PK Anemia dr. Bastiana, SpPK

Report
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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)
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
 Hb ↓
 PCV ↓
 RBC ↓
→ Otak , Otot
Hypoxia
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
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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= 1μm3)
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, Ø 7-8 μ
dengan area central pallor di bagian tengah
CP≤ 1/3 Ø Eri = normokromik
CP> ½ Ø 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=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
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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
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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 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
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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
cell’s 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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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)
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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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LOGO
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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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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
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The development of IDA
• 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
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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
TIBC
N
(1/3 mol.Trsf)
N
IDA
↓
↑
An.of Chronic
Disease
↓
N/↓
↑↑
N/↑
Fe Overload
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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)
– 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)
2. SI
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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 Marrow’s 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, phagocyte’s product , even
storage-Fe is still enough .
2. Inadequate EPO Respons towards
anemia (effects of cytokine production by
macrophage) .
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LOGO
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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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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 )
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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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LOGO
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
synthesis’s defect ) or cytoplasmic maturation ↑
( increase of EPO’s activities ) → critical level of
Hb achieved earlier → Macrocyte
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LOGO
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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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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 ↑.
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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)
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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)
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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 )
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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 ,
fruits)
-Heat labile
-Storage enough only for 3
mths
-Higher folate needs
CAUSE OF DEFICIENCY
CAUSE OF DEFICIENCY
-Vegetarian (seldom)
-Impaired Intrinsic Factor
(pernicious anemia)
-Gastrectomy
-Atropic Gastritis
-Anticonvulsant, alcoholism
LOGO
-Nutrition (alcoholism, goat’s
milk diet)
-Prematurity
-Hemodyalisis
-Bowel resection
-Pregnancy
-Anticonvulsant , MTX
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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 .
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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)
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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 → 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
LOGO
 find oval-Macrocyte cell and hypersegmenteneutrophil .
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Diagnosis of Megaloblastic Anemia
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
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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 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 (+) .
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Definition of Hemolytic Anemia :
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 .
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LOGO
- 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 (+).
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Diagnostic approach in Hemolytic Anemia LOGO
:
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 .
75
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
- Leg’s 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
77
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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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85
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)
87
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Hereditary Spherocytosis :
88
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Hereditary Ovalocytosis :
89
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Lanjutan……klasifikasi 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)
90
- 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.
91
Thalassemia :
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 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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α-Thalassemia
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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)
95
Clinical consequences in α-Thalassemia
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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 β4tetramers (HbH) as intracellular inclusion →
detected by BCB-stain .
96
HbH-inclusion (β4) in HbH Disease as shown
in BCB staining (compare with reticulocyte)LOGO
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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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100
- β-Thalassemia
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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)
101
Β-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 (mongoloid’s eye)
102
- β-chain deletion forms :
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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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104
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)
105
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106
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
107
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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-α-trait : HbH inclusion +
in 1: 10000 eritrosit .
108
Defisiensi G-6PD
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- 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)
109
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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 .
111
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- Substances causing lysis in G-6PD
deficiency :
1. Antimalaria
6. Fava beans
7. Naphtalene
8. Uremia
9. Antibiotics
(Penicilline ,
streptomycine
2. Sulfonamides
3. Vit.K, Vit.C
4. Lung Infection
(virus,bacteria)
5. Antipyreticum
112
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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)
113
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
114
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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
115
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
116
Lanjutan….acquired hemolytic anemia
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 .
117
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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 .
118
Hemolytic Disease of the Newborn (HDN) –
Rh-neg mother , with Rh-Pos fetus , during I and second
pregnancy
119
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Antiglobulin Tests (Coombs) :
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
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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 membrane’s
structure → detected as foreign cell → Autoantibody
production .
121
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122
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
123
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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 .
124
- 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
125
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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 / 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
+
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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
LOGO
• 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: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
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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
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
following:
Laboratory test
Patient
Normal
LOGO
RBC (red blood cell count)
3.5 T/L
HCT (hematocrit ratio)
28%
4.5-6.0
T/L
40-52%
Hb (hemoglobin)
8.0g/dL
13-17g/dL
MCV (mean corpuscular
volume)
MCH (mean corpuscular
hemoglobin)
MCHC (mean corpuscular
hemoglobin concentration)
70fL
78-95fL
22.8pg
29pg
28%
34%
QUESTIONS
1.
2.
3.
4.
LOGO
Case history questions:
What general medical condition is suggested by
the person’s 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
1.
2.
3.
4.
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Answers:
Anemia
A reduction in oxygen-carrying capacity of
the blood and thus a reduction in the delivery
of oxygen to various body tissues
An iron defficiency anemia
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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