Sahyuddin

Tutik Hardjianti
A.Fachruddin Benyamin
 Outline

13 Introduction

42 Classification

3 Problem in dx

4 Problem in tx

53 Summary
 Objectives

1. In this hour we will review:

 Definition of anemia
 Utility of the CBC & reticulocyte count

2. Give you a simple plan to:

 Categorize anemias into 3 morphologic groups
 Develop a differential diagnosis
 Decide on further laboratory evaluation
 Introduction

Definition:
 Anemia : level of red cells, Hb,
or Ht is below the lower limit
of normal for age & sex :
< 13 gm/100 ml for adult male
< 11.5 gm/100 ml for adult
female & infant
< 14 gm/100 ml for new born
 Anemia is not a disease, it is
a sign of disease
Mechanisms :

1. Increased loss (external)

- hemorrhage
2. Increased destruction (internal)
- Inherited & acquired hemolytic anemia
3. Decreased production
- Lack of nutrients (B12, folate, iron)
- Bone Marrow Disorder
- Bone Marrow Suppression
 Classification of Anemia

Depends on:
I. Etiology.
2. Morphology of RBCs
both are complementary
 Etiology of Anemia

1. Anemia due to excess red cell loss :

a. Post-haemorrhagic anemia
- Acute haemorrhagic Anemia
- Chronic Haemorrhagic Anemia
b. Haemolytic anemia
- Corpuscular defect
- Extra corpuscular defect
2. Anemia due to impaired red cell formation
a. Disturbance of B.M function due to deficiency
of substances essential for erythropoiesis :
- Substance essential for HB synthesis :
( Iron def. anemia, protein def. )
- Substance necessary for DNA synthesis :
( Folic acid, B12 )
b. Disturbance of B.M. function Not due to def.
of substances essential for erythopoiesis
- B.M. infiltration
- Aplastic Anemia
3. Anemia due to other causes :
a. Endocrine disorders
b. Renal failure
c. Infections
d. Liver disease
e. Malignant disease
f. Collagen diseases
 Morphology Anemia
Classification:
 Hypochromic, microcytic (small)
 Normochromic, normocytic (medium)
 Macrocytic (large)

Microcytic, hypochromic Normocytic, normochromic Macrocytic

 Morphological Classification

Microcytic anemia
1. Iron deficiency anemia
Macrocytic anemia
2. Thalassemia
1. Megaloblastic anemia
3. ACD
4. Sideroblastic anemia 2. Reticulocytosis especially
in hemolytic anemia
Normocytic anemia 3. Myelodysplastic syndrome
1. Hemolytic anemia 4. Hypothyroidism
2. Acute post hemor.anemia
3. Stem cell failure
4. ACD
5. Anemia of organ failure
 Microcytic Anemias

DIFFERENTIAL DX : MCV < 80

Check also MCH, MCHC, RDW
 Iron Deficiency Next Lab testsIron studies
Anemia Serum Iron
TIBC/transferrin
 Thalassemias Serum Ferritin, % sat
 Sideroblastic Anemia
 Lead poisoning
 Anemia of chronic
disease (usually
normocytic)
 Thalassemia

 Inherited disorders
 Classified according to deficient
chain, severity varies based on
mutations
 α-thalassemia
 β-thalassemia
 Inadequate production of either the
alpha- or beta-globin chain of Hb
 Microcytic, hypochromic
 RDW usually normal
 High RBC count
 Can see tear drop cells, target cells “Thalassa” means “sea” in Greek
 Normal or increased iron
 Dx by Hb electrophoresis
 Macrocytic Anemias

MCV > 100

DIFFERENTIAL DX : Next labs to check:
serum vit B12
 Vitamin B12 Deficiency serum folate
(MCV>115) serum homocysteine
serum methylmalonic acid
 Folate Deficiency Intrinsic factor Ab
(MCV>115)
 Liver disease (MCV up to
115)
 Stimulated erythropoiesis
(MCV up to 110)
 Normocytic Anemias

MCV = 80 – 100
Next Labs:
DIFFERENTIAL DX: Iron studies
Platelets, WBC counts
 Anemia of chronic LFTs
disease TSH
etc…
 Aplastic Anemia
 Renal, liver, or
endocrine disease
 Anemia of Chronic Disease

 Chronic infection, inflammation or malignancy

 TB, lung abscess, HIV
 RA, SLE, or other autoimmune dz
 Malignancy
 Release of inflammatory cytokines suppresses
erythropoiesis
 Hallmarks—low serum iron, low TIBC/transferrin,
normal/increased ferritin
 Treat underlying process. Do not give iron. Anemia
is usually mild.
 Aplastic Anemia

 Rare
 Low reticulocyte %
accompanied by pancytopenia
 Causes:
 Idiopathic (majority)
 Congenital : Fanconi anemia
 Radiation exposure
 Meds : chloramphenicol,
sulfonamides, gold,
carbamazepine
 Viral infection :
human parvovirus, HepB,
HepC, EBV, CMV, HZV, HIV
 Chemicals :
benzene, insecticides
 Aplastic Anemia

 Clinical:
 Fatigue, dyspnea, petechiae, easy bruising, frequent
infections
 Can transform into acute leukemia
 Diagnosis:
 Bone marrow biopsy—definitive—hypocellular marrow,
absence of progenitors
 Treatment:
 Bone marrow transplant, transfuse with PRBCs & platelets
if necessary, immunosuppression
 Hemolytic Anemias

 Reticulocyte index > 2%

 From excessive RBC destruction or loss
 If erythropoiesis cannot keep up with destruction, anemia results
 Acute or chronic
 Abnormally shaped RBCs in periphery—spherocytes or
fragmented RBCs (schistocytes and helmet cells)
 Increased LDH, elevated indirect bilirubin, decreased serum
haptoglobin
 Sudden onset anemia, jaundice, splenomegaly
 Classified based on mechanism OR based on site of hemolysis
 Hemolytic Anemias

 Classified based on mechanism

 Due to factors external to RBC defects (most are acquired)
• Immune hemolysis
• Mechanical hemolysis—prosthetic heart valves, microangiopathic
hemolytic anemia
• Medications, burns, toxins, infection
 Due to intrinsic RBC defects (most are inherited)
• Hemoglobin abnormality—sickle cell, hemoglobin C disease,
thalassemias
• Membrane defects—spherocytosis, paroxysmal nocturnal
hemoglobinuria
• Enzyme defects—G6PD deficiency, pyruvate kinase deficiency
 Classified based on site of hemolysis
 Intravascular—within circulation
 Extravascular—primarily in the spleen
 What’s the Plan?

1. CBC - define anemia ( Hb, Hmt, LED )

2. Look at red cell indices
3. Categorize the anemia based on RBC size
4. Reticulocyte count - marrow response
5. Note any RBC anisopoikilocytosis
6. Consider the differential diagnosis
7. Plan your laboratory evaluation
 The CBC in Classification

1. Parameters that define the anemia:

 Red cell #, Hgb, Hct
2. Parameters that classify the type of anemia:
 MCV
• Low = microcytic
• High = macrocytic (on the smear a normal RBC is the
size of a small lymphocyte nucleus)
 MCH & MCHC
• Low = hypochromic
 RDW = tells you about anisocytosis
 Reticulocyte count

 An elevated retic count tells you that the bone

marrow is responding to the anemia
 A low/normal retic count in the face of anemia
tells you there is something wrong with the bone
marrow
 Peripheral Smear Morphology

 The CBC will not give you any information about

abnormal red cell shape (poikilocytosis)
 In many cases review of the red cell morphology
will lead you to a diagnosis
 Figure 1. A sequential approach to the evaluation of anemia through three common
pathophysiologic mechanisms

Hct/Hb low Determine presence of Hct/Hb normal

No history of
bleeding, no sign of anemia
occult bleeding in
sputum, urine, and Stop
stool Determine presence of blood loss Bleeding

Determine production of bone marrow by CBC, Ret Determine source of bleeding

count

High Ret count, normal Low Ret count, normal WBC and PC
WBC and PC

Determine presence of RBC destruction, Determine cause of reduced production by

measure LDH, haptoglobin, and indirect bone marrow
bilirubin

Evaluate RBC morphology

No hemolysis Hemolysis Determine RBC indices, RDW, low

Ret count

Determine cause of hemolysis

Microcytic anemia Normocytic anemia Macrocytic anemia

Besa EC. Approach to patients with red cell disorders. In: Hematology. Philadelphia: Harwal Publishing.
Figure 2. A sequential approach to the analysis of normochromic normocytic anemia

Normochromic normocytic RBC

(MCV=80-96 fl, MCH=27-32 pg)

Reticulocyte count

Increased Low or normal

Determine presence of Bone marrow study

hemolytic anemia & blood loss

Abnormal Normal

Metastasis
Renal, liver,
Myelofibrosis
endocrine
Multiple myeloma
function tests
Leukemia
Myelodysplastic syndrome
Aplastic anemia
Systemic disease Chronic disease
Besa EC. Approach to patients with red cell disorders. In: Hematology. Philadelphia: Harwal Publishing.
Figure 3. A sequential approach to the analysis of hypochromic microcytic anemia

Hypochromic microcytic RBC

(MCV<80 fl, MCH<27pg)

RDW (automated blood counts)

Normal RDW High RDW

Serum iron, TIBC, % Sat, ferritin, BM iron stores

Increased iron Increased iron Normal iron Decreased

in BM & in BM & in BM & iron in BM &
ferritin ferritin ferritin ferritin

Anemia of Sideroblastic Hemoglobin Iron

chronic disease anemia electrophoresis defisiensi

Thalassemia

Besa EC. Approach to patients with red cell disorders. In: Hematology. Philadelphia: Harwal Publishing.
 Figure 4. A sequential approach to the analysis of macrocytic anemia
Macrocytic RBC
(MCV >100 fl, MCH > 33 pg)

Reticulocyte count
Increased Decreased

Serum B12 & folate

Hemolysis or blood loss

Low Normal

Megaloblastic anemia Nonmegaloblastic anemia

Drugs B12 def Folate def Bone marrow

study
Schillin
Part I N Part I A, part II A, part III N
g test Aplastic anemia
Part I A, part II N Part I A, part II A, part III A
MDS
Myelophthisic anemia
Vegetarian diet Blind-loop syndrome
Pernicious anemia Malabsorption with mucosal damage

Besa EC. Approach to patients with red cell disorders. In: Hematology. Philadelphia: Harwal Publishing.
MACROCYTIC ANEMIA

Sahyuddin
Tutik Harjianti
A. Fachruddin B
 Macrocytic Anemias

MCV > 100

DIFFERENTIAL DX : Next labs to check:
serum vit B12
 Vitamin B12 Deficiency serum folate
(MCV>115) serum homocysteine
serum methylmalonic acid
 Folate Deficiency Intrinsic factor Ab
(MCV>115)
 Liver disease (MCV up to
115)
 Stimulated erythropoiesis
(MCV up to 110)
 Deficiency Cyanocobalamin

 B12 : all of it made from diet

 A food ingredients may from animal.
 Absorbtion : 5 ug / days
 Cofactor at 2 important reaction in a body

Division of Hematology & Medical Oncology – Dept. of Internal Medicine

 The role of Cyanocobalamin

 Methyl-Cobalamin is a cofactor for methionine-

synthetase at rx change of homosystein 
metyonin.
 Adenosyl-Cobalamin is a cofactor at rx change
of methyl-malonyl CoA  succinyl-CoA

Division of Hematology & Medical Oncology – Dept. of Internal Medicine

 Deficiency Cyanocobalamin

An important sign :
1. macrocytic Anemia

3. Level of Vit B12 <100 pg/ ml

sign

2. Peripheral blood smear:

macro-ovalocyte & hypersegmented neutrophil

Division of Hematology & Medical Oncology – Dept. of Internal Medicine

Macrocytic Normocytic

Division of Hematology & Medical Oncology – Dept. of Internal Medicine

 The Cause

1. Deficiency vit B12 (diet)

2. The decrease production of intrinsic factor
(Anemia perniciosa, post-gastrectomy)
2. The decrease absorbtion of vit B12 at the ileum
(Post-op, Crohn ds)
3. Helmynthyasis (tape-worm)
4. Deficiency Transcobalamin II

Division of Hematology & Medical Oncology – Dept. of Internal Medicine

 Vitamin B12 Deficiency
 Causes—most due to poor
absorption
 Pernicious anemia
(lack of intrinsic factor)
 Gastrectomy
 Poor diet
 Alcoholism
 Crohn’s disease, ileal
resection
 Organisms competing for
Vit B12
 If untreated can lead to
demyelination in posterior
columns, lateral corticospinal
tracts, spinocerebellar tracts
 Physiology

 Vit B12 come in from IT  binding with intrinsic

factor (made from parietal mucosa gaster cell)
 abs in ileum terminal by spesific receptor 
come in to the plasma  liver .
 There are 3 protein transporter in the plasma :
Trans-cobalamin I, II & III (by leukocyte).
Only Trans-cobalamin II that can transport vit
B12 into the cell.

Division of Hematology & Medical Oncology – Dept. of Internal Medicine

Division of Hematology & Medical Oncology – Dept. of Internal Medicine
 Phatogenesis
 Hepar consist 2.000 – 5.000 ug vit B12

 Need : 3 – 5 ug / hari

 Defs vit B12 will be happen in 3 years after no

more absorpsi.

 Defs caused by diet less vit B12 vary rare

( vegetarian )
 Example :

 Gastrectomy  the area produce factor

intrinsik will decrease
 Over-growth bactery in intestinal
 Reseksi ileum  the area of absorpsi vit
B12 will decrease
 Helmenthyasis
 Crohn’s disease  ileum destruction
the area of absorpsi vit B12 will decrease
 Anemia Perniciosa

 Often cause defs B12

 Abnormality Auto-Imun herediter
 Seldom show before 35 years old
 Scandinavia / Eropa Utara
 A black skin teenager, a hispanic woman
 Anemia Perniciosa

 Clinic illustration :
Likely anemia caused byndefs vit B12,
- Gastritis atrophic
- Abnormal Auto-Imun ( rheumatoid arthritis
Grave’s disease, defs IgA )
- After several years some patient
Gastritis Atrophic => Carcinoma Gaster
 Folate Deficiency

 Stores are limited, can become depleted over

3 month period
 Main source—green vegetables
 Causes—“tea & toast” diet, alcoholism, long term
oral antibiotic use, increased demand, pregnancy,
hemolysis, methotrexate use, anticonvulsants
(phenytoin), hemodialysis
 Clinical—similar to Vit B12 deficiency, without
the neurologic symptoms
 Treat—daily oral folic acid replacement
 CLINIC ILLUSTRATION DEFS. VIT B12

 Megaloblastic anemia

 May a hard anemia ( hematokrit < 10 % )

 A change mucosa cell : glossitis, anorexia,

diare.
 Neurologic disturb:
1. Perifer  parestesi
2. Cerebral difunct
 Lab. Abnormal
 1. Megaloblastic Anemia
 2. MCV between 110 – 140 fl (increase)
at some patient : MCV normal
( thalassemia , defs Fe )

 3. Blood Perifer : anisocitosis &

poikilocitosis. Specif : makro-ovalosit.
 Blood Perifer
 4.Morfologi eritrosit very abnormal 
Likely Hemolytic Anemia

 5. Hypersegmentasi netrofil

 6. Reticulocit amount decrease

 Bone Marrow Asp

 Eritropoesis in-efektif ( ggn produksi RBC )

hiperplasi eritroid ( as respons )

 Cell megaloblast abnormal in SST diferent shape :

* big abnormal size,
* maturasi inti & sitoplasma tdk.sinkron.
Maturasi cytoplasm is normal,
DNA synthesis is bother

Seri mieloid : Giant sel meta-mielosit

 Other Lab. Abnormal :

In-efektif eritropoesis in SST  may happen

destruction eritroid cell that in the development
period  level LDH ( lactic-dehydrogenase )
very increase, and Bilirubin indireck increase
just for a little
 Diagnosis

 1. Level vit B12 serum is less

( normal : 150 -350 pg / mL )
 2. Schilling test ( for dx A Perniciosa /
the decrease absorpsi vit B12 oral )
1st step : the patient injection w/ Vit B12 i.m
Then give vit B12 that has di-label p.o
Retain urine 24 hours
 ( Normal : > 7 % )
 Test Schilling 2nd step

 Give vit B12 that has ……, with the intrinsic

factor.
 If the patient Anemia Perniciosa ( defs intrinsic
factor ), so absorpsi will fixed.
 At a hard case ( epitel usus abnormal ) 
malabsorption  the result of test Schilling II
may still abnormal sp defek mukosa usus pulih.
 THERAPY
* At Anemia Pernisiosa ( oral absorpsi
disfun)
 Intra-muscular Inj. Vit B12 ( IM )
 Dosis : 200 ug
 1st week : every day (replacement – tx)
 2nd – 4th week : every week
 Once a month
 Respons Therapy
 Usually easy to show, GC better, the complain
decrease.
 Retyculocitosys happen in 5 – 7 days.

 Abnormalitas hermatologic will be dissappear

after 2 months.
 SSP disorder will be dissappear if we give
therapy before 6 months sick.