REFERAT

PENDEKATAN DIAGNOSIS THALASSEMIA DAN

MANAJEMEN THALASSEMIA

Pembimbing
dr. Tuti Sri Hastuti, Sp.PD

Oleh
Wildan Baiti A (2014730099)

KEPANITERAAN KLINIK ILMU PENYAKIT DALAM

RSUD SAYANG CIANJUR
FAKULTAS KEDOKTERAN
UNIVERSITAS MUHAMMADIYAH JAKARTA
2018
 KATA PENGANTAR

Assalammualaikum wr.wb
Puji syukur saya panjatkan kepada Allah SWT yang telah melimpahkan rahmat dan karunia-
Nya kepada kita semua. Tidak lupa shalawat serta salam junjungan kepada Nabi Muhammad SAW
beserta para sahabatnya sehingga penulis dapat menyelesaikan tugas referat Thalassemia dengan
baik.
Dalam penulisan referat ini, tidak lepas dari bantuan dan kemudahan yang diberikan secara tulus
dari berbagai pihak. Oleh karena itu, penulis menyampaikan terima kasih yang sebesar-besarnya
kepada dr. Tuti Sri Hastuti, Sp.PD sebagai dokter pembimbing.
Dalam penulisan referat ini tentu saja masih banyak kekurangan dan jauh dari sempurna, oleh
karena itu dengan segala kerendahan hati, kritik dan saran yang bersifat membangun akan sangat
penulis harapkan demi kesempurnaan referat ini.
Wassalammualaikum wr.wb

Cianjur, 29 November 2018

Penyusun

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 THALASSEMIA

Thalassemia adalah sekelompok anemia hipokromik herediter dengan berbagai derajat

keparahan. Defek genetik yang mendasari meliputi delesi total atau parsial gen globin dan
substitusi, delesi, atau insersi nukleotida. Akibat dari berbagai perubahan ini adalah penurunan
atau tidak adanya mRNA bagi satu atau lebih rantai globin atau pembentukan mRNA yang cacat
secara fungsional. Akibatnya adalah penurunan dan supresi total sintesis rantai polipeptida Hb.
Kira-kira 100 mutasi yang berbeda telah ditemukan mengakibatkan fenotip thalassemia; banyak
di antara mutasi ini adalah unik untuk daerah geografi setempat. Pada umumnya, rantai globin
yang disintesis dalam eritrosit thalassemia secara struktural adalah normal. Pada bentuk
thalassemia-α yang berat, terbentuk hemoglobin hemotetramer abnormal (β4 atau γ4) tetapi
komponen polipeptida globin mempunyai struktur normal. Sebaliknya, sejumlah Hb abnormal
juga menyebabkan perubahan hemotologi mirip thalassemia.
Gen thalassemia sangat luas tersebar, dan kelainan ini diyakini merupakan penyakit
genetik manusia yang paling prevalen. Distribusi utama meliputi daerah-daerah perbatasan Laut
Mediterania, sebagian besar Afrika, Timur Tengah, sub-benua India, dan Asia Tenggara. Dari 3%
sampai 8% orang Amerika keturunan Itali atau Yunani dan 0,5 % dari kulit hitam Amerika
membawa gen untuk thalassemia-β. Di beberapa daerah Asia Tenggara sebanyak 40 % dari
populasi mempunyai satu atau lebih gen thalassemia.

A. Epidemiologi

Di seluruh dunia, 15 juta orang memiliki presentasi klinis dari thalassemia. Fakta ini
mendukung thalassemia sebagai salah satu penyakit turunan yang terbanyak; menyerang hampir
semua golongan etnik dan terdapat pada hampir seluruh negara di dunia.
Beberapa tipe thalassemia lebih umum terdapat pada area tertentu di dunia. Thalassemia-β
lebih sering ditemukan di negara-negara Mediteraniam seperti Yunani, Itali, dan Spanyol.
Banyak pulau-pulau Mediterania seperti Ciprus, Sardinia, dan Malta, memiliki insidens
thalassemia-β mayor yang tinggi secara signifikan. Thalassemia-β juga umum ditemukan di
Afrika Utara, India, Timur Tengah, dan Eropa Timur. Sebaliknya, thalassemia-α lebih sering
ditemukan di Asia Tenggara, India, Timur Tengah, dan Afrika.

Mortalitas dan Morbiditas

Thalassemia-α mayor adalah penyakit yang mematikan, dan semua janin yang terkena
akan lahir dalam keadaan hydrops fetalis akibat anemia berat. Beberapa laporan pernah
mendeskripsikan adanya neonatus dengan thalassemia-α mayor yang bertahan setelah mendapat
transfusi intrauterin. Penderita seperti ini membutuhkan perawatan medis yang ekstensif
setelahnya, termasuk transfusi darah teratur dan terapi khelasi, sama dengan penderita
thalassemia-β mayor. Terdapat juga laporan kasus yang lebih jarang mengenai neonatus dengan

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thalassemia-α mayor yang lahir tanpa hydrops fetalis yang bertahan tanpa transfusi intrauterin.
Pada kasus ini, tingginya level Hb Portland, yang merupakan Hb fungsional embrionik,
diperkirakan sebagai penyebab kondisi klinis yang jarang tersebut.
Pada pasien dengan berbagai tipe thalassemia-β, mortalitas dan morbiditas bervariasi
sesuai tingkat keparahan dan kualitas perawatan. Thalassemia-β mayor yang berat akan berakibat
fatal bila tidak diterapi. Gagal jantung akibat anemia berat atau iron overload adalah penyebab
tersering kematian pada penderita. Penyakit hati, infeksi fulminan, atau komplikasi lainnya yang
dicetuskan oleh penyakit ini atau terapinya termasuk merupakan penyebab mortalitas dan
morbiditas pada bentuk thalassemia yang berat.

Mortalitas dan morbiditas tidak terbatas hanya pada penderita yang tidak diterapi; mereka
yang mendapat terapi yang dirancang dengan baik tetap berisiko mengalami bermacam-macam
komplikasi. Kerusakan organ akibat iron overload, infeksi berat yang kronis yang dicetuskan
transfusi darah, atau komplikasi dari terapi khelasi, seperti katarak, tuli, atau infeksi, merupakan
komplikasi yang potensial.

Usia
Meskipun thalassemia merupakan penyakit turunan (genetik), usia saat timbulnya gejala
bervariasi secara signifikan. Dalam talasemia, kelainan klinis pada pasien dengan kasus-kasus
yang parah dan temuan hematologik pada pembawa (carrier) tampak jelas pada saat lahir.
Ditemukannya hipokromia dan mikrositosis yang tidak jelas penyebabnya pada neonatus,
digambarkan di bawah ini, sangat mendukung diagnosis.

Gambar 1. Sapuan apus darah tepi Penyakit Hb H pada neonatus

Namun, pada thalassemia-β berat, gejala mungkin tidak jelas sampai paruh kedua tahun
pertama kehidupan; sampai waktu itu, produksi rantai globin γ dan penggabungannya ke Hb Fetal
dapat menutupi gejala untuk sementara.
Bentuk thalassemia ringan sering ditemukan secara kebetulan pada berbagai usia. Banyak
pasien dengan kondisi thalassemia-β homozigot yang jelas (yaitu, hipokromasia, mikrositosis,
elektroforesis negatif untuk Hb A, bukti bahwa kedua orang tua terpengaruh) mungkin tidak
menunjukkan gejala atau anemia yang signifikan selama beberapa tahun. Hampir semua pasien

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dengan kondisi tersebut dikategorikan sebagai thalassemia-β intermedia. Situasi ini biasanya
terjadi jika pasien mengalami mutasi yang lebih ringan.
B. Klasifikasi Thalassemia dan Presentasi Klinisnya

Saat ini dikenal sejumlah besar sindrom thalasemia; masing-masing melibatkan penurunan
produksi satu atau lebih rantai globin, yang membentuk bermacam-macam jenis Hb yang
ditemukan pada sel darah merah. Jenis yang paling penting dalam praktek klinis adalah sindrom
yang mempengaruhi baik atau sintesis rantai α maupun β.

Thalassemia-α

Anemia mikrositik yang disebabkan oleh defisiensi sintesis globin-α banyak ditemukan di
Afrika, negara di daerah Mediterania, dan sebagian besar Asia. Delesi gen globin-α menyebabkan
sebagian besar kelainan ini. Terdapat empat gen globin-α pada individu normal, dan empat
bentuk thalassemia-α yang berbeda telah diketahui sesuai dengan delesi satu, dua, tiga, dan
semua empat gen ini

Tabel 1. Thalassemia-α

Genotip Jumlah gen α Presentasi Klinis Hemoglobin Elektroforesis

Saat Lahir > 6 bulan

αα/αα 4 Normal N N

-α/αα 3 Silent carrier 0-3 % Hb Barts N

--/αα atau 2 Trait thal-α 2-10% Hb Barts N

–α/-α

--/-α 1 Penyakit Hb H 15-30% Hb Bart Hb H

--/-- 0 Hydrops fetalis >75% Hb Bart -

Ket : N = hasil normal, Hb = hemoglobin, Hb Bart’s = γ4, HbH = β4

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  Silent carrier thalassemia-α

o Merupakan tipe thalassemia subklinik yang paling umum, biasanya ditemukan

secara kebetulan diantara populasi, seringnya pada etnik Afro-Amerika. Seperti
telah dijelaskan sebelumnya, terdapat 2 gen α yang terletak pada kromosom 16.
o Pada tipe silent carrier, salah satu gen α pada kromosom 16 menghilang,
menyisakan hanya 3 dari 4 gen tersebut. Penderita sehat secara hematologis, hanya
ditemukan adanya jumlah eritrosit (sel darah merah) yang rendah dalam beberapa
pemeriksaan.
o Pada tipe ini, diagnosis tidak dapat dipastikan dengan pemeriksaan elektroforesis
Hb, sehingga harus dilakukan tes lain yang lebih canggih. Bisa juga dicari akan
adanya kelainan hematologi pada anggota keluarga ( misalnya orangtua) untuk
mendukung diagnosis. Pemeriksaan darah lengkap pada salah satu orangtua yang
menunjukkan adanya hipokromia dan mikrositosis tanpa penyebab yang jelas
merupakan bukti yang cukup kuat menuju diagnosis thalasemia.

 Trait thalassemia-α

o Trait ini dikarakterisasi dengan anemia ringan dan jumlah sel darah merah yang
rendah. Kondisi ini disebabkan oleh hilangnya 2 gen α pada satu kromosom 16 atau
satu gen α pada masing-masing kromosom. Kelainan ini sering ditemukan di Asia
Tenggara, subbenua India, dan Timur Tengah.
o Pada bayi baru lahir yang terkena, sejumlah kecil Hb Barts (γ4) dapat ditemukan
pada elektroforesis Hb. Lewat umur satu bulan, Hb Barts tidak terlihat lagi, dan
kadar Hb A2 dan HbF secara khas normal.

Gambar 3. Thalassemia alpha menurut hukum Mendel

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  Penyakit Hb H

o Kelainan disebabkan oleh hilangnya 3 gen globin α, merepresentasikan

thalassemia-α intermedia, dengan anemia sedang sampai berat, splenomegali,
ikterus, dan jumlah sel darah merah yang abnormal. Pada sediaan apus darah tepi
yang diwarnai dengan pewarnaan supravital akan tampak sel-sel darah merah yang
diinklusi oleh rantai tetramer β (Hb H) yang tidak stabil dan terpresipitasi di dalam
eritrosit, sehingga menampilkan gambaran golf ball. Badan inklusi ini dinamakan
sebagai Heinz bodies.

Gambar 4. Pewarnaan supravital pada sapuan apus darah tepi Penyakit Hb H yang menunjukkan Heinz-Bodies

 Thalassemia-α mayor

o Bentuk thalassemia yang paling berat, disebabkan oleh delesi semua gen globin-α,
disertai dengan tidak ada sintesis rantai α sama sekali.
o Karena Hb F, Hb A, dan Hb A2 semuanya mengandung rantai α, maka tidak satupun
dari Hb ini terbentuk. Hb Barts (γ4) mendominasi pada bayi yang menderita, dan
karena γ4 memiliki afinitas oksigen yang tinggi, maka bayi-bayi itu mengalami
hipoksia berat. Eritrositnya juga mengandung sejumlah kecil Hb embrional normal
(Hb Portland = ζ2γ2), yang berfungsi sebagai pengangkut oksigen.
o Kebanyakan dari bayi-bayi ini lahir mati, dan kebanyakan dari bayi yang lahir hidup
meninggal dalam waktu beberapa jam. Bayi ini sangat hidropik, dengan gagal
jantung kongestif dan edema anasarka berat. Yang dapat hidup dengan manajemen
neonatus agresif juga nantinya akan sangat bergantung dengan transfusi.

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Thalassemia-β
Sama dengan thalassemia-α, dikenal beberapa bentuk klinis dari thalassemia-β; antara lain
:
 Silent carrier thalassemia-β
o Penderita tipe ini biasanya asimtomatik, hanya ditemukan nilai eritrosit yang
rendah. Mutasi yang terjadi sangat ringan, dan merepresentasikan suatu
thalassemia-β+.
o Bentuk silent carrier thalassemia-β tidak menimbulkan kelainan yang dapat
diidentifikasi pada individu heterozigot, tetapi gen untuk keadaan ini, jika
diwariskan bersama-sama dengan gen untuk thalassemia-β°, menghasilkan sindrom
thalassemia intermedia.

Gambar 5. Thalassemia beta menurut Hukum Mendel

 Trait thalassemia-β

o Penderita mengalami anemia ringan, nilai eritrosit abnormal, dan elektroforesis Hb

abnormal dimana didapatkan peningkatan jumlah Hb A2, Hb F, atau keduanya

o Individu dengan ciri (trait) thalassemia sering didiagnosis salah sebagai anemia
defisiensi besi dan mungkin diberi terapi yang tidak tepat dengan preparat besi
selama waktu yang panjang. Lebih dari 90% individu dengan trait thalassemia-β
mempunyai peningkatan Hb-A2 yang berarti (3,4%-7%). Kira-kira 50% individu
ini juga mempunyai sedikit kenaikan HbF, sekitar 2-6%. Pada sekelompok kecil

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 kasus, yang benar-benar khas, dijumpai Hb A2 normal dengan kadar HbF berkisar
dari 5% sampai 15%, yang mewakili thalassemia tipe δβ.
 Thalassemia-β yang terkait dengan variasi struktural rantai β
o Presentasi klinisnya bervariasi dari seringan thalassemia media hingga seberat
thalassemia-β mayor
o Ekspresi gen homozigot thalassemia (β+) menghasilkan sindrom mirip anemia
Cooley yang tidak terlalu berat (thalassemia intermedia). Deformitas skelet dan
hepatosplenomegali timbul pada penderita ini, tetapi kadar Hb mereka biasanya
bertahan pada 6-8 gr/dL tanpa transfusi.
o Kebanyakan bentuk thalassemia-β heterozigot terkait dengan anemia ringan. Kadar
Hb khas sekitar 2-3 gr/dL lebih rendah dari nilai normal menurut umur.
o Eritrosit adalah mikrositik hipokromik dengan poikilositosis, ovalositosis, dan
seringkali bintik-bintik basofil. Sel target mungkin juga ditemukan tapi biasanya
tidak mencolok dan tidak spesifik untuk thalassemia.

o MCV rendah, kira-kira 65 fL, dan MCH juga rendah (<26 pg). Penurunan ringan
pada ketahanan hidup eritrosit juga dapat diperlihatkan, tetapi tanda hemolisis
biasanya tidak ada. Kadar besi serum normal atau meningkat.
 Thalassemia-β° homozigot (Anemia Cooley, Thalassemia Mayor)
o bergejala sebagai anemia hemolitik kronis yang progresif selama 6 bulan kedua
kehidupan. Transfusi darah yang reguler diperlukan pada penderita ini untuk
mencegah kelemahan yang amat sangat dan gagal jantung yang disebabkan oleh
anemia. Tanpa transfusi, 80% penderita meninggal pada 5 tahun pertama
kehidupan.
o Pada kasus yang tidak diterapi atau pada penderita yang jarang menerima transfusi
pada waktu anemia berat, terjadi hipertrofi jaringan eritropoetik disumsum tulang
maupun di luar sumsum tulang. Tulang-tulang menjadi tipis dan fraktur patologis
mungkin terjadi. Ekspansi masif sumsum tulang di wajah dan tengkorak
menghasilkan bentuk wajah yang khas.

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 Gambar 6. Deformitas tulang pada thalassemia beta mayor (Facies Cooley)

o Pucat, hemosiderosis, dan ikterus sama-sama memberi kesan coklat kekuningan.

Limpa dan hati membesar karena hematopoesis ekstrameduler dan hemosiderosis.
Pada penderita yang lebih tua, limpa mungkin sedemikian besarnya sehingga
menimbulkan ketidaknyamanan mekanis dan hipersplenisme sekunder.

Gambar 7. Splenomegali pada thalassemia

o Pertumbuhan terganggu pada anak yang lebih tua; pubertas terlambat atau tidak
terjadi karena kelainan endokrin sekunder. Diabetes mellitus yang disebabkan oleh
siderosis pankreas mungkin terjadi. Komplikasi jantung, termasuk aritmia dan gagal
jantung kongestif kronis yang disebabkan oleh siderosis miokardium sering
merupakan kejadian terminal.
o Kelainan morfologi eritrosit pada penderita thalassemia-β° homozigot yang tidak
ditransfusi adalah ekstrem. Disamping hipokromia dan mikrositosis berat, banyak
ditemukan poikilosit yang terfragmentasi, aneh (sel bizarre) dan sel target. Sejumlah
besar eritrosit yang berinti ada di darah tepi, terutama setelah splenektomi. Inklusi
intraeritrositik, yang merupakan presipitasi kelebihan rantai α, juga terlihat pasca

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 splenektomi. Kadar Hb turun secara cepat menjadi < 5 gr/dL kecuali mendapat
transfusi. Kadar serum besi tinggi dengan saturasi kapasitas pengikat besi (iron
binding capacity). Gambaran biokimiawi yang nyata adalah adanya kadar HbF yang
sangat tinggi dalam eritrosit.

C. Stadium Thalassemia

Terdapat suatu sistem pembagian stadium thalassemia berdasarkan jumlah kumulatif

transfusi darah yang diberikan pada penderita untuk menentukan tingkat gejala yang melibatkan
kardiovaskuler dan untuk memutuskan kapan untuk memulai terapi khelasi pada pasien dengan
thalassemia-β mayor atau intermedia. Pada sistem ini, pasien dibagi menjadi tiga kelompok, yaitu
:
 Stadium I
o Merupakan mereka yang mendapat transfusi kurang dari 100 unit Packed Red Cells
(PRC). Penderita biasanya asimtomatik, pada echokardiogram (ECG) hanya
ditemukan sedikit penebalan pada dinding ventrikel kiri, dan elektrokardiogram
(EKG) dalam 24 jam normal.
 Stadium II
o Merupakan mereka yang mendapat transfusi antara 100-400 unit PRC dan memiliki
keluhan lemah-lesu. Pada ECG ditemukan penebalan dan dilatasi pada dinding
ventrikel kiri. Dapat ditemukan pulsasi atrial dan ventrikular abnormal pada EKG
dalam 24 jam
 Stadium III
o Gejala berkisar dari palpitasi hingga gagal jantung kongestif, menurunnya fraksi
ejeksi pada ECG. Pada EKG dalam 24 jam ditemukan pulsasi prematur dari atrial
dan ventrikular.

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 Hemoglobin normal manusia dewasa terdiri dari 2 rantai beta dan 2 rantai
alfa yang membentuk tetramer α2β2 (HbA). Komposisi HbA dalam sirkulasi darah
mencapai >97%, sedangkan HbA2 2-3% dan HbF <1%.Dengan komposisi seperti
ini hemoglobin dapat mengangkut oksigen ke jaringan dengan baik.8

Gambar 4.a Hemoglobin Gambar 4.b Pembentukan hemoglobin

normal sesuai usia

Thalassemia alfa terjadi akibat mutasi pada kromosom 16. Rantai globin alfa
terbentuk sedikit atau tidak terbentuk sama sekali sehingga rantai globin yang
ada membentuk HbBart (γ4) dan HbH (β4). Tetramer tersebut tidak stabil dan
badan inklusi yang terbentuk mempercepat destruksi eritrosit.

Hb Normal Gangguan sintesis

rantai beta

Gambar 5. Keseimbangan rantai globin pada mutasi gen globin beta.

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 Thalassemia beta terjadi akibat mutasi gen globin beta sehingga produksi
rantai globin beta menjadi berkurang atau tidak terbentuk sama sekali. Rantai
globin alfa yang terbentuk tidak semua dapat berikatan dengan rantai globin
beta sehingga terjadi peningkatan HbF dan HbA2. Selain itu terbentuk pula
rantai tetramer alfa yang tidak stabil yang mudah terurai. Rantai globin alfa
bebas tersebut tidak larut, kemudian membentuk presipitat yang memicu lisis
eritrosit di mikrosirkulasi (limpa) dan destruksi di sumsum tulang.

Gambar 6. Patofisiologi thalassemia beta

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 Pada akhirnya gangguan oksigenasi karena kelainan hemoglobin ini
menimbulkan hipoksia jaringan dan tubuh akan mengkompensasi dengan
membentuk eritrosit baru namun kondisi yang terjadi adalah eritropoesis
inefektif. Patofisiologi tersebut menjelaskan manifestasi klinis yang muncul pada
thalassemia.

A. DIAGNOSIS
Thalassemia yang bergantung pada transfusi adalah pasien yang
membutuhkan transfusi secara teratur seumur hidup. Diagnosis
thalassemia ditegakkan dengan berdasarkan kriteria anamnesis,
pemeriksaan fisis, dan laboratorium. Manifestasi klinis thalassemia mayor
umumnya sudah dapat dijumpai sejak usia 6 bulan.
1. Anamnesis :
a. Pucat kronik; usia awitan terjadinya pucat perlu ditanyakan.
a. Pada thalassemia β/HbE usia awitan pucat umumnya didapatkan
pada usia yang lebih tua.
b. Riwayat transfusi berulang; anemia pada thalassemia mayor
memerlukan transfusi berkala.
c. Riwayat keluarga dengan thalassemia dan transfusi berulang.
d. Perut buncit; perut tampak buncit karena adanya
hepatosplenomegali.
e. Etnis dan suku tertentu; angka kejadian thalassemia lebih tinggi
pada ras Mediterania, Timur Tengah, India, dan Asia Tenggara.
Thalassemia paling banyak di Indonesia ditemukan di Palembang
9%, Jawa 6-8%, dan Makasar 8%.
f. Riwayat tumbuh kembang dan pubertas terlambat.

2. Pemeriksaan Fisis
Beberapa karakteristik yang dapat ditemukan dari pemeriksaan fisis
pada anak dengan thalassemia yang bergantung transfusi adalah
pucat, sklera ikterik, facies Cooley (dahi menonjol, mata menyipit,
jarak kedua mata melebar, maksila hipertrofi, maloklusi gigi),
hepatosplenomegali, gagal tumbuh, gizi kurang, perawakan pendek,
pubertas terlambat, dan hiperpigmentasi kulit.

3. Laboratorium
Darah perifer lengkap (DPL)
a. Anemia yang dijumpai pada thalassemia mayor cukup berat

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 dengan kadar hemoglobin mencapai <7 g/dL.
b. Hemoglobinopati seperti Hb Constant Spring dapat memiliki MCV dan
MCH yang normal, sehingga nilai normal belum dapat menyingkirkan
kemungkinan thalassemia trait dan hemoglobinopati.
c. Indeks eritrosit merupakan langkah pertama yang penting untuk
skrining pembawa sifat thalassemia (trait), thalassemia δβ, dan
high Persisten fetal hemoglobine (HPFH)13,
d. Mean corpuscular volume (MCV) < 80 fL (mikrositik) dan mean
corpuscular haemoglobin (MCH) < 27 pg (hipokromik).
Thalassemia mayor biasanya memiliki MCV 50 – 60 fL dan MCH
12 – 18 pg.
e. Nilai MCV dan MCH yang rendah ditemukan pada thalassemia,
dan juga pada anemia defisiensi besi. MCH lebih dipercaya karena
lebih sedikit dipengaruhi oleh perubahan cadangan besi (less
suscpetible to storage changes).

Gambaran darah tepi

a. Anisositosis dan poikilositosis yang nyata (termasuk fragmentosit
dan tear-drop), mikrositik hipokrom, basophilic stippling, badan
Pappenheimer, sel target, dan eritrosit berinti (menunjukan defek
hemoglobinisasi dan diseritropoiesis)
b. Total hitung dan neutrofil meningkat
c. Bila telah terjadi hipersplenisme dapat ditemukan leukopenia,
neutropenia, dan trombositopenia.

Gambar 7 . Gambaran darah tepi pada thalassemia mayor

RED CELL DISTRIBUTION WIDTH (RDW)

RDW menyatakan variasi ukuran eritrosit. Anemia defisiesi besi memiliki
RDW yang meningkat >14,5%, tetapi tidak setinggi seperti pada thalassemia
mayor. Thalassemia trait memiliki eritrosit mikrositik yang uniform

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sehingga tidak / hanya sedikit ditandai dengan peningkatan RDW.
Thalassemia mayor dan intermedia menunjukkan peningkatan RDW
yang tinggi nilainya.

Tabel 1. Gambar darah tepi dan analisis Hb thalassema-β minor

dan ADB

Diagnosis Hb MCV MCH RDW

(g/dL) (fL) (pg) (%)
Thalassemia-β 12,6 (SB 67,2 (SB 22,2 (SB 2,8) 16,9 (SB 1,4)
minor 1,7) 7,8)
ADB 10 (SB 1,7) 74,3 (SB 24,1 (SB 2,1) 21 (SB 4,0)
6,8)

Data Divisi Hematologi-Onkologi Dep IKA 2009.

RETIKULOSIT.
Jumlah retikulosit menunjukkan aktivitas sumsum tulang. Pasien
thalassemia memiliki aktivitas sumsum tulang yang meningkat,
sedangkan pada anemia defisiensi besi akan diperoleh hasil yang
rendah.

HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC)

a. Sebagai alat ukur kuantitatif HbA2 dan HbF, dan dapat dipakai
untuk mengidentifikasi dan menghitung varian hemoglobin
secara presumtif. Pemeriksaan alternatif dapat dilakukan jika
varian hemoglobin yang terdeteksi pada HPLC relevan dengan
klinis pasien.
b. HbF dominan (>90%) pada hampir semua kasus thalassemia β
berat, kecuali pasien telah menerima transfusi darah dalam
jumlah besar sesaat sebelum pemeriksaan. HbA tidak terdeteksi
sama sekali pada thalassemia β0 homozigot, sedangkan HbA
masih terdeteksi sedikit pada thalassemia β+. Peningkatan HbA2
dapat memandu diagnosis thalassemia β trait.
1) Kadar HbA2 mencerminkan derajat kelainan yang terjadi.
2) HbA2 3,6-4,2% pada thalassemia β+ ringan.

17
 3) HbA2 4-9% pada thalassemia heterozigot β0 dan β+ berat.
4) HbA2 lebih dari 20% menandakan adanya HbE. Jika
hemoglobin yang dominan adalah HbF dan HbE, maka
sesuai dengan diagnosis thalassemia β/HbE.

Gambar 8. Gambaran Analisis Hb dengan metode High performance liquid chromatography

thalassemia

3)
normal tidak langsung menyingkirkan diagnosis
thalassemia.
4) 1) HbAc2 dapat menjadi lebih rendah dari kadar
. HbA2
sebenarnya akibat kondisi defisiensi besi, sehingga
diperlukan terapi defisiensi besi sebelum melakukan HPLC
ulang untuk menilai kuantitas subtipe Hb.
2) Feritin serum rendah merupakan petunjuk adanya defisiensi
besi, namun tidak menyingkirkan kemungkinan thalassemia
trait. Bila defisiensi besi telah disingkirkan, nilai HbA2
normal, namun indeks eritrosit masih sesuai dengan
thalassemia, maka dapat dicurigai kemungkinan
thalassemia α, atau koeksistensi thalassemia β dan δ.

18
 ELEKTROFORESIS HEMOGLOBIN
Beberapa cara pemeriksaan elektroforesis hemoglobin yang dapat
dilakukan adalah pemeriksaan Hb varians kuantitatif (electrophoresis
cellose acetat membrane), HbA2 kuantitatif (metode mikrokolom), HbF
(alkali denaturasi modifikasi Betke 2 menit), atau pemeriksaan
elektroforesis menggunakan capillary hemoglobin electrophoresis.

ANALISIS DNA
Analisis DNA merupakan upaya diagnosis molekular thalassemia,
yang dilakukan pada kasus atau kondisi tertentu:
1. Ketidakmampuan untuk mengonfirmasi hemoglobinopati dengan
pemeriksaan hematologi:
a. Diagnosis thalassemia β mayor yang telah banyak
menerima transfusi. Diagnosis dapat diperkuat dengan
temuan thalassemia β heterozigot (pembawa sifat
thalassemia beta) pada kedua orangtua
b. Identifikasi karier dari thalassemia β silent, thalassemia β
dengan HbA2 normal, thalassemia α0 , dan beberapa
thalassemia α+.
c. Identifikasi varian hemoglobin yang jarang.
2. Keperluan konseling genetik dan diagnosis prenatal.

REKOMENDASI

Diagnosis thalassemia didukung oleh temuan dari gambaran darah

tepi, elektroforesis hemoglobin, dan HPLC. (GRADE A)

MCH < 27 pg dapat digunakan sebagai ambang batas identifikasi karier pada

skrining thalassemia. (GRADE A)

Tes DNA dilakukan jika pemeriksaan hematologis/analisis Hb tidak mampu

menegakkan diagnosis hemoglobinopati. (GRADE B)

Bila pasien sudah sering mendapat transfusi berulang, dilakukan pemeriksaan

HPLC kedua orangtua kandung. (GRADE B)

19
 4. Alur diagnosis thalassemia

* Bila sudah transfusi, dapat dilakukan pemeriksaan DPL dan dilanjutkan pemeriksaan
analisis Hb kedua orangtua.
** Pemeriksaan DNA dilakukan apabila telah transfusi darah berulang, hasil skrining orangtua
sesuai dengan pembawa sifat thalassemia, hasil pemeriksaan esensial tidak khas (curiga ke
arah thalassemia α delesi 1 gen atau mutasi titik).

20
Management of Thalassemia
B2. Transfusion Support in Thalassemia

II. Red Cell Transfusion Practices and Monitoring

Principles
• To ensure that children and adults are transfused to an acceptable hemoglobin level
necessary to suppress endogenous erythropoiesis and to promote normal development
with good quality of life.
• To prevent complications related to under-transfusion.
• To ensure that safe blood transfusion practices are closely followed.
• To deliver transfusion services in a way that is least disruptive to the patient’s routine
of daily life.

Guidelines • All patients should be prophylactically

• Patients should receive leucodepleted blood
as set out by Canadian Blood Services/Héma
Québec policies and prophylactically matched
for D, C, E, c, e and K1 blood group
antigens.3,4 (GRADE B)
• Patients with thalassemia major, based on
clinical status and genotypic analysis, should
receive regular transfusions to maintain pre-
transfusion hemoglobin levels between
90 – 100 g/l.5-7 (GRADE B)
• Each patient should have a chart with
accurate documentation of transfusion
requirements, blood bank antibody
monitoring, and transfusion reactions.
Interventions
i. Blood Product Parameters
• A full cross-match and antibody screen
should be performed prior to each
transfusion. Every patient should have
a complete record of antigen typing,
antibodies, and transfusion reactions.
matched for D, C, E, c, e and K1 blood
group antigens to reduce the risk of
alloimmunization.3,4 Depending on patient
history or other local factors, centres may
choose to use extended antigen
matching. (GRADE B)
ii. Transfusion Parameters
• Regular transfusions should be administered
to maintain pre-transfusion hemoglobin
levels between 90 – 100 g/l.5-7 (GRADE B)
• Complete records should be kept and
reviewed regularly to identify patients who are
being under-transfused or who have
increased transfusion requirements.
• Total transfusion requirements should be
calculated regularly at 6 – 12 month intervals.
If the transfusion requirement is greater than
250 – 275 ml/kg/year, the cause for such
high transfusion needs should be determined.
These may include hypersplenism,
accelerated destruction of donor cells due to
allo- or autoantibodies, or blood loss.

21
 iii. Transfusion Safety and Policies controversial due to lack of sufficient evidence
and is reflected by different recommendations in
• Transfusions should take place in a designated the literature.40-42 The Canadian Pediatric Society
recommends antimicrobial prophylaxis post-
environment with staff experienced in
splenectomy until 5 years of age or
transfusion and intravenous cannulation. Where in older children for at least 1 year post-
possible, efforts should be made to provide splenectomy, but prophylaxis may be
extended hour (evening, weekend) services to continued, depending on individual
decrease the impact on patient’s quality of life clinical circumstances.41
including attending school or work.
• Blood products should be administered in
accordance with applicable standards.37
Each centre should have regular reviews
and audits by a transfusion committee.
• The patients should be tested at least every 2
– 3 years for transfusion-transmissible
infections including Hepatitis B, C, and HIV.

iv. Role of Splenectomy for Management of

Transfusion Requirements

• Splenectomy may be considered for patients

with thalassemia major with transfusion
requirements greater than 250 – 275 ml/
kg/year.7 However, this should be balanced
with known adverse effects of splenectomy
including arterial and venous thrombosis,
pulmonary hypertension, and life-
threatening infection.38 (GRADE B)
• The need for splenectomy due to hypersplenism
has significantly decreased due to improved
transfusion practices, stressing the importance
of adequate transfusion.
• Prior to splenectomy, if not already done,
patients should be vaccinated against
pneumococcus, Haemophilus influenzae
B, and meningococcus as per Canadian
Immunization Guidelines.39 (GRADE B)
• Patients and families should be educated
about the risks of sepsis post-splenectomy
and the need for immediate medical
attention, if fever develops.
• The role and duration of antimicrobial
prophylaxis in post-splenectomy patients is still

20

22
B. Management of Thalassemia
B3. Iron Overload and Chelation Therapy
Background on Iron Overload, Assessment of Iron Overload, and Iron Chelation
I. Iron Overload Overview
Red cell transfusion is the mainstay of treatment
for thalassemia major; however, over time this
therapy results in significant iron overload. Once
the body’s ability to store iron is exceeded, free
iron accumulates and participates in the
formation of reactive hydroxyl radicals, which
cause denaturation of proteins and membrane
damage. Iron overload, mainly from blood
transfusions and, to a lesser degree, from
increased gastrointestinal absorption, is the
major cause of morbidity and mortality in
transfused thalassemia patients. If untreated, it
is fatal in the first or second decade of life.
Major complications of iron overload, including
cardiac, liver and endocrine toxicities, can be
avoided or ameliorated by the early detection
and treatment of iron overload.8-10
II. Assessment of Iron Overload
There are several indirect and direct methods for
iron load assessment. Serum ferritin, a simple
indirect measure of iron stores, is associated with
increased risk of cardiac complications when over
2500 ug/l.9 However, ferritin is an acute phase
reactant and may be falsely elevated in liver
disease, infection, or inflammatory processes. The
prediction of iron loading from ferritin is poor and
hence it should not be used in isolation.16,43 In each
patient, the serum ferritin should be periodically
correlated with other objective tests of iron
overload. Between periodic direct iron
assessments, the serum ferritin can be easily used
to follow response to treatment. Chelation therapy
should be started in patients with a ferritin over
1000 ug/l; however, once
chelation has been initiated, the ferritin should
be maintained between 1000 – 1500 ug/l.1,2,17
Liver iron concentration (LIC) measured on
ultrasound-guided liver biopsy material directly
determines liver iron load. The liver biopsy is
invasive and can be associated with morbidity
and rarely mortality. In addition, there may be
sampling error if iron deposition is patchy, and
poor reproducibility if the sample is small or
fibrotic.44 A liver iron level above 15 mg Fe/g dry
weight is associated with increased organ injury
and high risk of cardiac death in thalassemia. 8
Based on data from hereditary
hemochromatosis patients, liver iron should be
maintained below 7 mg Fe/g dry weight.1,2
Various magnetic resonance imaging (MRI)
based techniques have been developed
recently to determine organ iron load non-
invasively. Calibration curves for MRI R2 and
R2* (inverse of T2 and T2*) signals for the liver
have been developed and show a curvilinear
relationship between liver iron estimated by R2
or R2* and by biopsy.14,45-48
Iron concentration in the myocardium of the
interventricular septum is inversely related to
cardiac MRI T2* signal.14 Myocardial T2* values
less than 20 ms (normal 20 ms) are associated
with a progressive and significant decline in left
ventricular ejection fraction. Since other measures
of body iron load assessment including serum
ferritin, biopsy determined LIC, and liver MRI T2*
do not correlate with cardiac MRI T2*, cardiac MRI
T2* plays a pivotal role in detection of early cardiac
toxicity.14,47,49,50 Cardiac MRI is
21
23
 non-invasive and allows concurrent determination
of cardiac function. Early diagnosis of cardiac iron
overload and dysfunction may allow for earlier
intervention and better outcomes. The major
limitation of all MRI modalities at present is their
limited availability.
Liver iron estimation using the Superconducting
QUantum Interference Device (SQUID) also
correlates with liver iron load.51 It cannot be
used on the heart, and is available in only a few
centres. It therefore, has a limited role in routine
management.
III. Initiation of Chelation Therapy
Iron chelation with deferoxamine has been used
for more than 30 years and has prevented or
delayed complications of iron overload and has
also extended life.8,9,11 In the last few years, new
oral iron chelating agents have been developed,
adding new interest to the field and posing
many new questions.
i. Deferoxamine
Deferoxamine was the first iron chelator
available. Its use has resulted in decreased end
organ dysfunction and improved long-term
survival.8,9,11 Its main disadvantages are that it
must be administered by the parent or the
patient either by intravenous or subcutaneous
infusion driven by a pump.
The dose of deferoxamine is adjusted according
to body iron load and age, and ranges from 20 –
40 mg/kg/day for children and up to
50 mg/kg /day for adults given for 8 – 12
hours for 5 – 7 nights per week.
More aggressive chelation therapy is required
for patients with significant iron loading with
ferritin > 2500 mg/ml, liver iron concentration
22
24
> 15 mg/g dry weight or cardiac T2* < 10 ms.9,47
Aggressive chelation therapy consists of a
24-hour continuous infusion of deferoxamine to
the maximum daily dose. While an increase in the
dosage of deferoxamine can increase the amount
of iron chelation, the chelation efficiency of the
same dose of drug is significantly increased by
prolonging the duration of infusion, likely
decreasing the organ damage due to non-
transferrin bound iron. The constant presence of
chelator decreases damaging reactive radical
formation.
Side effects of deferoxamine include local skin
reactions, predisposition to infection with
Yersinia enterocolitica, severe allergy, divalent
ion deficiency (e.g., zinc) and dose-related
complications. Dose-related toxicities include
auditory problems, including high frequency
bilateral sensory neural loss, tinnitus, and
deafness. High doses of deferoxamine increase
the likelihood of night blindness, impaired color
vision, impaired visual fields, and decreased
visual acuity. For intravenous therapy at high
doses, renal dysfunction and hypotension have
been noted. Growth retardation can occur
especially in children under 3 years and on high
doses. Excessive doses of deferoxamine in
patients with low iron loading can cause skeletal
changes including vertebral demineralization
and flattening of vertebral bodies. Rare
complications include renal impairment and
interstitial pneumonitis at very high doses.
ii. Deferiprone
Deferiprone, the first and most studied oral iron
chelator, is currently approved in Europe and
other parts of the world but not in North America.
In Europe, it is licensed for treatment of iron
overload in patients with transfusion-dependent
anemias when deferoxamine is contraindicated
or inadequate.52,53 Typical dosage is 75 mg/kg/d
in 3 divided doses up to a maximum of
100 mg/kg/day. Deferiprone reduces iron stores,
as measured by ferritin or LIC, in thalassemia
major patients receiving transfusions.53,54
It causes less iron excretion compared to
deferoxamine on a molecule-to-molecule basis.
Because of its small size and lipophilic nature,
deferiprone is able to penetrate cells better and
chelate iron from organs such as the heart more
effectively.55-57 Myocardial T2* values and left
ventricular ejection fraction (LVEF) improve
more rapidly in deferiprone-treated patients
compared to deferoxamine-treated patients.
While deferiprone clearly has selectivity for cardiac
iron, deferoxamine chelates iron more efficiently
from the liver. Combination treatment with
deferoxamine and deferiprone is increasingly being
used to remove total body iron. Combination
treatment reduces myocardial iron load, lowers
ferritin and improves LVEF in thalassemia major
patients with mild to moderate cardiac iron loading
as defined by T2* values of 8 — 20 ms.58-62
The most serious complication of deferiprone is
agranulocytosis (neutrophils < 0.5 x 109/L), which
occurs in less than 1% of patients.54,63 Milder
neutropenia (0.5 – 1.5 x 109/L) occurs in 8% of
patients. Common side effects of deferiprone
include arthropathy, transient elevation in ALT, and
gastrointestinal upset. Initial concerns about drug-
induced fibrosis have not been supported by
multiple subsequent studies, and progressive liver
disease attributable to the drug has not been
reported in large clinical trials.54,63,64
iii. Deferasirox
Deferasirox is the only oral iron chelator approved in
Canada. It has been approved for the treatment of
chronic iron overload in patients with transfusion-
dependent anemias aged 6 years or older and
in those patients aged 2 – 5 years who cannot be
adequately treated with deferoxamine. Dosing is
adjusted based on the patient’s transfusion rate
and trend of iron load; treatment ranges from
10 – 30 mg/kg/day.
A phase III trial demonstrated the efficacy of
deferasirox and its non-inferiority to deferoxamine
at doses of over 20 mg/kg/day when used by
thalassemia major patients.12 Non-inferiority at
lower doses of deferasirox was not established
and may have been due to study design.
Individualized assessment of total iron load
and a tailored dosing regimen may be needed to
achieve optimal iron chelation.
Side effects of deferasirox include gastrointestinal
symptoms (26%), skin rash (7%), cytopenias, and an
increase in serum creatinine (34%). The optimal
dose of deferasirox for an individual patient, its
effectiveness at reducing cardiac iron, its role
in combination therapy, and its long-term
safety profile remain to be clarified.
A randomized, open-label, Phase III trial evaluated
Patient-Reported Outcomes (PROs) at the end
of one year and found that significantly more
patients on deferasirox as compared to those on
deferoxamine reported treatment satisfaction
(89% vs. 41%, respectively) and treatment
convenience (93% vs. 11%).65 Of those previously
treated with deferoxamine, 97% of those in
the deferasirox arm indicated a preference for
deferasirox and 86% indicated a willingness to
continue treatment as compared to 14% of those
assigned to the deferoxamine group. All of these
findings suggest a greater likelihood of
compliance with deferasirox therapy.
23
25
 iv. Iron Chelators Under Investigation
Other oral chelating agents are undergoing
clinical trials. Studies with newer chelators
(deferitrin) or modifications of old chelators
(starch attached to deferoxamine) are under
way. With limited available evidence,
recommendations cannot be made
regarding the use of these other drugs.
v. Chelating Agents Summary
The ideal chelating agent should be highly efficient
at binding iron, and be able to penetrate cells
effectively and remove intracellular iron. It should
be easy to administer orally, have a long half-life,
and lack significant side effects. Lastly, the ideal
chelating agent should be inexpensive and
accessible. Although two therapeutic options now
exist for iron-overloaded patients in Canada, each
agent at the present time has benefits and
limitations. Deferoxamine (Desferal) is a parenteral
drug with proven efficacy and a well-defined long-
term toxicity profile. Deferasirox, which can be
administered orally and is now commercially
available in Canada, presents a new option for
patients for whom deferoxamine
Principles
• To be aware of complications of iron
overload, to monitor routinely and
accurately for iron overload, and to
reduce iron accumulation using iron
chelators with the goal of preventing
organ damage and dysfunction.
• To reduce body iron load quickly in
patients with iron overload and end
organ toxicity.
• To monitor for and treat adverse
side effects of iron chelators.
24
26
is not effective or tolerated or those who are
noncompliant. Although Deferiprone has a
relatively well-defined efficacy and toxicity
profile, access to this oral agent is restricted
because it is not licensed for use in Canada.
Guidelines
• Transfusional iron loading and body iron
stores should be monitored routinely.
• Chelation therapy should be started early in
children receiving regular blood transfusion to
prevent iron-related toxicities.8-10 (GRADE B)
• The chelating agent used should be tolerable and
effective in reducing iron load. Intolerability of a
chelating agent leads to poor compliance, which
results in increased iron overload, subsequent
end organ complications, and overall increased
morbidity and mortality.
• In patients where deferoxamine is not
tolerated or is ineffective or in those patients
who are noncompliant, oral iron chelators
should be used.8,9,11,12 (GRADE B)
• Regular monitoring for specific chelator-
related toxicity should be carried out and the
appropriate action taken if toxicity is found.
• The effectiveness of chelation should be
routinely monitored and appropriate dose
and drug adjustments made when required.
• Patients and families should receive age-
appropriate education and access to an
experienced multidisciplinary team to
provide support in the practical and
psychological aspects of chelation therapy
and to promote independence and
motivation in managing chelation therapy,
• Patients should receive adequate monitoring to
identify early signs of inadequate adherence to
chelation therapy. If adherence is problematic
they should be provided with appropriate
culturally sensitive counseling or therapy to aim
for improved treatment outcomes.
Interventions
I. Monitoring
• Every patient should have serial serum ferritin
levels assessed every 3 months. Chelation
therapy should be initiated for a persistently
elevated ferritin > 1000 mg/ml and a liver iron
concentration > 7 mg Fe/g dry weight.2,9,17
• LIC should be determined after approximately
10 – 20 transfusions, prior to initiation of
chelation therapy, and every 1 – 2 years
(or as clinically indicated) thereafter.1,2
Modalities for measuring LIC may include
liver biopsy, liver MRI R2 or R2*, or SQUID.
• Cardiac function should be monitored every
1 – 2 years using echocardiophy or radioisotope
studies (MUGA) and ECG. Both cardiac iron load
and function can be measured more accurately
using cardiac MRI T2* every 1 – 2 years.
II. Treatment
• Young children needing chelation therapy
should be started on subcutaneous infusion
of deferoxamine. To help with adjustment,
the drug can be administered less frequently
and increased to the target dose over 1 year.
• The target dose of deferoxamine should be
20 – 40 mg/kg/day for children, and up to
50 mg/kg/day for adults, given over
8 – 12 hours for 5 – 7 days/week.
• Deferasirox, as an alternative, should
be available to patients who are intolerant
to deferoxamine or in whom it is
ineffective.12
• Deferiprone is currently not approved in
Canada; however, it should be considered
for patients in whom deferoxamine and
deferasirox are intolerable or ineffective. It
may also be considered in combination
with deferoxamine in certain clinical
situations such as cardiomyopathy.58-62
• The treating thalassemia specialist should
have access to the different drug options for
chelating iron and should be able to tailor the
use of the drugs based on specific individual
patient requirements and evidence from
clinical trials.
III. Toxicity
• For patients on deferoxamine, investigations
should include yearly audiometry and
ophthalmology examinations, bi-annual
growth assessments for children, and regular
screening x-rays for bone complications.
Baseline assessments for the above should
be done prior to initiating chelation.
• For patients on deferasirox, serum creatinine,
liver enzymes, and blood counts should be
monitored twice prior to commencement of
the drug, and then weekly for the first month
and then monthly thereafter for 3 – 6 months.
Once stabilized, serum creatinine, liver
enzymes, and ferritin should be monitored
every 3 months. Complete blood count should
be performed monthly. Audiometry and
ophthalmic testing should be done annually or
earlier, if clinically indicated.
• For patients on deferiprone, complete blood
counts with differential should be performed
weekly and ALT measurements done monthly for
3 – 6 months, and every 6 months thereafter.
IV. Support
• Patients and families should be educated
on the role and importance of iron
chelation therapy and the rationale for the
treatment regimen.
• Deferoxamine infusions are burdensome
and therefore compliance is poor. Every
effort should be made to provide education
for patients and their families. Issues such
as drug preparation, choice of infusion site,
25
27
 types of needles and infusers used, and
strategies for treatment of local reactions
should be addressed. Children should be
encouraged to participate in part of the
routine of drug administration at an early
age. This should be encouraged by the team
based on the development level of the child,
the family structure, and the cultural ideas of
the family around the illness and treatment.
The importance of chelation therapy should be
reinforced at every clinic visit.
• All patients and families should have access
to a multidisciplinary team to provide support
in the practical and psychological challenges
arising from daily chelation therapy and
regular transfusions.
• The satellite clinic and specialist centre should
have similar treatment and monitoring protocols.
Good communication between the patient,
family, local clinic, and specialist centre should
be maintained to optimize patient care.

26

28
Table 2: Comparison of Currently Available Iron Chelators

Characteristics Deferoxamine Deferiprone Deferasirox

Route of administration • Subcutaneous • Oral • Oral
or intravenous
Plasma half-life • Short • Moderate • Long
• 20 minutes • 2 hours • 8 – 16 hours
Primary route of • Urine and stool • Urine • Stool
iron excretion
Iron chelating efficiency • High (hexadentate) • Low (bidentate) • Moderate (tridentate)
Charge of iron (III) • Charged • Uncharged • Uncharged
complex (hydrophilic • Hydrophilic • Lipophilic • Lipophilic
or lipophilic)
Side effects • Hearing abnormalities • Severe • Rash
• Visual changes agranulocytosis • Gastrointestinal
• Growth retardation • Mild neutropenia discomfort
• Bone changes • Arthritis • Mild increase in
• Local skin reactions • Gastrointestinal creatinine
• Potential renal and discomfort
lung toxicity
Specific guidelines for • Annual audiometry • Weekly complete • Weekly serum
monitoring treatment and retinal exams blood count and creatinine for
• Regular growth differential— 1st month
assessment. ALT monthly for • Creatinine, liver
• Annual bone x-rays 3 – 6 months then enzymes monthly for
every 6 months 3 – 6 months, then
thereafter every 3 months once
stabilized
• Blood counts monthly
• Annual audiometry
and retinal exams
Advantages • Long-term experience • Oral • Oral
• Effective chelator • Established safety • Once a day dosing
— Intensive therapy profile
can reverse cardiac • Better at removing
disease cardiac iron
• May be combined • May be combined
with deferiprone with deferoxamine
Disadvantages • Prolonged parenteral • Agranulocytosis • Limited, long-term
infusions requiring weekly data, including safety
• Eye, ear, bone, growth monitoring profile
toxicities • Close monitoring of
• Poor compliance renal function

Guidelines for the Clinical Care of Patients with Thalassemia in Canada 27

29
 Start
Transfusions

After 10 – 20 transfusions
Iron Load
Ferritin 1000 – 2500 µg/ml OR
Monitoring LIC 7 – 15 mg Fe/g dry weight

Intolerant
Ineffective
Non-compliant

Deferoxamine Deferasirox
Start Chelation 20 – 40 mg/kg/d over 10 – 30 mg/kg/d
8 – 10 hours on 5 – 7 days
– Optimize/increase
chelation treatment
– Encourage compliance
– Re-assess every 6 months

Iron Load
Monitoring

Ferritin 1000 – 2500 µg/ml AND Cardiac Normal function

LIC 7 – 15 mg Fe/g dry weight AND
Cardiac T2* 10 – 20 msec assessment Abnormal

Ferritin > 2500 µg/ml AND/OR
LIC > 15 mg Fe/g dry weight OR
Cardiac T2* < 10 msec OR
abnormal cardiac function
Aggressive Chelation
1. Deferoxamine
Continuous infusion > 50 mg/kg/d
(max 6 g/24 hours), OR
2. Change to oral iron chelator, OR
3. Consider combination therapy with
deferiprone and deferoxamine

Figure 2: Monitoring of Iron Load and Appropriate Chelation Therapy

28 Guidelines for the Clinical Care of Patients with Thalassemia in Canada

30
B. Management of Thalassemia
B4. Psychosocial Aspects of Thalassemia Care
Principles
• To help patients and families cope with the changing social and psychological aspects
of living and growing up with thalassemia.
• To ensure patients’ emotional well-being and promote self-management.
Guidelines
• The multidisciplinary team at the
specialist centre should include a social
worker and psychologist with knowledge of
challenges faced by thalassemia patients
at different developmental stages of life.
• The psycho-social needs of thalassemia
patients should be prioritized in ongoing
planning for treatment.
• Support should also address age-specific
challenges and cultural influences.
Background
Thalassemia is a life long condition requiring
ongoing medical treatment and management of
complications, and hence, is a significant
burden on the patient and family in all facets of
life. Many diverse cultural, social,
developmental, psychological and behavioural
issues affect these patients and have bearings
on the overall effectiveness of treatment,
survival, and quality of life. In Canada, an
increasing percentage of newly diagnosed
patients are from families of recent immigrants,
which poses additional challenges of socio-
cultural adaptation. Greater social support may
be needed under these circumstances.
31
Interventions
• The psychologist and social worker should
regularly review patients, address issues and
provide support, especially at critical milestones
such as time of diagnosis, first transfusions,
initiation of chelation, puberty, transition to adult
care, and major life events such as marriage,
pregnancy, and parenthood.
• The psychologist and social workers should
function as integrated members of the
inter-disciplinary team and meet regularly
with other professionals to discuss patients
in an inter-disciplinary forum.
• Reviews should include all aspects of
psychosocial development such as assessing:
1) patient relationships with family, peers, and
significant others, 2) function at school, work
and within the community including
neuropsychological assessments, when
necessary, 3) adolescent concerns of
adjustment, 4) sexuality 5) self-esteem,
identity, autonomy, and coping-skills, 6)
search for and adaptation to vocations.
• All members of the multidisciplinary team
should emphasize the importance of good
communication between patient, family,
and the medical team. Communication
should be in both written and verbal forms,
as appropriate.
• Resources and support should be provided
to help patients develop a positive, coping
29
 attitude toward their illness and to develop
self-management skills, including healthy
lifestyle behaviours. The medical team should
provide support during times of complications,
hardship, and major stressors.
• The practical and psychological challenges of
regular transfusion and chelation, including
the consequences of non-compliance, should
be discussed with patients and families.
The team should encourage shifting age-
appropriate responsibilities from parent to
child on a continuous basis, allowing the
child to take control of disease management,
including drug administration. Psychological
issues such as needle phobia or fear of
blood should be treated at an early age to
allow for a smoother shift of responsibilities
during adolescence. The team should help
facilitate building a sense of autonomy, self-
reliance, and self-esteem.
• Adolescents and adults should receive phase-
specific support with regard to adjustments,
relationships, work, marriage, parenthood,
life-goals and societal expectations.
• Patients should have easy access
to psychology services.
• If serious psychological difficulty or
psychiatric illness is suspected, patients
should be referred to a psychiatrist.
• All psychological and social support should be
provided in a culturally sensitive manner.

30 Guidelines for the Clinical Care of Patients with Thalassemia in Canada

32
B. Management of Thalassemia
B5. Hematopoietic Stem Cell Transplantation (HSCT)
Background
HSCT is the only curative option available to
thalassemia major patients. Three major risk
factors that affect overall outcome include
inadequacy of chelation treatment, hepatomegaly,
and presence of portal fibrosis.66 Patients
undergoing HLA-matched related allogeneic HSCT
with no risk factors (Class 1) have an overall
survival (OS) of 93% and disease-free survival
(DFS) of 91%. OS and DFS are 87% and 83% for
Class II (1 or 2 risk factors), and 79% and 58% for
Class III (3 risk factors) patients respectively.
Treatment-related mortality is approximately 10%.
The best results are seen with children under the
age of 3 years. In adults (age > 16 years) overall
survival is 66% and event-free survival (EFS)
62%.66,67 Therefore, HSCT should be considered for
patients at an early age before complications due
to iron overload ensue. Transplant related
complications including acute and chronic graft
versus host disease should be weighed against the
potential for cure in making a decision for HSCT.
HLA-matched unrelated donor transplants are
associated with similar outcomes with high-
resolution donor typing, however, treatment-related
mortality is significant at 5–30% in some series.68-70
Acute and chronic graft-versus-host disease is a
major complication and is much higher in unrelated
donor transplants and in adult patients.
Related and unrelated umbilical cord transplants
are another potential curative option for
thalassemia patients and are associated with less
graft-versus-host disease (GVHD), quicker access to
stem cells, and no harm to the donor.71,72 The cord
transplants yield low total cell numbers which limits
their use to children or small adults. The cord
transplants are also associated with slower
engraftment and higher rejection risks.
33
Principles
• To ensure patients and families receive
adequate information on hematopoietic
stem cell transplantation (HSCT) for
informed decision-making.
• To ensure close follow-up of
patients who have undergone HSCT.
Guidelines
• The option of HSCT, including its indications
and complications, should be discussed with
families while the patient is at a young age.
• The discussions should be initiated by the
specialist centre and, if the patient is serious
about pursuing HSCT and it is appropriate,
referral should be made to a HSCT centre with
experience in transplanting thalassemia
patients where more detailed discussions
should take place.
• The options of HLA-matched related HSCT (cord
blood and bone marrow) should be discussed.
• Post-HSCT, patients should be closely
monitored and managed for iron overload
and other complications.
Interventions
• HSCT should be performed in centres with
experience in transplanting patients with
thalassemia.
• Discussions about the role of HSCT in
thalassemia should include benefits, risks,
short and long-term complications, quality of
life after HSCT and the psychosocial impact.
• The patient’s risk factors and organ
function should be assessed prior to HSCT.
• Long-term complications of HSCT include
Guidelines for the Clinical Care of Patients with Thalassemia in Canada 31

iron overload, chronic GVHD, delayed

pubertal development, growth and endocrine
deficiencies, infertility and secondary
malignancies. Complications should be
managed in collaboration with the appropriate
sub-specialist.
• After HSCT, reduction of pre-existing iron
overload should continue by routine phlebotomy
with or without chelation.73,74 Phlebotomy is safe
and effective for iron removal after HSCT and
has been shown to reduce iron load and liver
fibrosis. Patients should be phlebotomized to
achieve a ferritin < 300 ug/l.
• If the patient’s mother becomes pregnant, the
option of chorionic villous sampling (CVS) or
amniocentesis for pre-natal diagnosis should
be discussed. If the fetus does not have beta
thalassemia, the cord blood should be
harvested and stored for potential future
transplant. If antenatal testing has not been
done, all cord blood should be collected
and subsequently tissue typed and stored,
if matched.
• Transplanted individuals should be counseled
that they will still pass on a mutant thalassemia
gene to each of their children.
• Other modes of HSCT such as the use of
multiple cord blood units are currently
undergoing clinical trials. Updated
recommendations might be made as
new evidence becomes available.

34
Blood Transfusions
Blood transfusion is the mainstay of care for individuals with
thalassemia major and many with intermedia. The purpose of
transfusion is twofold: to improve the anemia and to suppress
the ineffective erythropoiesis. Chronic transfusions prevent
most of the serious growth, skeletal, and neurological
complications of thalassemia major. However, once started,
the transfusion-related complications become a major source
of morbidity. Standards must be developed and maintained to
ensure a safe and rational approach to the use of blood
transfusions in the management of these rare disorders.
Patients with ß+/ß+ thalassemia; hemoglobin E-ß thalassemia;
hemoglobin H disease; and hemoglobin H–Constant Spring often
have a thalassemia intermedia phenotype and do not necessarily
require chronic transfusion. However, the DNA mutations do not
reliably predict the clinical phenotype. ß0/ß+ and even ß0/ß0 may
occasionally have a thalassemia intermedia clinical phenotype. The
clinical phenotype of thalassemia intermedia patients may change
as they age and may require transfusion therapy. Ongoing
assessment of transfusion requirements are necessary for both
thalassemia major and intermedia.
The decision to start transfusions is based on inability to
compensate for the low hemoglobin (signs of increased cardiac
effort, tachycardia, sweating, poor feeding, and poor growth),
or less commonly, on increasing symptoms of ineffective
erythropoiesis (bone changes, massive splenomegaly). The
decision to institute chronic transfusion should not be based
exclusively on the presence of anemia.
The decision to initiate chronic transfusion therapy requires
significant input from the patient, family, and medical team.
Anemia alone is not an indication of the need for chronic
transfusion. Anemia should be linked with a significant
impairment in quality of life or associated morbidities. Factors
to consider include: poor growth; inability to maintain daily
routines and activities such as going to school and work;
evidence of organ dysfunction; evidence of cardiac disease;
pulmonary hypertension; and dysmorphic bone changes.
It may be necessary to initiate a six-month trial of blood
transfusions in patients of families whose decision to transfuse
is uncertain. After six months, transfusions can be stopped and
the patient observed for a brief period of time to give the family
and medical team information as to the clinical benefits and
psychological impact of the transfusions.
35
4.1 Assessing the need for routine transfusions
The decision to start regular transfusions is clear when the initial
hemoglobin level is well below 6 g/dL. To assess a child’s need for
routine transfusions due to thalassemia, anemia caused by sepsis or
viral infection must be ruled out. Assessment may be accomplished
by withholding transfusions and monitoring weekly hemoglobin
level. If the hemoglobin drops under 7 g/dL on two occasions, two
weeks apart, then regular transfusions should be commenced.
Patients with a hemoglobin level less than 7 g/dL may sometimes
require regular transfusions in the presence of growth impairment,
marked skeletal changes, or extramedullary hematopoiesis.
4.2 Baseline laboratory tests prior to regular transfusions
An extended red cell phenotype must be obtained to reduce the
future probability of developing alloantibodies. If a child has
already started transfusions, the red cell antigen genotype can
be determined by DNA testing, and at the minimum, should
include the C, E, and Kell alleles.
Although the hemoglobin level can define a patient’s disease
type, seldom does it alone determine the need for transfusion.
Antibodies to hepatitis B, hepatitis C, and HIV should also be
determined. Patients should demonstrate immunity to hepatitis
B. The bilirubin, transaminase, and serum ferritin levels should
be checked.
4.3 Transfusion administration and monitoring
The aim of transfusion therapy is to permit normal growth and
activity level and to prevent skeletal changes associated with
marrow hyperplasia. Adequate transfusion therapy will also
reduce splenomegaly and hypersplenism and decrease
absorption of dietary iron.
4.3.1 Transfusion facility
Transfusions should be administered in a designated outpatient
clinical area by staff experienced with transfusion policies.
Written transfusion policies—including maximum rate, volume
of transfusion, and protocol for transfusion reactions—are
required. The availability of access to outpatient transfusion
services on weekdays, weekends, and evenings is important for
school-aged children and working adults.
4.3.2 Type of blood product
The product of choice is packed red blood cells depleted of
leucocytes and matched with the patient’s red antigen
phenotype for at least D, C, c, E, e, and Kell.
Whole blood or blood without leukodepletion is unsuitable for
regular transfusions, since non-hemolytic transfusion reactions
are common. When possible, large units less than two weeks of
age are recommended.
Patients should be assessed for hemolytic reactions if any
adverse event is noted during a transfusion. Febrile and
allergic reactions may respond to acetaminophen and
diphenhydramine before future transfusions.
Patients who develop allergic reactions should be given
washed packed red blood cell units.
 STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 3
The development of alloantibodies can complicate transfusion
therapy and may require the use of frozen packed red blood cell
units of rare blood types. Some patients are transfused with
irradiated red cells. This process is used to prevent graft-versus-
host disease. It is largely unnecessary unless the patient is
undergoing a bone marrow transplant or has an underlying
immunodeficiency. Cytomegalovirus (CMV) infection is
transmitted via transfusion. Leukocyte depletion of a red cell
unit prevents its transmission. CMV negative units are usually
unnecessary once the unit is leukocyte-depleted.
4.3.3 Target hemoglobin and frequency of transfusions
The goal of transfusion is to shut off erythropoiesis as much as
possible. Transfusions should generally be given at an interval of
three to four weeks. (With aging patients, a transfusion every two
weeks may be necessary.) Transfusions should be scheduled in
advance and maintained at a fixed schedule. This enables patients
and families to establish routines and will improve quality of life.
The amount of blood received on transfusion day is determined
by pre-transfusion hemoglobin levels. The target is to maintain
the pre-transfusion hemoglobin level between 9 and 10 g/dL.
Attempts to maintain pre-transfusion hemoglobin at above 10 g/
dL increase transfusion requirements and the rate of iron
loading. Transfusions should be given in an outpatient setting
with an experienced transfusion team that uses proper safety
precautions (patient/blood identification bracelets). Blood
should be transfused at 5 mL/kg per hour, and the post-
transfusion hemoglobin should not exceed 14 g/dL.
In patients with severe anemia (hemoglobin less than 5 g/dL) or
cardiac compromise, the rate of transfusion should be reduced to
2 mL/kg per hour to avoid fluid overload. Diuretics such as
furosemide (1 to 2 mg/kg) may be necessary for some patients.
If cardiac insufficiency is present, higher pre-transfusion
hemoglobin levels (10 to 12 g/dL) should be maintained with
smaller volume transfusions given every one to two weeks.
The patient’s weight and pre-transfusion hemoglobin and the
volume of transfusion should be recorded at each visit. These
values should be periodically reviewed to assess the volume of
blood required to maintain the desired pre-transfusion
hemoglobin level. Annual blood transfusion requirement in
patients without hypersplenism is usually below 200 mL packed
red blood cells/kg per year.
4.4 Adverse reactions to transfusions
The very best practices for blood transfusion must be
employed, since the need for lifelong transfusions leads to a
cumulative increase in the risk of adverse reactions.
Alloimmunization is a frequent problem that can be prevented by
transfusing blood matched for the patient’s extended red blood cell
phenotype (not just the ABO and RhD antigens). An alloantibody
screen should be performed prior to each transfusion. An
alloantibody is an antibody made by the patient against an antigen
present on the transfused red cell. Once alloimmunized, patients
may be at risk for developing an antibody against their own red
cells (an autoantibody). Up to 10 percent of patients who develop
alloantibodies will develop an autoantibody. The presence of an
36
autoantibody does not always result in decreased red cell
survival, but it may. An autoantibody will delay the patient’s
cross match and transfusion program. Autoantibodies can best
be avoided by preventing alloantibodies.
If an autoantibody and/or alloantibody is detected, the specific
antibodies causing the transfusion reaction should be
determined by the blood bank or by a reference laboratory.
The management of patients who develop antibodies requires
use of blood matched by extended red cell antigen phenotype.
The risk of transfusion-transmitted infections, while low, is
still a concern for known and emerging pathogens, and annual
monitoring for hepatitis B, hepatitis C, and HIV is necessary.
The risk of bacterial infection is small, but the transmission
of parasitic infections (particularly malaria) is a significant
threat in certain geographical areas.
The other complications of blood transfusion include the risk
of mismatched transfusion, allergic reactions, and febrile,
non-hemolytic reactions.
4.5 Splenectomy
The use of splenectomy in thalassemia has declined in recent years.
This is partly due to a decreased prevalence of hypersplenism
in adequately transfused patients. There is also an increased
appreciation of the adverse effects of splenectomy on blood
coagulation. In general, splenectomy should be avoided
unless absolutely indicated.
Splenectomy is indicated in the transfusion-dependent patient
when hypersplenism increases blood transfusion requirement
and prevents adequate control of body iron with chelation
therapy. An enlarged spleen—without an associated increase in
transfusion requirement—is not necessarily an indication for
surgery. Patients with hypersplenism may have moderate to
enormous splenomegaly, and some degree of neutropenia or
thrombocytopenia may be present.
Annual transfusion volume exceeding 225 to 250 mL/kg per year
with packed red blood cells (hematocrit 75 percent) may indicate
the presence of hypersplenism. The volume calculation should be
corrected if the average hematocrit is less than 75 percent. The
possible development of alloantibody should also be ruled out.
Splenectomy should be avoided unless there is an inability to
maintain iron balance with optimal chelation, or if there are
clinically significant complications such as pancytopenia and
marked enlargement. Often, hypersplenism develops because of a
low pre-transfusion hemoglobin. Increasing the pre-transfusion
hemoglobin to between 9.5 and 10 may reverse hypersplenism.
If a decision to perform surgery is made, partial or full
splenectomy is the option. Partial splenectomy is a complicated
surgery utilized to preserve some splenic function. It should be
reserved for infants requiring splenectomy. Full splenectomy
can usually be performed by laparoscopic technique. However,
open procedure is necessary in cases of marked splenomegaly.
The indications for splenectomy in hemoglobin H–Constant
Spring patients are different than in beta-thalassemia disorders.
 STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 4

Transfusion-dependent infants with hemoglobin H–Constant Spring respond rapidly to splenectomy but
require prophylactic anticoagulation because of a high incidence of serious thrombosis.

Patients must receive adequate immunization against Streptococcus pneumoniae, Haemophilus

influenzae type B, and Neisseria meningitides prior to surgery. Splenectomy should be avoided
in children younger than five years because of a greater risk of fulminant post-splenectomy
sepsis.

After splenectomy, patients should receive oral penicillin prophylaxis (250 mg twice daily) and
be instructed to seek urgent medical attention for a fever over 101º Fahrenheit.

Post-splenectomy thrombocytosis is common, and low-dose aspirin should be given during

this time. Another complication following splenectomy is the development of a thrombophilic
state. Venous thromboembolism, more common in thalassemia intermedia and hemoglobin
H–Constant Spring, can develop following splenectomy.

Patients should have annual echocardiographic measurement of the pulmonary artery pressure
to monitor for development of pulmonary hypertension.

4.6 Thromboembolic disease

People with thalassemia are at increased risk of thrombosis. Thrombotic events include pulmonary
embolism, arterial occlusion, portal thrombosis, and deep vein thrombosis. Approximately 1 to 2
percent of thalassemia major patients and
5 percent of thalassemia intermedia patients experience a serious thrombosis. One of the most
common and serious complications is stroke. Recent brain MRI studies suggest that thalassemia
patients (particularly those with thalassemia intermedia) are at high risk for subclinical infarction
or silent stroke. Splenectomy significantly increases the prevalence of thrombotic events.
Inadequate transfusion may increase the risk of thrombosis secondary to increased release of
procoagulant red cell particles. Many people recommend that all post-splenectomy patients
should receive anti-platelet or anti-thrombosis therapy with aspirin or low dose warfarin.

37
 KEPUTUSAN MENTERI KESEHATAN REPUBLIK INDONESIA NOMOR HK.01.07/MENKES/1/2018
TENTANG PEDOMAN NASIONAL PELAYANAN KEDOKTERAN TATA LAKSANA THALASEMIA
 http://www.thalassemia.com/documents/SOCGuidelines2012.pdf
 Guidelines for the Clinical Care of Patients with Thalassemia in Canada

38