Thalassemia

Dr. Rino Arianto Marswita, Sp.PD

Bagian Penyakit Dalam
FK UNISSULA - RSI SULTAN AGUNG Semarang
Blood is Life,...
 Komponen Eritrosit

HEMOGLOBIN
HEME GLOBIN

Zat Besi Protein

GEN globin
(DNA)
 Globin
Ada 2 jenis rantai GLOBIN dan selalu
berpasangan  Rantai globin α dan β
Tabel Hemoglobin Manusia Normal
Hb Embrio Hb Fetus Hb Dewasa
Gower 1: Hb F : Hb A :
zeta (2), epsilon (2) Alpha (2), gamma (2) Alpha (2), beta (2)
( ξ2 / ε2 ) ( α2 / γ2 ) ( α2 / β2 )
Gower 2 : Hb A2 :
alpha (2), epsilon (2) Alpha (2), delta (2)
( α2 / ε2 ) ( α2, δ2 )
Portland :
Zeta (2), gamma (2)
( ξ2 / γ2 )
Perkembangan Globin
 Thalassemia
• Kelainan hemoglobin bawaan yang ditandai
dengan penurunan/tidak ada sintesis rantai
globin beta (thalassemia beta) atau rantai
globin alpha (thalassemia alpha)
• Kelainan hemoglobin lain:
– Perubahan jenis asam amino yang menyusun
rantai globin beta atau alpha tanpa ada
penurunan sintesis rantai globin alpha atau beta –
Hemoglobin variant (Hemoglobinopati)
– Defisiensi besi
 Epidemiologi Thalassemia
• ± 300 juta penduduk dunia  pembawa gen
thalassemia
• Prevalensi thalassemia di Indonesia 5% (1997) 
8-10% (2001)
• Dengan Persamaan Hardy-Weiberg :

p2 + 2pq + q2 = 1

• Jika kelahiran bayi 2.000.000/ tahun  1/1600 x

2.000.000 = 1.250 bayi homozigot thalassemia
mayor/tahun
Sabuk Penyebaran Thalassemia
Peta Gen Thalassemia
 Mutasi Gen Thalassemia
• Thalassemia α  Mutasi gen pada kromosom 16
• Thalassemia β  Mutasi gen pada kromosom 11
 Pewarisan Gen Thalassemia (1)
Salah satu orang tua karier Kedua orang tua karier

Pembawa Pembawa
Pembawa Tidak gen gen
gen membawa gen thalassemia thalassemia
thalassemia thalassemia
(normal)

r R R R r R r R

r R R R r R R R r r r R r R R R
 Pewarisan Gen Thalassemia (2)
Satu orang tua penderita Kedua orang tua penderita
Menderita Menderita
Menderita Tidak membawa
thalassemia thalassemia
thalassemia gen thalassemia
homozigot homozigot
homozigot (Normal)

r r R R r r r

r R r R r R r R r r r r r r r r
 Alpha thalassaemias

• Much less common in our country than Beta

thalassemias, and of much less clinical
significance.

• Due to reduced or absent synthesis of alpha ()

globin chains of hemoglobin.

• (Alpha () chains are constituents of all three

normal Hb A, A2 and F).
Thalassemia α
 An over-Simplified diagramatic representation of
the + and o thalassaemia genetic defects

Normal  chain production

Normal  
 genome
Two  genes


+
One  gene
reduced  chain production

o No Alpha chain production

No  genes

Normal  gene
Deleted  gene
Clinical Phenotypes of Alpha thalassaemia (relevant to number of alpha genes remaining):

o No alpha
No alpha
genes o chains

Incompatible with life 1. Hb Barts Hydropes Fetalis

One + Markedly reduced

Alpha alpha chain
o production
gene

2. Hb H disease
Thalassaemia
intermedia phenotype
Two + Moderately
alpha
 reduced Alpha
genes + chains

3.  Thalassemia minor

Normal  genes
Three Minimally
Alpha reduced Alpha
+
genes chains

4. Silent  thal. carrier state

 Hb Bart’s Hydrops Fetalis
• Common only in SEA.
• Genetics :
Due to inheritance of o defect from both parents, so (--/--).
So no Hb F but 4 (Hb Barts) which is ineffective as an
Oxygen carrier.

• Clinical :
Death in utero, or within hours of birth.
Severe hypochromic anemia with marked anisopoikylocytosis.
Hb electrophoresis;
• Electrophoresis :
~ 80% Hb Barts (4),
Hb Bart’s Hydrops Fetalis
Thalassemia β
Simplified diagram of types of Beta thal.
Genetic defect & relevance of Beta chain Normal  chain production
production
Normal  gene

+thal. Gene defect

reduced  chain production

o thal. Gene defect

No  chain production
  Defective  gene
Chr 11 Normal Normal  gene
 beta genes
Chr 11


Chr 11 Heterozygous to
Thalassamia
 beta thalassaemia
Chr 11 genetic defect Minor


Chr 11 Homozygous to Thalassamia
 beta thalassaemia
Major
Chr 11 genetic defect
Clinical features of β thalassaemia Major

• First diagnosis between age of 6 months and 2 years.

• Presentation usually with pallor, poor feeding, failure to

thrive , abdominal swelling (due to hepato-splenomegaly)
and sometimes Jaundice.

- Deformities in the skull due to bone marrow expansion

(Bossing , and mongoloid facies; hair-on-end appearance
on skull X-ray).
- Also dental problems and inadequate drainage of sinuses
and middle ear, leading to chronic sinusitis and deafness

- Increased frequency of infections.

Clinical features – thal. major
 SKEMA STRATEGI DIAGNOSIS
THALASSEMIA INDIVIDU

Penampilan normal / tanpa gejala Dengan gejala

Tanpa riwayat keluarga Dengan riwayat keluarga

(anemia, IUFD, kematian masa anak-anak)

PEMERIKSAAN DARAH TEPI LENGKAP

(INDEKS SDM)

Hb N, MCV turun, MCH turun, RDW N/naik sedikit Hb turun, MCV turun, MCH turun, RDW naik Hb turun, MCV turun, MCH turun, RDW naik
Morfologi : sel target (+), sel tear drop (+) Morfologi : sel pensil (+) hepatosplenomegali
hipokrom mikrositer hipokrom mikrositer Morfologi : mirip sel thallasemia
sel target (+), hipokrom mikrositer

Susp Thallasemia Anemia def Fe Anemia def Fe kronis /

kombinasi dg Thallasemia

Serum Ferritin

Analisis Hb

Elektroforesis
 Diagnosis Banding Anemia
Mikrositik hipokrom
An. Peny Kronik An. Def Fe Trait Thalassemia An. Sideroblastik

MCV ↓/N ↓ ↓ ↓

MCH ↓/N ↓ ↓ ↓

Fe Serum ↓ ↓ N/↑ N/↑

TIBC ↓ ↑ ↑ ↑

Saturasi Transferin ↓ ↓/N ↑ ↑

10-20 % < 15 % > 20 % > 20 %

Fe Ss. Tulang + - + kuat + ring sideroblas

Protoporfirin Eri. ↑ ↑ N N

Feritin serum ↓ N ↑ ↑
<20 ug/dl 20-50 ug/dl >50 ug/dl >50 ug/dl

Hb Elektroforesis N N HbA2/F N
 Pemeriksaan yang mendukung
kelainan Hemoglobin
• Darah tepi
• Pengec. supravital / BCB( inklusi HbH )
• Tes resistensi osmotik
• Tes Diclhloro Indopenol Presipitation ( DCPI )
• Penetapan fraksi Hb A2 kuantitatif (HPLC)
• Penetapan fraksi Hb F kuantitatif
• Sitokima HbF.
• Elektroforesis Hb
 Darah Tepi
• Anemia hipokromik, mikrositik disertai jumlah
retikulosit meninggi
• Eritrosit muda/berinti (normoblas)
• Eritrosit bervariasi dalam hal bentuk dan
ukuran (anisositosis dan poikilositosis)
• Sel target ini tidak patognomonik
• Sisa-sisa eritrosit yang sudah pecah
(fragmentosit)
 Gambaran Darah Tepi
SEL TARGET Tear Drops

Basophilik Stipling
 Hb Elektroforesis
Tipe Hb Nilai normal Thalassemia Thalassemia Thalassemia

β homozigot β heterozigot β minor

HbA (%) 96 - 98 0 10-30 92-95

HbF (%) <1 95-98 70-90 0,5-4

HbA2 (%) 2-3 2-5 2-5 >3,5

Manajemen Thalassemia
Transfusi

Terapi Kelasi

Splenektomi

Treatmen infeksi & Komplikasi

Dukungan Psikososial
 Transfusi
• Pengobatan suportif utama untuk menanggulangi
anemia pada thalassemia
• Pemberian sel darah merah : high transfusion
scheme dan low transfusion scheme
• Kadar hemoglobin pasien thalassemia umumnya
turun 1g/dl tiap minggu

• Komplikasi: penularan infeksi , isoimmunization dan

penimbunan besi
 Hemokromatosis pada Thalassemia

Hemokromatosis merupakan penyakit sistemik karena

penumpukan hemosiderin pada sel parenkim

kerusakan jaringan dan disfungsi pada organ:

•Hati
•Pankreas
•Jantung
•Kelenjar hipofisa
 Gejala klinis:

sirosis hati
hepato-splenomegali

hipogonadisme

kardiomiopati
Istilah hemosiderosis dipergunakan apabila terdapat
penumpukan hemosiderin pada jaringan tetapi tanpa
disertai kerusakan pada jaringan tersebut.
Kelainan endokrin pada thalassemia bisa diidentifikasi
menjadi 4 abnormalitas :

• Kegagalan maturasi seks karena gangguan produksi

1 LH dan FSH

• Gangguan TSH release untuk menstimulasi TRF

2

• Tes toleransi glukosa abnormal

3

• Disfungsi tiroid dan paratiroid.

4
 ENDOCRINE COMPLICATIONS
No. Complication Percentage Notes
1 Hypogonadotropic ± 50% above Oxidative damage caused by labile iron to the
hypogonadism 15 years anterior pituitary and hypothalamus
2 Secondary amenorrhea 10%-65%
3 Oligospermia and > 50%
asthenospermia
4 Hypothyroidism 5.6% - 31% Serum ferritin concentrations seems not to be
correlated
5 Hypoparathyroidism Up to 11% Can manifest with severe hypocalcemia and
hyperphosphatemia
6 Diabetes 6% - 17% Precede by insulin resistance and increased
insulin secretion
Risk factors: age at first transfusion, liver iron
overload, bad compliance with chelation and
male sex
7 Growth hormone 20% Also demonstrate low IGF-I and IGFBP-3
deficiency Stunted growth is observed in a third of the
older thalassemia patients

EJCMNO, 2011; 3: (1)

 Penanganan hemosiderosis
• Hemosiderosis dan Hemokromatosis bila tidak dikelola dengan
baik dapat menyebabkan kematian dini pada penderita
thalassemia mayor karena gangguan jantung akibat penimbunan
besi.
• Pengobatan hemosiderosis dan hemokromatosis yang optimal
secara jelas menunjukkan perpanjangan dari Complication Free
Survival.
• Standard baku emas untuk terapi chelasi masih mempergunakan
DESFERRIOXAMINE(DFO) karena efikasi jangka panjang sudah
didapatkan dari penelitian multisenter di Italia.
• Studi yang banyak dilakukan untuk obat chelasi oral adalah
DEFERRIPRONE (DFP), yang absorbsinya di usus juga bisa cepat.
• Studi menunjukkan bahwa DFP mungkin lebih efektif daripada
DFO dalam melindungi jantung dari penimbunan besi.
• Obat terbaru: DEFERASIROX (Exjade®) adalah tablet dispersibel
yang telah disetujui dan aman untuk jantung
 Causes of death in thalassemia
% 0 5 10 15 20 25 30 35 40 45 50 55 60 65
Cardiac 60.2
Cause n %
failure 50.8
6.8
Cardiac disease 82 71.3
Arrhythmia
6.6
Sepsis 9 7.8
Myocardial 1.8
infarction
AIDS 7 6.1
6.8
Infection
14.8
Liver disease 5 4.3
4.1
Cirrhosis
All patients (n=1073) Thromboembolism 4 3.5
4.1
Thrombosis Patients born after 1970 Bone marrow
3.3 4 3.5
3.6 (n=720) transplantation
Malignancy
3.3 Metabolic disorders 1 0.9
3.2
Diabetes
3.3 Lymphoma 1 0.9
2.7
Unknown
8.2 Accidental events 2 1.7
6.7
Other* Total 115 100
9.7

*Accident, renal failure, HIV/AIDS, familial autoimmune disorder, anorexia, hemolytic anemia and thrombocytopenia
Borgna-Pignatti C et al. Ann N Y Acad Sci 2005;1054:40–47
Ladis V et al. Ann N Y Acad Sci 2005;1054:445–450
Manajemen dan Komplikasi
 Pilihan Terapi Definitif
 Bone Marrow Transplants
 Mengganti sumsum tulang dari donor
 BMT pertama tahun 1981
 Masih sulit untuk dilakukan di Indonesia

 Cord Blood Transplants

 Menggunakan metode stem sel
 Pencegahan Thalassemia
• Identifikasi karier  Skrining Thalassemia
• Konseling genetik
• Prenatal Diagnosis
 Prenatal Diagnosis
Prenatal diagnosis 
Analisa DNA dari sel
fetus (amniosentesis
pada usia kehamilan
15-18 minggu) atau
sampel vili korionik
(usia kehamilan 11
minggu)  jika (+) 
akhiri kehamilan
 Pengelolaan Komprehensif
Kuratif

Preventif

Promotif

Rehabilitatif Tumbuh kembang anak

optimal sesuai potensi
Psikososial genetik anak
thalassemia

Kualitas hidup
meningkat
Terima Kasih