Thalassemia

Mechanism of iron overload in non-transfused patients

GDF15
Ineffective erythropoiesis
Chronic anaemia

Duodenal
iron absorption

Hepcidin
Release of
recycled iron from RES macrophages

Hypoxia

VHL/HIFs

Erythropoietin and ferroportin

Ferritin LIC

De Domenico I, et al. J Clin Invest. 2007;117:1755-8; Origa R, et al. Br J Hematol. 2007;136:326-32; Peyssonnaux C, et al. J Clin Invest. 2007;117:1926-32; Tanno T, et al. Nat Med. 2007;13:1096-101.

GDF15, growth differentiation factor 15; HIF, hypoxia-inducible transcription factor; RES, reticuloendothelial system; VHL, von Hippel-Lindau.

Hemoglobin Types

Hemoglobin Type Globin Chains Hgb A192%--------a2b2 Hgb A22.5%-------a2d2 Hgb F <1%--------a2g2 Hgb H -----------------b4 Barts Hgb-------------g4 gluval Hgb S-------------------a2b26 glulys Hgb C------------------a2b26
8

Patomekanisme thalassemia
Defek molekul (mutasi) Gen globin-a (thalassemia-a)
Rantai globin-a /-

Gen globin-b (thalassemia-b Rantai globin-b /-

- Sintesis Hb /- MCV dan MCH Anemia +/- Ekses: rantai globin-g (fetus) rantai globin-b (adult)

- Sintesis Hb /- MCV dan MCH Anemia +/- Ekses: rantai globin-a

PATOFISIOLOGI THALASSEMIA
Mutasi di gen globin-

b d

Produksi rantai globin- (-) atau

b
Kelebihan: Rantai globin- (janin) Rantai globin- (dewasa) 4 Hb Bart) 4 (HbH) Presipitasi di sel darah merah matang

g
a

d g

Hemolisis di limpa dan mikrosirkulasi

10

FENOTIP THALASSEMIA - a (CARRIER)

Normal aa/aa

-a/-a

- a /a a

a b
d
g
Normal MCH : 27-31 pg HbA2 : 2.5-3.5% HbF : <1%

b
d
g

d
g

N/anemia ringan < 25 pg normal or atau (-)

Normal 25-27pg normal or atau (-)

11

FENOTIP THALASSEMIA - a (PENDERITA)

Normal aa/aa
b
d

--/-b
d

- -/-a

g4=HbBart
a b a b g g a Fetus Kematian janin (28-32 minggu) Hydrops fetalis d g

b4=HbH

d g Adult

MCH : < 26-32 pg HbA2 : 2.5-3.5% HbF : <1%

HbH disease mild to severe anemia

12

THALASSEMIA ALFA ()
NormaL Silent carrier Minor aa/aa -a/aa -a/-a --/aa --/-a

Hb H disease Barts hydrops fetalis --/--

13

PATOFISIOLOGI THALASSEMIA

Mutasi di gen globin-

Produksi rantai globin- (-) atau

Hb Normal

Kelebiha n rantai globin-

Komposisi Hb Thalassemia-

Sintesis Hb (di tiap sel darah merah): Anemia dikompensasi dengan eritropoiesis Mikrositik (MCV ) Hipokrom (MCH )

14

PATOFISIOLOGI THALASSEMIA
Rantai globin berlebihan

4 (tidak stabil)
Terurai

Rantai globin bebas (tidak larut)

Presipitasi
Sumsum tulang Sirkulasi

Prekursor sel darah merah

Sel darah merah matang

Trauma fisik Perubahan metabolisme

Eritropoiesis tidak efektif Destruksi di sumsum tulang

Hemolisis di mikrosirkulasi (limpa)

15

THALASSEMIA-
HETEROZIGOT HOMOZIGOT o HOMOZIGOT + dan +

b
d
g

a
d
g Anemia berat sejak usia < 1 tahun Perlu transfusi rutin Hati dan limpa membesar MCV < 70 fl Jenis Hb hanya HbA2 and HbF HbF > 90%

b
d
g

Asimptomatik Anemia ringan s/d berat Hb 8-15 g/dL (rata-rata 12) MCV < 80 fl HbA2 > 3.5% HbF 1%

Anemia ringan sampai berat Hati dan limpa normal atau membesar Masih mempunyai HbA HbF dari 10 s/d > 90%
16

THALASSEMIA BETA ()
Normal Minor Intermedia Major b0/b+ b/b b/b0 b/b+ b0/b0 b+/b+

17

Thalassemia Minor

18

Thalassemia Mayor

19