DEFINISI
Benz EJ. Hemoglobinopathies. In: Kasper, Braunwald, Fauci, Hauser, Longo, Jameson editors. Harrison’s:Principles of internal
medicine. 16th ed.McGrawHill.New York.2005
HEMOGLOBIN
98% protein sitoplasmik eritrosit adalah hemoglobin
Hemoglobin merupakan tetramer heterodinamik yang terdiri dari 2
rantai globin α dan 2 rantai globin non- α
(, , atau ) yang berkonjugasi dgn 4 molekul heme
Setiap tetramer Hb mampu mengikat dan mengangkut maksimum
4 molekul oksigen
Tabel 1. Hemoglobin Menusia
Hemoglobin Komposisi Representasi
Rose MG, Nancy B. Red blood cell.In:Schiffman FJ editor. Hematologic pathophysiologiy.Lippincott Raven.Philadelphia.1998.p49-95
Benz EJ. Hemoglobinopathies. In: Kasper, Braunwald, Fauci, Hauser, Longo, Jameson editors. Harrison’s:Principles of internal
medicine. 16th ed.McGrawHill.New York.2005
Benz EJ. Hemoglobinopathies. In: Kasper, Braunwald, Fauci, Hauser, Longo, Jameson editors. Harrison’s:Principles of internal
medicine. 16th ed.McGrawHill.New York.2005
Hoffbrand AV, Pettit JE, Moss PAH. Essential Haematology.4 th ed.Blackwell Science.2001
KLASIFIKASI HEMOGLOBINOPATI
Benz EJ. Hemoglobinopathies. In: Kasper, Braunwald, Fauci, Hauser, Longo, Jameson editors. Harrison’s:Principles of internal medicine. 16th ed.McGrawHill.New York.2005
THALASSAEMIA BETA
DEFINISI THALASSAEMIA
Hoffbrand AV, Catovsky D, Tuddenham EGD. Postgraduate haematology. 5th ed. Oxford : Blackwell Publishing Inc.; 2005.p.87.
Kromosom 11 : globin-β
Kromosom 11 :
rantai β, δ, , dan ε
Rantai tdd 2 macam :
rantai G dg Glycin pd posisi 136 Sblm lahir G : A = 3 : 1
• Weatherall DJ, Cleg JB. The thalassaemia syndrome. 4th ed. London: Blackwell Science; 2001. p.121-132.
• Olivieri NF. The B thalassemias. N Engl J Med. 1999;341(2):99-109.
• Weatherall DJ, Cleg JB. The thalassaemia syndrome. 4th ed. London: Blackwell Science; 2001. p.287-356.
http://en.wikipedia.org/wiki/Image:Autorecessive.jpg
PATOGENESIS MOLEKULER
Patologi Molekular
kelebihan β
γ α Denaturasi, degradasi
Splenomegali (pooling,
hemopoiesis ekstrameduler, Eritropoeisis inefektif
Peningkatan HbF peningkatan volume plasma)
Anemia
Afinitas eritrosit terhadap
oksigen tinggi
Transfusi
Peningkatan
eritropoeitin
Oksigenasi ke Hipoksia jaringan
jaringan berkurang
Peningkatan aktivitas
sumsum tulang
Deformitas tulang Defisiensi endokrin
Peningkatan metabolisme Sirosis
Wasting Gagal jantung
Gout Peningkatan Besi berlebih Organ lain
Defisiensi folat absorbsi besi (termasuk intestinal)
Weatherall DJ, Cleg JB. The thalassaemia syndrome. 4th ed. London: Blackwell Science; 2001. p.287-356.
Patofisologi
McKenzie SB. Anemia caused by abnormalities in globin biosynthesis. In: Textbook of Hematology. Wiliams and Wilkins. Maryland USA. 1996.p165
Patofisologi
1. Penurunan produksi total hemoglobin eritrosit penurunan
produksi rantai globin-β penurunan produksi total
hemoglobin eritrosit hipokrom mikrositik
2. .Eritropoiesis inefektif
Presipitasi rantai globin α di sumsum tulang dihancurkan
oleh makrofag eritropoiesis inefektif berat
Di sirkulasi, presipitat eritrosit di „pitted‟ oleh lien mishapen
cell/bite cell
Kelebihan rantai globin α menyebabkan terjadi badan inklusi
apoptosis
3. Hemolisis intravaskuler
McKenzie SB. Anemia caused by abnormalities in globin biosynthesis. In: Textbook of Hematology. Wiliams and Wilkins. Maryland USA. 1996.p165
GAMBARAN LABORATORIUM THALASSEMIA-β MAYOR
•Borgna-Pignatti C, Galanello R. Thalassemias and related disorders: quantitative disorders of hemoglobin synthesis. In: Greer JP, Foerster J, Lukens JN, Rodgers GM,
Paraskevas F, Glader B, editors. Wintrobe's Clinical Hematology. Philadelphia: Lippincott Williams&Wilkins; 2004. p. 1319-65..
•Takeshita K. Thalassemia beta. 2007. Diunduh dari: www.emedicine.com. Pada tanggal 15 Maret 2010.
3. Elektroforesis Hb
• Peningkatan HbF 10-90%
• HbA2 normal atau meningkat 5-7%
• HbA rendah atau tidak ada
4. Pemeriksaan untuk menegakkan diagnosis besi berlebih
• Peningkatan besi serum
• Penurunan TIBC
• Peningkatan saturasi transferin >55% (♂) dan >50% (♀)
• Peningkatan feritin serum (bila >2500 ng/mL risiko jantung
•Takeshita K. Thalassemia beta. 2007. Diunduh dari: www.emedicine.com. Pada tanggal 15 Maret 2010.
•Weatherall DJ, Cleg JB. The thalassaemia syndrome. 4th ed. London: Blackwell Science; 2001. p.686-723.
•Worwood M. Iron deficiency anaemia and iron overload. In: Lewis SM, Bain BJ, Bates J, editors. Dacie and Lewis: Practical haematology. 10th ed. Philadelphia: Churchill Livingstone-Elsevier; 2006. p. 131-60.
GAMBARAN LABORATORIUM THALASSEMIA-β INTERMEDIA
Weatherall DJ, Cleg JB. The thalassaemia syndrome. 4th ed. London: Blackwell Science; 2001. p.121-132.
•Borgna-Pignatti C, Galanello R. Thalassemia and Related Disorders: Quantitative Disorders of Hemoglobin Synthesis. In: Wintrobe's Clinical Hematology. 11 ed. Philadelphia: Lippincott Williams &
Wilkins; 2004. p. 1346
Hoffbrand A, Pettit J, Moss P. Genetic disorders of haemoglobin. In: Essential Haemotology. 4 ed. Oxford: Blackwell Sience; 2001. p. 77-80.
Diagnosis dan skrining
Flow chart diagnosis Sindroms thalasemia
MCV fl > 78 <78 <78 ≤78
MCH Pg > 27 < 27 <27 ≤27
HbA2 <3% >3,5% <3,5% <3%
HbF <1,5% 1-5% <1,5% 5-20%
THALASSAEMIA ALPHA
DEFINISI THALASSAEMIA ALPHA
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
GENETIK
1. Borgna-Pignatti C, Galanello R. Thalassemias and related disorders: Quantitative Disorders of Hemoglobin Synthesis. In: Greer JP, Foerster J,
Lukens JN, Rodgers GM, Paraskevas F, Glader B, editors. Wintrobe's Medical Hematology. 11th ed. Philadelphia: Lippincott Williams & Wilkins; 2004.
p. 1321.
2. Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem,, Buletin WHO, 2001, 79: 704-712
KLASIFIKASI THALASSAEMIA ALFA
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
http://www.med-ed.virginia.edu/courses/path/innes/images/rcdgifs/thala12
Hydrops fetalis
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
Hydrops fetalis
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
KLASIFIKASI KLINIS
Marengo-Rowe AJ, The thalassemias and related disorders, Baylor Univ med cent, 2007;20:27-31
---- Laboratorium
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
Laboratorium silent carrier:
Hb Bart‟s (γ4) pada saat lahir 1-2 %
RBC indeks normal atau MCV dan MCH sedikit menurun
dan anemia ringan
Hb A2 dan Hb F normal
Analisis rantai globin penurunan rasio α/ß dengan
rentang 0.8 – 0.9
Α Thalassemia trait
Kehilangan 2 dari 4 gen α pada kromosom yang sama atau
kromosom pasangannya.
Sering didapatkan pada daerah Mediterania, Afrika barat dan Asia
tenggara.
Asimptomatik - anemia ringan
Laboratorium:
1. Hb 10-12 g/dL, eritrosit > 5x10 6/uL, MCV 60-70 fL, MCH 20-25
pg,
2. Gambaran darah tepi mikrositik hipokrom dengan sel target
3. Ketidakseimbangan sintesis α& ß ß >> ß4 (tetrad ß /HbH
inclusion)
4. Pewarnaan BCB dikumpai badan inklusi HbH
5. Elektroforesa Hb :
Bayi : Hb Bart‟s tinggi 5-6 % (<3 bulan)
Dws : HbA2 & HbF N, rasio rantai α : β 0,7 -0,8
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
Hemoglobin H (α-Thal 1/ α-Thal 2)
http://www.med.unibs.it/~marchesi/bohr.gif&imgrefurl
Penyakit HbH
Hemoglobin H disease
Borgna-Pignatti C, Galanello R. Thalassemias and related disorders: Quantitative Disorders of Hemoglobin Synthesis. In: Greer JP,
Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Glader B, editors. Wintrobe's Medical Hematology. 11th ed. Philadelphia:
Lippincott Williams & Wilkins; 2004. p. 1329.
Hemoglobin Bart’s Hydrops fetalis syndrome
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
Chui DHK, Waye JS. Hydrops fetalis caused by α Thalssemia: an emerging Health care problem, Blood, Vol 91 No 7,
Hb Bart’s Hydrops Syndrome
Laboratorium :
Hb : 6-8 g/dL
Perubahan gross thalassemia pd eritrosit banyak
ditemukan eritrosit berinti dlm drh
Hb tdd Hb Bart‟s 80 % & Hb Portland (δ2γ2) 20 %
Infant bertahan utk mjd matur krn menghslkan Hb
embrionik
Plasenta > komplikasi toksemia kehamilan
Weatherall DJ. Hemoglobin and the inherited disorders of globin synthesis. In: Hoffbrand A, Catovsky D, Tuddenham EG, editors. Postgraduate
Haematology. Oxford: Blackwell Publishing Ltd; 2005. p. 96-9.
Hydrops fetalis
Chui DHK, Waye JS. Hydrops fetalis caused by α Thalssemia: an emerging Health care problem, Blood, Vol 91 No 7,
1998
Chui DHK, Waye JS. Hydrops fetalis caused by α Thalssemia: an emerging Health care problem, Blood, Vol 91 No 7,
1998
Patofisiologi
Weatherall DJ. Hemoglobin and the inherited disorders of globin synthesis. In: Hoffbrand A, Catovsky D, Tuddenham EG, editors.
Postgraduate Haematology. Oxford: Blackwell Publishing Ltd; 2005. p. 96-9.
Non delesi α Thalassemia
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
Borgna-Pignatti C, Galanello R. Thalassemias and related disorders: Quantitative Disorders of Hemoglobin Synthesis. In: Greer JP,
Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Glader B, editors. Wintrobe's Medical Hematology. 11th ed. Philadelphia:
Lippincott Williams & Wilkins; 2004. p. 1329.
Legoh GN, Mutasi thalassemia α pada murid Sekolah Dasar perempuan usia 10-12 tahun di kecamatan
Teluk Naga dan Kosambi (tesis), FKUI, 2007, 6-23
TERAPI
McKenzie SB, Textbook of haematology. 2nd ed. Baltimore: William & Wilkins; 1996: 172-76
Tabel perbandingan thalassemia-α
Diagnosis Genotype Morfologi Elektroforesa Rata-rata Anemia Harapan
Eritrosit sintesa globin (Hb g/dl) hidup
di retikulosit
Hb barts hidrops --/-- ↑ MCV dan MCH, Hb Bart (80%), 0:1 Berat Fatal
fetalis ↑ NRBC Hb Potland Retikulositosis (4-10)
Thalassemia-α
minor
HEMOGLOBIN VARIANS
DEFINISI
Weatherall D, Clegg J. Inherited haemoglobin disorders: an increasing global health problem. Bulletin of the World Health Organization. 2001;79:704-12.
Bunn HF. Pathogenesis and treatment of sickle cell disease. The New England Journal of Medicine. 1997;337:762-9.
Bunn HF. Pathogenesis and treatment of sickle cell disease. The New England Journal of Medicine. 1997;337:762-9.
Patofisiologi
Lal A, Vichinsky EP. Sickle cell disease. In: Hoffbrand A, Catovsky D, Tuddenham EG, editors. Postgraduate haematology.
Oxford: Blackwell Publishing; 2005. p. 104-18.
Patofisiologi
Dehidrasi Sel
Pengulangan /
pemanjangan sickling scr
progresif
Kerusakan membran
eritrosit
Dehidrasi
sel
1. Bunn HF. Pathogenesis and treatment of sickle cell disease. The New
England Journal of Medicine. 1997;337:762-9.
2. Lal A, Vichinsky EP. Sickle cell disease. In: Hoffbrand A, Catovsky D,
Tuddenham EG, editors. Postgraduate haematology. Oxford: Blackwell
Publishing; 2005. p. 104-18.
Patofisiologi
Vasooklusi
Bunn HF. Pathogenesis and treatment of sickle cell disease. The New England Journal of Medicine. 1997;337:762-9.
Akibat
vasooklusi
Mutasi sickle adenin
timin (GAG GTG) pd
kodon ke-6 gen globin β
shg mengkode
glutamin valin pd posisi
6 rantai β perubahan
stabilitas & solubilitas
molekul
Deoksigenasi polimer
HbS menyebabkan
sickling sel & kerusakan
membran eritrosit bbrp
sel sabit menempel di sel
endotel vasooklusi
Steinberg MH. Management of sickle cell disease. The
New England Journal of Medicine. 1999;340:1021-30.
Patofisiologi
Vasooklusi
Aliran drh yg lambat krn
regulasi abN irama vaskular
akibat dr berkurangnya nitric
oxide yg dirgs vasodilatasi
memperburuk viskositas drh
krn eritrosit yg dpt berubah
btk reologi abN
Vasooklusi diawali adesi
eritrosit muda & dpt berubah
btk pd endotelium vaskuler
diikuti dgn trapping oleh sel
sabit yg kaku & ireversibel
Adesi tjd dlm venula post
kapiler diawali dgn
leukositosis, aktivasi
trombosit, sitokin
1. Steinberg MH. Management of sickle cell disease. The New England Journal of Medicine. 1999;340:1021-30.
2. Lal A, Vichinsky EP. Sickle cell disease. In: Hoffbrand A, Catovsky D, Tuddenham EG, editors. Postgraduate haematology. Oxford: Blackwell Publishing; 2005. p.
104-18.
3. Hebbel RP. Blockade of Adhesion of Sickle Cells to Endothelium by Monoclonal Antibodies. The New England Journal of Medicine. 2000;342:1910-2.
Patofisiologi
Hemolisis
SCD hemolisis intra & ekstravaskuler kronik
Sickling mrgs fragmentasi membran & lisis diperantarai
komplemen menyebabkan destruksi intravaskuler
eritrosit (?)
Kerusakan membran hemolisis ekstravaskuler tjd
krn sel ab Nterperangkap atau ditangkap oleh
makrofag
Masa hdp eritrosit dihitung dgn pemeriksaan Cr51
slm 4-25 hr dgn usia hdp sel padat lbh pendek
dibandingkan eritrosit yg mengandung HbF
Pasien memiliki ekspansi ss tlg yg besar memiliki
afinitas O2 HbS EPO serum lbh rendah dgn org yg
punya Hb sama (?) krn disfungsi ginjal (?)
Lal A, Vichinsky EP. Sickle cell disease. In: Hoffbrand A, Catovsky D, Tuddenham EG, editors. Postgraduate haematology.
Oxford: Blackwell Publishing; 2005. p. 104-18.
Laboratorium :
Pemeriksaan
Hb : 6 – 10 g/dL
RDW :
Leukosit :
Trombosit :
Retikulosit : 10 – 20 %
Kimia :
Bilirubin indirek :
As urat :
LDH :
SHDT :
Eritrosit : normositik normokrom, anisopoikilositosis, sel
sabit, sel target.
Hipofungsi limpa basofilik stippling, Howell Jolly bodies,
siderosit
McKenzie SB. Anemias caused by abnormalities in globin biosynthesis. Textbook of hematology. 2nd ed. Philadelphia: Williams & Wilkins; 1996. p. 156-8.
Elektroforesis Hb :
Pemeriksaan
Pd pH 8.5 selulosa asetat Hb S 85 -100 % terlihat antara Hb A &
Hb A2
Hb F ≤ 15 % jk Hb F (25 – 35 %) Hb S heterozygous & HPFH
Hb A2 N
Hb A -
Ss tulang :
Hiperplasia eritroid (4 – 5 x dr N) kompensasi hemolisis kronik
Bl disertai def folat dijumpai megaloblastosis
Besi tp bl ada hematuria besi tdk terlihat
Tes Solubilitas
Tes konfirmasi HbS heterozigot & homozigot
HbS didptkan dr eritrosit yg dilisiskan oleh lysing agent deoksigenasi
dgn ditionin polimerisasi HbS kekeruhan
False - : anemia berat kurang keruh
False + : jk Heinz bodies ++, Hb varian, prot plasma & lipid
McKenzie SB. Anemias caused by abnormalities in globin biosynthesis. Textbook of hematology. 2nd ed. Philadelphia: Williams & Wilkins; 1996. p. 156-8.
Pemeriksaan
Tes Sickling
Tes konfirmasi HbS yg lain
Darah dideoksigenasi dgn Na Metabisulfat
diletakkan di object glass ditutup rapat kemudian
diseal dgn vaseline (fungsi : mencegah reoksigenasi)
stlh 30 menit diperiksa dgn mikroskop sel
sabit +
+ : anemia sel sabit & sickle cell trait
Lain-lain :
HPLC (high performance liquid chromatography)
McKenzie SB. Anemias caused by abnormalities in globin biosynthesis. Textbook of hematology. 2nd ed. Philadelphia: Williams & Wilkins; 1996. p. 156-8.
Analisa DNA
Hemoglobin E Disease
Hb varian terbanyak di Asia tenggara &
Hb varian kedua terbanyak di seluruh dunia (no.1 HbS)
Hemoglobin E (β26 GluLys)
Hemoglobin E Trait
Heterozigot HbE (HbAE)
Carier, asimtomatik.
Dgn/tanpa anemia / tdk ada retikulositosis
SHDT: mikrositosis (MCV ± 65 fL), MCH ↓, sel target,
bassofilik stippling, eritrositosis ringan.
Elektroforesis Hb : 25-35 % HbE
Lukens JN. Hereditary Disorders of Hemoglobin Structure and Syntesis. In: Greer JP, Rodgers GM, Foerster J, Paraskevas F, Lukens JN, Glader
B, editors. In:Wintrobe's clinical hematology. 2 ed. Phiadelphia: Lippincott Wiliams & Wilkins. 2004. p. 1247-62..
Hemoglobin E Disease
Homozigot HbEE
Klinis:
Hanya splenomegali ringan.
anemia ringan
Lab:
SHDT: mikrositosis (MCV ± 55-65 fL), MCH↓, basofilic
stippling, sel target (++).
tdk ada retikulositosis
Elektroforesis Hb : HbE = 85-95 %,
(Hb E + Hb A2) = 95-99%*
Lukens JN. Hereditary Disorders of Hemoglobin Structure and Syntesis. In: Greer JP, Rodgers GM, Foerster J, Paraskevas F, Lukens JN, Glader
B, editors. In:Wintrobe's clinical hematology. 2 ed. Phiadelphia: Lippincott Wiliams & Wilkins. 2004. p. 1247-62..
* Bachir D. Galacteros F. Hemoglobin E. In: Orphanet Encyclopedia. 2004: p.1-4.
Hemoglobin E/Thalassemia β
HbE trait + thal β0/thal β+
Banyak di thailand, di Asia tenggara tersebar dari
Indonesia sampai Srilanka, India timur laut dan
Bagladesh.
Klinis
Bervariasi: thal β minor – intermedia - mayor
Gejala berat: hepatosplenomegali, jaundice berulang,
gangguan pertumbuhan, ekspansi sstlg deformitas
muka, ggn petumbuhan gigi,
HbE/HbS
Gen ΒS & βE
anemia hemolitik kronik ringan (mirip SCD),
vasooklusi jarang tjd.
Hb N / ↓ = 9-14 g/dL
Retikulosit ↑ ringan
SHDT: mikrositik (MCV ↓), sel target, sel sickle
jarang,
Elektroforesa: HbE (65%), HbF N/↑ ringan
Th/ bandingkan dgn HbS
* Bachir D. Galacteros F. Hemoglobin E. In: Orphanet Encyclopedia. 2004: p.1-4.