MASTER UKMPPD OPTIMA

I P D - H E M AT O L O G I
DR. MARCELA YOLINA
Jakarta
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w w w. o p t i m a p r e p . c o . i d
ANEMIA
DASAR TEMUAN ANEMIA
 Definisi Anemia
• Menurut WHO, anemia merupakan keadaan dimana terjadi pengurangan jumlah
sel darah merah, baik itu dalam kadar hemoglobin dan atau hematokrit, selama
volume darah total dalam batas normal
• WHO: Hb concentration 2 SDs below the mean Hb concentration for a normal
population of the same gender and age range.
• Secara umum, kriteria anemia pada orang dewasa adalah Hb <13.5 g/dL untuk
laki-laki dan Hb < 12 g/dL untuk perempuan.
• WHO 1968 kriteria anemia Hb <13 g/dL (laki-laki) dan Hb< 12 g/dL (perempuan)
 digunakan utk studi nutrisi internasional
• The revised WHO/National Cancer Institute kriteria anemia Hb <14 g/dL (laki-laki)
dan Hb< 12 g/dL (perempuan)  digunakan utk evaluasi anemia sebagai
komplikasi kemoterapi
• Kriteria ini bisa sedikit berbeda tergantung populasi dan standar laboratorium

Uptodate. 2017
Gejala Anemia
• Gejala dapat bervariasi
• Pada anemia karena kehilangan
darah yang akut, lemah atau
pun tidak sadar.
• Sementara pada keadaan
pendarahan kronisbadan
lemah atau bahkan tidak
bergejala sama sekali.
• Pada anemia hemolisis
perubahan warna kulit menjadi
warna kuning (ikterus) karena
proses hemolisis yang
menghasilkan bilirubin
Riwayat Penyakit yang Berguna untuk
Diagnosis Anemia
 Indeks Eritrosit
• Red cell indices/ Indeks eritrosit/
indeks kospouskuler adalah batasan
untuk ukuran dan isi hemoglobin
eritrosit.
• terdiri atas :
– (MCV : mean corpuscular volume)
– (MCH : mean corpuscular hemoglobin)
– (MCHC : mean corpuscular
hemoglobin)
– (RDW : RBC distribution width atau
luas distribusi eritrosit)  perbedaan/
variasi ukuran
• Indeks eritrosit dipergunakan secara
luas dalam mengklasifikasi anemia
atau sebagai penunjang dalam
membedakan berbagai macam
anemia.
• mean corpuscular volume (MCV)
– Volume/ ukuran eritrosit :
mikrositik (ukuran kecil),
normositik (ukuran normal), dan
makrositik (ukuran besar).
• mean corpuscular hemoglobin (MCH)
– bobot hemoglobin di dalam
eritrosit tanpa memperhatikan
ukurannya.
• mean corpuscular hemoglobin
concentration (MCHC)
– konsentrasi hemoglobin per unit
volume eritrosit.
• Hipokrom: MCH ˂ normal
• Hiperkrom: MCH ˃ normal
• Mikrositik: MCV ˂ normal
• Makrositik: MCV ˃ normal
 Parameter Pengukuran Anemia

Measurement Normal Range

A. RCC (Jml Eri) 5 million 4 to 5.7
B. Hemoglobin 15 g% 12 to 17
C. Hematocrit 45 % 38 to 50

MCV C ÷ A x 10 = 90 fl
MCH B ÷ A x 10 = 30 pg
MCHC (%) B ÷ C x 100 = 33%
www.drsarma.in
Anemia Berdasarkan MCV dan MCH
 Retikulosit
• Retikulosit : eritrosit muda yang masih
mengandung sisa ribosome + RNA dari sisa inti dari
prekursornya (sel darah muda).
• Jumlah retikulosit yg meningkat menunjukkan
kemampuan respon sumsum tulang ketika
mengalami anemia
• Indikator aktivitas sumsum tulang:
– Peningkatan jumlah retikulosit di darah tepi • RETICULOCYTE COUNT:
menggambarkan akselerasi produksi eritrosit dalam
persentase retikulosit dari
sumsum tulang, misal pada anemia hemolisis dan
anemia perdarahan. total jumlah eritrosit (Normal
– hitung retikulosit yang rendah dapat mengindikasikan 0.5-1.5% )
keadan hipofungsi sumsum tulang seperti anemia • RETICULOCYTE INDEX:
aplastik, defisiensi besi, defisiensi B12, dsb. penyesuaian reticulocyte
• Hati-hati! Karena retikulosit berukuran 20% lebih count berdasarkan
besar, pada anemia dengan retikulosit yang hematokrit yang didapatkan
meningkat bisa didapatkan MCV (dan RDW) yang (RI = Reticulocyte Count x (Ht
meningkat pula / normal Ht); nilai normal RI
http://www.fpnotebook.com/
1-3%)
 RDW (RBC
Distribution Width)
• Mengukur variasi ukuran eritrosit  perbedaan
ukuran  jika nilainya besar berarti anisositosis
www.studyblue.com
 • Pappenheimer bodies are abnormal granules of iron found inside
red blood cells on routine blood stain. They are a type of inclusion
body formed by phagosomes that have engulfed excessive
amounts of iron .

Eritrosit Normal
 High-power view of a normal peripheral blood smear. Several platelets (arrows) and a normal
lymphocyte (arrowhead) can also be seen. The red cells are of relatively uniform size and shape.
The diameter of the normal red cell should approximate that of the nucleus of the small
lymphocyte; central pallor (dashed arrow) should equal one-third of its diameter.
Basophilic stippling : Coarse basophilic
stipplingindicates impaired hemoglobin
synthesis, probably due to the instability of
RNA in the young cell.
Howell-Jolly bodies: inclusions of nuclear
chromatin remnants.
 Target Cell
• Target Cells (Codocytes) are RBCs that have the
appearance of a shooting target with a bullseye.
• Target cell have a dark center (a central,
hemoglobinized area) surrounded by a white ring
(an area of relative pallor), followed by dark outer
(peripheral) second ring containing a band of
hemoglobin.
• Target cells are more resistant to osmotic lysis
and abnormally resistant to saline.
• Hypochromic cells in iron deficiency anemias also
can show a target appearance.
 Target cell can be found in:
• Liver disease:
– Lecithin—cholesterol acyltransferase (LCAT) activity may be decreased
in obstructive liver disease  increases the cholesterol to
phospholipid ratio, producing an absolute increase in surface area of
the red blood cell membranes.
• Iron deficiency:
– Decrease in hemoglobin content relative to surface area is probably
the reason for the appearance of target cells.
• Alpha-thalassemia and beta-thalassemia
• Hemoglobin C Disease
• Post-splenectomy
• Myelofibrosis
• Cancer in the bone marrow
• Anemia caused by bone marrow not producing normal blood cells
due to toxins or tumor cells (myelophthisic process)
Target Cell
ANEMIA DEFISIENSI BESI
ANEMIA MIKROSITIK HIPOKROM
 Anemia Mikrositik Hipokrom

MCV & MCH ↓

GDT

Besi serum

Besi serum ↑ Besi serum N/↑ Besi serum ↓

Besi sumsum tulang  Pemeriksaan Hb F/A2 Kadar ferritin

Ferritin↓ Ferritin N/↑

Anemia sideroblastik Talasemia, Kelainan Hb Defisiensi besi penyakit kronik

 Anemia Defisiensi Besi
Kegagalan pembentukan Hb akibat defisiensi besi yang berperan
dalam pembentukan heme.

Tanda Anemia Defisiensi Besi

Kuku Spoon nail (koilonychia)
Lidah Atrofi papila lidah
Mulut Keilitis angularis, pagophagia (e.g crave ice to suck or chew)
Hipofaring Dysphagia, upper (postcricoid) esophageal webs, and iron
deficiency anemia, disebut Plummer-Vinson syndrome (PVS) di
AS dan Paterson-Brown Kelly syndrome di Inggris
Gaster Gastritis akibat infeksi kronik H. Pylori, aklorhidria (absence of
hydrochloric acid in gastric secretions)  bisa menyebabkan ADB

Emedicine
Anemia Defisiensi Besi

Hoffbrand essential hematology.

 Polypohenols present in tea, coffee and wine,
Phosphates and phosphoproteins present in
egg yolk, bovine milk

LUMINAL
IRON ABSORPTION

BASOLATERAL SURFACE
Penggunaan Besi
dalam Tubuh
Penyimpanan Besi
 Anemia
Defisiensi
Besi
Stadium Anemia Defisiensi Besi

Harrison’s principles of internal medicine.

 Profil Zat Besi
• Ferritin
– Ferritin : intracellular protein which safely stores excess
iron.
– Tiny amounts of ferritin can be detected in serum 
measured surrogate for body iron stores
– Serum ferritin shows an acute phase response and can be
elevated in a variety of inflammatory, metabolic,hepatic
and neoplastic disorders difficult to recognise iron
deficiency in patients with inflammatory disorders
– normal range for serum ferritin is generally regarded as
15- 300μg/l.
 Profil Zat Besi
• Total iron binding capacity
– is a measurement of the maximum amount of iron that can be carried.
– Indirect measurement of transferrin.

• Transferrin saturation
– The most useful test in assessing iron supply to the tissues
– Transferrin is a glycoprotein synthesised in the liver and is responsible
for the transportation of iron (Fe3+) in serum
– In iron deficiency anaemia, the serum iron level falls. As a result the liver
is stimulated to synthesise more transferrin and the transferrin
saturation falls (usually <15%).
– Transferrin saturation is obtained by the following formula: serum iron
x 100 ÷ TIBC  Normal range 25–50%,
 Profil Zat Besi
• Serum iron concentration is a measurement of
circulating iron (Fe³+) bound to transferrin
• Only 0.1% of total body iron is bound to transferrin
at any one time
 Conclusion: Iron Panel

NB: Pemeriksaan TIBC memiliki ketersediaan yang lebih luas dibandingkan pemeriksaan Transferin
Gambaran Darah Tepi Anemia Defisiensi Besi
 Tatalaksana ADB
• The recommended daily dose for the treatment of iron deficiency in
adults has been in the range of 150 to 200 mg of elemental iron
daily
• Sediaan oral:
– Ferrous sulfate (contains 20% elemental iron per mg of mineral salt)
– Ferrous fumarat (contains 33% elemental iron per mg of mineral salt)
– Ferrous gluconate (contains approximately 10 to 14% elemental iron
per mg of mineral salt)
• Lama terapi oral
– Selama 6-12 bulan Atau sampai Hb normal + 8 minggu (WHO)
– dapat ditambah suplemen vitamin C untuk menambah penyerapan
besi
• Transfusi PRC dibutuhkan
– bila Hb < 6g/dl atau
– Hb > 6g/dl dengan penyerta (dehidrasi, persiapan operasi, infeksi
berat, gagal jantung dan distress pernapasan)
 Tx: Intravenous Iron Indication
• Patients who are unable to tolerate
gastrointestinal side effects of oral iron.
• Patients with severe/ongoing blood loss (eg,
telangiectasias, varices).
• Gastric surgery (bypass, resection) that reduces
gastric acid may severely impair intestinal
absorption of oral iron.
• Malabsorption syndromes (celiac disease,
Whipple's disease, bacterial overgrowth) may
limit absorption of oral iron.
Uptodate. 2017
 Response & Monitoring
• In patients with moderate to severe anemia, a modest reticulocytosis will
be seen, peaking in approximately 7 to 10 days.
• The hemoglobin concentration will rise slowly, usually beginning after
approximately one to two weeks of treatment, and will rise
approximately 2 g/dL over the ensuing three weeks.
• The hemoglobin deficit should be halved by approximately one month,
and the hemoglobin level should return to normal by six to eight weeks.
• For patients receiving oral iron, re-evaluate the patient two weeks after
starting: hemoglobin and reticulocyte count.
• For IV iron, we generally see patients four to eight weeks after the iron
has been administered.
• Iron is generally given until levels of ferritin and transferrin saturation
normalize.
Uptodate. 2017
THALASSEMIA
ANEMIA MIKROSITIK HIPOKROM
 Anemia Mikrositik Hipokrom

MCV & MCH ↓

GDT

Besi serum

Besi serum ↑ Besi serum N/↑ Besi serum ↓

Besi sumsum tulang  Pemeriksaan Hb F/A2 Kadar ferritin

Ferritin↓ Ferritin N/↑

Anemia sideroblastik Talasemia, Kelainan Hb Defisiensi besi penyakit kronik

 Hemoglobin Defects
• Heme and globin chains (alpha and beta) in adults are
manufactured in separate cell compartments—mitochondria
and cytoplasm, respectively—and then combined in
cytoplasm in an amazingly accurate manner.
• Four major problems can manifest during this delicate
process:
– Qualitative defects of globin chain synthesis 
hemoglobinopathies such as sickle cell disease.
– Quantitative defects of globin chain synthesis 
hemoglobinopathies such as thalassemia.
– Defects in synthesis of the heme portion  porphyrias.
– Defects involving incorporation of iron into the heme molecule
 sideroblastic anemias.
 THALASSEMIA
• Penyakit genetik dgn supresi produksi hemoglobin karena defek pada
sintesis rantai globin (pada orang dewasa rantai globin terdiri dari
komponen alfa dan beta)
• Diturunkan secara autosomal resesif
• Secara fenotip: mayor (transfusion dependent), intermedia (gejala klinis
ringan, jarang butuh transfusi), minor/trait (asimtomatik)
• Secara genotip:
– Thalassemia beta (kromosom 11, kelainan berupa mutasi)  yang mayoritas
ditemukan di Indonesia
• Tergantung tipe mutasi, bervariasi antara ringan (++, +) ke berat (0)
– Thalassemia alfa (Kromosom 16, kelainan berupa delesi)
• -thal 2 /silent carrier state: delesi 1 gen
• -thal 1 / -thal carrier: delesi 2 gen: anemia ringan
• Penyakit HbH: delesi 3 gen: anemia hemolitik sedang, splenomegali
• Hydrops foetalis / Hb Barts: delesi 4 gen, mati dalam kandungan
Wahidiyat PA. Thalassemia and hemoglobinopathy.
 Klasifikasi
α-Thalassemia syndromes
Number of α-Globin Syndrome Hematocrit MCV
Genes Transcribed
4 Normal Normal Normal
3 Silent carrier Normal Normal
2 Thalassemia minor (or Trait) 28–40% 60–75 fL
1 Hemoglobin H disease 22–32% 60–70 fL
0 Hydrops fetalis

Β-Thalassemia syndromes
α-Globin Genes Hb A Hb A2 Hb F Transfusions
Transcribed
Normal Homozygous β 97–99% 1–3% <1%

Thalassemia minor Heterozygous β0 80–95% 4–8% 1–5% None

Heterozygous β++ 80–95% 4–8% 1–5% None

Thalassemia Homozygous β++ 0–30% 0–10% 6–100% Occassional

intermedia (mild)

Thalassemia major Homozygous β0 0% 4–10% 90–96% Dependent

Thalassemia major Homozygous β++ 0–10% 4–10% 90–96% Dependent

Papadakis MA, McPhee SJ. Current Medical Diangnosis and Treatment.2014. New York : McGraw-Hill Companies
 http://elcaminogmi.dnadirect.com/grc
/patient-site/alpha-thalassemia-

Pewarisan Genetik Thalassemia-β

carrier-screening/genetics-of-alpha-
thalassemia.html?6AC396EC1151986D
584C6C02B56BBCC0

Penurunan genetik
thalassemia beta jika kedua
orang tua merupakan
thalassemia trait

NB: need
two genes
(one from
each parent)
to make
enough beta
globin
protein
chains.
   

2 2   4

2  2 = 97 %
(Hb A)
2 2  4
(Hb H)
 

   2  2 (Hb F) 
  2  2 (Hb F)< 1 % 2  2   4 (Hb Bart`s)
 2  2 (Hb A2) 2-3 %    2  2 (Hb A2) 
 2  2  4 ?

Normal  - Thal  - Thal

  
Excess

22 Precipitation Fe free radicals

HbF
Selective survival of Haemolysis Destruction of RBC precursors
HbF-containing cells

Splenomegaly Ineffective
(pooling, plasma Erythropoiesis
volume
High oxygen expansion)
affinity of red cells

Tissue hypoxia
Anaemia
Erythopoietin

Marrow expansion Transfusion

Increased iron
absorption
Bone deformity
Increased metabolic rate
Iron loading
Wasting
Gout
Folate deficiency Endocrine deficiencies
Cirrhosis
Cardiac failure
Death
Modified from Weatherall, DJ

The pathophysiology of  thalassaemia

Post Graduate Haematology, 1999
 ANAMNESIS + TEMUAN KLINIS

• Pucat kronik
• Hepatosplenomegali
• Ikterik
• Perubahan penulangan
• Perubahan bentuk wajah
 facies cooley
• Hiperpigmentasi kulit
akibat penimbunan besi
• Riwayat keluarga +
• Riwayat transfusi
• Ruang traube terisi
• Osteoporosis
• “Hair on end” pd foto
kepala
 Hepatosplenomegali & Ikterik

Pucat

Hair on End

Hair on End & Facies Skully

Excessive iron in a bone marrow preparation

 Diagnosis thalassemia
(cont’d)
• Pemeriksaan darah
– CBC: Hb , MCV , MCH , MCHC , Rt ,
RDW  
– Apusan darah: mikrositik, hipokrom,
anisositosis, poikilositosis, sel target,
fragmented cell, normoblas +, nucleated
RBC, howell-Jelly body, basophilic
stippling
– Hiperbilirubinemia
– Tes Fungsi hati abnormal (late findings
krn overload Fe)
– Tes fungsi tiroid abnormal (late findings
krn overload Fe)
– Hiperglikemia (late findings krn overload
Fe)

• Analisis Hb peripheral blood smear of patient with homozygous beta

– HbF , HbA2 n/, Tidak ditemukan HbA,
Hb abnormal (HbE, HbO, dll), Jenis Hb
kualitatif
thalassemia with target cells, hypochromia, Howell-Jolly
bodies, thrombocytosis, and nucleated RBCs.Image from
Stanley Schrier@ 2001 in ASH Image Bank 2001;
doi:10.1182/ashimagebank-2001-100208)
Thalassemia
 Tata laksana thalassemia
• Transfusi darah, indikasi pertama kali • Splenektomi  jika memenuhi
jika: kriteria
– Hb<7 g/dL yg diperiksa 2x berurutan
dengan jarak 2 minggu • Splenomegali masif
– Hb>7 disertai gejala klinis spt facies • Kebutuhan transfusi PRC > 200-220
cooley, gangguan tumbuh kembang ml/kg/tahun
• Transfusi darah selanjutnya jika hb<8
g/dL SAMPAI kadar Hb 10-11 g/dL • Transplantasi (sumsum tulang,
(dlm bentuk PRC rendah Leukosit) darah umbilikal)
• Medikamentosa • Fetal hemoglobin inducer
– Asam folat (penting dalam
pembentukan sel) 2x 1mg/hari (meningkatkan Hgb F yg
– Kelasi besi  menurunkan kadar Fe membawa O2 lebih baik dari Hgb
bebas dan me<<< deposit hemosiderin).
Dilakukan Jika Ferritin level > 1000 A2)
ng/ul, atau 10-20xtransfusi, atau
menerima 5 L darah. • Terapi gen
– Vitamin E (antioksidan karena banyak
pemecahan eritrosit  stress oksidatif
>>)
– Vitamin C (dosis rendah, pada terapi
denga n deferoxamin)
• Nutrisi: kurangi asupan besi
• Support psikososial
ANEMIA SIDEROBLASTIK
ANEMIA MIKROSITIK HIPOKROM
 Anemia Mikrositik Hipokrom

MCV & MCH ↓

GDT

Besi serum

Besi serum ↑ Besi serum N/↑ Besi serum ↓

Besi sumsum tulang  Pemeriksaan Hb F/A2 Kadar ferritin

Ferritin↓ Ferritin N/↑

Anemia sideroblastik Talasemia, Kelainan Hb Defisiensi besi penyakit kronik

 Sideroblastic Anemia
• Defects involving incorporation of iron into the heme molecule
result in sideroblastic anemias
• The body has iron available but cannot incorporate it into
hemoglobin, which red blood cells need to transport oxygen
efficiently
• In some instances, both the synthesis of heme and the
incorporation of iron can be altered, and the result is a porphyria
with sideroblasts.
• Sideroblastic anemia is primarily a laboratory diagnosis, made on
the basis of bone-marrow examination with Prussian blue stain.
– Atypical, abnormal nucleated erythroblasts with granules of iron
accumulated in perinuclear mitochondria .
 Sideroblastic Anemia: Etiology
• Congenital
– X-linked recessive
– Autosomal recessive
– Mitochondrially inherited
• Acquired
– Clonal/neoplastic
• Myelodysplastic/myeloproliferative neoplasm with ring
sideroblasts
– Metabolic/reversible
• Alcoholism
• Drugs (eg, isoniazid, chloramphenicol, linezolid)
• Copper deficiency (zinc toxicity)
• Hypothermia
bone marrow aspirate stained with Prussian
blue to show red cell precursors with numerous
iron- positive granules surrounding the nucleus,
in some cases forming a complete ring (arrows).

Peripheral blood smears from

two patients with sideroblastic
anemia. Left panel: Mild degree
of changes, consisting mainly of
a small number of hypochromic
red cells. Right panel: Severe
changes, including hypochromia,
microcytosis, and many
misshapen red cells. (Wright's
stain)
A N E M I A D E F. A S A M F O L AT
& V I TA M I N B 1 2
ANEMIA MAKROSITIK
Anemia Makrositik

Wintrobe Clinical Hematology. 13 ed.

Absorbsi Vitamin B12
 Defisiensi vitamin B12
• Anemia makrositik megaloblastik disebabkan oleh defisiensi vit B12 dan
asam folat. Keduanya memberi gambaran makro-ovalosit dan neutrofil
hipersegmentasi.

• Gangguan pembentukan DNA akibat defisiensi vitamin tersebut

mengakibatkan kematian sel darah di sumsum tulang, yang dapat
memberi gambaran pansitopenia serta ikterus (hiperbilirubinemia indirek)

• Gejala anemia yang timbul, antara lain cepah lelah dan pucat, kekuningan.

• Gangguan neurologi hanya terjadi pada defisiensi vitamin B12, tidak pada
defisiensi folat. Gejala neurologi yang ditemukan:
– Neuropati perifer: kesemutan, kebas, lemas
– Kehilangan sensasi proprioseptif (posisi) dan getaran
– Gangguan memori, depresi, iritabilitas
– Neuropati optik: penglihatan kabur, gangguan lapang pandang
 Etiologi Defisiensi Vitamin B12
• Pernicious anemia (lack of intrinsic factor)—
most common cause in the Western
hemisphere -- caused by autoantibodies that
interfere with vitamin B12 absorption by
targeting intrinsic factor (IF), gastric parietal
cells, or both.
• Gastrectomy / Bariatric surgery
• Poor diet (e.g., strict vegetarianism); alcoholism
• Crohn’s disease, ileal resection (terminal
ileum approximately the last 100 cm)
• Other organisms competing for vitamin B12
 Diphyllobothrium latum infestation (fish tapeworm)
 Blind-loop syndrome (bacterial overgrowth)
• Penurunan asam lambung dapat menghambat
absorbsi vitamin B12
• Metformin dapat menyebabkan defisiensi
vitamin B12 .
Defisiensi Vitamin B12
 Diagnosis Defisiensi Vitamin B12
• MCV meningkat, hitung retikulosit rendah
• Apusan darah tepi
Makroovalosit (sel eritrosit besar dan berbentuk oval)
Hypersegmented neutrofil
• Vit B 12 serum rendah (< 100pg/mL)
• Meningkatnya kadar asam metilmalonic dan
homosistein
• Antibodi thdp faktor intrinsik (pd anemia pernisiosa)
• Schiling test
 Hipersegmentasi (segmen 5/lebih)

Makro-ovalosit pada anemia

makrositik megaloblastik
 Methylmalonic Acid (MMA) &
Homocysteine
• Can be used for cases in which initial test results for vitamin B12 and/or folate
levels are borderline or inconclusive, or if clinical findings are discordant with
initial testing values
• THF/ tetrahydrofolate participates in homocysteine but not MMA metabolism.
Where as Cobalamin participate both in homocysteine and MMA metabolism
• Thus, B12 deficiency is characterized by elevations in the serum levels of both
homocysteine and MMA metabolism, while only homocysteine levels are
elevated in folate deficiency.
• Interpretation:
– MMA and homocysteine normal – No deficiency of vitamin B12 or folate.
– MMA and homocysteine elevated – Deficiency of vitamin B12 (does not
eliminate the possibility of folate deficiency).
– MMA normal, homocysteine elevated – No deficiency of vitamin B12. Consistent
with deficiency of folate.
Tx Defisiensi • Vitamin B12 and folic acid can be
administered orally or
Vitamin B12 parenterally.
• For vitamin B12, formulations
are available for
intramuscular/deep
subcutaneous injection and oral,
sublingual, and nasal
administration.
• For folic acid, formulations are
available for intravenous,
intramuscular, and subcutaneous
use, as well as oral ingestion.
• Numerous treatment regimens
have been proposed, including
cobalamin 1000 mcg IM/SC daily
for 5 days followed by 1000
mcg/wk for 5 weeks, then 100-
1000 mcg/mo for life.
 Defisiensi Vitamin B9

Clinical laboratory hematology. 3rd ed.

Folic Acid Deficiency
A N E M I A P E N YA K I T K R O N I K
ANEMIA NORMOSITIK NORMOKROM
Anemia Normositik

Wintrobe Clinical Hematology. 13 ed.

 Anemia Penyakit Kronis
• Inflammatory anemia or
anemia of chronic disease is
a disorder of iron
homeostasis promoted by
hepcidin-25 in response to
an inflammatory condition.
• The anemia is usually
normocytic and
normochromic; it is
microcytic and hypochromic
in less than 25 percent of
the cases
 Anemia
Penyakit
Kronik
(block iron
release from
macrophage)
• Proinflammatory cytokines 
hepcidin  from liver
• Hepcidin block iron release
from macrophage in order to
limit iron serum from being
used by bacteria and also
deacreasing iron absorption
from GI tract A proposed mechanism for the anemia of chronic disease (ACD) is shown here. In the
presence of infection, inflammation, or malignancy, the macrophage is stimulated to
• If inflammation doesn’t produce interleukin-6 (IL-6) and interleukin-1 beta (IL-1β), which induce the production
of hepcidin by the liver. Hepcidin, in turn, through its interaction with the iron export
resolve  normocytic protein ferroportin, inhibits iron absorption from the gastrointestinal tract and
normochromic anaemia  decreases release of iron from macrophages. Both effects lead to the reduced plasma
iron levels (hypoferremia) characteristic of ACD. Inflammatory cytokines such as IL-1β
microcytic hypochromic and TNF-α reduce erythropoietin production and the efficiency of erythropoiesis, which
are also components of ACD.
anaemia Uptodate
 Section of a bone marrow aspirate taken from a patient with the anemia of chronic disease. The slide
has been stained for iron (Prussian blue reaction) and counterstained with safranin to show nuclear
detail. Note the increased iron staining within the voluminous cytoplasm of macrophages (thick black
arrows), while there is no staining for iron within the cytoplasm of red blood cell precursors (thin black
arrows). This pattern (abundant iron in macrophages and reduced to absent iron in red cell precursors)
is quite typical for the anemia of chronic disease, and contrasts with iron deficiency, in which iron is
absent from both macrophages and red cell precursors, while normal subjects demonstrate iron in
macrophages and red cell precursors.
 Conclusion: Iron Panel

NB: Pemeriksaan TIBC memiliki ketersediaan yang lebih luas dibandingkan pemeriksaan Transferin
ANEMIA HEMOLITIK
ANEMIA NORMOSITIK NORMOKROM
Anemia Normositik

Wintrobe Clinical Hematology. 13 ed.

 Anemia hemolitik
• Hemolysis is the destruction or removal of red
blood cells from the circulation before their
normal life span of 120 days
• Hemolysis presents as acute or chronic
anemia, reticulocytosis, or jaundice.
• Premature destruction of erythrocytes occurs
intravascularly or extravascularly
• The etiologies of hemolysis often are
categorized as acquired or hereditary
• There are two mechanisms of hemolysis.
1. Intravascular hemolysis
• destruction of red blood cells in the circulation with the release of
cell contents into the plasma.
• Mechanical trauma from a damaged endothelium, complement
fixation and activation on the cell surface, and infectious agents
may cause direct membrane degradation and cell destruction.

2. Extravascular hemolysis
• the removal and destruction of red blood cells with membrane
alterations by the macrophages of the spleen and liver.
• Circulating blood is filtered continuously through thinwalled
splenic cords into the splenic sinusoids (with fenestrated
basement membranes), a spongelike labyrinth of macrophages
with long dendritic processes
Anemia Hemolitik
AIHA
ANEMIA NORMOSITIK NORMOKROM - HEMOLITIK
 Klasifikasi AIHA
Anemia hemolitik autoimun (AIHA)
• AIHA tipe hangat: diperantai oleh IgG, berikatan dengan antigen
permukaan sel eritrosit pada suhu tubuh.
– Idiopatik
– Sekunder: leukemia, limfositosis kronis (LLK), limfoma, lupus eritematosus
sistemik (LES)
• AIHA tipe dingin: diperantarai oleh IgM, berikatan dengan antigen
permukaan sel eritrosit pada sihu dibawah suhu tubuh.
– Idiopatik
– Sekunder: infeksi Mycoplasma, mononucleosis, keganasan limforetikuler
• Paroksismal cold hemoglobinuria
– Idiopatik
– Sekunder: sifilis
• AIHA atipik
– AIHA tes antiglobulin negatif
– AIHA kombinasi tipe hangat dan dingin
 Klasifikasi AIHA
• AIHA diinduksi obat:
– golongan penisilin, kinin, kuinidin, sulfonamid,
sulfonilurea, tiazid, metildopa, nitrofurantoin,
fenazopiridin, asam aminosalisilat (aspirin)

• AIHA diinduksi aloantibodi:

– Reaksi hemolitik transfusi
– Penyakit hemolitik pada bayi baru lahir.
 Anemia Hemolitik Autoimun (AIHA)
• Anemia hemolitik autoimun
merupakan anemia yang
disebabkan oleh
penghancuran eritrosit oleh
autoantibodi.
• Dibagi menjadi :
– Primer : tanpa adanya
underlying disease
– Sekunder: ada underlying
diseas, seperti limfoma, Evans
syndrome, SLE,
antiphospholipid syndrome,
IBD.
Hematology: basic& principle practice, Ed.6
• Onset dapat gradual atau
subakut, berupa mudah
lelah, sesak napas, malaise,
ikterik. Pada pemeriksaan
fisik dapat ditemuan
organomegali.
• Hasil lab:
– Anemia NN
– Retikulositosis (>2%)
– Peningkatan LDH
– Peningkatan bil.indirek
– Direct antiglobulin test (DAT)/
Coombs test  untuk
membedakan anemia
hemolitik autoimun dengan
non-autoimun.
 Tatalaksana Anemia Hemolitik
Autoimun (AIHA)
LINI PERTAMA: KORTIKOSTEROID
• Steroid dimulai dengan dosis
inisial Prednison 1 mg/kg/hari
oral atau dapat diberikan
metilprednnisolon iv.
• Dosis inisial diberikan hingga Hb
>10 g/dl.
• Bila target Hb tidak tercapai
dalam 3minggu pemberian
steroid , maka perlu
dipertimbangkan terapi lini
kedua.
• Setelah target Hb tercapai,
dilakukan tappering down
Prednison hingga 20-30 mg/hari
dalam beberapa minggu.
How I treat autoimmune hemolytic anemias in adults
http://www.bloodjournal.org/content/116/11/1831?sso-checked=true#F1
LINI KEDUA
• Terapi lini kedua yang
memberikan efikasi paling baik
adalah splenektomi dan anti-
CD20 (Rituximab).
TERAPI LAINNYA
• Pada AIHA yang refrakter, dapat
digunakan imunosupresan
(seperti Azathiopirine,
Cyclosporine, Mycofenolate
mofetil) dan pemberian
Cyclophosphamide dosis tinggi.
ANEMIA DEFISIENSI G6PD
ANEMIA NORMOSITIK NORMOKROM - HEMOLITIK
 Anemia Defisiensi G6PD
• Defisiensi Glukosa-6-FosfatDehidrogenase (G6PD) merupakan enzimopati
terkait kromosom X yang paling umum diderita manusia.
• Prevalensi tinggi terutama di daerah endemis malaria termasuk Asia
Tenggara  Indonesia
• Defisiensi G6PD diturunkan melalui kromosom X
• Gen G6PD terletak pada regio telomerik lengan panjang kromosom X
(band Xq28), dekat dengan gen hemofi lia A, diskeratosis kongenital dan
buta warna

Kurniawan LB. Skrining, Diagnosis dan Aspek Klinis Defi siensi Glukosa-6-FosfatDehidrogenase (G6PD). CDK-222/ vol. 41 no. 11, th. 2014
 Patogenesis defisiensi G6PD
• Glukosa-6-fosfat dehidrogenase (G6PD)  enzim pengkatalisis reaksi
pertama jalur pentosa fosfat dan memberikan efek reduksi pada semua
sel dalam bentuk NADPH
• NADPH memungkinkan sel-sel bertahan dari stres oksidatif yang dapat
dipicu oleh beberapa bahan oksidan dan menyediakan glutathione
dalam bentuk tereduksi
• Eritrosit tidak memiliki mitokondria  jalur pentosa fosfat merupakan
satu-satunya sumber NADPH  pertahanan terhadap kerusakan
oksidatif tergantung pada G6PD
What happens in G6PD deficiency?
 Manifestasi Klinis
• Sebagian besar penderita defisiensi G6PD bersifat asimtomatik
• Gejala muncul bila eritrosit mengalami stres oksidatif dipicu obat,
infeksi, maupun konsumsi kacang fava.
• Manifestasi Klinis berupa anemia hemolitik akut yang diinduksi obat
maupun infeksi, favisme, ikterus neonatorum maupun anemia
hemolitik non-sferosis kronis.
• Beberapa kondisi seperti diabetes, infark miokard, latihan fi sik
berat telah dapat menginduksi hemolisis pada penderita defisiensi
G6PD.
• Hemolisis akut  rasa lemah, nyeri punggung, anemia dan ikterus.
Terjadi peningkatan kadar bilirubin tidak terkonjugasi, laktat
dehidrogenase dan retikulositosis.
 Anemia Hemolitik Terinduksi Obat

• Obat obat spesifik penyebab langsung krisis hemolisis penderita

defisiensi G6PD sulit ditentukan dengan tepat.
– Suatu obat yang dinyatakan aman untuk satu penderita defi siensi G6PD
belum tentu aman untuk penderita lain perbedaan farmakokinetik tiap
individu.
– Obat yang memiliki efek oksidan sering diberikan pada pasien dengan
keadaan klinis (misalnya infeksi) yang dapat menyebabkan hemolisis.
– Pasien mengkonsumsi lebih dari satu jenis obat.
– Hemolisis pada defisiensi G6PD biasanya sembuh sendiri, tidak
menyebabkan anemia dan retikulositosis yang signifikan
• Hemolisis dan ikterus klinis biasanya muncul 24-72 jam setelah
konsumsi obat.
• Anemia memburuk hingga 7-8 hari, kadar hemoglobin akan
kembali meningkat setelah 8-10 hari obat dihentikan
 Heinz body pada pewarnaan supravital
presipitat hemoglobin terdenaturasi

red cells with characteristic bite-like deformity

(arrows).
 Medicines and other substances likely
to be UNSAFE in moderate to severe
G6PD deficiency
Anti-infectives
Dapsone
Nitrofurantoin and related, including nifuratel and nitrofurazone (nitrofural)
Primaquine
Miscellaneous
Methylene blue (methylthioninium chloride) (antidote, also contained in some urinary tract
combination products)
Phenazopyridine
Chemical exposures and foods
Aniline dyes
Naphthalene (mothballs, lavatory deodorant)

Henna compounds (black and red Egyptian) and related dyes used for hair and tattoos

Fava beans
Some prefer to avoid red wine, legumes, blueberries, soya, and tonic water
 Medicines previously considered unsafe, but
PROBABLY SAFE given in usual therapeutic
doses in G6PD deficiency
Analgesics
Acetaminophen (paracetamol)
Aspirin (acetylsalicylic acid)
Aminophenazone and related NSAIDs (dipyrone, metamizole)
Anti-infectives
Antimalarials: chloroquine, mepacrine, quinine
Fluoroquinolones: ciprofloxacin, levofloxacin, nalidixic acid, norfloxacin, ofloxacin
Sulfonamides: co-trimoxazole, sulfacetamide (topical), sulfanilamide, sulfisoxazole, sulfamethoxazole,
trimethoprim-sulfamethoxazole
Other anti-infectives: chloramphenicol, furazolidone, isoniazid, mepacrine
Miscellaneous
Ascorbic acid (vitamin C)
Glyburide (glibenclamide)
Hydroxychloroquine (see chloroquine)
Isosorbide dinitrate
Quinine
Sulfasalazine
ANEMIA APLASTIK
ANEMIA NORMOSITIK NORMOKROM - HEMOLITIK
 Pansitopenia ec Anemia Aplastik

Manifestasi klinis disebabkan

oleh sitopenia

Anemia Trombositopenia Leukopenia

Ptekiae, epistaksis,
Pucat, lemah,
perdarahan gusi, Demam, infeksi
dispnea
menoragia

Tidak ada limfadenopati atau splenomegali

Lichtman MA, Segel GB. Aplastic anemia: acquired and inherited. In: Lichtman et al, editors. William’s hematology. 8th ed. New York: McGraw Hill; 2010. p.463-79
 APLASTIC ANEMIA:
• Failure of two or more cell lines
• Anaemia, leukopenia, thrombocytopenia
(pancytopenia) + hypoplasia or aplasia of the marrow
• Pathology: Reduction in the amount of haemopoietic
tissue  inability to produce mature cells for
discharge into the bloodstream
• no hepatomegaly; no splenomegaly; no
lymphadenopathy;
• Hallmark: peripheral pancytopenia with
hypoplastic/ aplastic bone marrow
ACQUIRED APLASTIC ANEMIA - CAUSES
• Radiation • Immune diseases:
• Drugs and chemicals – eosinophilic fascitis
– chemotherapy – thymoma
– Benzene • Pregnancy
– Chloramphenicol: idiosyncratic; • PNH
sudden onset after several
months; 1 of every 20,000, • Marrow replacement:
irreversible – leukemia
– organophosphate – Myelofibrosis
• Viruses: – myelodysplasia
– CMV
– EBV
– Hep B, C,D
– HIV
 PATHOPHYSIOLOGY

• Direct destruction of haemopoietic

progenitors
• Disruption of marrow micro-environment
• Immune mediated suppression of marrow
elements
 Cytotoxic T cells in blood and marrow
release gamma IFN and TNF  inhibit early
and late progenitor cells
 CLINICAL FEATURES

RBC (anemia)
• Progressive and persistent pallor
• Anemia related symptoms
WBC (Leucopenia/neutropenia)
• Prone to infections - Pyodermas, OM, pneumonia, UTI, GI
infections, sepsis
Platelets (Thrombocytopenia)
• Petechiae, purpura, ecchymoses
• Hematemesis, hematuria, epistaxis, gingival bleed
• Intracranial bleed-headache, irritability, drowsiness, coma
 Blood picture:
• Anemia-normocytic, normochromic
• Leukopenia (neutropenia)
• Relative lymphocytosis
• Thrombocytopenia
• Absolute reticulocyte count low
• Mild to moderate anisopoikilocytosis
 Gold Standard

• Bone Marrow Puncture : dry aspirate,

hypocellular with fat (>70% yellow marrow)
 Management:
• Identification and Definitive therapy
elimination of • Bone marrow transplantation
underlying cause – Treatment of choice
– HLA matched donor. Usually
• Supportive therapy: siblings
– Red cell transfusion for – Long term survival rates: 60-70%
anemia • Immunosuppression
– Prevention and – Antithymocyte globulin (ATG)
treatment of – Antilymphocyte glubulin (ALG)
haemorrhage – Cyclosporin
– Prevention and – Intensive immunosupression :
treatment of infection cyclophosphamide
– Corticosteroids
H E M O S TA S I
S
 Hemostasis
1. Fase vaskular: vasokonstriksi
2. Fase platelet: agregasi dan adhesi
trombosit
3. Fase koagulasi: ada jalur
ekstrinsik, jalur intrinsik dan
bersatu di common
pathway
4. Fase retraksi
5. Fase destruksi / fibrinolisis

http://www.bangkokhealth.com/index.php/health/health-
general/first-aid/451-ขบวนการห้ามเลือด-hemostasis.html
Hemostasis
 Gangguan hemostasis
perdarahan

Vaskular Trombosit Koagulasi

Contoh
Penyakit Scurvy ITP Hemofilia
Gangguan
Hemostasis DIC (baik trombosit
Henoch DHF maupun faktor
dengan Schonlein
purpura
koagulasi menurun)

Manifestasi Anemia aplastik,

Liver disease
Perdarahan leukemia

Deficiency factor
VWF disease
VII
 BLEEDING

Mild Severe

intervention

stopped
continues

prolonged delayed

Platelet disorder Coagulation disorder

Kuliah Hemostasis FKUI.
 Spontaneous bleeding
(without injury)

SUPERFICIAL, MULTIPLE DEEP, SOLITARY

petechiae, hematoma,
purpura, hemarthrosis
ecchymoses

platelet disorder coagulation disorder

Kuliah Hemostasis FKUI.
 Coagulation factors

Components of coagulation factor:

~ fibrinogen factor I
~ prothrombin factor II
~ tissue factor (thromboplastin) factor III
~ Ca-ion (Ca++) factor IV
~ pro-accelerin (labile factor) factor V
~ pro-convertin (stable factor) factor VII
~ anti-hemophilic factor factor VIII
~ Christmas-factor factor IX
~ Stuart-Prower factor factor X
~ plasma tromboplastin antecedent factor XI
~ Hageman factor factor XII
~ fibrin stabilizing factor(Laki-Roland) factor XIII

Kuliah Hemostasis FKUI.

 Bleeding Time
• It indicates how well platelets interact with blood vessel
walls to form blood clots.
• BT is the interval between the moment when bleeding
starts and the moment when bleeding stops.
• Used most often to detect qualitative defects of platelets.
• BT is prolonged in purpuras, but normal in coagulation
disorders like haemophilia.
• Purpuras can be due to
– Platelet defects - Thrombocytopenic purpura (ITP & TTP)
– Vascular defects - Senile purpura, Henoch Schonlein purpura
• Platelets are important in preventing small vessel bleeding
by causing vasoconstriction and platelet plug formation.

http://www.indianmedicinalplants.info/articles/BLEEDING-TIME.html
 Clotting Time
• CT the interval between the moment when bleeding
starts and the moment when the fibrin thread is first
seen.
• BT depends on the integrity of platelets and vessel
walls, whereas CT depends on the availability of
coagulation factors.
• In coagulation disorders like haemophilia, CT is
prolonged but BT remains normal.
• CT is also prolonged in conditions like vitamin K
deficiency, liver diseases, disseminated intravascular
coagulation, overdosage of anticoagulants etc.

http://www.indianmedicinalplants.info/articles/BLEEDING-TIME.html
 PT, APTT, TT
• Activated partial thromboplastin time (aPTT)
 untuk mengevaluasi jalur intrinsik kaskade
koagulasi (normal 30-40”)
• Prothrombin time (PT)  untuk mengevaluasi
jalur ekstrinsik kaskade koagulasi (normal 9.5-
13.5”)
• Thrombin time (TT) is a screening coagulation
test designed to assess fibrin formation from
fibrinogen in plasma (normal <20”).
http://practical-haemostasis.com/Screening%20Tests/aptt.html
 Kalsium berperan menjadi
jembatan yang menghubungkan
faktor koagulasi dengan fosfolipid
trombosit.
Simple schematic diagram to diagnose hemostasic disorders

Kuliah Hemostasis FKUI.

Bleeding Disorder
Finding Disorders of Coagulation Disorders of Platelets or
Vessels
Petechiae Rare Characteristic
Deep dissecting Characteristic Rare
hematomas
Superficial ecchymoses Common; usually large Characteristic; usually
and small and
solitary multiple
Hemarthrosis Characteristic Rare
Delayed bleeding Common Rare
Bleeding from Minimal Persistent often profuse
superficial cuts and
scratches
Sex of patient 80–90% of inherited forms Relatively more common
occur only in male patients in females
Positive family history Common Rare (exc. vWF , hereditary
hemorr.
telangiectasia)
Kelainan Pembekuan Darah

http://periobasics.com/wp-content/uploads/2013/01/Evaluation-of-bleeding-disorders.jpg
HENOCH SCHONLEIN
PURPURA
K E L A I N A N H E M O S TA S I S P R I M E R
 Henoch-Schönlein Purpura
• Henoch-Schönlein Purpura (HSP) merupakan vaskulitis generalisata akut yang
dimediasi oleh immunoglobulin A (IgA), yang melibatkan pembuluh darah ukuran
kecil pada kulit, traktus gastrointestinal, ginjal, sendi, dan dapat melibatkan paru
dan SSP (jarang)
• Gejala tipikal dari HSP adalah nyeri kepala, demam, dan anoreksia
• 90% of cases reported in children
• Male:Female (1.5:1)
 CLINICAL FEATURES: Tetrad of
symptoms
• Abdominal pain
– GI INVOLVEMENT: more
common in children. Symptoms
include abdominal pain, nausea,
vomiting, diarrhea, constipation
or bowel intussusception. May
present with GI bleeding.
• Renal disease
– in up to 50% of patients; May
present with hematuria; Usually
resolve spontaneously.
– Can have mild
glomerulonephritis leading to
microscopic hematuria and can
lead to a rapidly progressive
glomerulonephritis with RBC
casts
• Palpable purpura
– most commonly seen on lower
extremities and buttocks,
however can also been seen on
the trunk and arms.
– Lesions begin as erythematous
macules and progress to
purpuric, non-blanching,
nonpruritic lesions that may
become confluent
• Arthritis/arthralgias
– more common in adults and
most common in knees and
ankles. Generally self-limiting
 Tatalaksana
• Tatalaksana HSP bersifat suportif, prinsipnya
menjaga status hidrasi, nutrisi, dan analgetik.
• Penggunaan prednisone (1 mg/kg/hari untuk
1-2 minggu, diikuti dengan tappering off dapat
mengurangi gejala
• Pada kasus berat dapat dipertimbangkan
untuk menggunakan IVIG
ITP
K E L A I N A N H E M O S TA S I S P R I M E R
 Idiopathic (Immune) Thrombocytopenic Purpura
• Purpura trombositopenia
– penyakit autoimun yang ditandai dengan trombositopenia menetap (angka
trombosit darah tepi <150.000 ml/dl) akibat autoantibodi yang mengikat antigen
trombosit menyebabkan destruksi prematur trombosit dalam sistem
retikuloendotelial terutama di limpa
• 10% ITP + anemia hemolitik autoimun  Evan’s syndrome
• Etiologi
– Primer: dx eksklusi
– Sekunder: virus (HIV, HCV, HBV, EBV), H. Pylori, ANA
– Anak: akut pasca infeksi
– Dewasa: kronik
• Manifestasi klinis: perdarahan mukokutan, petechiae, purpura.
Perdarahan spontan bila Tr <20,000/mm3
• Pemeriksaan lab
– BT, CT
– Hapus darah tepi: megakariosit
– Biopsi sumsum tulang: ↑ megakariosit
 ITP
• Diawali dari adanya autoantibodi (sebagian besar
merupakan IgG) → melawan membran trombosit
glikoprotein IIb-IIIa atau Ib-IX.
• Antibodi antiplatelet berkerja sebagai opsonin yang dikenali
oleh reseptor IgG Fc pada makrofag → apabila ia melekat
pada trombosit, makrofag akan mengenali kompleks
tersebut sebagai substansi yang harus dihancurkan →
terjadi peningkatan destruksi platelet.
• ITP ringan:
– hanya trombosit yang diserang
– megakariosit mampu mengkompensasi kondisi itu dengan jalan
meningkatkan produksi trombosit.
• ITP berat:
– autoantibodi juga menyerang megakariosit, sehingga produksi
trombosit juga menurun.
 ITP
• ITP akut
• umumnya ringan dan lebih dari 90% penderita sembuh
dalam 3-6 bulan karena merupakan self-limited disease
• bentuk pendarahannya  purpura pada kulit dan mukosa
(hidung, gusi, saluran cerna dan traktus urogenital).
• ITP kronik
• pendarahannya dapat berupa ekimosis, peteki, purpura;
umumnya berat
• Traktus urogenital merupakan tempat pendarahan paling
sering.
• Spleenomegali ringan tanpa limfadenopati dapat
dijumpai pada kedua ITP, namun hanya 10-20% kasus.
 Manifestasi Klinis
• Trombositopenia.
• Morfologi eritrosit, leukosit, dan retikulosit biasanya
normal, kadang dapat dijumpai adanya megatrombosit
• Bleeding time memanjang.
• Pemeriksaan aspirasi sum-sum tulang
• hanya dilakukan pada dewasa tua (>40 tahun), gambaran
klinis tidak khas, atau pasien yang tidak berespon baik
terhadap terapi.
• Kecurigaan ITP sekunder → pemeriksaan laboratoris
diperlukan untuk menginvestigasi penyakit dasarnya.
 Tatalaksana
• Pasien dengan angka trombosit (AT) >30.000/µL, asimptomatik atau
purpura minimal
– tidak diterapi rutin.
• Pendarahan mukosa dengan AT <20.000/µL atau pendarahan ringan
dengan AT <10.000/µl
– Pengobatan dengan kortikosteroid
– Prednison 1-2 mg/kgBB/hari, dievaluasi 1-2 minggu
– Bila responsif, dosis diturunkan perlahan hingga AT stabil atau dipertahankan
30.000-50.000/ µL
– Prednison juga dapat diberikan dosis tinggi 4 mg/kgBB/hari selama 4 hari, bila
tidak ada respon maka pengobatan yang diberikan hanya suportif.
• Pemberian suspensi trombosit dilakukan bila
– AT <20.000/µL dengan pendarahan mukosa berulang
– pendarahan retina
– pendarahan berat
– AT <50.000/µL
– kecurigaan pendarahan intrakranial
– menjalani operasi dengan AT <150.000/µL.
HEMOFILIA
K E L A I N A N H E M O S TA S I S S E K U N D E R
 Hemofilia

• Hemophilia is the most common inherited bleeding

disorder.
• There are:
– Hemophilia A : deficiency of factor VIII
– Hemophilia B : deficiency of factor IX (christmas disease)
• Both hemophilia A and B are inherited as X-linked recessive
disorders
• Symptoms could occur since the patient begin to crawl
• Incidence:
– hemophilia A (± 85%)
– hemophilia B (± 15%)
• Approximately 70% had family history of bleeding problems
• Clinical manifestasion: mild, Moderate, severe
 Genetic

• Inherited as sex (X)-linked recessive

• Genes of factor VIII/IX are located on the
distal part of the long arm (q) of X
chromosome
• Female (women) are carriers

Kuliah Hemofilia FKUI. Pustika A.

Clinical manifestation Diagnosis

• Bleeding: • history of abnormal bleeding in

– usually deep (hematoma, a boy
hemarthrosis) • normal platelet count
• bleeding time usually normal
– spontaneous or following • clotting time: prolonged
mild trauma
• prothrombin time usually
• Type: normal
• partial thromboplastin time
– Hemarthrosis prolonged
– Hematoma • decreased antihemophilic
factor
– intracranial hemorrhage
– Hematuria
– Epistaxis Antenatal diagnosis
• antihemophilic factor level
– bleeding of the frenulum • F-VIII/F-IX gene
(baby) identification (DNA
analysis)
Kuliah Hemofilia FKUI. Pustika A.
Classification of Hemophilia A & B

5-40% (emedicine)
Tatalaksana Hemofilia
 Blood Replacement Therapy
factor-VIII factor-IX
(unit/ml) (unit/ml) (ml)

fresh-frozen plasma ~ 0,5 ~ 0,6 200

cryoprecipitate ~ 4,0 - 20
factor - VIII concentrate 25 - 100 - 10
factor - IX concentrate - 25 - 35 20

Kuliah Hemofilia FKUI. Pustika A.

TRANSFUSI
DARAH
 PROSES PRODUK DARAH

https://www.nps.org.au/attachments/65e201efcb1e2d6a2b8b81114512600e837c8d62/store/27bed1b3d321dc4cec0d0f0d689b43fc8777fc654c91989602c573ed1a
d6/image.gif
 Indikasi Transfusi
Whole Blood Pack Red Cells
• Perdarahan akut • Pengganti sel darah
dengan hipovolemia merah pada anemia
• Transfusi Tukar • Anemia karena
(Exchange transfusion) perdarahan akut
• Pengganti darah merah (setelah resusitasi
endap (packed red cell) cairan kristaloid atau
saat memerlukan koloid)
transfusi sel darah
merah
Washed Erythrocyte Thrombocyte Concentrate
• Transfusi masif pada • Perdarahan akibat
neonatus sampai usia < 1 trombositopenia atau
tahun gangguan fungsi trombosit
• Transfusi intrauterin • Pencegahan perdarahan
• Penderita dengan anti-IgA karena trombositopenia
atau defisiensi IgA dengan (gangguan sumsum tulang)
riwayat alergi transfusi kurang dari 10.000 /micro
berat liter
• Riwayat reaksi transfusi • Profilaksis perdarahan pada
berat yang tidak membaik pre operatif dengan
dengan pemberian trombosit kurang atau sama
premedikasi dengan 50.000 /microliter,
kecuali operasi trepanasi
dan cardiovaskuler kurang
atau sama dengan 100.000
micro liter.
Fresh Frozen Plasma Cryoprecipitate
• Defisiensi faktor • Alternatif terapi F VIII
koagulasi (penyakit hati, konsentrat pada
overdosis antikoagulan- defisiensi :
warfarin, kehilangan – Faktor von Willebrand
faktor koagulasi pada (von Willebrand’s
penerima transfusi disease)
dalam jumlah besar) – Faktor VIII (hemofilia A)
– Faktor XIII
• DIC
• TTP • Sumber fibrinogen pada
gangguan koagulopati
dapatan misalnya DIC
KEGANASAN
LEUKEMIA
Proses Hematopoiesis
Jika Disederhanakan….
 Leukemia
CLL CML ALL AML
The bone marrow makes abnormal leukocyte  dont die when they
should  crowd out normal leukocytes, erythrocytes, & platelets. This
makes it hard for normal blood cells to do their work.
Prevalence Over 55 y.o. Mainly adults Common in Adults &
children children
Symptoms & Grows slowly  may Grows quickly  feel sick & go to
Signs asymptomatic, the disease is found their doctor.
during a routine test.
Fever, swollen lymph nodes, frequent infection, weak,
bleeding/bruising easily, hepatomegaly/splenomegaly, weight loss,
bone pain.
Lab Mature Mature granulocyte, Lymphoblas Myeloblast
lymphocyte, dominant myelocyte t >20% >20%, aeur rod
smudge cells & segment may (+)
Therapy Can be delayed if asymptomatic Treated right away
CDC.gov
 AML VS ALL
AML ALL

Epidemiologi Lebih banyak pada dewasa Lebih banyak pada anak-anak

Sel mieloblas imatur, terdapat

Morfologi Limfoblas
auer rod
• Mieloperoksidase (+)
• Mieloperoksidase (-)
• Terminal deoxynucleotidyl
• Terminal deoxynucleotidyl
transferase (TdT) (-)
Sitokimia transferase (TdT) (+)
• LDH & serum uric acid
• LDH & serum uric acid elevated 
elevated  tumor lysis
tumor lysis syndrome
syndrome

• B-precursor ALL (70% ALL subtype in

Immuno Children)  CD10, CD19, CD20,
phenotyping, CD13, CD14, CD15, and CD33 CD22, CD24
Cytogenetics & (>90% of leukemic cells) • T-cell ALL (16% ALL Subtype in
Molecular testing children)  CD2, CD3, CD4, CD5,
CD7, CD8
 CML VS CLL
CML CLL
Lansia (>65 tahun), tapi bisa juga
Epidemiologi Dewasa (50-60 tahun)
ditemukan pada usia lbh muda
• Sel mieloid • Limfosit B matur
• Basofilia, eosinofilia • Smudge cell/basket cell
Morfologi
• Anemia, • Neutropenia, anemia, and
Trombositosis/normal thrombocytopenia
• Mature granulocytes have
decreased apoptosis
Sitokimia accumulation of long-lived
cells with low or absent
alkaline phosphatase (ALP).
• Circulating clonal B-lymphocytes
expressing CD19, CD20, and CD23
Immuno
Philadelphia chromosome, the and expression of the T cell
phenotyping,
BCR-ABL1 fusion gene, or the associated antigen CD5
Cytogenetics &
BCR-ABL1 fusion mRNA • Cytogenetics: trisomy 12 (16%), and
Molecular testing
deletions of chromosomal regions
13q (55%), 11q (18%), and 17p (7%)
Sel blas dengan Auer rod pada leukemia Leukemia mielositik kronik
mieloblastik akut

Limfosit matur & smudge cell

Sel blas pada leukemia limfoblastik akut pada leukemia limfositik kronik
 AML & ALL
• Jenis leukemia yang paling sering terjadi pada
anak-anak adalah Acute Lymphoblastic
Leukemia (ALL) dan Acute Myelogenous
Leukemia (AML)
• ALL merupakan keganasan yg paling sering
ditemui pada anak-anak (1/4 total kasus
keganasan pediatrik)
• Puncak insidens ALL usia 2-5 tahun
 AML & ALL Clinical Manifestation
• More common in AML
– Leukostasis (when blas count >50.000/uL): occluded
microcirculationheadache, blurred vision, TIA, CVA, dyspnea,
hypoxia
– DIC (promyelocitic subtype)
– Leukemic infiltration of skin, gingiva (monocytic subtype)
– Chloroma: extramedullary tumor, virtually any location.
• More common in ALL
– Bone pain, lymphadenopathy, hepatosplenomegaly (also seen in
monocytic AML)
– CNS involvement: cranial neuropathies, nausea, vomiting, headache,
anterior mediastinal mass (T-cell ALL)
– Tumor lysis syndrome
 Diagnosis of AML
The diagnosis of AML requires both of the following:
• Documentation of bone marrow infiltration –
– Definitive diagnosis: Blast forms must account for at least 20
percent of the total cells of the bone marrow aspirate/biopsy.
– Presumptive diagnosis: The presence of 20 percent or more
blasts in the peripheral blood is also diagnostic of AML.
• The leukemic cells must be of myeloid origin as
demonstrated by either the presence of Auer rods,
cytochemical positivity for myeloperoxidase, or presence of
sufficient myeloid/monocytic markers recognized by
immunophenotyping.
Peripheral smear from a patient with acute myeloid leukemia. There are two myeloblasts, which
are large cells with high nuclear-to-cytoplasmic ratio and nucleoli. Each myeloblast has a
pink/red rod-like structure
 Leukemia Limfoblastik Akut
• Merupakan keganasan yang paling sering ditemukan pada
masa anak, meliputi 25-30% dari seluruh keganasan pada
anak.
• Lebih sering pada laki-laki, usia 3-4 tahun
• Manifestasi klinis
– Penekanan sistem hemopoetik normal, anemia (pucat),
neutropenia (sering demam), trombositopenia (perdarahan)
– Infiltrasi jaringan ekstramedular, berupa pembesaran KGB, nyeri
tulang, dan pembesaran hati serta limpa
– Penurunan BB, anoreksia, kelemahan umum
• Pemeriksaan Penunjang: Gambaran darah tepi dan pungsi
sumsum tulang untuk memastikan diagnosis
• Tatalaksana : Kemoterapi dan Pengobatan suportif
 ALL Classification
• In the WHO classification system for hematologic malignancies,
the lymphoblastic neoplasms (which may present as leukemia
and/or lymphoma) are divided into:
– Precursor B cell lymphoblastic leukemia/lymphoma, also called
precursor B cell acute lymphoblastic leukemia (precursor B cell ALL)
– Precursor T cell lymphoblastic leukemia/lymphoma (precursor T-LBL),
also called precursor T cell acute lymphoblastic leukemia (T cell ALL)
• These two entities are morphologically indistinguishable.
• FAB subtype is not currently used in either diagnosis or treatment
decisions
• ALL is the preferred term in the US when the bone marrow
contains more than 25% lymphoblasts, whereas lymphoma is the
preferred term when the process is confined to a mass lesion with
minimal or no blood and bone marrow involvement.
French-American-British (FAB) Classification
 ALL Diagnosis
• Evaluation will include clinical examination, and bone
marrow aspiration and biopsy, which will diagnose ALL and
determine the leukemia phenotype as well as the presence
or absence of cytogenetic abnormalities.
• Bone marrow aspirations are preferred for diagnostic
accuracy and often provide better cytogenetics results.
• It is not standard in children or adolescents to diagnose
leukemia from the peripheral blood when lymphoblasts are
present.
• However, in cases where it is difficult to obtain either bone
marrow aspirate or biopsy, peripheral blood can be
substituted for bone marrow.
 CML Clinical Course
• CML has a triphasic or biphasic clinical course:
– a chronic phase, which is present at the time of diagnosis in approximately
85% patients;
– an accelerated phase, in which neutrophil differentiation becomes
progressively impaired and leukocyte counts are more difficult to control
with treatment;
– and blast crisis, a condition resembling acute leukemia in which myeloid or
lymphoid blasts proliferate in an uncontrolled manner
• 20-50% patients are asymptomatic, with the disease first being
suspected from routine blood tests.
• Among symptomatic patients, systemic symptoms: fatigue (34%), malaise
(3%), weight loss (20%), excessive sweating (15%), abdominal fullness
(15%), and bleeding episodes due to platelet dysfunction (21%)
 Diagnosis of CML
• The diagnosis of CML is first suspected by identifying
the typical findings in the blood and bone marrow.
• Bone marrow aspiration and biopsy demonstrates
granulocytic hyperplasia with a maturation pattern that
reflects that seen in the peripheral smear.
• Confirmed by the demonstration of the Philadelphia
chromosome, the BCR-ABL1 fusion gene, or the BCR-
ABL1 fusion mRNA by conventional cytogenetics,
fluorescence in situ hybridization (FISH) analysis, or
reverse transcription polymerase chain reaction (RT-
PCR)
 CML Peripheral Smear
• Typically leukocytosis : all cells of the neutrophilic series, from
myeloblasts to mature neutrophils with peaks in the percent
myelocytes and segmented neutrophils.
• Blasts typically account for less than 2 percent.
• Absolute basophilia is a universal finding in the blood smears from CML
patients, and absolute eosinophilia is seen in about 90 percent of cases.
• The platelet count can be normal or elevated.
• Platelet counts above 600,000/mm3 are seen in 15-30% of patients.
• Thrombocytopenia, if present at diagnosis, should make one reconsider
other diagnostic possibilities.
• A normochromic, normocytic anemia is seen in 45 to 60 percent of
patients.
Uptodate. 2017
Characteristic peripheral blood smear of chronic myeloid leukemia shows basophilia
and granulocytosis with neutrophils and immature granulocytes.
 CLL Diagnostic Evaluation
• The diagnostic evaluation of CLL should include a complete blood count
with differential, examination of the peripheral smear, and an
immunophenotypic analysis of the circulating lymphocytes.
• Immunophenotypic analysis, usually by flow cytometry, is a key
component to the diagnosis of CLL
– Expression of B cell associated antigens including CD19, CD20, and CD23.
– Expression of CD5, an antigen commonly expressed by T cells.
• Bone marrow aspirate and biopsy are not required for the diagnosis of
CLL.
– demonstrate normal to increased cellularity, with lymphocytes accounting
for >30 percent of all nucleated cells
• Chromosomal changes seen in CLL are also not diagnostic features of the
disease.
Uptodate. 2017
 CLL Laboratory Abnormalities
Uptodate. 2017

• Lymphocytosis — The most noteworthy laboratory abnormality found in CLL is

lymphocytosis in the peripheral blood and bone marrow.
– The leukemic cells are typically small, mature appearing lymphocytes with a dense
nucleus, partially aggregated (clumped) chromatin, and without discernible nucleoli.
• Although the absolute blood lymphocyte threshold for diagnosing CLL has been
placed at >5.000/mm3 B lymphocytes, a significant proportion of patients
present with counts as high as 100.000/mm3
• Cytopenias — Neutropenia, anemia, and thrombocytopenia may be observed at
the time of initial diagnosis, and are usually not severe. These can be related to
autoimmune hemolytic anemia, pure red cell aplasia, autoimmune
thrombocytopenia, or agranulocytosis
– Patients with CLL have an increased incidence of autoimmune hemolytic anemia
(AIHA).
– Pure red cell aplasia (PRCA) is rare, occurring in approximately 0.5 percent of
patients.
– (Auto)immune thrombocytopenia occurs in 2 to 3 percent of patients with CLL
Rarely, agranulocytosis may be encountered in CLL (approximately 0.5 percent).
 Peripheral blood smear reveals five CLL cells with prominent chromatin clumping
(snickerdoodle-like) and two smudge (basket) cells. smudge cells are the artifacts produced
by the lymphocytes damaged during the slide preparation.Wright-Giemsa, 150x
magnification.
POLISITEMIA VERA
 POLISITEMIA VERA
• Polisitemia vera adalah kelainan mieloproliferatif dengan
ciri profilerasi sel pendahulu eritroid yang tidak terkendali.

• Penyakit ini merupakan penyakit kronik profresif dan

sebagian penderita penyakitnya berkembang menjadi
leukemia akut dan sisanya menjadi fibrosis sumsumtulang
dan metaplasia mieloid.

• Etiologi polisitemia terletak pada sel induk sedangkan pada

polisitemia sekunder etiologi oleh karena stimulasi
eritropoietin berlebihan dan respon tubuh terhadap
oksigenasi jaringan yang berkurang.

• Sering terjadi leukositosis dan trombositosis.

 Diagnosis Polisitemia Vera

http://imaging.ubmmedica.com/all/editorial/cancernetwork/cmhb/30M_Table1_large.png
POLISITEMIA VERA vs POLISITEMIA SEKUNDER

Polisitemia Vera Polisitemia Sekunder

• Etiology: diffuse marrow
hyperplasia of unknown
etiology
• Overproduction of red cells,
white cells, and platelets.
• Etiology: Reduced arterial
O2 saturation (emphysema,
pulmonary fibrosis,
congenital heart disease,
etc)  increased
erythropoietin production.

• Overproduction of red cells.

 Tatalaksana Polisitemia Vera

http://www.bloodjournal.org/content/bloodjournal/109/12/5104/F1.large.jpg?sso-checked=true
M U LT I P L E M Y E L O M A
 Multiple Myeloma

• Definition:
B-cell malignancy
characterised by abnormal
proliferation of plasma cells
able to produce monoclonal
immunoglobulin (M protein )

• Incidence:
3 - 9 cases per 100000
population / year more
frequent in elderly modest
male predominance
 Multiple Myeloma

• Clinical forms:
multiple myeloma
solitary plasmacytoma
plasma cell leukemia

• M protein:
 is seen in 99% of cases in serum and/or urine
 IgG > 50%, IgA 20-25%, IgD 2%, IgM 0.5%
 light chain 16% (Bence-Jones protein )
 1% of cases are nonsecretory
 Multiple Myeloma
Clinical manifestations are related to malignant
behavior of plasma cells and abnormalities produced
by M protein.

• plasma cell proliferation:

 multiple osteolytic bone lesions
 hypercalcemia
 bone marrow suppression ( pancytopenia )

• monoclonal M protein
 decreased level of normal immunoglobulins
 hyperviscosity
 Multiple Myeloma
Clinical symptoms:
Laboratory tests:
• bone pains, pathologic • ESR > 100
fractures • anaemia, thrombocytopenia
• weakness and fatigue • rouleaux in peripheral blood
• serious infection smears
• renal failure • marrow plasmacytosis > 10
• bleeding diathesis -15%
• hyperproteinemia
• hypercalcemia
• proteinuria
• azotemia
Multiple Myeloma
Kriteria Diagnosis Multipel Mieloma
International Myeloma Workshop
Consensus Panel 3 Tahun 2011
Lateral skull X-ray with typical findings of multiple myeloma:
multiple "punched-out" holes. The arrow is pointing at one of the
larger holes
Spinal radiograph showing generalized osteopenia
and multiple compression fractures.
 HIPER-
S E N S I T I V I TA
S
 Reaksi Hipersensitivitas
Type Prototype Disorder Immune Mechanisms Pathologic Lesions
Vascular dilation, edema,
Anaphylaxis; Production of IgE antibody ➙ immediate
smooth muscle
allergies; bronchial release of vasoactive amines and other
Tipe I Immediate contraction, mucus
asthma (atopic mediators from mast cells; recruitment of
production,
forms) inflammatory cells (late-phase reaction)
inflammation

Autoimmune Production of IgG, IgM ➙ binds to antigen

Antibody- hemolytic anemia; on target cell or tissue ➙ phagocytosis or
Tipe II Cell lysis; inflammation
mediated Goodpasture lysis of target cell by activated complement
syndrome or Fc receptors; recruitment of leukocytes

Systemic lupus
Deposition of antigen-antibody complexes
erythematosus;
Immune ➙ complement activation ➙ recruitment Necrotizing vasculitis
Tipe some forms of
complex of leukocytes by complement products and (fibrinoid necrosis);
III glomerulonephritis;
mediated Fc receptors ➙ release of enzymes and inflammation
serum sickness;
other toxic molecules
Arthus reaction
Contact dermatitis;
multiple sclerosis; Perivascular cellular
Cell- Activated T lymphocytes ➙ i) release of
Tipe type I, diabetes; infiltrates; edema; cell
mediated cytokines and macrophage activation; ii) T
IV transplant destruction; granuloma
(delayed) cell-mediated cytotoxicity
rejection; formation
tuberculosis
Sources: Robbins & Cotran’s Pathologic Basis of Disease. 7th ed. 2005.
Reaksi hipersensitivitas
 Fase Dini/ Initial Response
Terjadi beberapa menit setelah terpapar alergen yang sama untuk kedua
kalinya
puncaknya 15-20 menit pasca paparan
berakhir 60 menit kemudian

REAKSI HIPERSENSITIFITAS TIPE I

Fase Lanjut/ Late Phase Reaction

Disebabkan akumulasi dan infiltrasi eosinofil, neutrofil, basofil, limfosit
dan makrofag sehingga terjadi inflamasi
berlangsung 4-8 jam, dapat menetap beberapa hari
Tipe I (IgE-Mediated type)