 80 fl and MCH somewhere in the range of 16 and 24 pg. Thalassemia minor is portrayed by diminished MCV and MCH, with expanded Hb A2 level [31].

Complete blood count (CBC): This test really looks at the size, number, and development of various platelets in a set volume of blood.

#### **3.2 Smear of peripheral blood**

Affected individuals have RBC morphologic alterations, including nucleated RBC, microcytosis, hypochromia, anisocytosis, and poikilocytosis (spiculated tear-drop and extended cells) (i.e., erythroblasts). After splenectomy, the number of erythroblasts significantly increases and is correlated with the degree of frailty. Compared to influenced people, transporters exhibit less severe RBC morphologic alterations. Usually, erythroblasts are not visible [22].

#### **3.3 HPLC/electrophoresis**

The Hb design in beta-thalassemia changes as indicated by beta-thalassemia type. In beta0 thalassemia, homozygotes HbA is absent and HbF constitutes the 92-95% of the total Hb. In beta+ thalassemia homozygotes and beta+/ beta0 genetic compounds HbA levels are between 10 and 30% and HbF between 70-90%. HbA2 is variable in beta-thalassemia homozygotes, and it is upgraded in beta-thalassemia minor [22]. Hb electrophoresis and HPLC likewise identify different hemoglobinopathies (S, C, E, OArab, Lepore) that might cooperate with beta-thalassemia [11].

Hemoglobin electrophoresis with hemoglobin F and A2 quantitation: A lab test that separates the kinds of hemoglobin [10]. Subjective and quantitative Hb investigation distinguishes the sum and kind of Hb present [10].

#### **3.4 Molecular genetic analysis**

The pervasiveness of a predetermined number of changes in every populace has incredibly worked with sub-atomic hereditary testing. Generally happening transformations of the beta-globin quality are recognized by PCR-based systems [33, 46]. The most generally utilized techniques are converse dab smudge examination or groundwork explicit enhancement, with a bunch of tests or preliminaries corresponding to the most well-known transformations in the populace from which the influenced individual started. Whenever designated change examination neglects to recognize the transformation, beta-globin quality succession investigation can be utilized to distinguish changes in the beta-globin quality [12].

#### **3.5 Differential diagnosis**

Barely any conditions share similitudes with homozygous beta-thalassemia [11]:


Normal beta-thalassemia transporters are distinguished by examination of RBC files, which shows microcytosis (low MCV) and diminished substance of Hb per red cell (low MCH), and by subjective and quantitative Hb investigation, which shows the increment of HbA2 [11]. These examinations should be possible from a solitary blood test. In a pregnant lady, the child is analyzed utilizing CVS (chorionic villus inspecting) or amniocentesis.

Entanglements in transporter distinguishing proof by hematologic testing are:


*Overview of Beta-Thalassemia DOI: http://dx.doi.org/10.5772/intechopen.111682*

• Silent transformations, i.e., extremely gentle changes related with reliable remaining yield of Hb beta chains and with ordinary RBC files and typical or fringe HbA2. The above detailed gatherings of transporters are alluded to as abnormal transporters.

At the point when the hematologic investigation is unusual, atomic hereditary testing of beta-globin quality is performed to distinguish the infection causing change [46].

#### **3.6 Genetic counseling and prenatal diagnosis**

Anticipation of beta-thalassemia depends on transporter distinguishing proof, hereditary advising, and pre-birth analysis [47]. Transporter identification has been recently portrayed. Hereditary guiding gives data to people and in danger couples (e.g., the two transporters) with respect to the method of legacy, the hereditary danger of having influenced kids and the regular history of the sickness including the accessible therapy and treatments being scrutinized. Pre-birth detection for pregnancies with a higher risk of complications is possible by analyzing the DNA of fetal cells obtained by amniocentesis, which is typically done at roughly 15 to 18 weeks of gestation, or by chorionic villi inspection at 11 weeks of development. Before prebirth testing can be carried out, both alleles that cause the illnesses must be identified. Currently, fetal DNA in maternal plasma and fetal cells in maternal blood are being examined for the presence of the father's transformation [48]. Families with the identified disease-causing mutations may be eligible for preimplantation hereditary conclusion.

#### **3.7 Management of beta-thalassemia**

#### *3.7.1 Management of beta-thalassemia major*

Babies with thalassemia major are well upon entering the world due to a unique type of hemoglobin present in the hatchling and infant [49]. At last, notwithstanding, this hemoglobin is supplanted by deficient hemoglobin. Manifestations arise late in the main year of life. The youngster creates fair skin, crabbiness, development impediment, expanding of the midsection because of extension of the liver and spleen (hepatosplenomegaly) with jaundice. This is related with serious iron deficiency with burst of the red platelets (hemolytic weakness). The kid with thalassemia major becomes reliant upon blood bondings and, despite the fact that they do help, they make further issues including iron over-burden. Folic corrosive supplementation is frequently given. Right now, the essential medicines are aimed at diminishing manifestations of the sickness. Chosen patients might fit the bill for bone marrow or undifferentiated cell transfers. Quality treatment stays a likely treatment for what is to come. The drawn-out trust is that thalassemia significant will be restored by addition of the ordinary beta-chain quality through quality treatment or by one more methodology of atomic medication [33, 49].

#### *3.7.2 Transfusions*

The objectives of bonding treatment are amendment of pallor, concealment of erythropoiesis, and hindrance of gastrointestinal iron retention, which happens in non-bonded patients as an outcome of expanded, albeit insufficient, erythropoiesis. The choice to begin bonding in patients with affirmed determination of thalassemia ought to be founded on the presence of serious weakness (Hb < 7 g/dl for over about 14 days, barring other contributory causes like contaminations). Nonetheless, additionally in patients with Hb > 7 g/dl, different variables ought to be thought of, including facial changes, helpless development, proof of hard extension and expanding splenomegaly. Whenever the situation allows, the choice to begin ordinary bondings ought not be postponed until after the 2nd-3rd year, because of the danger of fostering various red cell antibodies and resulting trouble in discovering reasonable blood givers. A few diverse transfusional regimens have been proposed throughout the long term, yet the most broadly acknowledged focuses on a pretransfusional Hb level of 9 to 10 g/dl and a post-bonding level of 13 to 14 g/dl. This forestalls development hindrance, organ harm and bone deformations, permitting ordinary action and personal satisfaction [23].

#### *3.7.3 Management of thalassemia intermedia*

Treatment of people with thalassemia intermedia is indicative [23, 50]. As hypersplenism might cause demolishing sickliness, hindered development and mechanical unsettling influence from the huge spleen, splenectomy is an applicable part of the administration of thalassemia intermedia. Dangers related with splenectomy incorporate an expanded helplessness to contaminations fundamentally from exemplified microbes (Streptococcus Pneumoniae, Haemophilus Influenzae, and Neisseria Meningitidis) and an increment in thromboembolic occasions [49]. Sepsis after splenectomy can be prevented through vaccination against the aforementioned microbes, anti-infection prophylaxis, and early anti-toxin therapy for fever and agitation. The gallbladder should be examined during splenectomy and removed if necessary to treat or prevent gallstones due to the increased prevalence of cholelithiasis and the risks of cholecystitis in splenectomized patients. Radiation therapy with hydroxycarbamide is used to treat extramedullary erythropoietic masses that are detected by attractive reverberation imaging. Managing a leg ulcer after it has developed is extremely difficult. Zinc supplementation and pentoxifylline, and the utilization of an oxygen chamber have been proposed for ulcer treatment. Hydroxycarbamide additionally has some advantage, either alone or with erythropoietin. As of late encouraging outcomes have been gotten with platelet inferred development factor. Since patients with thalassemia intermedia have a high danger of apoplexy, exacerbated by splenectomy, know about thrombotic inconveniences. Suggested treatment choices incorporate appropriate anticoagulation before careful or other high danger systems, platelet hostile to totaling specialists if there should arise an occurrence of thrombocytosis (platelet count higher than 700,000/mm3 ) and low sub-atomic weight heparin in patients with recorded apoplexy [33]. Since people with thalassemia intermedia may foster iron over-burden from expanded gastrointestinal assimilation of iron or from incidental bondings, chelation treatment is begun when the serum ferritin fixation surpasses 300 ng/ml or when iron over-burden is exhibited by immediate or circuitous techniques [51]. Beneficial folic corrosive can be recommended to patients with thalassemia intermedia to keep inadequacy from hyperactive bone marrow.

#### *3.7.4 Improving ineffective erythropoiesis (IE) in thalassemia*

Several various therapy modalities are currently being researched throughout the world thanks to recent developments in our understanding of the pathogenic

#### *Overview of Beta-Thalassemia DOI: http://dx.doi.org/10.5772/intechopen.111682*

mechanism behind thalassaemia. The investigational drug products that have recently entered the clinical phase are discussed in the section that follows, with an emphasis on their present and potential future relevance for clinical practice. The current standard of care for IE in thalassaemia, which includes blood transfusions and stem cell transplants as well as novel therapeutic approaches based on gene therapies, is not covered in this study and is available elsewhere.

The US Food and Drug Administration (FDA) in 2019 and the European Medicines Agency (EMA) in 2020 have both approved the first treatment for thalassemia, luspatercept, for TDT patients.

Mitapivat is a small-molecule, oral allosteric activator of RBC pyruvate kinase (PK-R), a crucial enzyme to control the synthesis of ATP through glycolysis (**Figure 1**).

#### *3.7.5 Hematopoietic stem cell transplantation for thalassemia*

Hemoglobinopathies are treated by allogeneic HSCT; following conditioning to get beyond the immune barrier, allogeneic stem cells are employed as vehicles to rectify the fundamental genetic flaw by re-inserting genes required for healthy hematopoiesis. Allogeneic HSCT is essentially allogeneic stem cell gene therapy in the treatment

#### **Figure 1.**

*Distinction between healthy and erythropoiesis that is unsuccessful due to β-thalassemia [52, 53]. Erythropoiesis, which involves a number of proliferative and differentiation phases, is the process that converts hematopoietic stem cells into adult RBCs. The production of cell surface proteins, cell size reduction, progressive hemoglobinization, nuclear condensation, and nuclear extrusion are all temporally regulated processes that occur in conjunction with erythroid differentiation. The growth of extremely early erythroid precursors (proerythroblasts and earlier stages) and subsequent inefficient erythropoiesis are characteristics of β-thalassemia dyserythropoiesis in humans. A proliferating pool of immature erythroblasts is subject to ineffective erythropoiesis, which is characterized by (1) rapid erythroid differentiation, (2) maturation inhibition during the polychromatophilic stage, and (3) death of erythroid precursors [54–56].*

of various disorders. Autologous stem cells altered by the insertion of healthy genes may 1 day be used as vectors, but there is currently little sign that this strategy will be available in clinics anytime soon.

Thalassemia treatment with allogeneic hematopoietic stem cell transplantation (HSCT) has been a key component in the growth of HSCT. The allogeneic HSC with successful erythropoiesis is substituted for the thalassemic HSC having deficient erythropoiesis in order to treat thalassemia. This cellular replacement therapy results in the replacement of the entire hematopoietic system rather than just the damaged erythropoietic component. Nonetheless, it is a useful method to achieve a longlasting, possibly permanent, clinically successful correction of hemolytic anemia, eliminating the need for transfusions and the difficulties that go along with them (i.e., iron overload).

#### **3.8 Risk factors and complications of beta-thalassemia**

Family ancestry and heritage are factors that increment the danger of beta-thalassemia. Contingent upon family ancestry, in case an individual's folks or grandparents had beta-thalassemia major or intermedia, there is a 75% (3 out of 4) likelihood of the transformed quality being acquired by a posterity. Regardless of whether a youngster does not have beta-thalassemia major or intermedia, they can in any case be a transporter, potentially bringing about people in the future of their posterity having betathalassemia. Another danger factor is lineage. Beta-thalassemia happens regularly in individuals of Italian, Greek, Center Eastern, Southern Asian, and African heritage [57].

Complexities of beta-thalassemia change contingent upon the kind:


#### **3.9 Prevention of beta-thalassemia**

Beta-thalassemia is an innate sickness taking into consideration a safeguard therapy via transporter screening and pre-birth conclusion. It very well may be forestalled in the event that one parent has ordinary qualities, leading to screenings that engage transporters to choose accomplices with typical hemoglobin [58]. This screening technique demonstrated obtuse in populaces of West African family line in light of the markers has high pervasiveness of alpha thalassemia. Nations have programs dispersing data about the regenerative dangers related with transporters of haemoglobinopathies. Thalassemia transporter screening programs have instructive projects in schools, military, and through broad communications just as giving guiding to transporters and transporter couples [12]. Screening has shown diminished rate; by 1995 the commonness in Italy decreased from 1:250 to 1:4000, and a 95%

abatement around there. The reduction in occurrence has helped those influenced with thalassemia, as the interest for blood has diminished, accordingly working on the stock of treatment.

#### **4. Conclusions**

Thalassemia is a perplexing condition that needs in-depth approach for lab testing and analysis. High-throughput testing algorithms and procedures are needed for population screening in high-prevalence areas, which increases the difficulty of the diagnosis. Despite this, current best-practice guidelines and protocols are capable of the successful regulation of complicated laboratory procedures, coupled with essential EQA programs. Many novel methods are now being developed that have the potential to improve the accuracy, throughput, and efficacy of laboratory diagnostics of thalassemia and other hemoglobinopathies.

The majority of families cannot afford the estimated US \$ 3200 per child per year expense of treating serious thalassemia disease. Thalassemia management is not only distressing for the family but also has a significant socioeconomic impact on the nation, making its prevention and control a top priority. So, the first step toward easing the disease's burden is to prevent the birth of any afflicted fetuses.

Prenatal diagnosis (PND), genetic counseling, carrier screening, and termination of the afflicted fetus are all parts of prevention. This strategy is affordable and reducing the prevalence of thalassemia in many nations with remarkable results. Understanding the range and distribution of thalassemia mutations in a given population is a requirement for an efficient and quick prenatal diagnosis/genetic counseling.

### **Author details**

Kenneth Oshiokhayamhe Iyevhobu1 \*, Lucky E. Omolumen2 , Tobechukwu Joseph Okobi3 , Edidiong Raphael Usoro4 , A. Airefetalor Ivie1 , Benedicta A. Ken-Iyevhobu<sup>5</sup> and O. Omokpo Victoria6

1 CEPI/ISTH Lassa Fever Epidemiology Study, Irrua Specialist Teaching Hospital (ISTH), Nigeria

2 Faculty of Medical Laboratory Science, Department of Chemical Pathology, Ambrose Alli University, Nigeria

3 Biology Department, Georgetown University, Washington, USA

4 Department of Biomedical Sciences, Augusta University, Augusta, USA

5 Department of Microbiology, Ambrose Alli University, Nigeria

6 Department of Biological Sciences, School of Applied Science, Auchi Polytechnic Auchi, Nigeria

\*Address all correspondence to: kennylamai@yahoo.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 2**

## Effects of Beta-Thalassemia on COVID-19 Outcomes

*Simran Patel, Armaan Shah, Ryan Kaiser and Raj Wadgaonkar*

#### **Abstract**

Beta-thalassemia is a hemoglobinopathy caused by mutations in the beta-globin chain. This disrupts hemoglobin production and can potentially result in severe anemia. There has been a rise in COVID-19 cases over the last 2 years, with a predominant effect on the respiratory and vascular systems of the body. Since beta-thalassemia is the most common inherited single-gene disorder in the world, investigating the impact of COVID-19 on these patients is important. Some theories suggest that patients with beta-thalassemia will be more susceptible to COVID-19 and have worse outcomes due to their underlying comorbid conditions. However, majority of the literature found that beta-thalassemia is protective against COVID-19. This could be because SARS-CoV-2 proteins can attack the beta chain of normal hemoglobin, resulting in impaired oxygen transfer and increased ferritinemia. Thus, in hemoglobinopathies with beta-chain defects and low hepcidin levels, susceptibility to COVID-19 infection is potentially decreased. Higher levels of Hemoglobin F in thalassemia patients may also be protective against viral infections. Surprisingly, most studies and case reports focus on patients with beta-thalassemia major. There is yet much to learn about the outcomes of patients with thalassemia minor and other hemoglobinopathies.

**Keywords:** thalassemia, beta-thalassemia, COVID-19, SARSCoV-2, coronavirus

#### **1. Introduction**

Thalassemias are a group of autosomal recessive blood disorders caused by variations in alpha or beta globin genes that disrupt hemoglobin production and lead to ineffective erythropoiesis and hemolysis [1]. Given that hemoglobin serves as the oxygen-carrying component of red blood cells (RBCs), inadequate production can cause severe anemia and other life-threatening complications requiring frequent blood transfusions to maintain hemoglobin levels. Individuals affected by these disorders can start presenting with symptoms early in childhood and last for their entire lifetime.

Hemoglobin is made up of two chains: alpha-globin and beta-globin chains. Alpha thalassemia is generally caused by alpha-globin gene deletion that results in either reduced or absent alpha-globin production. Since the alpha-globin gene has four alleles, disease severity is dependent on the number of deleted alleles. One deletion can be clinically silent, whereas four deletions can be incompatible with life and lead

to hydrops fetalis [1]. Beta thalassemia is generally caused by beta-globin gene point mutations that are classified based on the zygosity of the gene mutation. A heterozygous mutation will result in one defective and one normal gene allowing for some production of the beta-globin chains. This is the mildest form of beta-thalassemia. A homozygous mutation will result in two defective genes causing a total absence of beta-globin chains. This mutation can lead to moderate to severe symptoms. Since the alpha and beta-globin chains are insoluble alone, they can precipitate and lead to damage to RBC membranes and intravascular hemolysis [1].

The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached the entire globe over the last 2 years and resulted in millions of deaths. It primarily targets the respiratory and vascular systems of the body. Since beta-thalassemia is the most common inherited single-gene disorder in the world and can affect the oxygen-carrying capacity of the body, investigating the impact of COVID-19 on these patients is important given the limited research data currently available [2].

#### **2. Classifications of beta-thalassemia**

The disease burden of beta-thalassemia depends on the zygosity of the beta-globin chain gene mutation. There are three main types of beta-thalassemia: beta-thalassemia major, beta-thalassemia intermedia, and beta-thalassemia minor [3].

#### **2.1 Beta-thalassemia major**

Individuals who are homozygous for the beta-globin chain mutation are classified as having beta-thalassemia major and completely lack beta chains. The manifestations of beta-thalassemia major are much more severe than beta-thalassemia minor and can result in jaundice, growth retardation, hepatosplenomegaly, endocrine abnormalities, and severe anemia. Symptoms begin at the age of 6 months when fetal hemoglobin is completely replaced by defective globin chains that accumulate and damage RBC membranes. Patients at this stage may present with failure to thrive and require lifelong blood transfusion and iron chelation therapy [3]. The classic clinical picture of betathalassemia major is primarily seen in underdeveloped countries where long-term transfusion facilities are not widely available. Patients who are inadequately treated for beta-thalassemia major commonly present with brown pigmentation of the skin, poor musculature, genu valgum, development of masses from extramedullary hematopoiesis, and skeletal changes in the long bones of the legs and craniofacial structures due to expansion of the bone marrow. Individuals not receiving regular transfusion therapy may die from high-out cardiac failure. Adequate maintenance of a minimum hemoglobin level between 9.0 and 10.5 g/dl ineffective erythropoiesis can be inhibited and regular growth and development can occur up to 10–12 years [3]. However, the complications of iron overload from repeated transfusions may manifest in children with growth retardation and failure of sexual maturation and in adults with liver fibrosis and cirrhosis, endocrine dysfunction resulting in diabetes mellitus and parathyroid insufficiency, and cardiac disease including dilated cardiomyopathy and arrhythmias. Hence, adequate iron chelation therapy is necessary as well. In the early 2000s, 50% of beta-thalassemia major patients died before the age of 35 due to all these complications. With the advent of new developments of noninvasive methods to measure organ iron levels and chelation therapy, the prognosis of beta thalassemia major has greatly improved [1–3].

#### **2.2 Beta-thalassemia intermedia**

Patients with beta-thalassemia intermedia can present much later in life than those with beta-thalassemia major. They have milder anemia symptoms and may still require transfusions but much less frequent, if at all. They can remain asymptomatic until adulthood, during which they may develop clinical features such as pallor, jaundice, cholelithiasis, hepatosplenomegaly, extramedullary masses of hyperplastic erythroid marrow, osteopenia, osteoporosis, and thrombotic complications. Patients can present with cardiac manifestations as well, including high-cardiac output and pulmonary hypertension with preserved systolic function [3]. Pseudoxanthoma elasticum, a disease caused by the accumulation of calcium deposits in elastic fibers in the skin, eyes, and blood vessels, is also common among beta-thalassemia intermedia patients [3]. Although the rate of iron loading is slower in these patients, similar complications can still occur if proper iron chelation therapy is not administered [1–3].

#### **2.3 Beta-thalassemia minor**

Heterozygotes of the beta-globin chain mutation are classified as having betathalassemia minor in which beta chains are being produced to a lesser degree than normal. Patients are generally asymptomatic or have mild anemia symptoms [1–3].

#### **3. Epidemiology of beta-thalassemia**

Beta-thalassemia is most prevalent in the Mediterranean and Middle East populations but is also common in regions of Southeast Asia. It has been less prevalent in regions of Northern Europe and North America. It is reported that 80–90 million people are carriers of this disease, making up about 1.5% of the global population [4]. According to a report published by the World Health Organization in 2008, more than 40,000 infants are born with beta-thalassemia annually, the majority of whom are transfusion-dependent. Roughly 205,000 newborns with beta-thalassemia are born in Southeast Asia, 10,000 in the Eastern Mediterranean region, 1000 in Europe, and 350 in North, Central, and South America. Thailand alone has close to 4000 new cases of beta-thalassemia annually. Only a few European countries have reported incidences of beta-thalassemia major, including Belgium which reported 1 in 25,000 neonates being born with beta-thalassemia, and 1 in 113,000 neonates in France between 2005 and 2008. In the United States, an incidence of 1 in 55,000 newborns was reported in California [4]. The high prevalence of beta-thalassemia in certain regions can be explained by multiple factors. There is a higher carrier rate and a cultural preference for consanguineous marriages in the Middle East. Increases in rates of migration from areas with a higher prevalence of beta-thalassemia to non-endemic areas have led to a higher prevalence of the disease in some European and Northern American regions. Also, with the improvement of health resources and access to blood transfusion centers, and adequate iron chelation therapy, survival rates have increased significantly, adding to the prevalence of beta-thalassemia [3, 4].

Comprehensive prevention programs have been put in place in endemic areas of beta-thalassemia, with a focus on public education, genetic counseling, population screening, and prenatal diagnostic testing. The Greek National Registry for Hemoglobinopathies reported a lower incidence of beta-thalassemia compared to what was expected based on the prevalence of carriers in the population [4]. Similar trends have been noted in Iran and Iraq as well, suggesting that thalassemia these programs have been effective in reducing the prevalence of the disease in some regions.

#### **4. Beta-globin gene mutations causing beta-thalassemia**

The beta-globin chain is encoded by a structural gene on chromosome 11 that is clustered with five other beta-like genes including ε(HBE), Gγ (HBG2), Aγ (HBG1), δ (HBD), and β (HBB) [5]. These genes are arranged on the chromosome based on the order of their developmental expression and are dependent on local promotor sequences and upstream control regions which bind to various erythroid-specific transcription factors (e.g. GATA-1, GATA-2, NF-E2, KLF1) and co-factors (e.g. FOG, p300). The controlled gene expression leads to the production of specific hemoglobin tetramers including embryonic (Hb Gower-1 (ζ2ε2), Hb Gower-2 (α2ε2), and Hb Portland (ζ2β2)), fetal (α2γ2), and adult (HbA, α2β2 and HbA2, α2δ2). Each is produced at a distinct stage of development, allowing for the process of hemoglobin switching to occur between the embryonic, fetal, and adult stages of life [5].

Fetal hemoglobin (HbF) is the primary hemoglobin from birth till about 6 months of age. Since it is made up of two alpha and two gamma chains and no beta chains, the manifestations of beta-thalassemia are not seen until after 6 months. When HbF levels drop and make up less than 5% of the total hemoglobin content of the body, it is replaced with adult hemoglobin (HbA), which is made up of two alpha and two beta chains. Since beta chain production is disrupted in beta-thalassemia, symptoms begin during this time. Hydroxyurea is an agent that upregulates gamma-globin gene production leading to increased HbF production. Though this therapy is widely used in sickle cell disease, its efficiency in beta-thalassemia is still being investigated [5–7].

There have been more than 300 beta-thalassemia alleles reported in the literature. However, only about 40 account for more than 90% of beta-thalassemia worldwide likely because only a few mutations are common in endemic regions. Downregulation of the beta-globin chain can be caused by a variety of molecular changes such as point mutations, small deletions limited to the beta-globin genes, or even extensive deletions of this region. However, most mutations are non-deletional. They may be single-base substitutions and small insertions or deletions of only a few bases within the gene. These mutations can lead to downregulation of the beta-globin gene throughout all stages of gene expression including transcription of the gene from DNA into mRNA to translation of the mRNA into a functional protein [5, 6]. Very rarely do larger deletions in the beta-globin gene result in beta-thalassemia. There are 18 deletions specifically on the beta-globin gene that have been found to cause betathalassemia. They range from 25 base pairs to about 6000 base pairs [5].

#### **5. Pathophysiology of beta-thalassemia**

Hemoglobin A is a tetrameter made up of two heterodimers each consisting of one alpha and one beta globin chain, attached to a heme moiety in the center. A balanced production these chains is crucial and tightly regulated. Once the globin chains combine, they are highly soluble in RBCs. However, if left unbound, these globin chains are highly insoluble and can accumulate in the blood. In beta-thalassemia, excess alpha-globin chains begin aggregating as soon as they accumulate in erythroid precursors and precipitate adjacent to the RBC membrane in early marrow erythroid precursors. This disrupts proper membrane assembly and can accelerate apoptosis [8–11].

#### **5.1 Effects of beta-thalassemia on red blood cells**

In normal physiology, hemoglobin in RBCs is oxidized to methemoglobin and subsequently reduced back to native hemoglobin. However, in patients with betathalassemia, the unpaired alpha chains attached to a heme moiety are more susceptible to oxidation and proteolysis, leading to the formation of hemichromes. These hemichromes can generate reactive oxygen species that in turn oxidize adjacent RBC membrane proteins and lipids. This can cause damage to the membrane by affecting the globin chains that bind to the membrane and directly altering cytoskeletal and integral membrane proteins [8–11].

Normal RBC precursors undergo cytoskeletal and membrane assembly via spectrin, band 4.1, band 3, and several other proteins. The asymmetry of the phospholipid bilayer that naturally exists between the inner and outer leaflets of the membrane is disrupted with oxidative damage and results in a disorderly and discontinuous pattern of membrane protein incorporation, especially in the regions with alpha chain aggregates [12]. There is also a lack of membrane stability caused by an oxidative injury that hinders the ability and inability to handle sheer stress [13]. All these changes are responsible for the abnormal maturation of RBCs in beta-thalassemia. Although the use of proteases may be used to treat membrane damage caused by an accumulation of globin chains by directly attacking and partially destroying the chains, they do not aid in their elimination from the body [14].

Beta-thalassemia can also affect the hydration of RBCs and result in their dehydration. This may be due to excessive activation of the potassium-chloride cotransport system, which is responsible for controlling potassium chloride loss in the body. Excessive activation results in the loss of these ions, leading to the loss of water as well. The resultant dehydration can cause a high mean cell hemoglobin concentration and a dense appearance on peripheral blood smears [13]. The flexible nature of RBCs allows for them to travel through the capillary circulation and the reticuloendothelial system lined by phagocytic cells lie within the spleen, liver, and lungs. The dehydration of RBCs caused by beta-thalassemia can affect this essential property and cause a delay in RBC passage and increased engulfment by macrophages [13, 15].

#### **5.2 Causes of anemia in beta-thalassemia**

Ineffective erythropoiesis refers to a decrease in the production of RBCs due to the destruction of maturing erythroblasts from either apoptosis or hemolysis. In patients with thalassemia, ineffective erythropoiesis leads to the expansion of the erythroid progenitor cell population and acceleration of differentiation, and mature arrest at the polychromatophilic erythroblast stage [16].

Some causes of ineffective erythropoiesis include apoptosis of erythroid precursors. Studies have shown that a possible mechanism for this apoptosis in beta-thalassemia patients involves the sequestration of heat shock proteins by free alpha-globin chains contained within the cytoplasm of precursor RBCs. These heat shock proteins are generally expressed in response to stress and play an important role in the stabilization of the cell [17]. The caspase and cytochrome proteins, which regulate apoptosis, were also found to be abnormally phosphorylated in the bone marrow erythroblasts of some beta-thalassemia patients [18]. Apoptosis of cells can

result in the movement of phosphatidylserine from the inner to the outer leaflet of RBC membranes, which serves as a signal for the removal of the cell by macrophages in the reticuloendothelial system [19].

Adverse consequences of ineffective erythropoiesis can arise at peripheral locations and result in extramedullary hematopoiesis, which is the production of RBCs outside of the bone marrow. This process is driven by a rise in erythropoietin levels and can manifest with the expansion of bone marrow cavities that can distort long bone, head, and facial bones that are not common sites of erythropoiesis. Ineffective erythropoiesis can also result in increased iron absorption, which is accompanied by its own set of complications.

Hemolysis can also lead to anemia in beta-thalassemia patients and can shorten the lifespan of the RBC by a third. This hemolysis is caused by the aggregation and oxidation of RBC membranes, resulting in mechanical property changes such as increased rigidity and dehydration that inhibit their smooth passage within the reticuloendothelial system and allow more time for macrophages to phagocytose the cells. Studies show that patients who have undergone splenectomies are more likely to be observed with unstable and deformed RBCs [20–22].

#### **6. COVID-19**

In late 2019, the first cases of mysterious pneumonia of unspecified origin were seen in Wuhan, the capital of Hubei province, China. Later, it would be confirmed that these cases were caused by the coronavirus disease 2019 (COVID-19). This pathogen belongs to the enveloped RNA beta coronavirus family. Due to its similarities with the original severe acute respiratory syndrome coronavirus (SARS-CoV-2) and Middle East Respiratory Syndrome (MERS) viruses, it was named SARS-CoV-2. Over the past 2–3 years, a staggering number of studies have explored the epidemiology and clinical presentation of COVID-19. However, there remains much to be learned regarding how the virus impacts the respiratory system both in the short and long term and how it affects those with chronic conditions such as hemoglobinopathies. Taking a macroscopic view, data classifies the presentation of the disease as mild, severe, or critical [23, 24]. A common symptom that is independently associated with in-hospital mortality is the severity of hypoxemia; this symptom has been described as a potentially important predictor of whether a patient requires intensive care.

#### **6.1 Pathophysiology of hypoxemia in COVID-19**

Arterial hypoxemia, an early sequela of COVID-19 infection, is caused mainly due to a V/Q mismatch. Continued blood flow to non-ventilated alveoli increased the P(A-a) O2 gradient. Infection also causes interstitial edema, particularly in structures with elastic properties responsible for withstanding stress and strain. This edema can lead to the appearance of ground-glass opacities and consolidation on chest X-ray or computerized tomographic imaging. Additionally, the edema causes loss of surfactant and increased superimposed pressure on lung parenchyma, eventually leading to alveolar collapse. While this occurs, a moderate amount of cardiac output continues to perfuse these collapsed areas, causing intrapulmonary shunting. The body's response to this is increased effort of breathing and use of accessory muscles, causing a rise in tidal volume, and subsequently, negative inspiratory intrathoracic pressure. Inflammation also causes increased lung permeability, which when combined with

the increase in negative intrathoracic pressure, leads to progressive edema, alveolar flooding, and effusions. Over time, this causes a severe decline in the quality of oxygenation and increases shunt fraction which is difficult to correct by increasing FiO2 [25].

While useful, clinicians should take caution when using oxygen saturation measured by pulse oximetry (SpO2) to detect hypoxemia. Tachypnea and hyperpnea due to infection, as described above, cause respiratory alkalosis and subsequent drop in PaCO2. This leads to a left shift in the oxyhemoglobin dissociation curve. Increased affinity of hemoglobin for oxygen during these periods can result in a paradoxical finding of preserved SpO2 during states of low PaO2 [25–27]. Another theory for the left-ward shift of the oxy-hemoglobin curve in COVID-19 was put forth by Rapozzi et al. Their hypothesis states that serum heme levels increase in COVID-19 infection, along with harmful iron ions (Fe3+) which cause inflammation and cell death. However, the interaction of the virus and abnormal heme groups remains to be studied. The apparently increased oxygen affinity of hemoglobin leads to lower tissue perfusion and extremity ischemia in patients with normal hemoglobin structure. However, for patients with thalassemias or sickle cell disease that may be on HbF treatment, the changes in the oxy-hemoglobin curve may shed light on if having hemoglobinopathies is protective or not against infection [26].

Further exploration of how COVID-19 affects erythrocytes and hemoglobin was done by the group. They propose that viral protein ORF8 and a surface glycoprotein of COVID-19 damaged the 1-beta chain of deoxyhemoglobin via docking with porphyrin and lead to the release of iron-free porphyrins. This interaction is intriguing. If it can be proven in vitro settings, this apparent interaction could explain cases where having beta-thalassemia has been shown to be protective against COVID- 19 infections. An absence of a beta-hemoglobin chain would leave the virus unable to negatively affect the oxygen binding capacity of existing hemoglobin chains, especially in patients that have increased HbF due to hydroxyurea therapies [26].

#### **6.2 COVID-19 and beta-thalassemia**

Multiple studies have been conducted to study the relationship between betathalassemia and COVID-19 infection. These studies have been piloted by groups mainly from countries where thalassemias have a higher prevalence, such as the Mediterranean and Middle Eastern nations. Researchers from these nations posit two hypotheses regarding the susceptibility of beta-thalassemia patients to COVID-19. One theory states that patients with beta-thalassemia may be more susceptible to COVID-19 infection and have worse outcomes due to chronic conditions such as heart disease, liver disease, iron overload, adrenal insufficiency, diabetes, and splenectomy. Being in a prolonged state of oxidative stress can lead to immunosuppression and thus worsen the body's innate ability to combat infection. A latent effect of beta-thalassemia is the need for ongoing medical treatment and attention that these patients need. Frequent visits to hospitals or medical centers for blood transfusion and complication management increase these patients' exposure to COVID-19. A second theory, however, proposes a different possibility. It suggests that patients who are heterozygous for beta-thalassemia may have immunity against COVID-19 infection. This is in part because beta-thalassemia patients have a higher concentration of HbF, which possesses a unique tetramer structure. The exact protective potential of HbF in COVID-19 infection remains to be studied [27].

**Figure 1** is a hypothetical representation of the interaction between the SARS-CoV-2 virus and the erythrocytes infected [28]. The internalization process is the virus is dependent on TMPRSS2, a serine protease, and angiotensin-converting enzyme type 2 (ACE-2), which allow entry of the virus into the cell. Once in the cell, the infection would activate metabolic processes that would result in oxidative stress. This negatively affects erythrocytes and would cause their destruction. The release of Fe2+ from damaged erythrocytes would further propel the metabolic reactions leading to oxidative stress. Remnants of alpha and beta hemoglobin chains would also be released into the intercellular space [28].

#### *6.2.1 Review of published studies*

A study from Iran describes 43 patients with beta-thalassemia from the ages of 9–67 years who contracted COVID-19. These patients were both transfusion-dependent and transfusion-independent. Results showed that transfusion-independent patients had a higher mortality rate (27.3%) than patients who were receiving regular transfusions (4.71%). Patients in the transfusion-independent category were found to be in a persistent chronic anemic state with hypercoagulability. Additionally, micro thrombosis made these patients more likely to develop pulmonary artery hypertension and heart failure. However, overall, the study found that the prevalence of COVID-19 infections in the beta-thalassemia population was lower than in the general population. Another report from the same group describes that in 48 patients with beta-thalassemia from ages 9–67, 8 (16.7%) died from COVID-19. Compared to the general population, while patients with beta-thalassemia had a lower prevalence of COVID-19 infection, those that did contract the disease had higher mortality [29, 30].

An Italian group studied individuals with thalassemia who contracted COVID-19 and had 15 days of follow-up from symptom onset of positive SARS-CoV2 positivity. They collected data on 11 patients, mainly centered in northern Italy. Patients ranged from ages 31–61 years with a majority being female. Ten patients were transfusiondependent, and one was not. Eight of these patients were splenectomized and all patients had thalassemia-associated comorbidities. Six of the patients were hospitalized with mild-moderate upper respiratory symptoms but did not require mechanical

**Figure 1.** *SARS-CoV-2 entry into host cell and resultant erythrocyte damage.*

#### *Effects of Beta-Thalassemia on COVID-19 Outcomes DOI: http://dx.doi.org/10.5772/intechopen.110000*

ventilation. Three patients were asymptomatic. One patient developed severe symptoms of high fever, agranulocytosis, and lymphopenia. This patient also required intensive ventilation support with continuous positive airway pressure. Of the six hospitalized patients, the clinical course ranged from 10 to 29 days. Splenectomy was not found to affect the clinical course of any of the patients. One surprising finding was the apparent lack of severe acute respiratory syndrome in the patients, as well as a lack of signs of cytokine storm or death given the mean age and comorbidities of the patient population. From their preliminary data, the research team concluded that thalassemia did not increase the severity of COVID-19 disease progression [31].

A French study showed that most of the cases of COVID-19 and thalassemia had a favorable outcome in France. The study proposed that this was most likely due to the rarity of the most severe hemochromatosis-related complications such as diabetes, heart failure, cirrhosis, or iron overload in transfusion-dependent patients. However, the study also reported that patients with signs of iron overload detectable via MRI had an increased risk of thromboembolism events, particularly renal or hematological side effects [32].

Most recently, a systematic review meta-analysis of three papers from France in July 2022 described the susceptibility of beta-thalassemia carriers and COVID-19 susceptibility. Based on their findings and after conducting statistical analysis the study found that beta-thalassemia patients were less susceptible to COVID-19 but had higher mortality if infected when compared to the general population. Those that had an ICU course that did not result in death tended to have a shorter ICU stay when compared to patients with no hemoglobinopathies. While the sample size of this systematic review was small, it shows interesting evidence to further showcase the potential protective effects of beta-thalassemia in COVID-19 infections [33].

#### *6.2.2 Review of case reports*

A multitude of case reports showcasing the outcomes of COVID-19 infection in patients with hemoglobinopathies has been published. From Indonesia, four beta-thalassemia pediatric patients developed mild COVID-19 infection with one developing thrombosis supported by elevated D-dimer [34]. In Italy, a 59-year-old woman who was transfusion-dependent developed a mild COVID-19 infection [35]. In Pakistan, two patients developed a mild infection as well, with one of the patients having a prior splenectomy [36]. Most case reports describe the infection progression in pediatric patients, while also reporting benign infection courses for all patients.

#### *6.2.3 Summary of findings*

Almost universally, the presented studies highlight the relatively young population of patients with COVID-19 and thalassemia had a favorable outcome probably due to the rarity of the most severe hemochromatosis complications. Specific risks related to both thalassemia-related co-morbidities and long-term treatments should be considered. No clear-cut separation between the direct effect of thalassemia on hemoglobin structure and the effect of systemic comorbidities on COVID-19 outcomes has been established.

SARS-CoV-2 proteins can attack the beta chain of hemoglobin, resulting in impaired oxygen transfer and increased ferritinemia. Thus, in hemoglobinopathies with beta chain defects and low hepcidin levels, susceptibility to COVID-19 infection might decrease. Higher levels of HbF in thalassemia patients may be protective against viral infections; the anti-parasitic effect of HbF has been well-documented in areas where malaria is endemic. Studies have attributed lower COVID-19-related mortality in tropical countries where there is a higher prevalence of thalassemias/sickle cell disease due to the increased use of hydroxyurea which induces HbF production. This theory supports the pursuit of clinical studies analyzing the role of HbF-inducing therapies as treatment for COVID-19. Hydroxyurea is a medication used in patients with thalassemia intermedia. Its anti-inflammatory function, antiviral effect, and induction of HbF levels might suggest the benefit of hydroxyurea against the severe forms of COVID-19 [37, 38].

Splenectomy is a common therapeutic intervention in thalassemias, but it might increase the risk of coagulopathy and cytokine storms. However, there is no evidence that splenectomy increases the risk of severe COVID-19 in asplenic/hyposplenic patients [39]. High ferritin levels might be a negative prognostic factor in patients with COVID-19, and iron chelation might be beneficial against COVID-19 [40]. Patients with hemoglobinopathies, including those with thalassemias, are at increased risk of developing severe complications of COVID-19. Lifestyle and nutrition controls are important in controlling their infection, and vitamin D supplementation is beneficial against viral and bacterial infections. Two trace elements, zinc, and selenium are involved in the immune system's integrity and are necessary for beta-thalassemia patients during the COVID-19 pandemic.

#### *6.2.4 Socio-economic factors affecting patients with beta-thalassemia*

Most infants born with beta-thalassemia are in Southeast Asia and the Middle East. Nations in these geographical locations are still developing standardized and accessible healthcare for their citizens. While patient education and screening measures have been taken and some countries, such as Iran and Greece, have reported a lower incidence of thalassemias, there remains a stark asymmetry in access to proper healthcare in developing nations when compared to nations of the European Union and North America. As a result, it is possible that many patients who suffer from hemoglobinopathies may not have access to or be educated about when to seek healthcare. This results in lower data from clinical sources for studies such as those listed above. Additionally, due to the small sample size of the studies listed above, the power of each outcome is low. While some of the results reported are seen as significant after statistical analysis, it is not possible to generalize these findings without further inquiry. The potential protective nature of thalassemias in COVID-19 infection may not be relevant if patients who do contract the disease have higher mortality when compared to the general population [41].

#### **6.3 Vaccines for patients with beta-thalassemia**

While exact SARS-CoV-2 vaccination rates among patients with thalassemias are difficult to ascertain, vaccination is imperative in this community. The efficiency of the humoral response to the new vaccines against SARS-CoV-2 is currently a topic of great scientific relevance. The importance of vaccination in vulnerable patients is highlighted by the increased mortality rates in patients with hemoglobinopathies that contract COVID-19. A recent study by Anastasia et al. describes the humoral immune system response to the Comirnaty vaccine in beta-thalassemia major patients. In the study, beta thalassemia major patients were boosted with BNT162b2, an mRNA vaccine, produced by Pfizer-Biontech. Sixty-seven patients met the inclusion criteria. *Effects of Beta-Thalassemia on COVID-19 Outcomes DOI: http://dx.doi.org/10.5772/intechopen.110000*

Blood samples were collected from participants after receiving two doses of the vaccine. Antibody titers were measured against the receptor binding domain (RBD) in the S1 subunit of the Spike protein by using a quantitative Elecsys anti-SARS-CoV-2 ROCHE automated system. The study observed that 73.3% of splenectomized transfusion-dependent thalassemia patients showed anti-S ab titers in the second quartile, while non-splenectomized transfusion-dependent thalassemia patients had anti-S ab titers below 800 BAU/mL.

One month after administration of the second vaccine dose, there were no notable side effects in the patients. The production of immunoglobulin levels was robust in asplenic patients, arising several issues concerning the unusual humoral immune response in this vulnerable population. The group suggests that after splenectomy, memory B cells are deficient in patients. The role of humoral immunity then falls on perilymphatic tissue and bone marrow. The group suggests that this paradoxical increase in antibody titers in splenectomized patients may be due to unknown interactions between a novel mRNA vaccine and pathways in the immune system yet to be elucidated [42].

#### **7. Conclusion**

In conclusion, the current literature supports the conclusion that beta-thalassemia is protective against COVID-19. Surprisingly, most studies and case reports focus on patients with beta-thalassemia major. There is yet much to learn about the outcomes of patients with thalassemia minor and other hemoglobinopathies. The relative protective factors of beta-thalassemia major may not be present in other manifestations of the disease. Due to the limited patient population and lack of resources in nations where thalassemia is more common, it is possible a widescale study is not feasible. A lack of evidence-based medicine for such patients is glaring in the age of modern medicine. Leaders and researchers in hematology should focus efforts on expanding the current data available by controlled testing using in vitro samples. A keen understanding of the interactions between COVID-19 and abnormal hemoglobin chains is needed to better treat this vulnerable patient population.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Thalassemia Syndromes – New Insights and Transfusion Modalities*

#### **Author details**

Simran Patel, Armaan Shah, Ryan Kaiser and Raj Wadgaonkar\* SUNY Downstate Health Sciences University, Brooklyn, USA

\*Address all correspondence to: raj.wadgaonkar@downstate.edu

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 2
