Co esponding au ho : Tu dalie sama bek O ozalie ich.
Copy igh © 2025 Au ho (s) e ain he copy igh o his a icle. This a icle is published unde he e ms o he C ea i e Commons A ibu ion Liscense 4.0.
Thalassemia: A li elong ba le wi h hemoglobin de iciency
Madhu Kushwaha, Tu dalie sama bek O ozalie ich *, Ansy Abdul Rasheed, Gau a kushwaha, As a ul alom,
Mohammad ubaid u ehman, Shahid a idi and Akshay pa as am chau mal
Depa men o Public heal h, In ec ious disease a ul y, Osh S a e Uni e si y, Ky gyzs an.
Wo ld Jou nal o Biology Pha macy and Heal h Sciences, 2025, 21(01), 323-334
Publica ion his o y: Recei ed on 01 Decembe 2024; e ised on 08 Janua y 2025; accep ed on 10 Janua y 2025
A icle DOI: h ps://doi.o g/10.30574/wjbphs.2025.21.1.0042
Abs ac
Thalassemia is a he e ogeneous g oup o inhe i ed diso de s o haemoglobin caused by educed o absen p oduc ion
o one o mo e o he globin chains. They a e he commones single gene disease wo ldwide. The disease was i s
desc ibed by Thomas Cooley (a paedia ician om De oi , USA) in 1925. he wo common ypes, majo i y o β
halassaemias a e caused by poin mu a ions, while mos o he α halassaemias esul om gene dele ions.The esul ing
imbalance in globin syn hesis is esponsible o he ine ec i e e y h opoiesi sand hemolysis ypically obse ed in he
halassemia synd omes.Abou 3.2 % o he wo ld’s popula ion (152 million people) ca y β- halassemia genes.The
ini ial symp oms o he disease appea in he la e hal o he i s yea o li e, when he syn hesis o γ-chains is no
eplaced by he syn hesis o β-chains.The imp o ed su i al o pa ien s wi h halassemia majo has been a ibu ed o
imp o emen in ans usion he apy, be e unde s anding o mechanisms o o gan damage om i on, mo e e ec i e
i on chela ion, he a ailabili y o magne ic esonance o he e alua ion o ca diac i on o e load, and he e e al o
pa ien s o cen e s o excellence.
Keywo ds: Thalassemia; Hemoglobin; Alpha- halassemia; Be a- halassemia; Anemia; Gene ic Diso de s; Blood
T ans usions; I on Chela ion; Bone Ma ow T ansplan ; P ognosis; Gene ic Sc eening
1. In oduc ion
1.1. Thalassemia Synd omes
Thalassemia synd omes a e a g oup o inhe i ed hema ological diso de s cha ac e ized by educed o absen syn hesis
o one o mo e globin subuni s ha cons i u e no mal human hemoglobin (Hb). The mos common o ms include α-, β-
, γ-, and δβ- halassemia. Acco ding o he la es Bulle in o he Wo ld Heal h O ganiza ion, halassemia mu a ions (2013)
pose a signi ican public heal h bu den, a ec ing 71% o 229 na ions globally. I is es ima ed ha app oxima ely 1.5%
o he global popula ion ca ies gene ic mu a ions ha impai hemoglobin p oduc ion.
1.2. Geog aphical Dis ibu ion
Thalassemia gene mu a ions a e p edominan ly ound ac oss a b oad geog aphical egion ex ending om he
Medi e anean basin h ough he Middle Eas , he Indian subcon inen , Bu ma, Sou heas Asia, Melanesia, and he
Paci ic Islands. Α- halassemia is pa icula ly p e alen in Sou heas Asia (e.g., China, Thailand, Vie nam, Malaysia, and
he Philippines), he eas e n Medi e anean, and pa s o he Middle Eas . In con as , i is less common in A ica and
India; howe e , α+ halassemia is ela i ely mo e equen in India.
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Figu e 1 P e alence o halassemia majo in di e en coun ies
The high p e alence o halassemias, alongside sickle-cell disease and glucose-6-phospha e dehyd ogenase (G6PD)
de iciency, in mala ia-endemic egions is likely due o he p o ec i e ad an age he e ozygous ca ie s possess agains
Plasmodium alcipa um mala ia. Mu a ions a ec ing he α- and β-globin genes a e highly a iable, wi h dis inc
equencies ac oss coun ies and egions. E en wi hin speci ic coun ies, a ia ions in mig a ion pa e ns and he
p e alence o consanguineous ma iages ha e led o di e ences in he dis ibu ion o halassemic mu a ions.
1.3. Pa hophysiology o α-Thalassemia
The unde lying de ec in α- halassemia is an imbalance in globin chain syn hesis, causing an excess o β- and/o γ-globin
chains. Unlike he uns able α-globin chains, excess γ-globin chains du ing e al li e and excess β-globin chains in
pos na al li e o m soluble e ame s: γ4 (Hb Ba ) and β4 (HbH), espec i ely. These e ame s, al hough soluble, impai
ed blood cell (RBC) unc ion and s abili y, leading o hemolysis and, o a lesse ex en , ine ec i e e y h opoiesis.
Despi e he iden i ica ion o o e 100 α- halassemia mu a ions, clinical mani es a ions a e ca ego ized in o ou
pheno ypes o inc easing se e i y: silen ca ie , α- halassemia ai , HbH disease, and Hb Ba hyd ops e alis.
• Fou -Gene Dele ion (Hb Ba Hyd ops Fe alis): In ol es he dele ion o all ou α-globin genes (bo h alleles on
bo h ch omosomes), esul ing in comple e absence o α-globin chain syn hesis.
Only γ4 e ame s (Hb Ba ) a e p oduced, which canno anspo oxygen e ec i ely. The condi ion is incompa ible
wi h li e, leading o in au e ine dea h (s illbi h a 28–40 weeks) o dea h sho ly a e bi h.
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• Th ee-Gene Dele ion (HbH Disease): Cha ac e ized by a se e e educ ion in α-globin chain syn hesis. Resul s
in he p oduc ion o β4 e ame s (HbH) alongside educed le els o HbA and Hb Ba . HbH is ine ec i e o
oxygen anspo and p ecipi a es in e y h ocy es and e y h oblas s, leading o mode a e anemia (hemoglobin
le els 70–100 g/L) and splenomegaly, a p esen a ion consis en wi h halassemia in e media.
Mos indi iduals a e no ans usion-dependen . HbA2 le els a e ypically no mal o educed.
• Two-Gene Dele ion (α-Thalassemia T ai ): Causes mild mic ocy osis wi h o wi hou minimal anemia. HbH
inclusion bodies may be obse ed in a pe iphe al blood smea s ained wi h b illian c esyl blue.
• One-Gene Dele ion (Silen Ca ie ): Typically, asymp oma ic wi h a no mal blood pic u e.
Re e ence: The alpha Thalassaemia (Fessas P, Loukopoulos D, Kal soya A. Pep ide analysis o he inclusions o e y h oid
cells in be a halassemia. Biochim Biophys Ac a. 1966; 124:430-432)
Figu e 2 The alpha Thalassaemias
1.4. Β-Thalassemia
Β-Thalassemia e e s o a g oup o inhe i ed diso de s cha ac e ized by educed o absen syn hesis o he β-globin
chains o hemoglobin, leading o imbalanced globin chain p oduc ion. The esul ing accumula ion o unpai ed α-globin
chains causes hemolysis, ine ec i e e y h opoiesis, and a ying deg ees o anemia. Β-Thalassemia is classi ied in o
h ee clinical o ms: β- halassemia majo , β- halassemia in e media, and β- halassemia mino , depending on he
se e i y o clinical p esen a ion and ans usion equi emen s.
1.5. Β-Thalassemia Majo
Β-Thalassemia majo , also known as Cooley’s anemia o Medi e anean anemia, ep esen s he mos se e e o m o he
diso de . I esul s om homozygosi y o compound he e ozygosi y o β- halassemic mu a ions. Clinically, i is
cha ac e ized by se e e ans usion-dependen anemia equi ing mo e han eigh ed blood cell ans usions annually.
The majo pa hological ea u es o β- halassemia majo include:
• Se e e Anemia: Reduced hemoglobin syn hesis due o absen o ma kedly dec eased β-globin chain p oduc ion.
• Sho ened ed cell li espan caused by he p ecipi a ion o insoluble excess α-globin chains.
• Ine ec i e e y h opoiesis esul ing om e y h oid p ecu so apop osis.
• Rela i e ola e de iciency.
o Skele al Abno mali ies:Expansion o e y h oid ma ow leads o bone de o mi ies, including dis o ion o he
skull, acial bones, and long bones.
o Splenomegaly:Signi ican spleen enla gemen occu s due o ex amedulla y hema opoiesis and ch onic
hemolysis.
o Red Cell Mo phology:Pe iphe al blood smea shows ma ked mic ocy osis, hypoch omia, a ge cells, and
ex ensi e anisopoikilocy osis ( a ia ions in size and shape).
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o Hemoglobin F Pe sis ence:Hemoglobin F (HbF, α₂γ₂) emains ele a ed h oughou li e, as β-globin syn hesis
is se e ely impai ed. Symp oms ypically appea a ound 6 mon hs o age when HbF le els begin o decline.
o I on O e load (Hemoside osis): Ch onic hemolysis, ine ec i e e y h opoiesis, and epea ed blood
ans usions cause gene alized i on o e load, leading o o gan damage.
1.6. β-Thalassemia In e media
β-Thalassemia in e media desc ibes a milde o m o he disease, cha ac e ized by mode a e anemia (hemoglobin le els
be ween 70–100 g/L) ha does no necessi a e egula blood ans usions. Symp oms a e less se e e, and ans usions
may only be equi ed in e mi en ly, such as du ing pe iods o physiological s ess.
The clinical p esen a ion may esul om:
• Milde Geno ypes:Homozygosi y o mild β⁺ mu a ions ha pe mi pa ial β-globin chain
syn hesis.Coinhe i ance o α-Thalassemia:
• Reduced α-chain p oduc ion mi iga es α/β-globin chain imbalance, alle ia ing ine ec i e e y h opoiesis and
hemolysis.He edi a y Pe sis ence o Fe al Hemoglobin (HPFH).Inc eased γ-globin chain syn hesis (HbF) helps
compensa e o he β-globin de iciency, educing he impac o α-chain excess.
1.7. β-Thalassemia Mino
β-Thalassemia mino , o β- halassemia ai , occu s in he e ozygous indi iduals who inhe i one mu a ed β-globin
allele. I is ypically asymp oma ic o associa ed wi h mild clinical mani es a ions, including:
• Minimal hypoch omic mic ocy ic anemia.Ele a ed le els o hemoglobin A₂ (HbA₂, α₂δ₂), a mino hemoglobin
componen ha becomes mo e p ominen in β- halassemia mino .
1.7.1. Pa hophysiology o β-Thalassemia
The undamen al de ec in β- halassemia is he educed o absen p oduc ion o β-globin chains, leading o a ela i e
excess o unpai ed α-globin chains. The key pa hological consequences include:
• Dec eased Hemoglobin P oduc ion:Reduced β-globin chain syn hesis esul s in o e all lowe hemoglobin
le els.
• Α-Globin Chain Imbalance:Unpai ed α-globin chains p ecipi a e in e y h oid p ecu so s and ma u e ed blood
cells, dis up ing e y h oid ma u a ion and memb ane in eg i yThe ex en o α-chain accumula ion de e mines
he se e i y o clinical mani es a ions.
• E y h oid Damage:Excess α-globin chains lead o oxida i e s ess, apop osis o e y h oid p ecu so s, and
sho ened ed cell li espan, esul ing in hemolysis and ine ec i e e y h opoiesis.
In β⁺- halassemia (pa ial β-globin syn hesis), esidual β-globin p oduc ion helps educe he se e i y o α-chain
imbalance. Simila ly, pe sis ence o γ-globin chain syn hesis in β- halassemia in e media pa ially compensa es o he
β-chain de ici , imp o ing he clinical ou come.O e all, he deg ee o α/non-α globin chain imbalance de e mines he
clinical se e i y o β- halassemia, anging om asymp oma ic ca ie s o ans usion-dependen β- halassemia majo .
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Figu e 3 Pa hophysiology o β- halassemia. Ig, immunoglobulin. (Fessas P, Loukopoulos D, Kal soya A. Pep ide
analysis o he inclusions o e y h oid cells in be a halassemia. Biochim Biophys Ac a. 1966; 124:430-432)
1.8. Clinical Fea u es o β-Thalassemia
In β- halassemia, he ansi ion om e al hemoglobin (HbF, α₂γ₂) o adul hemoglobin (HbA, α₂β₂) occu s pos na ally.
Consequen ly, he anemia de elops g adually du ing in ancy, ypically a ound 6 mon hs o age, and p og essi ely
wo sens.
1.9. Key Clinical Mani es a ions
1.9.1. Se e e Anemia
P og essi e anemia leads o symp oms such as pallo , a igue, and ailu e o h i e in ea ly childhood. G ow h and
De elopmen al Delays Re a ded physical g ow h and ailu e o achie e de elopmen al miles ones a e common.
1.9.2. Skele al Abno mali ies
Expansion o e y h oid ma ow causes skele al de o mi ies, including: F on al bossing o he skull. Maxilla y
o e g ow h, esul ing in he cha ac e is ic “chipmunk acies.”
1.9.3. Radiological Changes
These include widening o he diploic space o he skull, “hai -on-end” appea ance on X- ays, co ical hinning, and
widening o he medulla y ca i ies o long bones, wi h a p edisposi ion o pa hological ac u es.
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Figu e 4 (A) Child wi h halassaemia, showing he ypical acial ea u es. (B) Skull X ay o a child wi h β- halassaemia,
showing he ‘hai -on-end’ appea ance. (C) X- ay o a hand, showing expansion o he ma ow and a hinned co ex.
(Cou esy o D . O zincolo C, Cas aldi G, Scu ella i PN, F anceschini F. The be a- halassaemia.Skele al Radiol. 1989;
18:373-376.)
1.9.4. Hepa osplenomegaly
Enla gemen o he li e and spleen occu s due o ex amedulla y hema opoiesis and ch onic hemolysis.
1.9.5. Recu en In ec ions
Inc eased suscep ibili y o in ec ions is associa ed wi h i on o e load, as ele a ed se um i on le els p omo e bac e ial
g ow h.
1.9.6. I on O e load Complica ions
Ch onic i on o e load, esul ing om epea ed ans usions and hemolysis, can lead o sys emic complica ions,
including: G ow h e a da ion, Skin hype pigmen a ion., Hepa ic damage p og essing o ci hosis, Endoc ine
dys unc ion, such as insulin-dependen diabe es melli us, delayed pube y, hypopa a hy oidism, and hypo hy oidism,
Ca diac ailu e due o myoca dial i on deposi ion.
1.9.7. Fola e De iciency
The inc eased e y h oid u no e in β- halassemia o en esul s in ela i e ola e de iciency
1.10. Sc eening o Thalassemia
Sc eening is an essen ial p e en i e s a egy, pa icula ly du ing an ena al ca e:
• Ma e nal Sc eening: All p egnan women should be sc eened du ing hei i s an ena al isi .
• Pa e nal Sc eening: I he mo he is iden i ied as a ca ie , he a he is sc eened o assess he isk o se e e
halassemia in he e us.
• P ena al Diagnosis: Cho ionic Villus Sampling (CVS): Pe o med a ≥10 weeks o ges a ion, CVS p o ides e al
DNA o gene ic analysis using ad anced me hods such as PCR, Sou he n blo ing, o RFLP analysis.
• Fe al Blood Sampling: Conduc ed a 18 weeks o ges a ion o analysis o globin chain syn hesis.
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• P eimplan a ion Gene ic Diagnosis: Emb yonic biopsy allows o gene ic analysis be o e implan a ion, educing
he isk o a ec ed p egnancies.
1.11. Labo a o y Fea u es
• Pe iphe al Blood Examina ion:Se e e mic ocy ic hypoch omic anemia wi h hemoglobin le els anging om 2
o 6 g/dL.Red blood cells exhibi ma ked anisopoikilocy osis, a ge cells, basophilic s ippling, Howell-Jolly
bodies, and nuclea ed ed cells on blood smea examina ion.
• Tes o Inclusion Bodies:Agg ega es o unpai ed α-globin chains can be isualized in e y h oblas s using
sup a i al s aining (e.g., me hyl iole ). Pos -splenec omy, hese inclusion bodies may also appea in pe iphe al
blood.
• Hemoglobin Elec opho esis:Ele a ed le els o HbF ( anging om 10% o 98%).HbA₂ may be no mal o mildly
ele a ed.In homozygous β⁰- halassemia, HbA is absen ; in β⁺/β⁺ o β⁰/β⁺ o ms, educed le els o HbA a e
de ec ed.
• Bone Ma ow Examina ion:Shows ma ked e y h oid hype plasia, indica i e o ine ec i e e y h opoiesis.
• I on S udies:Inc eased se um i on and e i in le els.Unconjuga ed bili ubin is ele a ed due o hemolysis.
• Osmo ic F agili y:Dec eased ed cell osmo ic agili y is no ed.
Β-Thalassemia majo ep esen s a signi ican public heal h conce n, pa icula ly in egions su ounding he
Medi e anean, he Middle Eas , and Sou heas Asia. In esou ce-limi ed se ings, inadequa e ans usion suppo and
i on chela ion he apy esul in poo su i al a es and educed quali y o li e.
Β-Thalassemia Majo : Wi hou egula blood ans usions and i on chela ion he apy, a ec ed in an s a ely su i e
beyond ea ly childhood. Inadequa e ea men leads o se e e complica ions, including i on o e load and o gan
dys unc ion.
Β-Thalassemia In e media: Rep esen s a milde pheno ype whe e egula ans usions a e no equi ed, bu pa ien s
may expe ience anemia- ela ed symp oms and g ow h e a da ion.
1.12. P inciples o The apy
1.12.1. Blood T ans usion
His o ically, ans usions we e adminis e ed only when anemia became symp oma ic. This “on-demand” app oach
esul ed in skele al de o mi ies, hepa osplenomegaly, and poo su i al.The hype ans usion p o ocol was de eloped
o main ain hemoglobin le els ≥9.5–10 g/dL. Regula ans usions help supp ess ine ec i e e y h opoiesis, p e en
skele al de o mi ies, and imp o e quali y o li e.
1.12.2. I on Chela ion The apy
Ch onic ans usions esul in i on o e load, which equi es chela ion he apy o p e en o gan
damage.Des e ioxamine (DFO): Adminis e ed subcu aneously ia in usion pumps (25–60 mg/kg/day) o 12 hou s, 5–
6 days pe week, o en combined wi h i amin C o enhance i on exc e ion.
1.12.3. Bone Ma ow T ansplan a ion (BMT)
BMT is he only cu a i e op ion o β- halassemia majo , hough i ca ies signi ican isks o mo bidi y and mo ali y.
The decision o pu sue BMT depends on a ca e ul assessmen o indi idual isk-bene i p o iles.
Re e ence: P ope ies o i on chela ing d ugs used in halassaemia. (Cohen AR, Glimm E, Po e JB. E ec o ans usional
i on in ake on esponse o chela ion he apy in be a- halassemia majo . Blood. 2008; 111:583-587.)
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Table 1 P ope ies o i on chela ing d ugs
1.13. P e en ion o Thalassemia: S a egies and P io i ies
Thalassemia p e en ion should be p io i ized due o i s signi ican heal h and economic bu den. E ec i e s a egies ely
on public awa eness, ca ie sc eening, gene ic counseling, and p ena al diagnosis.
1.13.1. Public Heal h Educa ion
Raising awa eness h ough mass communica ion pla o ms, such as media campaigns, helps educa e he popula ion
abou he na u e o halassemia, i s socioeconomic impac , and he impo ance o p e en i e measu es.
1.13.2. Ca ie Sc eening and Gene ic Counseling
Ca ie sc eening in ol es iden i ying indi iduals who a e he e ozygous o halassemia mu a ions h ough simple,
cos -e ec i e diagnos ic es s.Gene ic counseling plays a pi o al ole in in o ming a - isk indi iduals abou he gene ic
implica ions and isks o inhe i ance.I is s ongly ecommended ha he e ozygous ca ie s a oid ma ying ano he
ca ie o he same halassemia gene o educe he likelihood o ha ing o sp ing wi h se e e disease.
1.13.3. P ena al Diagnosis
P ena al diagnosis is a c i ical in e en ion o couples a isk o ha ing a child wi h halassemia. I can be di ided in o
wo app oaches:
• Re ospec i e Diagnosis: Pe o med in couples who al eady ha e an a ec ed child.
• P ospec i e Diagnosis: Conduc ed in couples iden i ied as ca ie s h ough sc eening p og ams.
• Ad ances in p ena al diagnos ic echniques allow ea ly de ec ion o a ec ed e uses, enabling in o med
decisions, including he op ion o selec i e e mina ion o p egnancy whe e pe missible.
• By in eg a ing heal h educa ion, ca ie sc eening, gene ic counseling, and p ena al diagnos ics in o public
heal h ini ia i es, he incidence o halassemia can be e ec i ely educed.
1.14. p ognosis
Thalassemia is a g oup o inhe i ed blood diso de s ha impac hemoglobin p oduc ion, esul ing in anemia. The
se e i y o he condi ion can a y widely based on he speci ic ype o halassemia, he mu a ions in ol ed, and he age
a which i is diagnosed. P ognosis o hose wi h halassemia is in luenced by se e al ac o s, including he ype o
halassemia, he a ailabili y o ea men s, and how well complica ions a e managed. Bo h alpha and be a halassemia
ypes o en equi e egula blood ans usions, i on chela ion he apy, and o he medical in e en ions. I le un ea ed,
halassemia can lead o se ious complica ions such as endoc ine dys unc ion (which may include g ow h e a da ion,
hypo hy oidism, and diabe es), splenomegaly (enla gemen o he spleen), and hepa omegaly (enla gemen o he
li e ). Addi ionally, bone de o mi ies can occu due o inc eased e y h opoiesis, which is he expansion o bone
ma ow.The ou look o indi iduals wi h halassemia is con ingen on a ious ac o s, including whe he i is alpha o
be a halassemia, he se e i y o he condi ion, he age a which i is diagnosed, and he e ec i eness o ea men .
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2. Resul s
Thalassemias a e inhe i ed as au osomal ecessi e diso de s. Hemoglobin A (HbA) is composed o wo α-globin and wo
β-globin chains (α2β2). The syn hesis o α-globin chains is egula ed by wo gene clus e s loca ed on ch omosome 16,
while β-globin chain p oduc ion is con olled by genes on ch omosome 11. Each globin gene con ains h ee exons
(coding sequences) and wo in ons (non-coding egions). The syn hesis o bo h α- and β-globin chains is media ed by
RNA ansc ip ion. S udies ha e consis en ly demons a ed ha egula blood ans usions, combined wi h i on
chela ion he apy, signi ican ly imp o e he quali y o li e and su i al a es in pa ien s wi h halassemia. Howe e ,
long- e m managemen emains challenging due o complica ions such as i on o e load, which can cause i e e sible
o gan damage.
Figu e 5 Kaplan-Meie su i al cu e a e he i s decade o li e, subdi ided by coho o bi h o pa ien s om an
I alian coope a i e s udy. The su i al da a we e collec ed in 2009. The ole o he coho o bi h is e iden
Bone ma ow ansplan a ion has eme ged as a cu a i e app oach o some pa ien s, hough i s widesp ead use is
limi ed by he a ailabili y o sui able dono s and he isks associa ed wi h he p ocedu e. A la ge coope a i e I alian
s udy epo ed imp o ed su i al a es o pa ien s bo n in ecen yea s, wi h emales exhibi ing be e ou comes
compa ed o males. Despi e hese ad ancemen s, mo ali y a es in halassemia pa ien s emain ele a ed compa ed o
he gene al popula ion. Da a om 2010 indica ed ha 68% o pa ien s su i ed beyond 35 yea s o age, wi h hea
disease accoun ing o 67% o dea hs. I on-induced oxida i e damage emains a majo con ibu o o complica ions in
halassemia, emphasizing he need o ongoing su eillance, in ec ion p ophylaxis, and ea ly in e en ion. Ch onic
hepa i is, which is o en obse ed in ans usion-dependen pa ien s, should be app op ia ely managed. As su i al
a es con inue o imp o e, new complica ions a e eme ging, shi ing he clinical landscape o halassemia and
necessi a ing no el he apeu ic s a egies o add ess hese e ol ing challenges.
