LOGO

Gangguan Eritrosit:

Anemia
Hj. Tisnawati, SSt, M.Kes
 Gangguan Eritrosit LOGO

Anemia

Polisitemia

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 ANEMIA LOGO

Definisi Anemia:
 Sindroma klinis yang disebabkan penurunan massa
eritrosit total dalam tubuh.
 Keadaan dimana massa eritrosit dan atau massa
hemoglobin tidak dapat memenuhi fungsinya untuk
menyediakan oksigen bagi jaringan tubuh
 Penurunan di bawah normal kadar Hb, hitung
eritrosit, dan hematokrit

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 ANEMIA LOGO

Penurunan Hb dan Hct :

< batas bawah 95% interval referens
dari kelompok usia, jenis kelamin
dan lokasi geografis (ketinggian)

Hb12-14 g/dl ; (Hct 36-41%),

Anemia
Hb7g/dl  symptom (+)
Akut: hipovolumia (pucat,
ggn penglihatan, syncope, tachycardia) ;
Kronis: tissue hypoxia (fatique, dyspnea,
Headache, angina)

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ANEMIA → symptoms / syndrome LOGO

 Hb ↓
 PCV ↓ Hypoxia → Otak , Otot
 RBC ↓
Kompensasi :
- heart rate ↑→ tachycardia → flow rate ↑ →
cardiomegaly → heart failure → †
- blood flow priority (pallor)
- RBC 2,3-DPG content ↑→ O2 dissoc.curve
shift to the right → O2 release to the
tissues ↑ .

5
Klasifikasi Anemia LOGO

Berdasarkan patofisiologi:
I. Kegagalan produksi sel darah merah:
A. Gangguan sel induk hematopoesis
 Anemia Aplastik
B. Gangguan sintesis DNA
 Anemia Megaloblastik
C. Gangguan sintesis Hemoglobin (Hb)
 Anemia Defisiensi Besi, Thalasemia
D. Gangguan sintesis eritropoetin
 Anemia karena GGK

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 Lanjutan…..anemia berdasarkan patofisiologi LOGO

E. Gangguan karena mekanisme lain:

 Anemia karena penyakit kronis,
 anemia sideroblastik
 Anemia karena infiltrasi sumsum tulang

II. Peningkatan destruksi sel darah merah:

 Anemia Hemolitik
III. Kehilangan darah (Blood Loss)
 Anemia karena perdarahan akut

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 Anemia LOGO

Anemia berdasarkan morfologi

 Anemia sec. morfologi eritrosit, dilihat dari:
- ukuran dan warna di bawah mikroskop atau
- indeks eritrosit (MCV, MCH, dan MCHC)

Kriteria Ukuran (size): Normositik, Mikrositik,

Makrositik
Kriteria Warna (pucat): Normokromik,
Hipokromik

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Cara Mengetahui Ukuran eritrosit: LOGO

* membandingkan dengan inti sel limfosit kecil (di

bawah mikroskop) :
→ ukuran sama = normositik
lebih kecil = mikrositik
lebih besar = makrositik

* Menghitung MCV (Mean Cell Volume)

MCV= PCV/Ery X 10 (fL)
(1 fL=10-12L= 1μm3)
N : dewasa = 80-100 fL , di bawah 1 thn = 76- 86 fL
MCV : normositik , mikrositik, makrositik

* Eritrosit dengan variasi ukuran yang abnormal

anisositosis

9
Bandingkan ukuran sel eritrosit dengan inti limfosit LOGO

10
 LOGO

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Perhatikan Warna sel eritrosit : LOGO

- Bandingkan diameter central pallor(CP)

dengan diameter sel eritrosit tersebut .

- Normal, bentuk sel eritrosit adalah seperti cakram

bikonkaf (biconcave disk) →
pada hapusan darah tepi terlihat bulat, Ø 7-8 μ
dengan area central pallor di bagian tengah

CP≤ 1/3 Ø Eri = normokromik

CP> ½ Ø Eri = hipokromik

12
Eritrosit dengan central palor (CP) LOGO

Bandingkan diameter CP dengan diameter sel eritrosit

13
 LOGO

Warna, dapat diketahui juga dari MCH (Mean Cell Hb)

MCH= Hb/RBC x 10 (pg)
Dewasa: MCH=27-32 pg, Anak-anak: MCH=23-31 pg
(1pg=10-12g=1μμg)

MCH normal → normokromik

MCH < normal → hipokromik

MCHC (Mean Cell Hb Concentration) :

MCHC=Hb/PCV x 100 (g/dL)
Normal: MCHC = 32-36 g/dL

14
 Klasifikasi Anemia secara morfologi LOGO

1. Anemia Hipokromik-Mikrositik.

Anemia Normokromik-
2. Normositik

Anemia Makrositik
3.

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 LOGO

Anemia Anemia Anemia makrositik

hipokromik- normokromik-
mikrositik normositik

1 2 3
Contoh: Contoh: A. Megaloblastik,
- Anemia pasca contoh:
- Anemia perdarahan akut - Anemia defisiensi
defisiensi Fe - Anemia aplastik Folat,
- Thalasemia - Anemia hemolitik - Anemia defisiensi
- Anemia akibat - Anemia akibat vitamin B12
penyakit kronik B. Nonmegaloblastik
Penyakit Kronik - Anemia pada contoh:
- Anemia GGK - Anemia pd peny.
sideroblastik - Anemia pada Hati kronis
mielofibrosis - Anemia pd
- dll hipotiroid, dll

MCV <80 fl; MCV 80 -95 fl MCV > 95 fl

MCH <27 pg MCH 27-34 pg

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Hipokromik-Mikrositik LOGO

17
Normokronik-normositik LOGO

18
 Makrositik LOGO

 makrosit-oval
(Anemia megaloblastik ditandai oleh makrosit oval ini)

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Pendekatan diagnostik Anemia: LOGO

 Anamnesis:
onset /bleeding tendency / routine
medicinal / occupation / hobby / travel
history / family / diet / GI symptoms /
menstruation cycle / history of previous
pregnancy-delivery / alcohol consumption ,
etc

 Pemeriksaan fisik :
conjunctiva & lips (pallor) / mouth
(cheilosis) / tongue (glossitis) / gum / nails
(koilonychia) , hair (signa de bandera,
alopecia) , jaundice , petechiae , liver &
spleen , lymphenodes ,rectal / vaginal
toucher , feet (ulcer,arthritis)

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 LOGO

 Pemeriksaan Laboratorium
- CBC (complete blood count )→ to confirm
anemia (Hb, PCV, RBC) & the type of anemia
(MCV; MCH; MCHC), RDW
- Reticulocyte count → reflects marrow’s responses .
- PBS : to look for the RBCs’ shape and any abnormalities of
RBCs besides the other blood cell lines
- Iron status ( Serum Iron ,TIBC, % Transferrin
saturation , Iron storage )
- Blood chemistry ( direct/total bilirubin,LDH
and stool examination for occult blood test , etc) .
PBS: Pheripheral blood smear

21
Lanjutan…. Pendekatan Doagnostik… LOGO

- Radiological examinations ( Chest X-ray,

USG , MRI )
- Cardiological examinations (EKG,Treadmill,
Echocardiography)

Notes ! :

- First confirm Anemia ( Hb , PCV , RBC )

- Classify the anemia (MCV, MCH, MCHC)
- Causes of anemia

22
 LOGO

23
 LOGO

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Anemia Hipokromik-Mikrositik LOGO

Setiap kondisi yang menimbulkan gangguan

sintesis Hb  gambaran hipokromik
mikrositik
Anemia Defisiensi Besi penyebab tersering
dari anemia Hipokromik-Mikrositik
Perhatikan penyebab lain (DD=diff diagnosis)
sebelum mendiagnosis Anemia def. besi, spt:
- anemia akibat penyakit kronis
- Thalasemia
- anemia Sideroblastik, dll

25
 LOGO

26
 ANEMIA DEFISIENSI BESI LOGO

 Definisi:
Anemia yang timbul akibat kosongnya cadangan besi
tubuh besi utk eritropoeisis  pembentukan Hb
 Anemia def. Fe, ditandai dgn:
- anemia hipokromik mikrositik
- besi serum
- TIBC (Total Iron Binding Capacity)
- Saturasi transferin
- Feritin serum
- Pengecatan Besi sumsum tulang negatif
- Respon terhadap pengobatan dengan preparat Fe

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 LOGO

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Faktor Penyebab (Etiologi) LOGO

I. Keseimbangan negatif Fe (Negative Iron

balance):
- Asupan Fe ↓
(inadequate diet , impaired absorption)
- Fe loss ↑
(GI bleeding, excessive menstrual flow,
bleeding diathesis)
- ↑ demands
(infancy, pregnancy, lactation)

29
Lanjutan….Faktor Penyebab LOGO

II. Inadequate presentation to erythroid

precursors:
- atransferrinemia
- Anti TrfR Ab

III. Abnormal Fe balance :

- Aceruloplasminemia
- Autosomal dominant hemochromatosis
( mutations in ferroportin )

30
Patogenesis desifisiensi Fe LOGO

 3 pathogenetic factors:
- Impaired Hb synthesis (consequence of
reduced Fe supply)
Transferin saturation< 16% inadequate Fe-supply
to marrow → Hb contents of RBC ↓ → hypochromic
& microcytosis
- Generalized defect in cellular proliferation
- Fe-deficient → oxidative damage to the red
cell’s membrane → RBC deformability ↓ → RBC
viability ↓→ RBC destruction ↑ especially in spleen
→ reduced RBC survival

31
Status besi tubuh: LOGO

 Serum Iron = SI
 Total Iron Binding Capacity (TIBC)
 % Transferrin Saturation = SI/TIBCx100%
 Simpanan besi (Iron storage):
- Hemosiderin →produk degradasi feritin yang tidak
larut dalam air → mayoritas tdd aggregat kristal
ferric oxyhydroxide, FeOOH (di Hepar danSutul→
dideteksi dengan biopsi/aspirasi dan pengecatan
besi (prosedur invasif)

- Ferritin → kompleks garam Fe3+dan apoferitin

yang larut dalam air, dengan jumlah yang sangat
kecil di serum.
(dideteksi dengan metode imunoasai)

32
 LOGO

 Kandungan besi tubuh = 35-50 mg/kgBB:

±80% - Fe fungsional, sebagai heme-Iron
(65% Hb, myoglobin, enzim
heme : cytochrom-C,A,A3,B,
catalase , peroxidase)
- Non-heme-Fe (sebagian kecil)
20% - simpanan besi / Iron storage (ferritin,
hemosiderin)
hanya ± 15% pada wanita
0.2% - circulating (terikat padaTransferrin)

33
Iron Cycle in the body : LOGO

 Fe-diet → as heme-Fe (Hb, myoglobin,

enzyme-Fe), 5-35% adsorbed
from animal/meat sources ,
adsorbed easily .
→ as non-heme-Fe (vegetables ,
legumes), 90% of diet-Fe but
only 2-20% of it absorbed →
depends on the iron-status and
the ratio of Enhancer:Inhibitor

34
 LOGO

Enhancers (zat yang menstimulasi

penyerapan (absorbsi) :
Ascorbate, Cytrate, organic acids / other
amino acids , by reducing Fe3+ to Fe2+.

Inhibitors (zat yang menghambat absorbsi) :

Carbonate, Phytate, Tannins, Phosphate,

Oxalat chelate Non-heme-Fe →
unabsorbable

35
 LOGO

 Bahan makanan yang menghambat absorbsi

besi non heme (Non-heme Iron) :
- Phytate (dari legumes, sayuran)
- Tannin & Polyphenol (dari teh, kopi, wine,
coklat )
- Phosphate/phosphoprotein dari kuning
telur
- Minerals (Ca, Zn, Cd)
- Tetracycline yang bereaksi dengan Fe →
menghambat absorbsi

36
Siklus Fe dalam tubuh : LOGO

Diet’s Iron → duodenum / proximal jejunum .

Iron from gut → released into circulation ,

bound to transferin → distributed to body’s
organ / tissues( to bone marrow as a part of
heme / Hb ) → circulate inside red blood cells
with blood flow

37
The development of IDA LOGO

• Stage-1 (prelatent Fe-deficient):

- progressive loss of storage-Fe
- body’s Fe reserve is still sufficient to
maintain both the transport and functional
compartment , so RBC development is
still normal .
- peripheral blood picture is normal , no
symptoms of anemia , but ferritin is ↓ .

*IDA= Iron Deficiency Anemia

38
 LOGO

* Stage-2 (latent Fe-deficient)

- Exhaustion of storage-Fe , RBC
production is still normal , Ferritin ↓↓

- Circulating-Fe (SI) begin ↓ , Transf-

Receptor ↑ .

* Stage-3 (Fe-Deficiency Anemia)

- Stadium of Iron Deficiency Anemia

39
 LOGO

Stage-1 Stage-2 Stage-3

(prelatent) (latent) (IDA)
Marrow ↓ (-) (-)
Ferritin ↓ <12ug/L <12ug/L
Transf-Sat N <16% <16%
sTrfR N ↑ ↑
Retic Hb N ↓ ↓
content
Hb N N <
MCV N N <
Symptoms fatigue fatigue pallor

40
 LOGO

Symptoms Morphology SI - TIBC Ferritin

IDA Anemia Hypo – SI↓ - ↓↓

Micro TIBC ↑

A.C D Anemia Hypo – SI ↓ - N/ ↑

Micro TIBC
↓/N

41
Pendekatan Diagnostik Anemia Defisiensi Fe LOGO

1. Anamnesis – pola menstruasi, kehamilan /

persalinan, tendensi perdarahan,
penyakit kronis, diet, pekerjaan,
riwayat bepergian

2. Pemeriksaan fisik – sistematik dari seluruh

permukaan tubuh sampai ke organ dalam ( hati,
limpa, kelenjar getah bening (lymphnodes)

42
 LOGO

3. Laboratorium- Hema (DL, LED, Hapusan

darah tepi, Retikulosit)
- Serum (SI,TIBC,Ferritin, Bilirubin)
- BMA (Bone Marrow Aspiration)
- Pemeriksaan Urine dan tinja

4. Penunjang - Radiology (EKG, USG)

- Endoscopy

43
 SI TIBC LOGO

Normal N N
(1/3 mol.Trsf)
IDA ↓ ↑

An.of Chronic ↓ N/↓

Disease

Fe Overload ↑↑ N/↑

44
Pemeriksaan Lab. Anemia def. Fe LOGO

1. CBC – confirm Anemia & find hypochromic

microcytic picture from BSE and Red
Cells Indices ( Hb, PCV ,MCV , MCH ,
MCHC)

2. SI – Fe2+ released from Transferrin + ferrozine

(chromagen) → measured colored
complex
TIBC – serum + excess FeCl2 → to fill all Transferrin-
binding sites → the excess Fe is fixed by Mg-
carbonate → Fe-saturated Transferrin is
measured with Ferrozine (= TIBC)

45
 LOGO

% Saturasi Transferrin = SI/TIBC X 100%

Erythropoeisis impaired when % Tf.Sat < 15%

3. Ferritin Serum :
Serum Ferritin level ~ Fe-storage
Ferritin <15 ug/L → Definitive Fe-Deficient
N/↑ Ferritin in IDA , if :
- impaired liver function ( damaged
hepatocyte),
hemolysis, inflammation / infection /
malignancy ( Ferritin = acute-phase
protein )

46
 LOGO

4. Transferrin Serum :
measured by immunodiffusion methode
Normal value : 2-4 g/L

5. Bone Marrow’s Aspirate evaluation :

( using Perls or Prussian Blue stain )

47
Anemia of Chronic Infection LOGO

 Gejala klinis miripdengan anemia def.Fe

 Gambaran lab. hematologi = Anemia def. Fe
(An.Hypo-Micro, MCV↓, MCH↓, SI↓) , tapi
TIBC N/↓ and Ferritin N/↑)
 Pathogenesis :
Fe → storage // Transferrin

Tissues / RES

48
Penyebab menurunnya ‘circulating LOGO
Fe’ :

1. Impairment of Fe release from

macrophage in competing with
lactoferrin, phagocyte’s product , even
storage-Fe is still enough .

2. Inadequate EPO Respons towards

anemia (effects of cytokine production by
macrophage) .

49
Diagnosis Anemia akibat penyakit kronis:
LOGO

 lab hematologi:
- Anemia hipokromik mikrositik
- SI ↓ , TIBC ↓/N , Ferritin N/↑
( jika Ferritin ↓, An. Def.Fe )
- Inflamasi / infeksi (+) :
CRP and LED ↑

Problem: IDA with inflammation → ferritin ↑

(falsely diagnosed as ACD) ; it can be
differentiated by sTfR exam (serum
transferrin receptor) that ↑ in IDA but normal
in ACD .

50
Anemia Sideroblastik LOGO

 Defek pada sintesis Heme → akumulasi Fe di

mitochondria → degenerasi Fe → granula Fe
di sekitar inti normoblast, membentuk
struktur spt cincin {paling jelas terlihat
dengan pengecatan Perl (Perls’ stain) } →
Ringed Sideroblast (karakteristik anemia
Sideroblastik)

 Sideroblast bisa dijumpai secara normal di

sutul

51
 LOGO

Sideroblast and Ringed Sideroblast ( in

Sideroblastic Anemia )

52
 LOGO

53
 LOGO

 Classification of Sideroblastic
Anemia

1. Hereditary : X-linked, defect in heme-

synthesis enzyme pathway

Fe absorption ↑ → % of Transferrin
saturation and Ferritin level ↑

54
 LOGO

2. Acquired :
- Primary :
Stem cell clonal mutations(MDS =
MyeloDysplastic Syndromes , RA-RS)
Normochromic-macrocytic anemia .
Marrow : erythroid hyperplasia with
dysplastic or megaloblastic appearance
- ringed sideroblast in normoblast .

55
 LOGO
-
- Secondary;
Abnormal metabolism of Vit.B6 (alcoholism,
malabsorption) , impairment of heme
synthesis ( Pb intoxication) , Rhematoid
Arthritis , or An.megaloblastik .

Usually related to myeloproliferative

diseases ( AML, Myelofibrosis, Polycythemia
or another types of MDS )

56
Macrocytic Anemia LOGO

- Non-Megaloblastic Macrocytic Anemia :

 Reticulocytosis
 Liver disease / Alcoholism
 Myelodysplastic Syndrome
 Erythroleukemia (FAB-M6)

- Megaloblastic Macrocytic Anemia

57
Megaloblastic Macrocytic Anemia LOGO

macrocyte = erythrocyte with MCV > normal .

macrocyte/microcyte depend on the balance
between nuclei & cytoplasmic maturation .

(nuclear dividing stopped when intracellular Hb

production reach a proper level ) .
If nuclear maturation delayed ( in DNA
synthesis’s defect ) or cytoplasmic maturation ↑
( increase of EPO’s activities ) → critical level of
Hb achieved earlier → Macrocyte

58
 LOGO

Megaloblast = bigger than normal

normoblast .
Megaloblastic changes = increased size of
hemopoietic precursor cells in bone marrow
( not only in normoblast !)

Primary defect : Defect of DNA synthesis

( altered almost all active cells / organs i.e :
hemopoietic tissue, epithelial cells , mucous
cells, etc )

59
 LOGO

 Etiology of DNA synthesis defect :

deficiency of vit.B12 and folic acid →

maturation dysharmony between nuclei &
cytoplasm (delayed nuclei maturation) →
increased cels (megaloblastic changes) →
marrow’s ineffective erythropoiesis →
intramedullary hemolysis → total/indirect
Bili and LDH ↑.

60
 LOGO

Deficiency of Folic acid:

- Inadequate diet
(intake < / demand ↑ in pregnancy -
lactation , child’s growth / malabsorption
in tropical sprue / bowel resection / small
intestine inflammation )

- Drug’s effect (anti-epilepsi)

- FA loss ↑ (dialysis)

61
 LOGO

Deficiency of Folic acid:

- Inadequate diet
(intake < / demand ↑ in pregnancy -
lactation , child’s growth / malabsorption
in tropical sprue / bowel resection / small
intestine inflammation )

- Drug’s effect (anti-epilepsi)

- FA loss ↑ (dialysis)

62
 LOGO

Deficiency of Vit.B12:
- Inadequate diet :
Intake < in vegetarians , demand ↑ ,
impaired absorption caused by
decreased Intrinsic Factor
( gastrectomy , pernicious anemia )
Malabsorption (bowel infection , worms
/ blind loop syndr )

63
VITAMIN B12 ASAM FOLAT
LOGO
-Food from animal products -Limited sources (vegetable ,
-Heat stabile
-Storage : enough for 3 yrs fruits)
-Relatively low needs (only -Heat labile
1% of folate requirements) -Storage enough only for 3
mths
-Higher folate needs
CAUSE OF DEFICIENCY CAUSE OF DEFICIENCY
-Vegetarian (seldom) -Nutrition (alcoholism, goat’s
-Impaired Intrinsic Factor milk diet)
(pernicious anemia) -Prematurity
-Gastrectomy -Hemodyalisis
-Atropic Gastritis -Bowel resection
-Anticonvulsant, alcoholism -Pregnancy
-Anticonvulsant , MTX

64
Pathogenesis of Megaloblastic Anemia :LOGO

 Megaloblastic changes
 atrophy of tongue papilla & mucosal GI →
glossitis , gastritis, nausea , constipation.
 B12 defic → demyelinisation of spinal cord &
peripheral nerve → loss of foot’s balance /
sensory (Neuropatia)
 FA defic → hyperhomocysteinemia →
thrombosis and vascular occlusion .

65
B12 Metabolism LOGO

 Vit.B12 → purine & pyrimidin synthesis →

synthesis DNA & RNA → mitosis and
maturation
 Vit.B12 made from microbiological source
because plants do not produce B12 ( meat ,
liver, eggs and milk are rich of Vit B12 ).
 Vit.B12 content in the daily diet is 5-3ug ,
daily requirement of B12 is 1-3 ug, and B12
body’s storage is 2-5 mg (enough for 3 yrs)

66
Vit.B12 absorption LOGO

 B12 diet → in gaster bind by IF (Intrinsic Factor)

produced by parietal cells → IF-B12 complex →
ileum : B12 absorbed , IF freed into the lumen

 impaired IF : gastrectomy/gastritis/ Auto-Ab-antiIF or

Auto-Ab-antiparietal) → no absorption of B12 →
impaired DNA synthesis → (Pernicious Anemia
with Achlorhydria)

 Pernicious Anemia = autoimmune disease → auto-

Ab to parietal cells (Anti-IF or Anti-Parietal)

67
Hematological pictures of Megaloblastic AnemiaLOGO

 Bone Marrow :
- megaloblastosis
- ineffective erythropoiesis

 Peripheral blood :
- Oval macrocytosis
- Hypersegmented neutrophil ( five 5-lobed
cells or one 6-lobed cell) or the mean lobes
of 100 neutrophils is > 3.4

68
Megaloblastic Anemia LOGO

 find oval-Macrocyte cell and hypersegmenteneutrophil .

69
Diagnosis of Megaloblastic Anemia LOGO

 Screening :
- CBC , Neutrophil’s lobe count
- Serum Indirect Bilirubin , LDH (lactate
dehydrogenase)

 Spesific tests :
- Bone Marrow Aspiration: megaloblastosis &
megaloblastic changes, erythropoietic activitiy ↑ ( ineffective
erythropoiesis)
- Folate & Vit.B12 assay
- Gastric juice analysis
- Schilling Tests
- Antibody Assay

70
 Anemia Hemolitik LOGO

 Anemia hemolitik: anemia yang disebabkan

oleh proses hemolitik.
 Hemolisis: pemecahan eritrosit sebelum
waktunya (sebelum masa hidup rerata eritrosit,
yaitu 120 hari).
(Proses pemecahan eri karena sdh waktunya
senescence=penuaan)
 Hemolisis dapat terjadi di dalam pembuluh
darah (hemolisis intravaskular) dan di luar
pembuluh darah (hemolisis ekstravaskular).

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HEMOLYTIC ANEMIA LOGO

 Normal red cell’s survival = 110-120 days →

destructed by macrophage in marrow and
spleen .
When the survival are shortened → EPO
production is stimulated (compensated) →
no Hb changes → anemia (–) .
 If the destruction is acute or chronic with
very shortened life of red cells , there will no
compensation → anemia (+) .

72
Definition of Hemolytic Anemia : LOGO

 anemia caused by shortened red cell’s

survival as a result of excessive
uncompensated destruction of red cells .

 Hemolytic process = every process of red

cells destruction with still / without
compensated by bone marrow → anemia is
not always present .

73
- Compensation ability of bone marrow LOGO
:
 Ability to ↑ red cells production ( 6-8 x
normal ) :
- survival shorten ½ → production ↑ 2x
- survival shorten ¼ → production ↑ 4x
- survival shorten 1/6 → production ↑ 6x
- survival shorten 1/8 → production ↑ 8x

↑ of production 6-8 x is maksimum .

 If red cells live only 20 days → anemia (+).

74
Diagnostic approach in Hemolytic Anemia LOGO
:
1. Confirm anemia (Hb/PCV/RBC)
an acute case usually acquired , and
chronic case is mostly hereditary .

2. To find the signs of hemolytic process .

3. Extra or Intravascular ?
4. Hereditary or acquired ?
5. The cause of hemolysis episodes .

75
The signs of Hemolytic process : LOGO

1. Increased of red cells destruction

- Unconjug.bilirubin serum ↑ → jaundice
- Urobilinogenuria
- Hb-uria → sign of intravascular hemolysis
- Abdom.pain → splenomegaly, spleen infarction
- Leg’s Ulcer → intrinsic defect of erythrocyte
- Haptoglobin serum ↓↓/neg → intravascular
hemolisys .

76
 LOGO

2.Destruksi eritrosit :
Microspherocyte, Fragmentocyte,
Poikilocyte
Erythrocyte Osmotic Fragility ↑
Positive Autohemolysis test
Shortened of red cells’ survival

3. Tanda Peningkatan Eritropoisis:

Reticulocytosis
Normoblastosis
Erythropoietic Hyperplasia in bone marrow
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 LOGO

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 Hemolisis Ekstra vaskular LOGO

 Hemolisis ekstravaskular lebih sering dijumpai

dibandingkan hemolisis intravaskular
 Hemolisis terjadi di sel makrofag dari sistem
retikuloendothelial (RES) terutama pada Lien, hepar
dan sutul karena sel ini mengandung enzim heme
oksigenase
 Lisis terjadi karena kerusakan membran eritrosit
(misal Akibat reaksi Ag-Ab; presipitasi hb di
sitoplasma, menurunnya fleksibilitas eri,dll)
 LOGO

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 Klasifikasi Anemia Hemolitik LOGO

Dibagi atas 2 golongan besar, yaitu:

1. Anemia hemolitik karena faktor di dalam
eritrosit sendiri (gangguan intra korpuskuler)
2. Anemia hemolitik karena faktor di luar
eritrosit (gangguan ekstra korpuskular)

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 LOGO
lanjutan….Klasifikasi anemia hemolitik :

1. Gangguan intra korpuskular (Hereditary

Hemolytic Anemia )

- Membrane abnormality (hereditary

spherocytosis , hereditary ovalocytosis )
- defect of globin chain (Thalassemia, Hb-
pathia)
- enzyme defect ( G-6PD deficiency , PK-
deficiency)

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Hereditary Spherocytosis : LOGO

88
Hereditary Ovalocytosis : LOGO

89
Lanjutan……klasifikasi anemia hemolitik
LOGO

2. Gangguan ekstrakorpuskular
(Acquired Hemolytic Anemia):

- physical / chemical substances

- infections (bacteria, parasites, viruses,
fungi)
- mechanical trauma (prostetic heart valves)
- Immune mechanism (Alloimmune /
Autoimmune / Drug-Induced HA)

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- Hereditary Spherocytosis : LOGO

 autosomal dominant
 Spherocytosis, decreased membrane surface area
relative to cell volume → osmotic fragility test (OFT)↑
among the family member .
 The primary lesion is caused by membrane protein
defects (↓of spectrin) → cytoskeleton instability .
 60% - chronic anemia , jaundice, splenomegaly, 20%
without hemolysis / splenomegaly .
Bilirubin excretion ↑ ,causing bilestone in USG.

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Thalassemia : LOGO

 Defect of 1 or more globin-chain synthesis (the

amount = quantitatively) :

- deficiency of α globin-chain → α-thalassemia

- deficiency of β globin-chain → β-thalassemia
- deficiency of δβ globin-chain → δβ-thalassemia

the primary defects in Hb-pathia is in the globin

amino acids structure (qualitatively)

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 LOGO

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 LOGO

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α-Thalassemia LOGO

 α-Thalassemia = is caused by the impairment

of α-globin chain production/synthesis .

 α-globin chain synthesis is directed by 2

pairs of α-gene (4 locus α-gen) → depending
of the number of defected locus → 3 types of
α-Thalassemia (α-thal trait , HbH Disease,
and HbBart’s Hydrops Fetalis)

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Clinical consequences in α-Thalassemia LOGO

 Deficiency of α-globin chain → excess of β, γ

chain since fetal life to form β4-tetramers
(HbH) or γ4-tetramers (HbBart) .

 Defect of 1-2 α-Gen = α-trait (clinically good)

 Defect of 3 α-Gen = HbH disease ( Hb 10-11

g/dl) → excess of β-chain → to form β4-
tetramers (HbH) as intracellular inclusion →
detected by BCB-stain .

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HbH-inclusion (β4) in HbH Disease as shown
in BCB staining (compare with reticulocyte)LOGO

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 LOGO

 Defect of 4 α-gene (HbBarts’hydrops fetalis)

→ clinically severe , stillborn baby with
hydrops fetalis ( severe hypoxia ) .
HbBarts = γ4-tetramers (excess of γ-chains
that unable to form HbF ) .

 HbBarts and HbH inclusions precipitated in

red cell’s membrane → mechanical trapping
in spleen → macrophagic phagocytosis →
hemolysis .

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 LOGO

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- β-Thalassemia LOGO

 Clinically consequences in β-Thalassemia :

- No problems during fetal life because HbF
synthesis is normally produced
(normal α and γ chains)
- When HbA is dominantly needed , the
clinically
problems exist as incapability to synthesize
HbA (α2β2) → excess of α-chain →
compensated ↑ of δ and γ production →
HbA2
↑ (in β-Thalassemia minor) and HbF ↑ (in
β-Thalassemia mayor)
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 Β-Thalassemia mayor : LOGO

- severe anemia → repeated transfusion is

oftenly needed → Fe↑↑ → hemochromatosis

- chronic ineffective erythropoiesis →

medullary hypertrophy in childhood → facial
malformation:
* Frontal bossing
* Maxillary hypertrophy
* Hypertelorism (mongoloid’s eye)

102
- β-chain deletion forms : LOGO

 β0-Thalassemia : no β-chain
production.
 β+Thalassemia : β-chain production
<<
in heterozygous case : medium severe
in homozygous : severe (Cooley’s
anemia)

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 LOGO

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Laboratory Diagnosis in Thalassemia LOGO

1. CBC, Peripheral Blood Smear

2. Hb-Electrophoresis : in Celulose-Acetat (pH

8.4) for thalassemia and Hb-pathia
screening
Using hemolysate → formed bands of
different types of Hb ( normal : bands A, F,
and A2 , measured densitometrically)

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 LOGO

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 Lanjutan…..Lab diagnosis in thalasemia LOGO

3. HbA2 mesurement to diagnose β-Thalassemia trait

using anion-exchange resin column chromatography

in both HbELP and chromatography , HbC, HbE and

HbO can interrupt the conclusion because of the
same band location with HbA2 .

4. HbF determination :
- Alkali Denaturation Test
- Acid-elution (Kleihauer) test
- RID or ELISA methods

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 LOGO

5. HbH Inclusion detection :

- Supravital staining using Brilliant

Cresyl Blue (BCB) or NewMethylene
Blue (NMB)
- HbH inclusion seen as dispersed blue-
green granules in red cells
(compare with reticulocyte as a filament)
- in HbH disease : HbH inclusion +++
- in Thalassemia-α-trait : HbH inclusion +
in 1: 10000 eritrosit .

108
Defisiensi G-6PD LOGO

- Oxidant → produce H2O2 → oxidizing

Hb’s free sulfhydryl → to form Sulf-Hb →
aggregates that precipitated as Heinz
Bodies → destructed in spleen .

- Oxidant / Sulf-Hb are controlled by

Reduced Glutathione (GSH)

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 LOGO

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 LOGO

 - X-linked, ± 300 variants .

normal G-6PD genes : - type B (GdB)
- type A (GdA)
- Abnormal enzyme types :
1. GdA– (type A–)
2. Gd-Mediterranean (GdMed)
3. Gd-Canton : many in Asia

- G-6PD deficient red cells are resistent

to Plasmodium Falciparum .

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 LOGO

- Substances causing lysis in G-6PD

deficiency :

1. Antimalaria 6. Fava beans

2. Sulfonamides 7. Naphtalene
3. Vit.K, Vit.C 8. Uremia
4. Lung Infection 9. Antibiotics
(virus,bacteria) (Penicilline ,
5. Antipyreticum streptomycine

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 LOGO

 The highest G-6PD activity is in

reticulocyte .
 G-6PD screening test :

Test’s principle :
G-6PD
G-6P + NADP 6-PG + NADPH
UV
(fluorescence)

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 LOGO
Acquired Hemolytic Anemia :

- Secondary Hemolytic Anemia caused by

infection / systemic disorders :

 Malignancy – Autoimmune-reacted
hemolysis , microangiopathy or
hypersplenisme , appearing Anemia of
chronic disease, bleeding tendencies, and
marrow’s suppression

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 LOGO

 Disseminated Intravascular Coagulation

(DIC):
Systemic intravascular coagulation → fibrin
deposit intravascularly / endothelial damage
(microangiopathyi) caused by sepsis → red
cells destruction .

 Chronic Liver Disease : hemolysis caused by

hypersplenism .

 Chronic Renal Disease: hemolysis caused by

microangiopathy

115
Acquired Hemolytic Anemia (extracorpusc.)
LOGO

Immune Hemolytic Anemia

 Red cell membrane-bound Ab hemolysis .
 The speed & hemolysis location depend on
IgG or IgM, and the ability to activate
complement .
 Optimal temperature to bind Ab :
370C – Warm-IgG-Type
<300C – Cold-IgG-Type

116
 Lanjutan….acquired hemolytic anemia LOGO

 Cell+IgG → destructed by spleen

Cell+IgM → enhance the activation of
complement’s cascade → intravascular
hemolysis

 Immune destruction often cause minimally

membrane damage → shape change into
spherocyte .

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 LOGO

 Immune Hemolytic Anemia classification :

1. Alloimmune : Transfusion Rx , Hemolytic

Disease of the Newborn (HDN)

2. Autoimmune : Warm/Cold AIHA,

Paroxysmal Cold Hb-uria (PCH)

3. Drug-induced HA : penicilline type,

aldomet, and stibophen type .

118
Hemolytic Disease of the Newborn (HDN) –
Rh-neg mother , with Rh-Pos fetus , during I and second LOGO
pregnancy

119
Antiglobulin Tests (Coombs) : LOGO

 Direct Coombs Test (Direct Antiglobulin

Test/DAT) = Ab detection test (IgG and or C3d
/complement-bound red cells) .

Indirect Coombs Test = test for serum free Ab

.

 DAT usually positive in AIHA (.

120
Drug-Induced hemolytic anemia : LOGO

 Penicilline type : drug as hapten binds red cell

membrane → antigenic → stimulate Ab production
against Drug in drug-red cell complex

Phenacetin/Quinidin type : Drug (hapten) adsorbed

protein → stimulated-Ab binds drug-protein complex
→ activate complement → red cell lysis.

 Aldomet type : drug change red cell membrane’s

structure → detected as foreign cell → Autoantibody
production .

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 LOGO

122
Aplastic (Hypoplastic?) Anemia LOGO

 Severe & fatal Anemia because of ↓ red

cells/leucocytes/platelet production
(pancytopenia) caused by Stem Cells
impairment (radiation, chemicals, drugs, or
genetic matters)

 Marrow aplasia / hypoplasia-causing

substances - radiation , benzene,
cytostatics (6-MP,
busulfan), arsen, chloramphenicol,
anticonvulsant (phenytoin), analgetic
(phenylbutazone) , DDT, etc

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Symptoms & Lab.appearance of Aplastic Anemia
LOGO

 fatigue, palpitation, infections, bleeding tendency

 Lab : - pancytopenia
- normochromic normocytic
- ‘dry-tap’ marrow , hypocellularity

 Prognosis :
- bad especially for < 40 yrs old patients →
marrow transplantation .

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- Treatment for Aplastic Anemia : LOGO

1. Avoid every toxic material

2. Avoid infections / bleeding tendency
3. Use Washed-Erythrocyte if transfusion is
needed or Plat.Concentrate (PC) for any
profuse bleeding ( give corticosteroid if
bleeding is minimal)
4. Marrow stimulants (androgenic hormon )
5. Marrow Transplantation

125
POLISITEMIA LOGO
(ERITROSITOSIS)

 Peningkatan patologis massa eritrosit

 massa eritrosit normal : (sea level)
- o : 26 - 32 ml / kg BB
- o : 23 - 29 ml / kg BB
 eritrositosis : massa eritrosit > normal
( PCV : o >51% ; o >48% )
 LOGO

• Klasifikasi :
I. Primer (Otonomik)
A. Polisitemia Vera
B. Eritrositosis Murni (Eritremia)
II. Sekunder
A. Fisiologis (Oksigenasi Jaringan )
B. Non-fisiologis (Oksigenasi Jaringan N)
III. Eritrositosis Relatif
 ERYTHROCYTOSIS - DIAGNOSTIC TESTS LOGO

• Complete Blood Count

• Bone Marrow examination
• Arterial Blood Gas analysis
• Leukocyte Alkaline Phosphatase
• P5O
• IVP or renal ultrasound
• Liver ultrasound or CT scan
• Erythropoietin level
• Erythroid progenitor assay
• Sleep apnea evaluation
 LOGO
POLISITEMIA VERA
• Proliferasi klonal neoplastik sel
progenitor hematopoitik pluripoten
• Kriteria diagnosis P.V. :

Kategori A
1.Massa eritrosit:
Lk > 36 ml / kgBB (PCV > 54%)

Pr > 32 ml / kg BB (PCV > 51%)

2. Saturasi oksigen > 92%
3. Splenomegali
 LOGO

Kategori B
1. Trombositosis (> 400.000 / ml)
2. Lekositosis (> 12.000 / ml)
3. Skor LAP
4. B12 serum > 900 pg/ml

• Diagnosis PV bila :
+
A1 ++A2 ++A3 + atau
A1 ++A2 ++dan 2 dari kategori B +
 LOGO
PRIMARY “PURE” ERYTHROCYTOSIS
( ERYTHREMIA )

• peningkatan massa eritrosit murni

• tidak ada penyebab eritrositosis sekunder
• kadar eritropoitin normal atau rendah
• mungkin akibat mutasi gene reseptor
eritropoitin ® progenitor eritroid jadi lebih
sensitif terhadap eritropoitin.
 LOGO
II. ERITROSITOSIS SEKUNDER

• Merupakan respons terhadap keadaan lain

yang bersifat :
- fisiologis : akibat oksigenasi jaringan yang ¯
- non fisiologis : tanpa penurunan oksigenasi
jaringan
 LOGO
III.ERITROSITOSIS RELATIF

• Sindroma Gaisbock
• Stress erythrocytosis
• Pseudo erythrocytosis

- Massa eritrosit tinggi normal

- Volume plasma rendah
LOGO

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 SOAL LATIHAN : LOGO

1. Nyonya Ana, usia 40 tahun, MRS (Masuk Rumah Sakit)

dengan keluhan pusing, dan badan terasa lemah. Pemeriksaan
fisik: KU lemah, Tensi: 100/60 mmHg, Nadi:90 x/menit, RR: 20
x/menit, suhu:37˚C. Kepala/Leher: anemia (+), tidak dijumpai
ikterus, dyspnea dan sianosis, Thorak/Cor dan Abdomen :dalam
batas normal (dbn). Extremitas: dbn. Hasil laboratorium: Hb 8
g/dl, RBC 3,20 x 1012/L, Hematokrit 24 %, MCV 75 fl, MCH 25
pg, MCHC 33 g/dl. Jika anda adalah dokter jaga di RS tersebut,
dari data yang ada, kemungkinan diagnosis pasien tersebut adalah:

A. Anemia normokromik-normositik
B. Anemia hipokromik-mikrositik
C. Anemia makrositik
D. Anemia makrositik-megaloblastik
E. Anemia makrositik-non megaloblastik
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 Lanjutan …...soal latihan LOGO

2. Dari kasus ny. Ana, 40 tahun tersebut, diagnosis diferensial untuk

penyebab anemianya adalah:

A. Anemia defisiensi folat, anemia defisiensi Vitamin B12,

B. Anemia karena perdarahan akut, anemia aplastik
C. Anemia defisiensi besi, thalasemia, anemia sideroblastik
D. Anemia hemolitik, anemia pada penyakit mielofibrosis
E. Anemia pada penyakit liver, anemia pada penyakit hipotiroid

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 Lanjutan …...soal latihan LOGO

3. Dari soal kasus Ny. Ana, 40 tahun tersebut, langkah

pemeriksaan laboratorium selanjutnya yang perlu
dilakukan untuk konfirmasi diagnosis adalah:

A. pemeriksaan bilirubin, haptoglobin, hitung

retikulosit
B. Serum Iron, TIBC dan Feritin
C. Pemeriksaan B12 dan asam folat dalam darah
D. Pemeriksaan T3, T4 dan TSH
E. Pemeriksaan Aspirasi sumsum tulang

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 CLINICAL CASE LOGO

A 35-year-old man complains of chronic physical fatigue, which

began 3-4 weeks ago. He said he felt tired all of the time even
through his occupation as a software developer was mentally but
not physically demanding. He breathed comfortably at rest but,
when he exerted himself, he experienced difficulty in breathing and
had hard time catching his breath. He also complained of „more
than usual” mental fatigue, confessing an increasing inability to
concentrate and focus his attention on tasks at hands. Colleagues
noticed his pallor and his inattentiveness at brainstorming sessions
and suggested he reschedule his annual physical examination for
an earlier date. He complained of vague abdominal pain and sense
of abdominal fullness. His appetite was depressed, and he thought
perhaps his physical and mental symptoms were caused by poor
diet. However, attempts to increase eating resulted in nausea. His
stools, he said, were sometimes loose and tarry. Eventually,
increased heart palpitations and chest pain made him seek medical
advice
Laboratory findings revealed the LOGO

following:
Laboratory test Patient Normal
RBC (red blood cell count) 3.5 T/L 4.5-6.0
T/L
HCT (hematocrit ratio) 28% 40-52%
Hb (hemoglobin) 8.0g/dL 13-17g/dL
MCV (mean corpuscular 70fL 78-95fL
volume)
MCH (mean corpuscular 22.8pg 29pg
hemoglobin)
MCHC (mean corpuscular 28% 34%
hemoglobin concentration)
 QUESTIONS LOGO

Case history questions:

1. What general medical condition is suggested by
the person’s symptoms?
2. What fundamental change in function of blood
related to the red blood cells could
simultaneously affect the function of several
systems (cardiovascular, respiratory,
gastrointestinal, and others)?
3. What specific diagnosis is supported by the
laboratory findings?
4. How could the stool be related to the laboratory
findings?
 ANSWER LOGO

Answers:
1. Anemia
2. A reduction in oxygen-carrying capacity of
the blood and thus a reduction in the delivery
of oxygen to various body tissues
3. An iron defficiency anemia
4. Most cases of iron-defficiency anemia result
from internal blood loss.
Dark, tarry loose stools suggest bleeding
from the gastrointestinal tract and warrant
further tests to determine the exact cause
LOGO

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