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RESUME THALLASEMIA
Darah manusia dewasa mengandung tiga jenis hemoglobin. Hemoglobin A (HbA)
merupakan Hb terbanyak dengan struktur molekular α2β2. Selain HbA, terdapat dua jenis Hb lain,
antara lain HbF (fetal haemoglobin) dengan struktur molekular α2γ2 dan HbA2 dengan struktur
molekular α2δ2. Jadi, hemoglobin manusia dewasa (HbA) merupakan suatu tetramer yang
tersusun atas dua rantai α dan dua rantai β. Rantai α dikode oleh dua gen α-globin (α1 dan α2)
pada kromosom 11, sedangkan rantai β dikode oleh sebuah gen β-globin pada kromosom 16.
Mutasi atau delesi pada gen tersebut dapat terjadi pada thalassemia.1

What is Thalassaemia?
Thalassaemia is an inherited genetic disorder that affects the production of red blood cells
(RBC), which can lead to severe anemia. Thalassaemias are produced by many different genetic
abnormalities that result in the absence or deficiency of a globin chain, which disrupts the
production of haemoglobin.

Haemoglobin is an oxygen carrying protein made in RBC’s. It is made up of two alpha globin
chains and two beta globin chains and each contains a heme molecule. The heme molecule has
an iron atom in the center giving haemoglobin the ability to carry oxygen; it also gives it a
reddish color, which is why our blood appears red. 
If the production of one of the globin chains is disrupted, then haemoglobin does not assemble
properly and it loses its ability to carry oxygen. The improper assembly of haemoglobin also
results in increased destruction of RBC’s.

  Alpha Thalassaemia
There are 4 alpha-globin genes on chromosome 16; therefore alpha thalassaemia has 4 different
manifestations that correlate with the number of alpha-globin genes affected.
 Silent Carrier
 Alpha Thalassaemia Trait
 Haemoglobin H Disease

 Alpha Thalassaemia Major (hydrop fetalis)

  Beta Thalassaemia
Individuals with beta thalassaemia have deficiency in one or more of their beta-globin genes.
There are only 2 genes on chromosome 11 that code for beta-globin chains, therefore the
incidence of beta thalassaemia major is higher than alpha thalassaemia major or haemoglobin H
disease because the probability of having a deficiency in 2 genes versus a deficiency in 3 or 4
genes is higher.

 Beta Thalassaemia Trait

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 Beta Thalassaemia Intermedia

 Beta Thalassaemia Major

Darah manusia dewasa mengandung tiga jenis hemoglobin. Hemoglobin A (HbA)

merupakan Hb terbanyak dengan struktur molekular α2β2. Selain HbA, terdapat dua jenis Hb lain,
antara lain HbF (fetal haemoglobin) dengan struktur molekular α2γ2 dan HbA2 dengan struktur
molekular α2δ2. Jadi, hemoglobin manusia dewasa (HbA) merupakan suatu tetramer yang
tersusun atas dua rantai α dan dua rantai β. Rantai α dikode oleh dua gen α-globin (α1 dan α2)
pada kromosom 11, sedangkan rantai β dikode oleh sebuah gen β-globin pada kromosom 16.
Mutasi atau delesi pada gen tersebut dapat terjadi pada thalassemia.1

Pada proses pembuahan, anak hanya mendapat sebelah gen globin beta dari ibunya dan
sebelah lagi dari ayahnya. Bila kedua orang tuanya masing-masing pembawa sifat thalassemia
maka pada setiap pembuahan akan terdapat beberapa kemungkinan. Kemungkinan pertama si
anak mendapat gen globin yang berubah (gen thalassemia) dari bapak dan ibunya, maka anak
akan menderita thalassemia. Sedangkan bila anak hanya mendapat sebelah gen thalassemia
dari ibu atau ayah, maka anak hanya membawa penyakit ini. Kemungkinan lain adalah anak
mendapatkan gen globin normal dari kedua orang tuanya.

Penyakti thalassemia disebabkan oleh adanya kelainan / perubahan / mutasi pada gen
globin alpha atau gen globin beta sehingga produksi rantai globin tersebut berkurang dan
sel darah merah mudah sekali rusak atau umurnya lebih pendek dari sel darah normal (120 hari).
Bila kelainan pada gen globin alpha maka penyakitnya disebut THALASSEMIA
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ALPHA, sedangkan kelainan pada gen globin beta akan menyebabkan penyakit
THALASSEMIA BETA.

KARENA DI INDONESIA THALASSEMIA BETA LEBIH SERING DIDAPAT, MAKA

SELANJUTNYA KAMI HANYA AKAN MENJELASKAN MENGENAI
THALASSEMIA BETA.

Klasifikasi Thalassemia-β dan Manifestasinya5

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Homozigot Thalassemia αo.

Patofisiologi thalassemia α sebanding dengan jumlah gen yang terkena. Pada homozigot (--/--) tidak ada
rantai α yang diproduksi.1

Sekilas Tentang Thalasemia

Penyakit thalasemia merupakan suatu kelainan darah bersifat genetik dimana kerusakan DNA
akan menyebabkan tidak optimalnya produksi sel darah merah penderitanya serta mudah rusak
sehingga kerap menyebabkan anemia.

Pusat dari mekanisme kelainan ini terletak pada salah satu gen pembentuk hemoglobin pada sel
darah merah manusia, yang sekaligus juga berfungsi utama sebagai pengangkut oksigen.
Terkait dengan sifat genetik yang diturunkan pendahulunya ini, dikenal istilah 'thalasemia
trait' (pembawa sifatnya).

Sebagaimana orang-orang normal, individu-individu pembawa gen ini sama sekali tidak
menunjukkan adanya suatu gejala. Masalah yang lebih serius akan terjadi bila sang pasangan
juga merupakan seorang pembawa sehingga lebih berpotensi melahirkan anak dengan thalasemia
mayor yang nantinya akan memerlukan transfusi darah secara rutin selama hidupnya.

Tindakan transfusi ini pun bukan merupakan suatu terapi penyembuh namun hanya bersifat
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suportif dalam mengurangi gejala dan punya resiko menyebabkan penumpukan zat besi dalam
tubuh pula, yang lebih lanjut bisa menyebabkan pembengkakan hati dan limpa.
Ada dua jenis thalasemia yang dikenal berdasarkan gejala klinis dan tingkatan keparahannya,
yaitu thalasemia mayor dimana kedua orang tuanya merupakan pembawa sifat, serta thalasemia
minor dimana gejalanya jauh lebih ringan dan sering hanya sebagai pembawa sifat saja.

Pada thalasemia mayor gejala dapat muncul sejak awal masa anak-anak dengan kemungkinan
bertahan hidup terbatas.

Beberapa kasus yang ditemukan selama ini juga membuat munculnya penggolongan yang lebih
baru, yaitu thalasemia intermedia dimana kondisinya berada di tengah-tengah kedua bentuk
tersebut.

Ferriprox (Deferiprone) therapy should be initiated and maintained by a physician

experienced in the treatment of patients with thalassaemia.
Deferiprone is usually given as 25 mg/kg body weight, orally, three times a day for a total
daily dose of 75 mg/kg body weight. Dosage per kilogram body weight should be calculated
to the nearest halftablet. See table below for recommended doses for body weights at 10 kg
increments.
Doses above 100 mg/kg/day are not recommended because of the potentially increased risk
of adverse reactions; chronic administration of more than 2.5 times the maximum
recommended dose has been associated with neurological disorders (see sections 4.4, 4.8,
and 4.9).
There are limited data available on the use of deferiprone in children between 6 and 10
years of age, and no data on deferiprone use in children under 6 years of age.
Due to the serious nature of agranulocytosis, that can occur with the use of deferiprone,
special monitoring is required for all patients. Cation must be used when the patients
abosolute neutrophil count (ANC) is low, as well as when treating patients with renal
insufficiency or hepatic dysfunction.
Ferriprox® (deferiprone) is an oral iron chelator. Ferriprox® is indicated for the
treatment of iron overload in patients with thalassemia major when deferoxamine therapy is
contraindicated or inadequate.Ferriprox® tablets first obtained marketing approval from The
European Medicines Agency (EMEA) in August 1999. It is now approved in 58 countries and is
under review by local regulatory authorities in many other jurisdictions. It is estimated that
thousands of individuals with iron overload are being treated with Ferriprox. Recently, the
EMEA has also approved Ferriprox® 100 mg/mL oral solution..

MORE RECENTLY, THE ORAL IRON CHELATOR DEFERASIROX (EXJADE,

ICL670 , [NOVARTIS PHARMA AG, Basel, Switzerland]) has been approved for the treatment
of iron overload in children and adults in several countries, including the United States, where it
received orphan drug designation and was granted priority review status. Good bioavailability
and a long half-life of 11 to 19 hours mean that deferasirox is suitable for once-daily dosing,
for oral tablet, which may overcome the compliance problems associated with deferoxamine.39
Clinical trials have established the efficacy and safety of deferasirox in a range of transfusion-
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dependent patients, including a large proportion of pediatric patients (42% of the total patients
enrolled in the program).40–43 During a period of 2.5 years, these trials have demonstrated that
deferasirox effectively reduced liver iron concentration and serum ferritin levels in pediatric, as
well as adult, patients in a dosage-dependent manner.44 Deferasirox dosing recommendations are
the same for pediatric and adult patients, taking into account changes in weight over time. A
starting dosage of 20 mg/kg body weight is recommended.45 After commencing therapy, serum
ferritin should be monitored monthly and, if required, the dosage of deferasirox adjusted in steps
of 5 or 10 mg/kg every 3 to 6 months on the basis of serum ferritin trends. The dosage can
tailored to the individual patient's response and therapeutic goals (maintenance or reduction of
body iron burden). Dosages of deferasirox should not exceed 30 mg/kg per day because there has
been limited experience with dosages above this level.

Iron overload is an inevitable clinical consequence for patients with transfusion-dependent

anemias. Iron chelation therapy is, therefore, an important and integral part of their supportive
care. Pediatric patients who are not adequately chelated risk delayed sexual maturation, retarded
growth, progressive liver and heart disease, and a reduced life expectancy. To date, the reference-
standard iron chelator has been deferoxamine, but the demanding regimen of regular and
prolonged infusions presents a significant challenge, particularly for pediatric patients. Recent
advances have led to the development of the oral chelators deferiprone and deferasirox. The
potential for deferiprone to decrease cardiac disease is important. Its benefit outweighs the risk
for neutropenia for many patients. Oral chelators, such as deferasirox and deferiprone, signify a
notable change in clinical practice, presenting the option of a convenient oral therapy to adults
and children with a range of chronic anemias.

Adult

Initial: 20 mg/kg PO qd on empty stomach 30 min ac; calculate dose to nearest whole tab
Maintenance: Adjust dose by 5- to 10-mg/kg/d
Note: Dissolve tab completely in water, orange juice, or apple juice, then immediately drink
susp; resuspend any remaining residue in small volume of liquid and swallow

Pediatric

<2 years: Not established

>2 years: Administer as in adults
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Figure 6. The concept of combination therapy.

Abbreviations: DFO, deferoxamine; DFP, deferiprone; NTBI, non-transferrin-bound iron.

Modified from Liu et al.20

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Hematology 2006 © 2006 The American Society of Hematology

New Advances in Iron Chelation Therapy ; Alan R. Cohen .

Table 1. Deferoxamine.

Characteristics
    Route of Administration SQ, IV
    Half-life 20 minutes
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    Primary routes of iron excretion Urine/Stool

    Dose range 20–60 mg/kg/d
Guidelines for Monitoring Therapy
    Audiometry and eye exams annually
    Serum ferritin level quarterly
    Assessment of liver iron annually
    Assessment of cardiac iron annually after 10 years of age
Advantages
    Long-term experience
    Effective in maintaining normal or near normal iron stores
    Reversal of cardiac disease with intensive therapy
    May be combined with deferiprone
Disadvantages
    Requires parenteral infusion
    Ear, eye, bone toxicity
    Poor compliance

Table 2. Deferiprone.

Characteristics
    Route of administration PO
    Half-life 2 to 3 hours
    Primary route of iron excretion Urine
    Dose range 50–100 mg/kg/d
Guidelines for Monitoring Therapy
    CBC with differential weekly
    ALT level monthly for first 3–6 months, then every 6 months
    Serum ferritin level quarterly
    Assessment of liver iron annually
    Assessment of cardiac iron annually after 10 years of age
Advantages
    Orally active
    Safety profile well established
    Enhanced removal of cardiac iron
    May be combined with deferoxamine
Disadvantages
    May not achieve negative iron balance in all patients at 75 mg/kg/day
    Risk of agranulocytosis and need for weekly blood counts

Table 3. Deferasirox. ( EXJADE, ICL670 , NOVARTIS PHARMA AG, Basel, Switzerland) (DFX).3

Characteristics
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    Route of administration PO
    Half-life 8 to 16 hours
    Primary route of iron excretion Stool
    Dose range 20–30 mg/kg/d
Guidelines for Monitoring Therapy
    Serum creatinine level monthly
    ALT level monthly
    Serum ferritin level monthly
    Assessment of liver iron annually
    Assessment of cardiac iron annually after 10 years of age
Advantages
    Orally active
    Once daily administration
    Demonstrated equivalency to deferoxamine at higher doses
    Trials in several hematologic disorders
Disadvantages
    Limited long-term data
    Need to monitor renal function
    May not achieve negative iron balance in all patients at highest recommended dose

IRON CHELATION THERAPY

A. Victor Hoffbrand, DM, FRCP*

These are exciting times for patients with thalassemia major (TM) and other transfusion-
dependent patients with refractory anemias who need chelation therapy. Although at present
deferoxamine (DFO) remains the standard of care recent data suggest that deferiprone, orally
active and in clinical trials for 16 years, may for many patients be a safe and effective alternative
to the more cumbersome drug DFO. There is the new possibility of combination chelation
therapy with DFO and deferiprone, and a second orally active iron chelator, ICL 670, is now in
early clinical trials. Figure 4 shows the chemical structures of these three compounds.
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Figure 4. The structural formulae of deferoxamine, ICL 670, and deferiprone.

 Pharmacokinetic and clinical characteristics of three iron chelators.
ICL 670 (deferasirox)
Deferoxamine Deferiprone (DFX).3

Hexadentate Bidentate Tridentate

Molecular 560 139 373
weight
Iron:chelator 1:1 1:3 1:2
complex
Plasma 20 minutes 53–166 minutes 1–16 hours
clearance, T
Oral absorption Negligible Peak 45 minutes Peak 1–2.9 hours
Iron excretion Urine + fecal Urine Fecal
Therapeutic 40 mg/kg 75 mg/kg 20 mg/kg
daily dose
Route Parenteral Oral Oral
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Clinical 30 years 16 years 1–2 years

experience
Side effects Ototoxicity, retinal Agranulocytosis, arthropathy, Skin rashes,
toxicity, growth, gastrointestinal disturbance, gastrointestinal
cartilage transient transaminitis, zinc disturbance, transient
deficiency transaminitis

Patogenesis dan Patofisiologi Thalassemia-β.8