Anemia Normositer dan anemia

Macrocytic

Dr . Yenny Dian Andayani SpPD -KHOM

Division Hematologic Oncology Medic

Dept Internal Medicine Moh Hoesin General Hospital /
Faculty of Medicine Sriwijaya University
Palembang
 PENDAHULUAN

 Definisi fungsional: penurunan jumlah massa eritrosit (redcell

mass)  tidak dapat memenuhi fungsi membawa O2 yg cukup
ke jaringan perifer (penurunan O2 carrying capacity).

 Anemia bukan kesatuan penyakit tersendiri, tp merupakan

gejala gejala berbagai peny dasar.

 Parameter : kadar Hemoglobin, Hematokrit, & hitung eritrosit.

 Di Indonesia, Hb < 10g/dl  awal work up anemia
 Prevalensi di Ind, Husaini dkk (1989):
 Anak prasekolah: 30-40%
 Anak usia sekolah: 25-35%
 Perempuan dewasa tidak hamil: 30-40%
 Perempuan hamil: 50-70%
 Laki-laki dewasa: 20-30%
 Pekerja berpenghasilan rendah: 30-40%
Morphological classification of anemias
Anemia ?  etiologi - Morfologi
MCV, MCH , MCHC nilai normal ?
1. Microcytic, hypochromic anemia
( decreased MCV < 80 dan MCH 27 pg )
2. Normocytic, normochromic anemia
( normal MCV 80 -95 fl dan MCH 27-34 pg)
3. Macrocytic, normochromic anemia
( increased MCV > 95 pg )
 Etiology of anemia
• Production  : anemia aplastic
• Destruction : anemia hemolytic
• Loss of blood : anemia cause hemorrhagic
• Disturbance metabolism : anemia chronic disease,
Anemia Deff. Folat acid , Vit B12.
 GEJALA ANEMIA

 Gejala umum:
Sindroma anemi :
lemas, pusing, cepat lelah , mata berkunang, tinitus, mual,
kaki dingin dan sesak nafas, jantung berdebar-debar.
 Timbul pd setiap anemia apapun penyebabnya

 Timbul -- akibat anoksia organ target dan

kompensasi tubuh thd berkurangnya daya angkut O2
Pemeriksaan Fisik :
* Pucat pd konjungtiva , mukosa mulut, telapak tangan,
jaringan bawah kuku.
 Gejala Khusus:

 Anemia def besi: disfagia, atrofi papil lidah, stomatitis

angularis, dan kuku sendok (koilonychia)
 Anemia megaloblastik: glositis, gangguan neurologik
(pd def vit 12).
 Anemia hemolitik: ikterus, splenomegali, dan
hepatomegali
 Anemia aplastik: perdarahan & tanda-tanda infeksi
 Thalasemia mayor : deformitas tulang ( fasies
thalasemia )
 PEMERIKSAAN UNTUK DIAGNOSIS ANEMIA

 Pemeriksaan Laboratorium:
 Darah rutin : Hb, WBC, Trombosit, LED, Ht, RBC
 Darah lengkap :
Darah rutin, MCH, MCV,MCHC, apusan darah tepi, RDW,
Diff count
 Pemeriksaan sumsum tulang:
 Mengetahui keadaan hemopoesis

 Mutlak utk Dx anemia aplastik, megaloblastik, dan

kelainan hematologik yg dapt mensupresi sistem eritroid.
 Pemeriksaan khusus: sesuai etiologi
atas indikasi
 Anemia def besi: kadar besi serum, TIBC, saturasi
transferin, protoporfirin eritrosit, feritin serum, reseptor
tranferin, dan pengecatan besi pada ss tulang (perl’s
stain).
 Anemia megaloblastik: folat serum, vit B12 serum, tes
supresi deoksiuridin, dan tes schiling.
 Anemia hemolitik: bilirubin serum, tes coomb,
elektroforesis Hb.
 Anemia aplastik: BMP
HEMOLYTIC ANEMIA
 Classification of Hemolytic Anemia

• Intracorpuscular factor
• Extracorpuscular factor
. Intracorpuscular factor
Red cell abnormality
A. Hereditary
1. Membrane defect (spherocytosis, elliptocytosis)
2. Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD)
deficiency, Pyruvate kinase (PK) deficiency)
3. Hemoglobinopathies (unstable hemoglobins,
thalassemias, sickle cell anemia )

B. Acquired
1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH)
Mechanisms of hemolysis /
Pathogenesis:

1. Intra vascular
2. Extra vascular
 Hemolysis - RBC destruction

Extravascular Hemolysis Intravascular Hemolysis

Ingested by RE cell ( spleen & Hgb liberated in

liver) blood vessel

 Serum
Heme Globin Hgb + haptoglobin
haptoglobin

Reutilized + hemalbumin &

Hgb + albumin
Iron Protoporphyrin plasma Hgb

Hgb excreted in + hemoglobinuria &

Reutilized bilirubin urine hemosidenuria
Intravascular hemolysis :

- Red cells destruction occurs in vascular space

- Clinical states associated with Intravascular hemolysis:
Acute hemolytic transfusion reactions
Severe and extensive burns
Paroxysmal nocturnal hemoglobinuria (PNH)
Severe microangiopathic hemolysis
Physical trauma
Bacterial infections and parasitic infections (sepsis)
- Laboratory signs of intravascular hemolysis:
Indirect hyperbilirubinemia
Erythroid hyperplasia
Hemoglobinemia
Methemoalbuminemia
Hemoglobinuria
Absence or reduced of free serum haptoglobin
Hemosiderinuria
 Extravascular hemolysis :
- Red cells destruction occurs in reticuloendothelial system (RES)
- Clinical states associated with extravascular hemolysis :
Autoimmune hemolysis
Delayed hemolytic transfusion reactions
Hemoglobinopathies
Hereditary spherocytosis
Hypersplenism
Hemolysis with liver disease

- Laboratory signs of extravascular hemolysis:

Indirect hyperbilirubinemia
Increased excretion of bilirubin by bile
Erythroid hyperplasia
Hemosiderosis
 Anamnesa
• Fatigue
• Pallor
• Shortness of Breath
• Bleeding/petechiae
• Joint symptoms
• Rash-eg malar
• Family History
• Medications
 Physical Exam Findings
• Tachycardia
• Tachypnea
• Jaundice
• Splenomegaly
• Signs of congestive heart failure in rapidly
progressive anemia
Laboratory features:
Hematology test
1. Laboratory features
- Normocytic/macrocytic, hyperchromic anemia
- Reticulocytosis
- Increased serum iron
- Antiglobulin Coombs’ test is positive

2. Blood smear
- Anisopoikilocytosis, spherocytes
- Erythroblasts
- Schistocytes

3. Bone marrow smear

- Erythroid hyperplasia
Extracorpuscular factor
Autoimmune Hemolytic Anemia (AIHA)
* warm-reactive antibodies:
I. Primary
II. Secondary
1.Acute
- viral infections
- drugs ( -Methyldopa, Penicillin, Quinine, Quinidine)
2. Chronic
- rheumatoid arthritis, systemic lupus erythematosus
- lymphoproliferative disorders
(chronic lymphocytic leukemia, lymphomas,
WaldenstrÖm’s macroglobulinemia)
- miscellaneous (thyroid disease, malignancy )
 * cold-reactive antibodies:

I. Primary cold agglutinin disease

II. Secondary hemolysis:
- Mycoplasma infections
- Viral infections
- Lymphoproliferative disorders
III. Paroxysmal cold hemoglobinuria
Diagnosis
- Positive Coombs’ test (DAT)

Treatment:
- Steroids
- Splenectomy
- Immunosupressive agents
- Transfusion If needed
Paroxysmal Nocturnal Hemoglobinuria (PNH)
1. Pathogenesis

- An acquired clonal disease, arising from a somatic mutation in a

single abnormal stem cell

- Glycosyl-phosphatidyl- inositol (GPI) anchor abnormality
- Deficiency of the GPI anchored membrane proteins
(decay-accelerating factor =CD55 and a membrane inhibitor
of reactive lysis =CD59)
-Red cells are more sensitive to the lytic effect of complement
- Intravascular hemolysis

2. Symptoms
- Passage of dark brown urine in the morning
3. PNH –laboratory features:

- Pancytopenia
- Chronic urinary iron loss
- Serum iron concentration decreased
- Hemoglobinuria
- Hemosiderinuria
 Lab Tests for PNH
• Acidified serum lysis test (Ham’s test)
• Sugar water (sucrose hemolysis) test
• Flow cytometry: lack of CD59 on RBCs, or lack of
CD59 or CD55 on granulocytes
 Treatment

- Washed RBC transfusion

- Allogenic bone marrow transplantion
 Intracorpuscular Factor
B. Herediter ( defect)
• Hemoglobinopathies
– Sickle Cell Disease, Sickle cell trait, Hemoglobin SC
– Thallasemias
• Unstable RBC Membrane
– Hereditary spherocytosis
• Metabolic Machinery
– G6PD deficiency
– Pyruvate kinase deficiency
MACROCYTER ANEMIAE
• MCV & MCH >>>>>>

• Macrocytic anemias are characterized by large

RBCs with a normal hemoglobin content.
• Macrocytic anemias 
Megaloblastic or non-Megaloblastic
 MEGALOBLASTIC ANEMIAS

– The cause usually deficiency folic acid and

vit B12,
– On rare occasions there is an inherited
disorder that affects DNA synthesis
– Howell joly bodies >>>
 NON-MEGALOBLASTIC
• Associated with anemia chronic of disease
( hypotyroid, hepatic disease.
• Note that the macrocytic RBCs are not oval, but
are round.
• There are no hypersegmented neutrophils or
Howell-Jolly bodies
NON-MEGALOBLASTIC MACROCYTIC
ANEMIA
 The peripheral blood smear
Macrocytic Anemia
• oval macrocytes, anisocytosis, poikilocytosis
• Hypersegmental neutrophils (>5% with more than
five nuclear lobes)
• Platelets bizarre in shape and size (giant platelets)
• Neutropenia
• Thrombocytopenia (not as severe as in AA)
• Low reticulocytosis
• The bone marrow shows a megaloblastic
erythropoesis
 Bone marrow smear in Macrocytic
Anemi

• Megaloblastic erythropoesis
• Bone marrow rich in cells,
• Giant metamyeolcytes
• Giant bands
• Many Howell-Jolly’es bodies
• Cabot’s rings
 Biochemical findings in MA
• Serum indirect (unconjugated) bilirubin 
• Serum LDH  (principally LDH-1)
• Serum iron 
– (unless the anemia is complicated with iron
deficiency)
• Vitamin B12 concentration ↓
• Folic acid concentration ↓
 The diagnosis of megaloblastic anemia

• Serum vitamin B12 concentration

• Serum folic acid concentration
• If vitamin B12 and folate assays are within
normal limits, then the bone marrow
examination is performed (before blood
transfusion or vitaminB12, folate administration).
• Schilling test
 Diagnosis

• Establised based on laboratory test.

• DD Macrocytosis
Dysplastic anemias,
Liver disease
Hemolysis  exposure to the
chemotherapeutic agents.
 Diagnosis

• Establised based on laboratory test.

• DD Macrocytosis
Dysplastic anemias,
Liver disease
Hemolysis  exposure to the
chemotherapeutic agents.
 Treatment
• Folic Acid and Vit B12 ( etiology must known
well)
• Severe with anemias : PRC transfusion
DEFISIENSI VIT B12 ANEMIAE
 CAUSES
• Inadequate diet (no animal products!)
• Malabsorption
• Pernicious anemia (PA)
• Partial or total gastrectomy
• Blind loop syndrome
• Fish tapeworm
• Primary hypothyroidism
VITAMIN B12 ABSORPTION

Mucosal cell
Folate/B12 DNA Synthesis
 Clinical Feature
Sympton and sign Vit B12 Def :
• Severe : anemia, neuropathy
• Other symptom : sore mouth,loss of taste, atropy
mucosa of the tongue.
• Disorder of the central nervous system :
paresthesias of the hands & feet, unsteadiness of
gait, memory loss etc.
 Folate deficiency
• Reduced intake ( nutritional & malabsorpsi)
• Increased utilisation (pregnancy, malignancy,
hyperthytoidsm)
• Defective utilisation : drugs (anticonvulsant, oral
contraceptive), alcoholism.
• Reduced hepatic stores
alcohosm, hepatoma
FOLATE DEFISIENSI
 Cause , Sypmtom & Sign folic acid def

• Often go undiagnosed, especially alcoholic who

have a very poor diet and maintain blood alcohol
levels above 100 mg/dl→ enteropatic cycle of
folate supply to the intestine and tissues impared.
• Diagnosis is made difficult → clinician must be
suspicious of the possibility of folate def. in the
alcoholic.
 Aplastic anemia
• Anemi aplastic - Anemi normositer with reticulocyte
normal or decrease.
• Aplastic anemia is a severe, life threatening syndrome in
which production of erythrocytes, WBCs, and platelets has
failed.
• Aplastic anemia may occur in all age groups and both
genders.
• The disease is characterized by peripheral pancytopenia
and accompanied by a hypocellular bone marrow.
Hypocellular bone marrow in aplastic
anemia
 Aplastic anemia
• Etiology
– Acquired
» Most cases of aplastic anemia are idiopathic and there is no
history of exposure to substances known to be causative agents of
the disease
» Exposure to ionizing radiation – hematopoietic cells are
especially susceptible to ionizing radiation. Whole body radiation
of 300-500 rads can completely wipe out the bone marrow. With
sublethal doses, the bone marrow eventually recovers.
» Chemical agents – include chemical agents with a benzene ring,
chemotherapeutic agents, and certain insecticides.
» Idiosyncratic reactions to some commonly used drugs such as
chloramphenicol or quinacrine.
 Aplastic anemia
» Infections – viral and bacterial infections such as
infectious mononucleosis, infectious hepatitis,
cytomegalovirus infections, and miliary tuberculosis
occasionally lead to aplastic anemia
» Pregnancy (rare)
» Paroxysmal nocturnal hemoglobinuria – this is a
stem cell disease in which the membranes of RBCs,
WBCs and platlets have an abnormality making
them susceptible to complement mediated lysis.
» Other diseases – preleukemia and carcinoma
 Aplastic anemia
– Congenital disorders
» Fanconi’s anemia – the disorder usually becomes
symptomatic ~ 5 years of age and is associated
with progressive bone marrow hypoplasia.
Congenital defects such as skin
hyperpigmentation and small stature are also seen
in affected individuals.
» Familial aplastic anemia – a subset of Fanconi’s
anemia in which the congenital defects are absent.
 Clinical features
• Fatique
• Heart palpitation
• Palor
• Infections
• Ptchiae
• Mucosal bleeding/gum bleeding
 Aplastic anemia
• Pathophysiology:
– The primary defect is a reduction in or depletion of
hematopoietic precursor stem cells with decreased production
of all cell lines. This is what leads to the peripheral
pancytopenia.
• This may be due to quantitative or qualitative damage to the
pluripotential stem cell.
• In rare instances it is the result of abnormal hormonal
stimulation of stem cell proliferation
• or the result of a defective bone marrow microenvironment
• or from cellular or humoral immunosuppression of
hematopoiesis.
 Aplastic anemia
Lab findings
Severe pancytopenia with relative lymphocytosis
(lymphocytes live a long time
Normochromic, normocytic RBCs (may be slightly
macrocytic)
Mild to moderate anisocytosis and poikilocytosis
Decreased reticulocyte count
Hypocellular bone marrow with > 70% yellow
marrow
 Differential Diagnosis of pancytopenia and hypoplastic
marrow

1. Aplastic anemia
2. Hypoplastic myelodysplastic syndrome or
hypoplastis AML
3. PNH
4. Hypoplastic antecedent phase of acute
lymphocytic leukemia
5.Hypoplastic antecedent of hairy cell leukemia
6. Idiopathic myelofibrosis
7. Pure red cell aplasia
8. Agranulocytosis.
 Diagnosis Criteria for Severe AA

• At least two of following

- Absolute neutrophil count < 0,5 x 10 9 /L
- Platelet count < 20 x 10 9/L
- Anemia with corrected reticulocyte count < 1 %.
• One of the following
- Bone marrow cellularity <25 %
- Bone Marrow cellularity < 50 % with fewer the
30 % the neutrophil cell
 Treatment
• Marrow tranplantation isI curative for < 40 years.
• Only one –third of patients have suitable donor.
• Immunosuppressive therapy : not curative
-ATG
-Cyclosporin
-Androgen
- Corticosteroids