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Hematopathology

Part-1

Red Cell Disorders

Abdulkareem Mohammad Jaafar

MB. ChB. PhD. (Hematopathology)

Department of Pathology

College of Medicine/ University of Baghdad


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●Anemia:

is defined as a reduction of the total circulating 

red cell mass below normal limits.

Which usually stems from:

●A reduction of the total circulating red cell mass to below-
normal amounts.

●Anemia 

is usually diagnosed based on

a reduction in the:

●Hematocrit

(

the ratio of packed red cells to total blood 

volume) 

and

●Hemoglobin concentration 

of the blood to levels that are 

below the normal range.  


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Classification of anemia:

Morphologic classification

: is based on the morphology of 

red cells.

This is often correlates with:

The cause of their deficiency.

Specific red cell features that provide etiologic clues 
include: 

●Cell size: 

(■Normocytic. ■Microcytic. ■Macrocytic).

●Degree of Hemoglobinization

: which is reflected in the 

color of the cells 

(■Normochromic. ■Hypochromic). 

●Shape of the cells. 


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Normal

Morphologic classification of anemia

Hypochromic

Microcytic

Macrocytic


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Iron Deficiency Anemia:

It is the most common form of nutritional deficiency.

Causes:

●Chronic blood loss.
●Low intake and poor availability.
●Malabsorption.
●Increased demands.


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Lab Findings of Iron Deficiency Anemia:

●Anemia (Reduced Hb or Hematocrit level).
●The red cells are microcytic and hypochromic, reflecting 
the reductions in MCV and MCHC.
●Low serum ferritin and serum iron levels.
●Low transferrin saturation.
●Increased total iron-binding capacity. 
●Normal Hb A

2

level.

●Absent storage iron in the bone marrow.


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The blood film 

shows 

hypochromic, microcytic 

cells with 

poikilocytosis.

Normal


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The serum iron, unsaturated serum iron-binding capacity (UIBC) and serum ferritin in:

Normal subjects.

Iron deficiency.

Anemia of chronic disorders.

The total iron-binding capacity (TIBC) is made up of:

Serum iron +

UIBC.


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Anemia of chronic 
disorders:

One of the most 
common anemias 

occurs inpatients with a 
variety of chronic 
inflammatory and 
malignant diseases .


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Lab findings of Anemia of Chronic Disorders:

●Anemia (Reduced Hb or Hematocrit level).

●The red cells can be:

■Normocytic and Normochromic. Or
■Hypochromic and Microcytic.

●The serum iron levels are usually low.
●Increased storage iron in the bone marrow.
●High serum ferritin concentration.
●Reduced total iron-binding capacity.


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Megaloblastic Anemias:

In megaloblastic anemia the red cells are abnormally:

Large (mean corpuscular volume, MCV >95 FL).

There are two principal causes of megaloblastic anemia:

●Folate deficiency.
●Vitamin B

12

deficiency.

Both vitamins are required for:

DNA synthesis.

The effects of their deficiency on hematopoiesis are quite 
similar.


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Lab Findings of Megaloblastic Anemia:

The RBCs are Macrocytic (MCV >95 fL) and the 

macrocytic RBCs are typically 

Oval

in shape.

The reticulocyte count is low.

The total white cell and platelet counts may be 

moderately reduced, especially in severely anemic 
patients.

A proportion of the neutrophils show:

Hypersegmented Nuclei 

(with six or more lobes).


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The Diagnostic Features (Lab Findings) of 

Pernicious 

Anemia

include:

Serum antibodies to intrinsic factor.

●Low serum vitamin B

12

levels.

●Normal or elevated serum folate levels.
● Megaloblastic anemia.
●Leukopenia with hypersegmented granulocytes.
●A dramatic reticulocytic response (within 2-3 days) to 
parenteral administration of vitamin B

12

.


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The RBCs are Macrocytic

. ●

The macrocytic RBCs are typically oval in shape.

Normal


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A proportion of the neutrophils 

show 

Hypersegmented Nuclei 

(with six or 

more lobes)


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Aplastic Anemia:

It is a disorder in which:

●Multipotent bone marrow stem cells are suppressed.

Leading to:

►Marrow Failure.
►Pancytopenia.


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Pancytopenia:

Pancytopenia describes a

reduction in the blood count

of

all the major cell lines:

Red cells.

White cells.

Platelets.


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Lab findings of Aplastic Anemia:

The bone marrow is markedly hypocellular, with greater 

than 90% of the intertrabecular spaces occupied by fat. 

The limited cellularity often consists of only lymphocytes 

and plasma cells.

Thrombocytopenia and granulocytopenia may result in 

hemorrhages and bacterial infections, respectively. 


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Bone marrow aspirate: shows myeloid 
precursors ranging from myeloblasts to 
segmented neutrophils. Several erythroid 
precursors with condensed nuclear chromatin 
are also seen. 

This specimen from a bone marrow 
aspirate is very hypocellular.

Normal


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Aplastic anemia (bone marrow biopsy). Markedly
hypocellular marrow contains mainly fat cells.

The general cellularity is 
normal and a few larger 
megakaryocytes are 
appreciated.

Normal


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Hemoglobinopathies

The hemoglobinopathies are:

●A group of hereditary disorders that are defined by the 
presence of:

●Structurally Abnormal Hemoglobins.


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Sickle cell anemia

Sickle cell disease is a group of hemoglobin disorders in 
which the sickle β-globin gene is inherited.


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Laboratory findings: 

(Homozygous Disease-

Sickle Cell Disease

)

●The hemoglobin is usually 6-9 g/dL.
●Sickle cells and target cells occur in the blood.
●Features of splenic atrophy 

(e.g. Howell Jolly bodies) may also 

be present.

●Screening tests for sickling are positive when the blood is 
deoxygenated.
●Hemoglobin electrophoresis:

In Hb SS: 

NO

Hb A is detected.

The amount of 

Hb F

is variable and is usually 

5-15%.

Larger amounts are normally associated with a milder disorder.


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Sickle cell anemia: ●

Deeply staining sickle cells, ●Target cells and 

●Polychromasia.


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Sickle cell anemia

●Hemoglobin electrophoresis:

In Hb SS: 

No Hb A is detected.

The amount of 

Hb F

is variable and is usually 

5-15%.


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Sickle cell trait:

This is a benign condition with no anemia and normal 

appearance of red cells on a blood film.

Hematuria is the most common symptom and is thought 

to be caused by minor infarcts of the renal papillae.

Hb S varies from 25 to 45% of the total hemoglobin.


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Thalassemias:

These are a heterogeneous group of genetic disorders 
that:

●Result from a reduced rate of synthesis of:

α- or 
β- chains.


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Laboratory findings: (β-Thalassemia Major)

There is a severe hypochromic, microcytic anemia.

Raised reticulocyte percentage. 

Normoblasts, target cells and basophilic stippling in the blood film.


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Laboratory findings: (β-Thalassemia minor):

This is a common, usually symptomless, abnormality 
characterized by:

●Mild anemia (hemoglobin 10-12.g/ dL).
●A hypochromic, microcytic blood picture (MCV and 
MCH very low). Some RBCs show Basophilic Stippling.

●The serum iron levels are usually normal.
●Normal storage iron in the bone marrow.
●Normal serum ferritin concentration.
●Normal total iron-binding capacity.

●A raised Hb A2 (>3.5%) confirms the diagnosis.


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●A hypochromic, microcytic blood picture (MCV and MCH very low). Some RBCs 
show Basophilic Stippling.

β-Thalassemia minor


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α-Thalassemia syndromes:

●These are usually caused by:

■Gene Deletions.

●As there are normally four 
copies of the α-globin gene:

■The clinical severity 

can be 

classified according to the 

number of genes 

that are 

missing or inactive.

The genetics of a-thalassemia. Each a gene may be deleted or 

(less frequently) dysfunctional. 


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Hydrops Fetalis

Loss of all four genes 

completely suppresses α-chain 

synthesis. 

Because the α chain is essential in fetal as well as in adult 

hemoglobin: 

This is incompatible with life and leads to death in utero.


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Hb H Disease: 

Three α gene deletions 

leads to a moderately severe 

(hemoglobin 7-11 g/dL) 

Microcytic, hypochromic anemia 

with 

splenomegaly.


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The α-thalassemia traits:

are caused by loss of 

One or Two 

genes 

and are 

usually not 

associated with anemia

.

But the (MCV) and (MCH) are 
low.

Hemoglobin electrophoresis is 
normal.


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The Hemolytic Anemias:

Anemias that are associated with accelerated 
destruction of red cells.

Destruction can be caused by:

1. Inherent (intracorpuscular) red cell defects, 

which 

are usually 

inherited. 

2. External (extracorpuscular) factors, 

which are 

usually 

acquired. 


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Extravascular and Intravascular hemolysis:

There are 

two main mechanisms 

whereby red cells are 

destroyed in hemolytic anaemia.

●Extravascular hemolysis:

There is excessive removal of 

red cells by cells of the reticuloendothelial system.

●Intravascular hemolysis:

The red cells are broken down 

directly in the circulation.

Whichever mechanism dominates will depend on the 
pathology involved.


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Red blood cell (RBC) breakdown


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Non-Immune Hemolytic Anemia:

Defective red cell metabolism:

GIucose-6-phosphate dehydrogenase deficiency:

The inheritance is:
●Sex-linked 

(

Affecting Males

and 

Carried by Females

) who 

show approximately half the normal red cell G6PD values.


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The blood film may show

contracted and fragmented cells, 'bite' cells and

'blister‘ cells

which have had Heinz bodies removed by the spleen.

GIucose-6-phosphate dehydrogenase deficiency


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Hereditary spherocytosis:

The inheritance is:
●Autosomal dominant with variable expression.

Rarely it may be:
●Autosomal recessive.


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Pathogenesis: 

HS is usually caused by defects in:

The proteins involved in the vertical interactions between the membrane skeleton and 
the lipid bilayer of the red cell.

Various mutations involving:

Spectrin and Ankyrin

that weaken the interactions between these proteins cause red 

cells to lose membrane fragments.


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The loss of membrane may be caused by the release of parts of the
lipidbilayer that are not supported by the skeleton.


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Note the anisocytosis and several dark-appearing spherocytes with no central pallor. 
Howell-Jolly bodies (small dark nuclear remnants) are also present in red cells of this 
asplenic patient.

Hereditary spherocytosis


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Traumatic hemolytic anemia:
These arise through physical damage to red cells 

either on:

●Abnormal surfaces 

(e.g. artificial heart valves or arterial grafts), 

arteriovenous malformations 

or 

●A microangiopathic hemolytic anemia.

This is caused by red cells passing through abnormal small vessels.

The latter may be caused by:

●Deposition of fibrin strands often associated with:

Disseminated intravascular coagulation (DIC)

or

●Platelet adherence as in:

Thrombotic thrombocytopenic purpura (TTP) 

or 

●Vasculitis

(e.g. polyarteritis nodosa).


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Blood film in microangiopathic hemolytic anemia. Numerous contracted and deeply 
staining cells and cell fragments are present.


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Immune hemolytic anemias

Autoimmune hemolytic anemias:

Autoimmune hemolytic anemias (AIHAs) 

are caused by:

●Antibody production by the body against its own red cells. 

They are characterized by:

Positive

Direct Antiglobulin Test (DAT) [

Coombs test

] .

Divided into:

●Warm. 
●Cold types.

According to whether the antibody reacts more strongly with red 

cells at 

37°C or 4°C.


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The antiglobulin test for antibody or 
complement on the surface of red blood 
cells (RBC).

The antihuman globulin reagent may be 
broad spectrum or specific for IgG, IgM, 
IgA or complement (C3).

Patient antibody screening: 10 tests with 
two controls (

Tube 11: Positive Control. 

Tube 12: Negative Control

).

The patient’s serum is tested against 
screening cells.

Tubes 1, 3, 5–8 and 10 show positive results.


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Laboratory findings (Warm type):

The hematological and biochemical findings are typical of 
an 

extravascular hemolytic anemia

with:

Spherocytosis prominent in the peripheral blood.

The DAT is positive as a result of Ig G, Ig G and 
complement or Ig A on the cells.


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The blood film shows 

Microspherocytes

which are densely staining with 

smaller diameters than normal red cells.

Warm type Autoimmune hemolytic anemia


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Laboratory findings (Cold type):

Are similar to those of warm AIHA 

EXCEPT

that:

●Spherocytosis is less marked.
●Red cells agglutinate in the cold.


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Red cell agglutination

. Several clumps of agglutinated red cells, two are 

marked by arrows. 

Cold type Autoimmune hemolytic anemia


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Polycythemia (Erythrocytosis):

It is an increase in the blood concentration of red cells, 
which usually correlates with an increase in the 
hemoglobin concentration.

Polycythemia are of two types:

●Relative polycythemia: 

that is associated with:

Hemoconcentration caused by dehydration

●Absolute polycythemia

:

When there is an increase in the total red cell mass

.


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Absolute polycythemia is either:

■Primary:

When the increase in red cell mass results from an 
autonomous proliferation  of the myeloid stem cells

■Secondary:

When the red cell progenitors are proliferating in response 
to an increase in erythropoietin. 


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●Primary polycythemia (polycythemia vera [PCV]) is:

A clonal, neoplastic proliferation of myeloid progenitors.

●Secondary polycythemias:

The increases in erythropoietin that are seen in secondary 
polycythemias have a variety of causes:

■Appropriate:

*Lung Disease. *High-altitude Living. *Cyanotic Heart 
Disease

■Inappropriate:

*Erythropoietin-secreting Tumors 

(▪Renal Cell Carcinoma. 

▪Hepatoma. ▪Cerebellar Hemangioblastoma).


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END




رفعت المحاضرة من قبل: Abdalmalik Abdullateef
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