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Purpose

Be able to explain definition of anemia

Be able to classify anemia

Knowledge of laboratory test for ane

1. Definition of anemia
2. Causes of anemia

Items

3. Classification of anemia
4. Differential diagnosis

5. Signs and symptoms of anemi


6. Laboratory diagnosis of anemia

Definition of anemia
Anemia is the condition associated

- With decrease of red cell mass (RCM) < 10%

of normal value M = 26-31 , F = 23-29 ml/K


- Anemia is a sign not disease
- Anemias are dynamic process

Hb levels to define anemia


Hb levels
NB (<1 wk)

< 14 g/dl.

6 mon 6 yrs

< 11 g/dl.

6-14 yrs

< 12 g/dl.

>14 yrs (male)

<13 g/dl.

>14 yrs (female)

< 12 g/dl.

Pregnant

< 11 g/dl.

Etiology of anemia
- Hypoproliferative
~rbc in BM < normal

lacking of vit B12 , Iron and chronic disea


- Maturation disorder

- Hemolytic disorder , abnormal of mature rb


by being destroyed
- Blood loss

Classification of anemia
- Morphologic classification by MCV
- Pathophysiologic classification
Pathophysiology of anemia by

various mechanism.

RBC indices
- Mean Corpuscular volume (MCV)
MCV = Hct

10

RBC (million/cm3)
Normal value

fl.

= 80-100 fl. (10-15 l.)

- Mean Corpuscular hemoglobin (MCH)


MCH = Hb

10

RBC (million/cm3)
Normal value

Pg.

= 27-32 pg. (10-12 g.)

- Mean Corpuscular Hemoglobin concentrat


(MCHC)
MCHC = Hb
Hct

X100

Normal value

g/dl

= 32 - 37 g/dl

Morphologic classification
3 kinds

1. Normocytic anemia rbc & MCV normal


MCV

= 80-100 fl.

2. Microcytic anemia
rbc small size MCV

< 80 fl.

3. Macrocytic anemia
rbc large size MCV

> 100 fl.

1. Normochromic normocytic anemia


MCV 80-100 fL
Commonly
MCHC 32-36 g/dL
Hypoproliferative anemia
Renal failure
Hemolytic anemia
Blood loss anemia
Anemia of chronic disease
Acquired sideroblastic anemia
Early iron deficiency

2. Microcytic hypochromic anemia


MCV < 80 fL
MCHC < 32 g/dL

Small and increase central pallor of red blo


cell
Commonly
Iron deficiency anemia
Thalassemia
Hereditary sideroblastic anemia

Occasionally

Anemia of chronic disease

Lead poisoning

3. Macrocytic anemia

MCV > 100 fL.

MCHC > 36 g/dL

Macro-ovalocyte

Commonly
Megaloblastic anemia
Vit B12 , folate deficiency , alcoholism ,
Pernicious anemia

Occasionally
Hypoproliferative anemia
Refractory anemia
Liver disease
Hemolytic anemia
blood loss anemia

Pathophysiologic classification

Anemia caused by decreased production of re


cell
Anemia caused by increased destruction
(intracorpuscular abnormality)
Anemia caused by increased destruction
(Extracorpuscular abnormallity)

1. Anemia caused by decreased production


red blood cell
Disorder of hematopoietic stem cell and
differentiation
: Aplastic anemia

Disorder of DNA synthesis : Megaloblastic ane

Disorder of Hb synthesis : iron deficiency ane


thalassemia

Disorder of proliferation and differentiation of


precursor erythroid cell
: Anemia of chronic renal failure
: Anemia of endocrine disorder
Unknown mechanism
: Anemia of chronic disease

: Anemia associated with marrow infiltratio


: Sideroblastic anemia

II. Anemia caused by increase destruction


(Intracorpuscular abnormality)
- Menbrane defect : hereditary spherocytosis,
hereditary ovalocytosis
- Enzymes deficiency : G 6PD deficiency
- Globin abnormality : hemoglobinopathies
- Increase susceptible to complement

: Paroxysmal nocturnal hemoglobinuria (PNH)


Paroxysmal cold hemoglobinuria (PCH)

3. Anemia caused by increase red blood cell


cel

destruction (Extracorpuscular abnormali

- Mechanical : Microangiopathic hemolytic anemi


(MAHA)
- Infection

: hemolytic anemia due to malarial

infection (black water fever in Falciparum mala

- Chemical and physical agent : drugs, toxin, bur

- Antibody mediated : Acquired hemolytic anemi

- Blood loss : Acute blood loss, chronic blood lo

Physiologic response to anemia


3 groups

1. Symptom of lacking of O2 nausea , fatigue, tire

2. Symptom of respiratory system is the compensa


mechanism : shortness of breath
3.

Symptom of heart and vascular system : tachyca

Hematologic response
-

Increase rbc production

Increase rate of proliferation, maturation and rel


from BM : increase reticulocyte to circulation.

Clinical Manifestation
- No symptom

- Cardiac stress may cause tachycardia, shortne


breath
- Pallor in the result of dermal vasoconstriction
blood supply redistribution

Laboratory evaluation
1. Complete blood count (CBC)
2. Red blood cell indices (MCV, MCH, MCHC)
3. Reticulocyte count
4. Platelet count

5. Iron studies
Serum iron
Total iron binding capacity (TIBC)
Transferrin saturation
Serum ferritin

6. Screening for hemoglobinopathies and thalasse


7. G-6-PD
8. Hams test
9. Coombs test
10. Bone marrow study

Iron deficiency anemia (IDA)


- Lacking of iron for synthesis hemoglobin

- RBC are hypochromia and microcyte so become


microcytic anemia
- BM accelerate to produce rbc

-This anemia is the most important because it of


found in Thailand and in the world
- At present time ~ 500 million of IDA

Iron metabolism
Iron uptake
10-20 mg/day

Hb 60-70% ~ 2 gm.
Storage form ~ 25-30%
Myoglobin ~ 5% or 140 mg.

Ferric iron
(Fe3+)

Iron containing enz. 0.5-1% or 10 mg


Transport iron ~ or 1%

Ferrous iron
(Fe2+)

Tf-iron

Absorption (10%)
1 mg/day

Tf

Hemoglobin
- Large amount of iron ~ 2 gm. Or 60-70 %

- Storage iron : iron in nucleaus of cells in RE cell


and BM in the form of ferritin and hemosiderin

- Myoglobin is the red substance in musele and ir


containing enzymes ~ 140 mg or 5-6 %
-Transport iron : transferrin is the major iron

transport protein synthesis by the liver and


macrophage
: each molecule of transferrin (Tf) can bind
atoms of iron

: about one-third (25-35%) of total transferrin


is bound to iron (referred as %
saturation)
: To determine transferrin in serum we use to
determine the capability to capture iron
which is total iron binding capacity
(TIBC)

Transferrin iron
+ TIBC

= Serum iron

Table
Distribution of body iron of man weight 70
Hemoglobin
Ferritin, hemosiderin
Myoglobin
Iron containing enzymes

2,500 mg.
1,000 mg.
140

mg.

10

mg.

Serum iron
Total

4
3,654

mg
mg.

Iron requirement
Adult
Daily iron uptake

= 1 mg/day
= 10-20 mg/day

Condition which increase iron requirement


- Children
- blood loss
- Pregnancy
- Chronic disease
Iron absorption
- luminal phase : stomach , intestine
- Cellular phase : duodenal mucosa cell

- Circulatory phase : binding to transferrin

- Only ferrous form (Fe2+)

- Maximum absorption : duodenum and jejunum

Regulation of iron absorption


- Storage iron

- Rate of erythropoiesis

Iron absorptive factors


Increase iron absorptive factors
- Iron deficiency anemia
- Increase erythropoiesis
- Fe2+
- Acid pH
- Vitamin C
- Pregnancy

Decrease iron absorptive factors


- Iron overload
- Fe3+
- Alkaline pH
- Tea
- Chronic inflammation

Iron deficiency anemia (IDA)


Etiology
1. Low intake
: increase iron requirement
: Low iron in food (vegetarian)
: Iron absorption disorder
- Peptic ulcer
- Gastrectomy
- lymphoma in small intestine
- heavy tea drink

2. High loss
: menstruation
: GI bleeding
: Parasitic infection hook worm

Iron distribution
1. Storage pool
2. Plasma pool
3. Erythron iron pool

Stage of IDA
1. Iron depletion decreasing of storage pool
2. Iron deficiency erythropoiesis-no iron in
storage pool

3. Iron deficiency anemia no iron in storage poo


: decreasing of erythron iron pool

Stage of IDA
Normal
1.

TIBC

330

2.

Serum ferritin

100

3.

Increase of %

Iron depletion
Iron deficiency Iron d
erythropoiesis
anemia

5-10

360

390
20

10-15

410
10

<

10-20

10-20

absorption
4.

Serum iron

115 50

5.

Tf-saturation

35 15

6.

% sideroblast

40-60

7.

FEP

8.

RBC

30
normal

115
30
40-60

< 60

<4

< 15
< 10

< 10

30

100

normal

normal

hypoch

microcytic

Incidence of IDA
20 % of female
30 % of pregnant
3 % of male

Laboratory diagnosis
1. CBC : Hb, Hct decrease
: WBC normal

: RBC morphology-hypochromic microc


2. RBC indices
: MCV decrease
: MCH decrease
: MCHC slightly decrease

3. Iron study
- Serum iron decrease
- Serum ferritin decrease
- TIBC increase
- % If. Saturation decrease
- FEP increase
- ZEP increase

Treatment
- Iron supplement are always required
(ferrous sulfate)
- Iron rich food : meat, liver, fish, eggs poultry,
legumes (peas and beans)

Symptom
- Fatigue
- tiredness
- Shortness of breath
- Nausea and headache
- Pinguecula stomatitis
- glossitis
- kailonychia
-Esophageal webbing
- Dysphagia

Diagnosis for the disease of hypochromic


microcytic red cell.
IDA

Thalassemia

chronic

Sideroblastic

disease
Serrum ferritin

Serum iron

D/N

TIBC

Transferrin

I/N

FEP/ZPP

BM iron

Sideroblast

None

I/N
I/N

anemia

I/N

Vary

D/N

I (++

I/N

I/N

None

N
I

(ring)

lead poiso

= decrease, I = increase, N = normal

++ = markedly, ring = ringed sideroblast

Aplastic anemia (AA)


- First reported by Paul ehrlich in 1888
- Important characteristics

: Abnormal in hypoproliferative disorder which


poliferation and maturation of all blood cell
below normal
: BM hypoplastic bone marrow
: Blood smear pancytopenia

Incidence in U.S.A ~ 2-3 cases for 1 million but in Korea


4-5 times than U.S.A and can find in every aging and sex

2 Kinds of A.A
1. Idiopathic aplastic anemia
- is the most common for AA
- Unknown causes

- Responsible for immune suppressive drugs


2. Primary or hereditary aplastic anemia
- Fanconis anemia abnormal at birth is AA
that rarely found
- Inherrit by autosoma recessive
- Easy braking DNA

- BM hypoplastic bone marrow all immature cell


below normal and abnormal of other organs
such as kidneys spleen skin and brain
- Can become leukemia later on
3. Secondary or acquired aplastic anemia
- developing after birth due to
: toxic substance
: Infection
: Rays
: become after other disease

Etiology of AA
: Low erythropoietin

: BM being destroyed by toxic substances or som


drugs
: Distribution of leukemic cell in to BM
: Infection by hepatitis C virus and EBV
: Other causes
- Prenancy
- Pancreatitis
- PNH
- Abnormal immunity
Pathophysiology
- Immunologic suppression
- Suppression of hematopoiesis

Symptom
- Pale
- Pancytopenia
- Fatigue
- Bleeding
- Infection
- Fever

- Splenomegaly and hepatomegaly rarely found


Laboratory diagnosis
- CBC - low
- Platetet low
- Reticulocyte low
- B.M. hypoplasia

Pancytopenia
1. Aplastic anemia
2. Bone marrow infiltration
- Leukemia
- Hodgkins lymphoma
- Lipid storage disease
- Myelodysplastic syndrome
- Myelofibrosis
- PNH
- Splenomegaly

- Infection
- VitB12 deficiency

Hypoplasia
- Aplastic anemia
- Pure red cell aplasia
- Myelodysplastic syndrome
- Other abnormality
: Anemia from renal failure
: Hormone disorder

Sideroblastic anemia
- Microcytic anemia cause by
1. Hereditary or X-linked sideroblastic anemia

1.1 Missene mutation of gene ALAS2 (5-amin


levulinate synthase) caused abnormal

synthesis of enzyme ALAS2 which is enzy


of heme synthesis

1.2 Increase absorption caused iron overload


1.3 Diagnosis by gene analysis found the
mutation of gene ALAS2
1.4 high incidence in male than female

2. Acquired sideroblastic anemia


2.1 Is abnormal in group of Myelodysplastic
syndrome (MDS) and can become AML

2.2 Can occur together with other hematologi

disease such as AML, PV, Myeloma and MDS


2.3 Drugs as chloramphenicol, isoniazid
2.4 Toxic substances as alcoholic, lead.
2.5 Idiopathic

Symptom
- Chronic hypochromic red cell
- Ring sideroblast in BM
- Increase of iron
- Ineffective erytheopoiesis

Laboratory diagnosis
- RBC normocytic/microcytic hypochromic
(dimorphic picture)
- Serum iron

serum ferritin increase

- B.M. : ring sideroblast


: Erythroid hyperplasia

- Reticulocyte may or may not change


Hereditary sideroblastic anemia
- Severe anemia
- Microcytic hypochromic rbc

- target cellan

basophilic stippling

- Ring sideroblast in B.M 0-49 % of nucleated c

- if fotale deficiency may be megaloblastic cha


- Response to pyridoxine

Acquired sideroblastic anemia


- Moderate anemia
- Normocytic hypochromic or macrocytic
hypochromic red cell
- B.M. erythroid hyperplasia
- ring sideroblast 45-95% of nucleated cell
- if folate deficiency may be megaloblastic
change
- Transferrin saturation > 90%
- 10% of patient develop to leukemia

Megaloblastic anemia
- Megaloblastic red cell in B.M
- Abnormal erythroid series
- Red cell is Macrocyte or Megalocyte

Etiology

- DNA synthesis disorder because lacking of VitB


or folate
- Ineffective erythropoiesis
- hemolytic anemia
- Increase membrane surface area

by

- hepatic disease
- Obstructive jaundice
- Post splenectomy

- Common cause are


- VitB12 deficiency

- Folate deficiency (diary requirement 100 mg


- VitB12 and folate deficiency
- Drug cytotoxic chemotherapy
Causes of folate deficiency
- decrease intake
- Increase requirement
- Malabsorption
- Alcoholism

Etiology of VitB12 deficiency


- Inadequale intake
- Abnormal gastric

- Unable to dissociated VitB12 from bloo


due to lack of stomach acid or enz.
- Abnormal mucosal event
: including malabsorption syndrome
and surgical removal or terminal ileum
- deficiency intrinsic factor cause
autoantibodies (pernicious anemia or PA)
-

infection with fish tape worm


(Diphyllobotrium latum)

Blood smeare
- Normochromic macrocytic rbcMacroovalocyle
MCV > 100 fl
- Aniso-poikilocytosis
- Basophilic stippling in severe cases
- Reticulocyte decrease
- hypersegment neutrophil
- Reticulocyte count decrease, ineffective
erythropoiesis
- Red cell

- asynchronous maturation or

asynchronism

Bone marrow
- Hypercellularity, erythroid hyperplasia and
megaloblastic erythroid series
- abnormal nucleus, many nucleus
- many mitotic cell
- Basophilic stippling

- WBC myelocyte or metamyelocyte in giant for

Laboratory diagnosis

- CBC - hypersegment neutrophil, macroovalocyt


- Blood indices
- Reticulocyte count
- Bone marrow
- VitB12 level
- Schilling test : VitB12 absorption
- LDH increase

- Bilirubin, homocysteine, methylmalonic increas

Schilling test
- For finding cause of lacking of Vit B12
- Taking radioactive cyanocobalamin and measure

radioactive substance of different urine sample if


low value
show that there is abnormal in absorption

- Repeat again by giving IF to gether with radioacti

cyanocobalamin, if higher value of radiative subst


show that the patient lack of IF

Pernicious anemia
- Megaloblastic anemia

- by lacking of IF (glycoprotein produce from stom


(function to help absorption of VitB12)

2 types
1. PA in children (chilhood type PA)
- hereditary abnormality of IF
- generally not show up until age of 2 yrs.
2. PA in adult (adult type)
- found > childhood type
- Chronic atrophic gastitis
- more in female > male
- > 60 yrs.
-

Autoimmune 90% of adult type

50% of patients with antibodies to IF

2 types

1. Block type is antibodies that resist the capture


of VitB12

with IF

2. Binding type is antibodies that capture of VitB

with IF (IF-ViTB12) can not attach to receptor


at the ileum for absorption

Laboratory diagnosis
- BM

- megaloblastic series rbc-

- VitB12 deficiency
- Lacking of IF