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Bone marrow stromal cells

Stemcells
Definisi klasik dari sel induk mengharuskan sel itu
memiliki dua sifat:
Pembaharuan diri

Kemampuan untuk melewati berbagai siklus pembelahan sel


dengan tetap menjaga status tidak berdifferensiasi.

Potensi
Kemampuan untuk berdiferensiasi menjadi jenis sel khusus,
dalam hal ini menjadi sel induk baik totipotent atau
pluripotent
Mampu menjadi berbagai jenis sel matang, meskipun
progenitor (leluhur) unipotent atau multipotent ini kadangkadang disebut sebagai sel punca (stemcells) juga.

Potency definitions
Sel induk Totipotent/omnipotent (mahamampu) dapat

berdiferensiasi menjadi sel embrionik dan ekstraembrionik.

Sel-sel tersebut dapat membuat organisme hidup lengkap.


Sel-sel ini dihasilkan akibat fusi dari sel telur dan sperma.
Sel-sel yang dihasilkan pada beberapa pembelahan pertama dari
telur dibuahi dapat juga totipotent.
Sel induk Pluripotent merupakan keturunan dari sel totipotent

dan dapat berdifferensiasi ke dalam hampir semua sel, yaitu sel


yang berasal dari salah satu dari tiga lapisan germinal
(endoderm, mesoderm, dan ectoderm).
Sel induk Multipotent dapat berdifferensiasi menjadi berbagai
sel, tetapi hanya dari keluarga (clone) sel yang berhubungan
erat.
Oligopotent stem cell dapat berdifferensiasi hanya ke dalam
beberapa sel, seperti sel induk limfoid atau myeloid.
Unipotent stem cell dapat menghasilkan hanya satu jenis sel
sendiri, tetapi memiliki sifat dapat memperbaharui diri yang
membedakannya dari non-stem sel (misalnya sel induk otot).

Omnipotent stemcells

Pluripotent stemcells

Endoderm

Mesoderm

Multiipotent stemcells

Hematopoeitic
(Progenitor)
stemcells

Oligopotent stemcells

CFU GEMM

CFU-Ba
CFU-Eo

CFU-M

Ectoderm
Mesenchymal
(Progenitor)
stemcells

CFU-L

Connective
tissue stemcells

BFU-E
BFU-Meg

CFU-G
Unipotent stemcells

Bone, Adipose, Muscle

Petanda hierarchy hemopoietic

Hematopoeitic progenitors (leluhur) :

Hematopoeitic precursor (awalan) :

CD34+CD10+CD3+

Early Bcells

CD34+TdT+CD10+/-

Early Tcells

lin-SCA-1-c-kit+CD34+CD33+CD16/32low

Common Lymphocyte precursor (CFU L)

lin-SCA-1-c-kit+CD34+CD33+CD16/32hi

Megakaryocyte-erythroid progenitor (MEP/CFC E-MK) :

lin-SCA-1-c-kit+CD34+CD33+

Granulocyte-macrophage progenitor (GMP/CFC GM) :

CD34+CD124+

Common myeloid progenitor (CMP/ CFU GEMM) :

CD7+CD117+CD164+

CD34+CD10+CD9+

Early NKcells

CD34+CD10+CD3-CD56+
TdT=terminal deoxynucleotidyl transferase, nuclear markers

Hematopoiesis
Multipotent stem cells
GM-CSF

Erythrocyte

Visible Hb

Maturasi

BFU Meg

CFC M

CFC Meg

IL-6

IL-8

IL-2

CFC G
GM-CSF

IL-4

CFC TL

IL-6

IL-4

CFC BL
IL-2

Monoblast

T Lymphoblast B

Myeloblast
IL-2

Promonocyte Promyelocyte

IL-8

Megakaryocyte

Myelocyte

Metamyelocyte
Band

Monocyte

LAK

IL-4

T Immunoblast

IL-12

IL-11
Thrombocyte

Pro B

B Centroblast

B Immunoblast

T cell

IL-6

Polychromatophylic

Reticulocyte

IL-6

Mega
karyoblast

IL-2

IL-6

Erythroblast :
Basophylic
Polychromatophylic

MGDF

EPO

Proerythroblast

CFU L

IL-1 IL-2

CFC GM

Pro Megakaryoblast

Hemocytoblast

INF

IL-2

CFC E

IL-3

IL-6

BFU E

IL-1 IL-6

GM-CSF
IL-6

MGDF, TPO

CFC E-MK

EPO

Proliferasi dan Maturasi

CFU GEMM
GM-CSF

IL-4
Centrocyte

Segmen
Lymphoplasmacytoid

Plasma cell

B cell

NK

Erythropoiesis
Time to circulation of
red blood cells from
Stem cell in BM have
app.120 days
2.3 million red blood
cells produced every
second in human bone
marrow
138 million every minute
18.4 billion between
now and lunch-time!
Main regulator is
erythropoietin (EPO)

Erythropoiesis: Growth Factors


___________SCF____________
___________ IL-11___________
______________ IL-3___________________________
______G-CSF _____ _______ GM-CSF_______
_______IL-6_______ _______IL-4_______
_________EPO_________
_______IL-9_______

Quiescent
stem cell

Activated
stem cell

BFU-E

CFU-E

Erythrocyte

SCF = stem cell factor; IL = interleukin; G-CSF = granulocyte colony-stimulating factor;


GM = granulocyte - monocyte colony-stimulating factor; EPO = erythropoietin;
BFU-E = blast-forming units-erythroid; CFU-E = colony-forming units-erythroid

Gabrilove (2000)

Erythropoeisis differentiation
Hemocytoblast (Blast)
Pronormoblast also commonly called

Proerythroblast.
basophilic normoblast also commonly
called basophilic erythroblast
polychromatophilic normoblast or
polychromatophilic erythroblast
orthochromatic normoblast or
polychromatophilic erythrocyte or
eosinophilic erythroblast; Nucleus is
Expelled before becoming a reticulocyte
Reticulocyte
Erythrocyte
7 days

Mechanism of action of EPO


Increase in total RNA synthesis
Increase Transferrin receptors expression Increase iron

uptake
Increase Heme synthesis
Increase rate of transcription of a and b-globin gene
Increase Hemoglobin synthesis

In absence of EPO
Decrease Fe influx into the cells
Decrease synthesis of cytochromes, catalase, peroxidase
Rapid DNA cleavage apoptosis

IRON ABSORPTION

Ferrokinetik masuknya besi ke dalam sel/jaringan

Fe+3
Ferri

Fe+2

Ferro

DCyt-b

DMT1

TFR2
NTBI

Ferritin

TFR1

Fe
Heme

Ferroportin

Hepaestin

Ferro

Ferri
Fe-transferin (TBI)
SI

Ferritin

Hemosiderin

cytochrome
Apoferritin

TFR1 TBI
TFR2 NTBI

Apotransferin

Ferrokinetik masuknya besi ke dalam plasma

Ferrokinetik
Duodenal
lumen

Duodenal
mucosa
b2 integrin

Fe+3

Paraferritin
DCyt-b
Fe+2
DMT1
Fe+2

Fe-transferin
Fe+3T

Fe+3

TFR

Fe+3
Fe+2

Hepaestin
Ferroportin

Tissue/Cells

Plasma

Fe+2
Ferritin
Hepcidin

Ferritin
Hemosiderin
Ferroportin

Status besi
iron depletion disebabkan karena simpanan

ferritin rendah. Feritin merupakan protein


mengandung besi yang terutama
bertanggung jawab untuk penyimpanan zat
besi dalam sumsum tulang.
Iron deficient disebabkan karena zat besi
dalam serum yang rendah menyebabkan
simpanan feritin rendah.
Anemia deficiensi besi adalah anemia yang
disebabkan rendahnya simpanan feritin.

Cellular organel in erythrocytes


lose all cellular organelles
Nuclei
Mitochondria, Ribosome
Golgi apparatus and
Endoplasmic reticulum.
Because of the lack of nuclei and organelles, mature

red blood cells do not contain DNA and cannot


synthesize any RNA, and consequently cannot divide
and have limited repair capabilities.
As a result of not containing mitochondria,

instead they produce the energy carrier ATP by lactic acid


fermentation of glucose.

Hemoglobin

Fe

Heme

Globin chain synthesis


a cluster chromosome 16
z

a2

a1
z2e2

Gower 1

z2g2

Portland

a2e2

Gower II

a2g2

a2d2

A2

a2b2
Gg Ag
e
d
b
b cluster - chromosome 11

Embryonic

Fetal

<2.5%

1.5-3.5%
Adult

>95%

Hemoglobin
Normal:

Foetal:

Hb F mengandung 2 pasang rantai a dan g (N > 95%), dan


Hb A2 mengandung 2 pasang rantai a dan d (N < 5%)

Dewasa:

Rantai g Hb F (ag ag) diganti b Hb A1(ab ab)


Hb F mengandung 2 pasang rantai a dan g (N < 2.5 %)
Hb A1 mengandung 2 pasang rantai a dan b (N > 95%)
Hb A2 mengandung 2 pasang rantai a dan d (N < 3.5%)

Intracellular site
protein (globins)
product
B=babies
A=adult

g
B

g
A

Fe

Fe

Fe

Heme

Heme

Heme

HbF

HbA2

HbA1

Hemoglobin
Genotype involvements normal globin

Hb F
Hb A2
Hb A1

: ag ag
: ad ad
: ab ab

DNA inti mRNA Ribosome Globin


DNA Mitochondria mRNA Ribosome Heme

Cytosol Heme + Globin Hemoglobin


Fungsi globin dalam hemoglobin:

Mengikat oksigen
Fe

Fe

Fe

Heme

Heme

Heme

HbF

HbA2

HbA1

a
a

a
a

b
d
g

b
d
g

Heme synthesis

Definisi anemia
Keadaan dimana kadar

hemoglobin lebih dari 10% dibawah


rerata nilai normal
WHO:
Pria

< 13 gr%,
Wanita < 12 gr%, dan
Kehamilan 10 gr%.

WHO's Hemoglobin used to


define anemia
Age or gender group
Children (0.55.0 yrs)
Children (512 yrs)

Hb (g/dl) Hb (mmol/l)
11.0
6.8
11.5
7.1

Teens (1215 yrs)


Women, non-pregnant (>15yrs)
Women, pregnant
Men (>15yrs)

12.0
12.0
11.0
13.0

7.4
7.4
6.8
8.1

1 g/dL = 0.6206 mmol/L

Grading anemia
Hb
Ringan (mild)

10 g/dL

Sedang (moderate)
Nyata (marked)
Berat (severe)

8 <10 g/dL
6 <8 g/dL
< 6 g/dL

Digunakan dalam diagnostik laboratorium sebagai research cutoff


Tidak dapat digunakan untuk batasan diagnostik klinis

Gejala umum dan khusus anemia


Symptom

System/organ

Mekanisme

End arteries
Jantung
Respiratory
Neuromuscular
Hearing
Sighting

Penurunan
kapasitas
angkut oksigen

Menorhagia, Polymenorhagia
Melena, hematoschezia
Epistaksis
Gusi berdarah

Haid
Feses
Hidung
Mulut

Perdarahan

Hypertrophy ginggiva, papilla (B6, B12, Folat)


Glossitis, hypotrophy papilla (Fe deficient)
Angina Vincent/dysphagia (Fe deficient)

Tongue
Tongue
Pharinx

Atropi-Nekrosis
Ulkus Mucosa

Kaki/Tangan

Neuritis

Urin

Hemolisis
Intravascular

Urin
Limpa

Hemolisis
Extravascular

Hati dan limpa

Extramedullar
hemopoesis

Pale (vasoconstriction)
Tachycardia, systolic ejection murmur, Forth gallop
Tachypneu, Exertional dyspneu
Faintness, Lack of concentration,
Tinnitus (ischemic)
Scotoma (edema papil)

Foot/Hand gloves periveral neuropathy (B12 deficient)


Hemoglobinuria: Reddish urine (PNH, DD/hematuria)
Hemosiderinuria: Blackish urine (Black water fever, Malaria)
Urobilinogenuria with/without Brownish urine (bilirubinuria)
Splenomegali
Hepato-splenomegali

Klasifikasi dan terminologi anemia


I.

Gangguan Produksi SDM


a. Proliferasi dan pematangan
1)
2)
3)
4)
5)

Inti Makrositik
Sitoplasma Mikrositik hipokrom
Defisiensi eritropoietin
Defisiensi ACTH
Defisiensi protein

b. Infiltrasi sel non eritroid kedalam sumsum tulang


c. Aplastik
II. Penghancuran SDM
a. Defect corpuscular:
1) Defisiensi enzim eritrosit:
2) Thalasemia
3) Hemoglobinopati

b. Defect extracorpuscular
III. Perdarahan

Gangguan Produksi SDM


1. Gangguan Proliferasi dan pematangan
a.

Inti (Makrositik):
1) Normal megaloblastik:

Defisiensi: B12, Asam folat, Vit.A, Vit.C, Cuprum

2) Abnormal megaloblastik:

b.

Sitoplasma (Mikrositik hipokrom):

c.

e.

Defisiensi Fe, def. Transferin (Protein transport)


Gangguan utilisasi Fe (MDS)
Gangguan re-utilisasi Fe (ACD, Thalasemia mayor)

Defisiensi eritropoietin

d.

Sindroma mielodisplasia (MDS)


Eritrolekemia (AML-M6)

Renal disease

Defisiensi ACTH
Defisiensi protein

Gangguan Produksi SDM


(lanjutan)
2. Infiltrasi sel non eritroid kedalam sumsum tulang

fibrosis, kanker, dll

3. Aplastik

Pure red cell aplasia (PRCA, e.g. thymoma)

Antibody erythropoietin
Antibody erythropoietin receptors

Hypoplastik marrow (Anemia aplastik)

Penghancuran SDM
a. Defect corpuscular:
1. Defect membrane
a. Congenital
a. Erythropoietic Porphyria Congenital
b. Elliptocytosis herediter
c. Spherocytosis herediter (congenital hemolytic jaundice)

b. Didapat
a. Stomacytosis
b. Hypophosphatemia

2. Defisiensi enzim eritrosit congenital


a. Pyruvate kinase deficient (< 13 mg/gHb)
Autosom recessive

b. Defisiensi G6PD (< 5 mg/gHb)


X linked

3. Defect synthesis Globin


a. Thalasemia
b. Hemoglobinopati

Penghancuran SDM
(lanjutan)
b. Defect extracorpuscular
1.
2.
3.
4.

Hypersplenism
Immune hemolysis (AIHA, SLE, APS, PCH)
Complement sensitivated (PNH)
Mekanik: Penurunan shear rate
a. Sistemik: CHF
b. Partial luas: TTP, KID, Vasculitis, Hemangioma, dll.

5. Toksin:
a. Obat-obatan: Sulfonamida, dll.
b. Metabolit: Uremia (HUS), Cyclosporin, dll.
c. Zat kimia: Bahan pewarna (Anilin), dll.

6. Infeksi:
a. Parasit: Malaria, Toxoplasma, dll.
b. Virus: CMV, Mycoplasma pnemoniae, Parvovirus, dll.

Penggolongan menurut
Morfologi volumetrik
Mikrositik
hipokrom
MCV < 80 fL
MCH 27 pg
MCHC 32-36 g/dL

Normositik
Makrositik
normokrom
80 100 fL
> 27 pg
32-36 g/dL

MCV= (Ht/Eritosit)x10 fL
MCH=(Hb/Eritrosit)x10 pg
MCHC=(Hb/Ht)x100 g/dL

> 100 fL
> 27 pg
32-36 g/dL

Anemia mikrositik hipokrom


Diagnostik:
Rerata volume eritrosit (VER) < 80 fL dan/atau
Rerata konsentrasi hemoglobin (HER) 27
pg/dL.
Penyebab:
Ineffective metabolisme besi.
Hambatan pasokan, transport,

defisiensi enzim, dsb

Pembentukan hemoglobin abnormal:

hemoglobinopati,

Retikulosit
Rasio retikulosit =

Hitung Retikulosit
x
Hitung Eritrosit

1000

Indeks/koreksi retikulosit (Normal: 5-15 .);


Ht
Pria
: 42 x Rasio retikulosit
Wanita
: Ht x Rasio retikulosit
39

Hb

Ht

18
17
16
15
14
13
12
11
10

54
51
48
45
42
39
36
33
30

Rasio Retikulosit ()
Pria
Wanita
4.0 11.8
3.6 11.0
4.2 12.5
3.9 11.7
4.4 13.2
4.1 12.4
4.7 14.1
4.4 13.1
5.0 15.0
4.7 14.0
5.4 16.1
5.0 15.0
5.8 17.3
5.4 16.2
6.3 18.8
5.8 17.5
6.8 20.5
6.4 19.1

Reticulocyte production index


4.5

RPI =

Corrected reticulocyte
Maturation time

Maturarion (Days)

4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0

20

40

Hematocrit (%)

60

Mentzer index
MI MCV
E
12
MCV<80fL

26

Thalasemia trait Def.Fe; Reutilisasi Fe

Utilisasi Fe

26
MCV80fL

Def.Fe; Reutilisasi Fe

Utilisasi Fe

FLOW CHART ANEMIA MIKROSITIK HIPOKROM


Anemia
MCV<80fl &/or MCH 27 pg/dL

Indeks retikulosit <10

Indeks retikulosit 10-15

SI/IBC, Transferin, Feritin

Normal/Tinggi

BMP

Defisiensi Fe

Indeks retikulosit >15

Elektroforesis hemoglobin

Normal

Abnormal

Dalam terapi Fe ?

Hemoglobinopati

Pasokan, Absorpsi ?
Hemolitik ?
Gangguan metabolisme Fe
Mielodisplasia (MDS)
Anemia of Chronic Diseases (ACD)

Thalasemia

Anemia Defisiensi Besi


Serum feritin <30 ng/mL, atau

Indeks saturasi transferin (IST)< 15%

(syarat: TIBC within normal limit)


SI
IST
* 100%
TIBC

Normal limit:
SI
50 -150 mg/dL
IBC
250-410 mg/dL
Serum feritin 20-200 ng/mL,
excess >400 ng/mL

Defisiensi Besi, dan Transferin


Defisiensi besi ringan

Serum iron 50 mg/dL


Indeks saturasi transferin (IST) 15%
IBC within normal limit or transferin within normal
Serum feritin < 20 ng/mL.

Defisiensi besi berat

Serum iron <50 mg/dL


Indeks saturasi transferin (IST) 15%
IBC within normal limit or transferin within normal limit
Serum feritin < 20 ng/mL.

Defisiensi transferin ringan

Serum iron 50 mg/dL


Indeks saturasi transferin (IST) >15%
IBC below normal limit or transferin below normal limit
Serum feritin 20 ng/mL.

Defisiensi transferin berat

Serum iron < 50 mg/dL


Indeks saturasi transferin (IST) >15%
IBC below normal limit or transferin below normal limit
Serum feritin 20 ng/mL.

IST

SI
* 100%
TIBC

Koreksi defisiensi besi serum


Untuk menaikkan Hb sebesar 1 gr/dL dibutuhkan

Fe endogen 2,5 mg/kgBB


Kebutuhan initial Fe:

Fe = (D Kadar Fe serum x 0,2 x BB) mg, atau


Fe = (D Hb x 2,5 x BB) mg

Iron Dextran max. 1,5 mg/kgBB/day


Jectofer 75 mg/2mL amp.
Cara 75 mg/deep im
Iron Sucrose
Venofer 100 mg/amp
Cara infusi 100 mg in 100cc NS 1jam

soluble transferrin receptor (sTFR) normal 1.8-4.6

Anemia tersering pada kehamilan


Makrositer (Normal Megaloblastik) akibat

defisiensi asam folat,

Suplemen asam folat 0,4 mg/hari dan


Suplemen vitamin B12 50 mg/hari mulai sejak
awal kehamilan.

Mikrositik hipokrom akibat defisiensi Fe,


Suplemen Fe 30-60 mg/hari mulai kehamilan
18-20 minggu.

Anemia makrositer
Diagnostik: MCV > 100 fL
Penyebab:
Ineffective metabolisme vitamin B12
dan/atau asam folat.
Hambatan:
Pasokan vit.B12 dan/atau asam folat,
Transport vit.B12 dan/atau asam folat, atau
Pengikatan vit.B12 dan/atau asam folat
oleh reseptornya (Defisiensi enzim).

FLOW CHART ANEMIA MAKROSITER


Anemia

MCV > 100 fl

Indeks retikulosit <10

Indeks retikulosit 10-15

Kadar B12 & Folat

Defisiensi Folat

Defisiensi B12

Analisis gizi

Schilling test

Baik

Kurang

Malabsorpsi

Perdarahan/Hemolisis ?

Normal

Terkoreksi

Tidak terkoreksi

Def. Intrinsik

Malabsorpsi

Inapropriate diet

Indeks retikulosit >15

TIDAK

YA

BMP

Megaloblastik

Cincin sideroblastik

Non Megaloblastik

Related increasing epo


Kongenital/Obat

Uji Schilling untuk defisiensi B12

Tes tahap Tes tahap


pertama
ke-dua

Normal
< 5%
< 5%

Normal
<5%

Diagnosis

Normal atau defisiensi B12


Anemia Perniciosa
Malabsorpsi

Tes dengan memberikan B12 terlabel cobalt (57Co atau 58Co)


per-oral, penilaian melalui ekskresi B12 isotop urin, Tes tahap
pertama sebelum pemberian GIF (Gaster Intrinsic factor), Tes
tahap ke-2 setelah pemberian GIF.

Algoritma untuk evaluasi anemia makrositik

(MMA = methylmalonic acid; Hcy=Homosistein; B9=folat, n=normal.)

FLOW CHART ANEMIA NORMOSITIK NORMOKROM


Anemia
MCV 80-100 fL and MCH > 27 pg/dL

Indeks retikulosit 10-15

Indeks retikulosit <10

Abnormal
Hambatan
Produksi/Pematangan

Indeks retikulosit >15

Kehilangan/Penghancuran Berlebihan
Periksa: Bilirubin indirek, LDH

BMP

Normal
Anemia hemolitik/def.Fe
dalam terapi ?
Periksa ACTH

Normal

Tinggi

Perdarahan ?

Anemia Hemolitik

Tidak

Ya

Periksa urin

Infiltrasi Keganasan
Hipoplasia SSTL
Cincin sideroblastik ?

Negatif

Positif Hb/
hemosiderin

Hemolisis
Ekstravaskular

Hemolisis
Intravaskular

Tes coombs, C3/C4


Anti dsDNA

Positif
AIHA Primer or Secunder
Negatif
Defect Intra corpuscular

Defect Extra corpuscular


Mekanik, Toksin, Infeksi

Anemia normositik normokrom


Diagnostik:
MCV

80-100 fL dan
MCH > 27 pg
Penyebab:
Kegagalan

distribusi.
Hambatan produksi,
Kehilangan/Destruksi berlebihan.

Anemia Hemolitik Auto Immun


Primer: Idiopatik
Sekunder:
Terjadi akibat adanya kelainan/ penyakit lain seperti:
Induksi obat atau bahan kimia
Kelainan limfoproliferatif
Kanker
Infeksi (HIV, Mycoplasma pnemoniae, Parvovirus, dll)
Penyakit Autoimmun lain (SLE, APS, dll)

Kriteria Diagnosis AHAI


Direct Coombs test positif (C3b &/ anti IgG pada eritrosit).
Perexclusionam menyingkirkan kemungkinan AHAI sekunder:

Anamnesis obat-obatan, alkohol, bahan kimia (Occupational


disease), adakah keganasan ?,
Pemeriksaan serologi virus dan bakteria misalnya Dengue, CMF,
EBV, HIV, Rubella,
Pemeriksaan ACA untuk mengetahui adanya Sindroma Anti
Fosfolipid (APS),
Pemeriksaan Rematoserologi, C3 dan C4, ANA, Anti dsDNA
(Penyakit Auto Immun),
Pemeriksaan combs apakah ada IgG/IgM atau C3b pada
eritrosit dan/atau antibody terhadap eritrosit, jenis reaktifitas
cold type jika bereaksi pada suhu 20oC
Pemeriksaan sidikan hati, limpa, KGB mediastinum dan para
aorta (Limfoma Non Hodgkins),
Pemeriksaan Immunoelektroforesis protein (Penyakit proliferasi
sel B limfosit atau plasma),
BMP Aspirasi dan Biopsi untuk menilai adanya Penyakit
limfoproliferasi non sekretorik.

Defect corpuscular
Defisiensi enzim eritrosit (G6PD, dll)
Pemeriksaan yang diperlukan:

Pemeriksaan enzim G6PD or GSH eritrosit intrasel.

Hemoglobinopati
Thalasemia, Sickel cels anemia, dll
Pemeriksaan yang diperlukan:

Morfologi mikroskopik eritrosit,


Pemeriksaan Sugar Water Test (SWT), dan
Elektroforesis Hb.

Herediter sferositosis
Pemeriksaan yang diperlukan:

Morfologi mikroskopik eritrosit, dan


Resistensi osmotik.

Defect corpuscular
PNH
Pemeriksaan yang diperlukan:

Pemeriksaan Hb urin pada urin pagi pertama dan


Acid test (HAM).

Porfiria
Pemeriksaan yang diperlukan:

Pemeriksaan Porfirin,
Pemeriksaa Fosfatidil-inositol.

Interpretation of CD55 and CD59 Results in


RBCs and Granulocytes (WBCs)
Results

Interpretation

<3% RBCs and WBCs deficient in Normal; consistent with


CD55 and CD59
absence of PNH
3-7% RBCs deficient in CD55
and/or CD59 and
<3% WBCs deficient in CD55 and
CD59

Normal, consistent with


absence of PNH

3-7% RBCs and WBCs deficient


in CD55 and CD59

Equivocal; repeat testing on


new sample recommended

>7% RBCs and WBCs deficient in Abnormal; consistent with


CD55 and CD59
presence of PNH

Defect Extra corpuscular


Manifestasi dapat:
Tanpa atau disertai AHAI.
Tanpa atau disertai Defect Intracorpuscular.
Penyebab:
Mekanik:

Toksik:

Obat-obatan: Sulfonamida, dll.

Metabolit:

Penurunan shear rate sistemik (CHF) atau


Penurunan shear rate partial luas (TTP, KID, vaskulitis,
hemangioma, dll)

Sindroma Hemolitik Uremik (Gagal ginjal),


Siklosporin, dll.

Zat kimia: Bahan pewarna (Anilin), dll.


Infeksi mengenai eritrosit:

Parasit: Malaria, Toxoplasma dll,


Virus: CMV, Mycoplasma pnemoniae, Parvovirus dll.

Thalassemia
Heterogenous group of disorders due to an

imbalance of a, d and b globin chain synthesis

a thalassemia: a globin chain production decreased


b thalassemia: b globin chain production decreased

The globin chains that are produced are normal


Quantitative deficiency:
bo thalassemia: No b-globin chain is made
b thalassemia: decreased b-globin chain is made
With 4 a genes and 2 b genes there is wide

phenotypic variation

Thalasemia
Thalasemia a : kegagalan produksi globin rantai a
Thalasemia a: Present Hb H or Barts
Single gene
Genotype Hb Barts : gg ag
Double gene
Genotype Hb H
: bb ab
Triple gene
Thalasemia b: kegagalan produksi globin rantai b
Heterozygot: defect gene b(allele) single haploid
Homozygotes: defect gene b(allele) diploid
Thalasemia bd: defect gene b dan d
Heterozygot: defect gene b and d (allele) single haploid
Homozygotes: defect gene b and d (allele) diploid

Alpha Thalassemia
Inadequate production of alpha chains
Hemoglobin analysis normal; can be detected by a globin gene

analysis
Absence of 1-2 alpha chains

Common
Asymptomatic
Does not require therapy

Absence of 3 alpha chains

Microcytic anemia (Hgb 7-10)


Splenomegaly

Absence of 4 alpha chains

Hydrops fetalis (non-viable)

Treatment of alpha thalassemia may include:

daily doses of folic acid


blood transfusions (as needed)
surgical removal of the spleen (if necessary).

b b
d d
g g

q 11

q 16

a a
a

a
a

Triple gene deletion

a a
a a

Double gene deletion

Hb F : ag ag
Hb A2 : ad ad
Hb A1 : ab ab

Single gene deletion

Genotype globins
a

d
g

b
d
g

bd Homozygote

d
g

bd Heterozygote

b
d d
g g

b Homozygote

b Heterozygote

Intracellular site
protein
(globins)
product
B=babies
A=adult

g
B

g
A

Globin abnormal
Abnormal hemoglobin:

Thalasemia
Insufficient of normal globin
Hb Barts (ggag)
Hb H (bbab).

Hemoglobinopati
Changes amino acid in
normal globin

Hb C,
Hb D,
Hb E,
Hb G,
Hb S, sickle cell
Hb variant

Thalasemia
Delesi

Anemia

HbF HbA2 other

b Heterozygote

Ringan

< 5%

> 3.5%

b Homozygote

Sedang-Berat > 85%

> 3.5%

bd Heterozygote

Ringan

bd Homozygote

Sedang-Berat 100 %

a single gene

Non

a double gene
a triple gene

> 5%

< 1%
Absent

Ringan

< 0.5%

< 2.5%

Sedang

< 0.5%

< 2.5%

HbH

Mix a*bHeterozygote Sedang

<0.5%

>3%

HbBart

* Triple gene a deletion

Clinical form
Thalasemia a
Silent carrier (no hematologic or clinical symptom)
Trait
HbH disease
Unusual form
Thalasemia a MDS
Thalasemia a and Mental retardation syndromes
Thalasemia a Associated with Structural Variants

Beta Thalassemia
Inadequate production of b chains
Clinical
Syndrome

Minor / Minima
Intermedia
Major

Genotype

Hemoglobin (g/dl)

b+/b or b+/b
b/b
b/b or b/b

10-13
7-10
<7

Clinical form
Thalasemia b
Mayor (Homo/Heterozygote) :
Transfusion dependent anemia

Intermedia (Homo/Heterozygote) :
Transfusion Independent anemia
Minor (Heterozygote) :
Asymptomatic
Minima (Heterozygote) :
Silent carrier (no hematologic or clinical symptom)

Dampak thalasemia pada


kehamilan
Fetal hanya membentuk:
Hb F mengandung 2 pasang rantai a dan g (N > 95%),
Hb A2 mengandung 2 pasang rantai a dan
Thalasemia a
agag; aa; gggg; gg;

Single genes
Double genes
Triple genes
Homozygotes

+++ +++
++ ++

+
+

+
++
+++

++
+
++ ++
+++ +++

Erythroblastosis foetalis
Hemolytic anemia of the foetus
Frequently caused by transplacental transmission of
maternal antibody

Immunogenisitas Eritrosit
ABO & Rhesus
Eritrosit
Reagen
Ab-A Ab-B

Serum
Ag

Reagen
Ag-A Ag-B

Ab

Blood
Type
ABO

None

A&B

A &B

None

AB

Ab-Rho

Ag-Rho

Rhesus

Rho

None

Rh+

None

Rho+

Rh-

Antibodi dan antigen eritrosit


Antibody

Antigen

A and B

None

Rho(C,c,D,E,e)

None

None

Rho(C,c,D,E,e)

Kell (K)

None

Duffy (Fy)

None

hr (c,e)

None

IgG labeled

C3d labeled

Blood type
B
A
O
Rh Rh+
K Fy hrc,e -

Rhesus genotypes
Genotype

symbol

Rh(D) status

Anti D

cde/cde

rr

Negative

Positive

CDe/cde

R1 r (heterozygous CD) Positive (heterozygous D) Negative

CDe/CDe R1R1 (homozygous CD) Positive (homozygous D) Negative


cDE/cde

R2 r (heterozygous DE) Positive (heterozygous D) Negative

CDe/cDE

R1R2 (homozygous D)

Positive (homozygous D) Negative

cDE/cDE

R2R2 (homozygous D)

Positive (homozygous D) Negative

Amniocentesis diagnostic probability for


Erythroblastosis foetalis Risk
Spectrophotometric

analysis of amniotic
fluid was routinely
performed to detect the
presence and severity
of fetal hemolysis and
anemia
Risk IgG anti D titers >
1/16

Incompatibilitas ABO & Rhesus


(erythroblastosis foetalis)
Transfusi darah

Ibu & Janin

Resepien
Donor O A

AB

Janin
AB

-/+ -/+ -/+

AB

AB

Rh+

Rh-

Rh+

Rh-

-/+

Antibodi: Donor
Antigen: Donor

Ibu O A

Resepien
Resepien

Rh+

Rh-

Rh+

-/+

Rh-

Antibodi: Ibu
Antibodi: Janin

Janin
Ibu

Program kelasi besi


Target feritin serum <1000 ng/mL.
Desferroxamine (Desferal vial 500 mg); for
im (max.adult 2gr, child 1gr), or
sc slow continuous infusion over 12h at night
iv infusion max.rate 15 mg/kgBW/h
Starting dose 500 mg increasing until 24h of

iron urin excression has plateau.


Kadar Feritin
Daily dose
< 2000
25mg/kgBW
2000-3000
35 mg/kgBW
>3000
40 mg/kgBW

Kelasi besi oral


Setelah penambahan PRC sebanyak 4000mL (20 bag) pada

feritin > 1000 mcg/L


Deferasirox
Doses not exceed 30mg/kgBW
By tailoring start 5mg/kg or 10mg/kg
Excretion via bile
Tab 125mg, 250mg, 500mg
Deferipront
Doses depend on feritin level
Excretion via urine
Tab 250mg, 500mg
Target Feritin <1000 mcg/L

Potentiation chelatable DFO


Vitamin C
Recommended

only in patient with not


affected by myocardiopathy
50 mg/day for <10 yrs old
100 mg/day for 10 yrs old

Anemia aplastik
Anemia
Low

reticulocyte (< 20,000/l or corrected


<1.5%)

Low white blood cells (<4000/l, or Low

platelets count (<100,000/l)

Staging
SAA
Hypocellular marrow: BM cellularity <25%, or 2550% with
<30% residual haemopoietic cells*, with
Two out of three criteria:

PMN< 500 / l
PLATELET COUNT < 20,000 / l
RETICULOCYTE COUNT < 1 % or < 20,000 / l

vSAA
SAA dengan PMN < 200/l

Moderate AA (NSAA)
Hypocellular marrow
Non SAA

Staging Aplastic Anemia

Gene function
(Suppressor genes)
Protein/Amino acid

(Proto-oncogenes)
Control
Protein/Amino acid

Inducers
Hyperplasia:
Control proliferation
Inducers proliferation
Hypoplasia:
Control proliferation
Inducers proliferation

Cells Proliferation
Cells Differentiation

Kanker
Sel kanker

Sel yang sifat pertumbuhannya berubah menjadi


tak terkendali
Onkogen
Gen

sel tumor
Muasal
Proto-onkogen: gen yang akan mengalami penambahan
atau relokasi material genetik (amplifikasi).
Gen supresor tumor atau gen anti tumor: gen yang akan
mengalami kehilangan material genetiknya (LOH).

Fungsi

Produk proteinnya akan mengendalikan pertumbuhan


(maturasi dan differensiasi) dan replikasi sel tumor
Proto-onkogen changes
Gen supresor tumor

Onkogen

Leukemia
Generalized neoplastic disorders of the

blood forming tissues, primarily those of


the leukocytic series
Marked proliferation
Acute

Minimal differentiation/maturation

Chronic
Normal differentiation/maturation

Cyto-morphology diagnoses by Bone


marrow aspirate
Blast > 30%

Blast 50%
ME ratio 1

ME ratio > 1

PAS

SBB/POX

Negative

Negative

Positive

Positive
M6/M7

M0/ALL
AP-L

Blast > 50%

Blast with blebs,


megakaryocytic
fragments are seen in
peripheral blood

Negative
Positive
ALL
B cell

NSE

M1 Blast > 90% (Blast + myeloid)

>3%

Blast < 90% (Blast + myeloid), and


M2 monocytoid < 20% myeloid

30%

M3 Promyelosit > Blast

M0

+
T cell

100%

monocytoid > 20% myeloid, and


M4 Monosit perifer > 5000/mm3

80%

monocytoid > 80% myeloid, and


M5a Blast > 80% monocytoid

90%

monocytoid > 80% myeloid, and


M5b Blast < 80% monocytoid

90%

Subclassification of ALL
Cell size

chromatin

nucleoli

cytoplasm

L1

Homogenous
Small

Homogenous

Rare

Minimal
No granules

L2

Heterogeneous
Heterogeneous
Larger

More present

Often moderately
Some deep
basophilic

Prominent one
or more
vesicular

Moderately
Deep basophilic
and prominent
vacuolation

L3

Homogenous
Larger

Finely
homogenous
stippled

Hypothetical scheme of lymphocyte


differentiation

CD5+

CD20+

Terima kasih

Pewarnaan besi
Samples were fixed and then decalcified overnight in

a decalcifying solution (1000 ml formic acid, 3250 ml


distilled water, and 250 ml formaldehyde).
Rinsed in distilled water and incubated for 20 minutes
in a solution of equal parts of 2% hydrochloric acid
and 2% potassium ferrocyanide,
Washed in distilled water then tap water, and rinsing
Finally counterstaining in 1% aqueous neutral red.