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Gangguan Eritrosit:

Anemia

dr. Bastiana SpPK

Gangguan Eritrosit

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Anemia
Polisitemia

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ANEMIA

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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

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Penurunan Hb dan Hct :


< batas bawah 95% interval referens
dari kelompok usia, jenis kelamin
dan lokasi geografis (ketinggian)
Hb12-14 g/dl ; (Hct 36-41%),

Anemia

Hb7g/dl symptom (+)


Akut: hipovolumia (pucat,
ggn penglihatan, syncope, tachycardia) ;
Kronis: tissue hypoxia (fatique, dyspnea,
Headache, angina)

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ANEMIA symptoms / syndrome


Hb
PCV
RBC

Hypoxia Otak , Otot

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 .

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Klasifikasi Anemia

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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


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

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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:

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* 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= 1m3)
N : dewasa = 80-100 fL , di bawah 1 thn = 76- 86 fL
MCV : normositik , mikrositik, makrositik
* Eritrosit dengan variasi ukuran yang abnormal
anisositosis
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Bandingkan ukuran sel eritrosit dengan inti limfosit LOGO

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Perhatikan Warna sel eritrosit

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- 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, 7-8
dengan area central pallor di bagian tengah
CP 1/3 Eri = normokromik
CP> Eri = hipokromik

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Eritrosit dengan central palor (CP)


Bandingkan diameter CP dengan diameter sel eritrosit

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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=1g)
MCH normal normokromik
MCH < normal hipokromik
MCHC (Mean Cell Hb Concentration) :
MCHC=Hb/PCV x 100 (g/dL)
Normal: MCHC = 32-36 g/dL

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Klasifikasi Anemia secara morfologi

1.

Anemia Hipokromik-Mikrositik.

2.

Anemia NormokromikNormositik

3.

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Anemia Makrositik

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Anemia
hipokromikmikrositik

Anemia
normokromiknormositik

Anemia makrositik

Contoh:
- Anemia
defisiensi Fe
- Thalasemia
- Anemia akibat
Penyakit Kronik
- Anemia
sideroblastik

Contoh:
- Anemia pasca
perdarahan akut
- Anemia aplastik
- Anemia hemolitik
- Anemia akibat
penyakit kronik
- Anemia pada
GGK
- Anemia pada
mielofibrosis
- dll

A. Megaloblastik,
contoh:
- Anemia defisiensi
Folat,
- Anemia defisiensi
vitamin B12
B. Nonmegaloblastik
contoh:
- Anemia pd peny.
Hati kronis
- Anemia pd
hipotiroid, dll

MCV <80 fl;


MCH <27 pg

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MCV 80 -95 fl
MCH 27-34 pg

MCV > 95 fl

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Hipokromik-Mikrositik

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Normokronik-normositik

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Makrositik

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

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Pendekatan diagnostik Anemia:

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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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Pemeriksaan Laboratorium
- CBC (complete blood count ) to confirm
anemia (Hb, PCV, RBC) & the type of anemia
(MCV; MCH; MCHC), RDW

- Reticulocyte count reflects marrows 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

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Lanjutan. Pendekatan Doagnostik

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- 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

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Anemia Hipokromik-Mikrositik

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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
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ANEMIA DEFISIENSI BESI

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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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Faktor Penyebab (Etiologi)

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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)

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Lanjutan.Faktor Penyebab
II. Inadequate presentation to erythroid
precursors:
- atransferrinemia
- Anti TrfR Ab

III. Abnormal Fe balance :


- Aceruloplasminemia
- Autosomal dominant hemochromatosis
( mutations in ferroportin )

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Patogenesis desifisiensi Fe

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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
cells membrane RBC deformability RBC
viability RBC destruction especially in spleen
reduced RBC survival

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Status besi tubuh:

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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)

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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)

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Iron Cycle in the body :


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

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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

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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

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Siklus Fe dalam tubuh :

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Diets Iron duodenum / proximal jejunum .


Iron from gut released into circulation ,
bound to transferin distributed to bodys
organ / tissues( to bone marrow as a part of
heme / Hb ) circulate inside red blood cells
with blood flow

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The development of IDA


Stage-1 (prelatent Fe-deficient):
- progressive loss of storage-Fe
- bodys 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

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* Stage-2 (latent Fe-deficient)


- Exhaustion of storage-Fe , RBC
production is still normal , Ferritin
- Circulating-Fe (SI) begin , TransfReceptor .
* Stage-3 (Fe-Deficiency Anemia)
- Stadium of Iron Deficiency Anemia

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Marrow
Ferritin
Transf-Sat
sTrfR
Retic Hb
content
Hb
MCV
Symptoms

Stage-1
(prelatent)

Stage-2
(latent)

Stage-3
(IDA)

N
N
N

(-)
<12ug/L
<16%

(-)
<12ug/L
<16%

N
N
fatigue

N
N
fatigue

<
<
pallor

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Symptoms

Morphology

SI - TIBC

Ferritin

IDA

Anemia

Hypo
Micro

SI TIBC

A.C D

Anemia

Hypo
Micro

SI TIBC
/N

N/

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Pendekatan Diagnostik Anemia Defisiensi Fe

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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)

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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

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SI
Normal

N
(1/3 mol.Trsf)

TIBC
N

IDA

An.of Chronic
Disease

N/

Fe Overload

N/

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Pemeriksaan Lab. Anemia def. Fe

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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 Transferrinbinding sites the excess Fe is fixed by Mgcarbonate Fe-saturated Transferrin is
measured with Ferrozine (= TIBC)

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% 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 )

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4. Transferrin Serum :
measured by immunodiffusion methode
Normal value : 2-4 g/L
5. Bone Marrows Aspirate evaluation :
( using Perls or Prussian Blue stain )

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Anemia of Chronic Infection

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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

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Penyebab menurunnya circulating


Fe :
1. Impairment of Fe release from
macrophage in competing with
lactoferrin, phagocytes product , even
storage-Fe is still enough .
2. Inadequate EPO Respons towards
anemia (effects of cytokine production by
macrophage) .

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Diagnosis Anemia akibat penyakit kronis:

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 .
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Anemia Sideroblastik

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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

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Sideroblast and Ringed Sideroblast ( in


Sideroblastic Anemia )

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Classification of Sideroblastic
Anemia
1. Hereditary : X-linked, defect in hemesynthesis enzyme pathway
Fe absorption % of Transferrin
saturation and Ferritin level

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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 .

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- 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 )

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Macrocytic Anemia
- Non-Megaloblastic Macrocytic Anemia :
Reticulocytosis
Liver disease / Alcoholism
Myelodysplastic Syndrome
Erythroleukemia (FAB-M6)
- Megaloblastic Macrocytic Anemia

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Megaloblastic Macrocytic Anemia


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
synthesiss defect ) or cytoplasmic maturation
( increase of EPOs activities ) critical level of
Hb achieved earlier Macrocyte

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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 )

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Etiology of DNA synthesis defect :


deficiency of vit.B12 and folic acid
maturation dysharmony between nuclei &
cytoplasm (delayed nuclei maturation)
increased cels (megaloblastic changes)
marrows ineffective erythropoiesis
intramedullary hemolysis total/indirect
Bili and LDH .

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Deficiency of Folic acid:


- Inadequate diet
(intake < / demand in pregnancy lactation , childs growth / malabsorption
in tropical sprue / bowel resection / small
intestine inflammation )
- Drugs effect (anti-epilepsi)
- FA loss (dialysis)

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Deficiency of Folic acid:


- Inadequate diet
(intake < / demand in pregnancy lactation , childs growth / malabsorption
in tropical sprue / bowel resection / small
intestine inflammation )
- Drugs effect (anti-epilepsi)
- FA loss (dialysis)

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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 )

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VITAMIN B12

ASAM FOLAT

-Food from animal products


-Heat stabile
-Storage : enough for 3 yrs
-Relatively low needs (only
1% of folate requirements)

-Limited sources (vegetable ,

CAUSE OF DEFICIENCY
-Vegetarian (seldom)
-Impaired Intrinsic Factor
(pernicious anemia)
-Gastrectomy
-Atropic Gastritis
-Anticonvulsant, alcoholism
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fruits)
-Heat labile
-Storage enough only for 3
mths
-Higher folate needs
CAUSE OF DEFICIENCY
-Nutrition (alcoholism, goats
milk diet)
-Prematurity
-Hemodyalisis
-Bowel resection
-Pregnancy
-Anticonvulsant , MTX

Pathogenesis of Megaloblastic Anemia

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

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B12 Metabolism

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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
bodys storage is 2-5 mg (enough for 3 yrs)

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Vit.B12 absorption

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

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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

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Megaloblastic Anemia

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find oval-Macrocyte cell and hypersegmenteneutrophil .

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Diagnosis of Megaloblastic Anemia


Screening :
- CBC , Neutrophils 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
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Anemia Hemolitik

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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

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Normal red cells 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 (+) .

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Definition of Hemolytic Anemia :


anemia caused by shortened red cells
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 .

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- Compensation ability of bone marrow LOGO


:
Ability to red cells production ( 6-8 x normal
):
- survival shorten production 2x
- survival shorten 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 (+).

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Diagnostic approach in Hemolytic


Anemia :
1. Confirm anemia (Hb/PCV/RBC)
an acute case usually acquired , and
chronic case is mostly hereditary .
2.
3.
4.
5.

To find the signs of hemolytic process .


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

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The signs of Hemolytic process :


1. Increased of red cells destruction
- Unconjug.bilirubin serum jaundice
- Urobilinogenuria
- Hb-uria sign of intravascular hemolysis
- Abdom.pain splenomegaly, spleen infarction
- Legs Ulcer intrinsic defect of erythrocyte
- Haptoglobin serum /neg intravascular
hemolisys .

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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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Hemolisis Ekstra vaskular


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)

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Klasifikasi Anemia Hemolitik

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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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lanjutan.Klasifikasi anemia hemolitik :


1. Gangguan intra korpuskular (Hereditary
Hemolytic Anemia )
- Membrane abnormality (hereditary
spherocytosis , hereditary ovalocytosis )
- defect of globin chain (Thalassemia, Hbpathia)
- enzyme defect ( G-6PD deficiency , PKdeficiency)

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Hereditary Spherocytosis :

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Hereditary Ovalocytosis :

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Lanjutanklasifikasi anemia hemolitik

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 :

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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 :
Defect of 1 or more globin-chain synthesis (the
amount = quantitatively) :
- deficiency of globin-chain -thalassemia
- deficiency of globin-chain -thalassemia
- deficiency of globin-chain -thalassemia
the primary defects in Hb-pathia is in the globin
amino acids structure (qualitatively)

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-Thalassemia

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-Thalassemia = is caused by the impairment


of -globin chain production/synthesis .
-globin chain synthesis is directed by 2
pairs of -gene (4 locus -gen) depending
of the number of defected locus 3 types of
-Thalassemia (-thal trait , HbH Disease,
and HbBarts Hydrops Fetalis)

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Clinical consequences in -Thalassemia

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Deficiency of -globin chain excess of ,


chain since fetal life to form 4-tetramers
(HbH) or 4-tetramers (HbBart) .
Defect of 1-2 -Gen = -trait (clinically good)
Defect of 3 -Gen = HbH disease ( Hb 10-11
g/dl) excess of -chain to form 4tetramers (HbH) as intracellular inclusion
detected by BCB-stain .

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HbH-inclusion (4) in HbH Disease as shown


in BCB staining (compare with reticulocyte)LOGO

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Defect of 4 -gene (HbBartshydrops fetalis)


clinically severe , stillborn baby with
hydrops fetalis ( severe hypoxia ) .
HbBarts = 4-tetramers (excess of -chains
that unable to form HbF ) .
HbBarts and HbH inclusions precipitated in
red cells membrane mechanical trapping
in spleen macrophagic phagocytosis
hemolysis .

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- -Thalassemia

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Clinically consequences in -Thalassemia :


- No problems during fetal life because HbF
synthesis is normally produced
(normal and chains)
- When HbA is dominantly needed , the
clinically
problems exist as incapability to synthesize
HbA (22) excess of -chain
compensated of and production
HbA2
(in -Thalassemia minor) and HbF (in
-Thalassemia mayor)
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-Thalassemia mayor :

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- severe anemia repeated transfusion is


oftenly needed Fe hemochromatosis
- chronic ineffective erythropoiesis
medullary hypertrophy in childhood facial
malformation:
* Frontal bossing
* Maxillary hypertrophy
* Hypertelorism (mongoloids eye)

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- -chain deletion forms :

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0-Thalassemia : no -chain
production.
+Thalassemia : -chain production
<<
in heterozygous case : medium severe
in homozygous : severe (Cooleys
anemia)

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Laboratory Diagnosis in Thalassemia

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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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Lanjutan..Lab diagnosis in thalasemia

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3. HbA2 mesurement to diagnose -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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5. HbH Inclusion detection :


- Supravital staining using Brilliant
Cresyl Blue (BCB) or NewMethylene
Blue (NMB)
- HbH inclusion seen as dispersed bluegreen granules in red cells
(compare with reticulocyte as a filament)
- in HbH disease : HbH inclusion +++
- in Thalassemia--trait : HbH inclusion +
in 1: 10000 eritrosit .
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Defisiensi G-6PD
- Oxidant produce H2O2 oxidizing
Hbs 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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- 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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- 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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The highest G-6PD activity is in


reticulocyte .
G-6PD screening test :
Tests principle :
G-6PD
G-6P + NADP

6-PG + NADPH
UV
(fluorescence)

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Acquired Hemolytic Anemia :

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- Secondary Hemolytic Anemia caused by


infection / systemic disorders :
Malignancy Autoimmune-reacted hemolysis
, microangiopathy or hypersplenisme ,
appearing Anemia of chronic disease,
bleeding tendencies, and marrows
suppression

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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

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Acquired Hemolytic Anemia (extracorpusc.)


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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

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Lanjutan.acquired hemolytic anemia

Cell+IgG destructed by spleen


Cell+IgM enhance the activation of
complements cascade intravascular
hemolysis
Immune destruction often cause minimally
membrane damage shape change into
spherocyte .

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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 .

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Hemolytic Disease of the Newborn (HDN)


Rh-neg mother , with Rh-Pos fetus , during I and second
pregnancy

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Antiglobulin Tests (Coombs) :

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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 (.

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Drug-Induced hemolytic anemia :

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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 membranes
structure detected as foreign cell Autoantibody
production .

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Aplastic (Hypoplastic?) Anemia


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

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 :


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

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POLISITEMIA
(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% )

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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

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

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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

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Kategori B
1. Trombositosis (> 400.000 / l)
2. Lekositosis (> 12.000 / l)
3. Skor LAP
4. B12 serum > 900 pg/ml
Diagnosis PV bila :
+
A1 +
+A2 ++ A3 + atau
A1 +
A2
+
dan
2
dari
kategori
B
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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.

II. ERITROSITOSIS SEKUNDER

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Merupakan respons terhadap keadaan lain


yang bersifat :
- fisiologis : akibat oksigenasi jaringan yang
- non fisiologis : tanpa penurunan oksigenasi
jaringan

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III.ERITROSITOSIS RELATIF
Sindroma Gaisbock
Stress erythrocytosis
Pseudo erythrocytosis
- Massa eritrosit tinggi normal
- Volume plasma rendah

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SOAL LATIHAN :

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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:37C. 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

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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

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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

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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

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Laboratory findings revealed the
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


volume)

70fL

78-95fL

MCH (mean corpuscular


hemoglobin)

22.8pg

29pg

MCHC (mean corpuscular


hemoglobin concentration)

28%

34%

QUESTIONS
1.
2.

3.
4.

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Case history questions:


What general medical condition is suggested by
the persons symptoms?
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)?
What specific diagnosis is supported by the
laboratory findings?
How could the stool be related to the laboratory
findings?

ANSWER

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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

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