ANEMIA

DEFINITION:
Reduction in the oxygen transport
capacity of the blood
Reduction below normal limits of the
total circulating red cell mass.
Reduction below normal in the volume of
packed red cells, as measured by the
hematocrit, or
Reduction in the hemoglobin
concentration of the blood.
 CLASSIFICATION OF ANEMIA ACCORDING TO
UNDERLYING MECHANISM
Blood Loss
1. Acute: trauma
2. Chronic: lesions of gastrointestinal tract,
gynecologic disturbances
Increased Rate of Destruction
( Hemolytic Anemia )
Impaired Red Cell Production
 Increased Rate of Destruction
(Hemolytic Anemias)
I. Intrinsic (intracorpuscular) abnormalities of RBC
Hereditary :
A. Red cell membrane disorders
1. Disorders of membrane cytoskeleton: -
spherocytosis, elliptocytosis
2. Disorders of lipid synthesis: - selective
increase in membrane lecithin
B. Red cell enzyme deficiencies
1. Glycolytic enzymes: - pyruvate
kinase deficiency, hexokinase deficiency
2. Enzymes of hexose monophosphate shunt: -
G6PD, glutathione synthetase

 C. Disorders of hemoglobin synthesis

1. Deficient globin synthesis: -
thalassemia syndromes
2. Structurally abnormal globin synthesis
(hemoglobinopathies): - sickle cell
anemia, unstable hemoglobins
Acquired:
A. Membrane defect: -
Paroxysmal nocturnal hemoglobinuria
II. Extrinsic (extracorpuscular) abnormalities
A. Antibody mediated
1. Isohemagglutinins: transfusion reactions,
erythroblastosis fetalis
2. Autoantibodies: idiopathic (primary), drug-
associated, systemic lupus erythematosus,
malignant neoplasms,
mycoplasmal infection
 B. Mechanical trauma to red cells
1. Microangiopathic hemolytic anemias:
- thrombotic thrombocytopenic purpura, -
disseminated intravascular coagulation
2. Cardiac traumatic hemolytic anemia
C. Infections: malaria
D. Chemical injury: lead poisoning
E. Sequestration in mononuclear phagocyte
system: Hypersplenism
Impaired Red Cell Production
I. Disturbance of proliferation and differentiation
of stem cells:
A. Aplastic anemia, Pure red cell aplasia,
Anemia of renal failure, Anemia of endocrine
disorders
II. Disturbance of proliferation and maturation of
erythroblasts
A. Defective DNA synthesis:
1. Deficiency or impaired use of vitamin B12
and folic acid (megaloblastic anemias)

Impaired Red Cell Production
B. Defective hemoglobin synthesis
1. Deficient heme synthesis: iron
deficiency
2. Deficient globin synthesis: thalassemias
C.Unknown or multiple mechanisms:
Sideroblastic anemia, Anemia of chronic
infections, Myelophthisic anemias due to
marrow infiltrations
TABLE 14-2 -- ADULT REFERENCE RANGES FOR RED BLOOD CELLS*

Units Men Women

Hemoglobin (gm/dl) 13.6-17.2 12.0-15.0
Hematocrit (% ) 39-49 33-43

Erythrocyte count (RBCs) 106 /uL 4.3-5.9 3.5-5.0

Reticulocyte count % 0.5-1.5

Mean cell volume (um 3 ) 82-96

Mean corpus-cular hemo-globin (pg ) 27-33

Mean corpuscular hemoglobin concentration (gm/dl) 33-37

RBC distribution width 11.5-14.5

 Mean cell volume: the average volume of a red blood
cell, expressed in femtoliters (cubic micrometers)

Mean cell hemoglobin: the average content (mass)

of hemoglobin per red blood cell, expressed in
picograms

Mean cell hemoglobin concentration: the average

concentration of hemoglobin in a given volume of
packed red blood cells, expressed in grams per deciliter

Red blood cell distribution width: the coefficient

of variation of red blood cell volume
With significant anemia
ACUTE BLOOD LOSS
If the patient survives

Triggers
The
Reduction
blood
resulting
the
volume
inproduction
the oxygenation
is rapidly
of erythropoietin,
restored
of tissues
by shift
andofthe
water
from theresponds
marrow interstitial
byfluid
increasing
compartment
 INTERNAL BLEEDING - iron can be
recaptured
EXTERNAL BLEDDING - the adequacy of
the red cell recovery may be hampered by
iron deficiency when insufficient reserves are
present.
Soon after the acute blood loss, the red blood
cells appear normal in size and color
(normocytic, normochromic).
However, as the marrow begins to
regenerate, changes occur in the
peripheral blood. Most striking is an
increase in the reticulocyte count,
reaching 10% to 15% after 7 days. The
reticulocytes are seen as
polychromatophilic macrocytes in the
usual blood smear.
These changes of red cell regeneration
can sometimes be mistaken for an
underlying hemolytic process.
Mobilization of platelets and
granulocytes from the marginal pools
leads to thrombocytosis and
leukocytosis in the period immediately
after acute blood loss.
CHRONIC BLOOD LOSS

Induces Anemia only when

1. Rate of Loss Exceeds
Regenerative Capacity of BM
2. Iron reserves are depleted
Chronic blood loss induces anemia only when:
A. The rate of loss exceeds the regenerative
capacity of the erythroid precursors or
B. When iron reserves are depleted.

Iron Deficiency Anemia

- Similar features with chronic blood loss
- Caused by :
a. Bleeding
b. Malnutrition
c. Malabsorption
HEMOLYTIC ANEMIAS
 Hemolytic Anemias

CHARACTERISTICS:
Shortening of the normal red cell life span, that
is, premature destruction of red cells

Accumulation of the products of hemoglobin

catabolism

A marked increase in erythropoiesis within the

bone marrow, in an attempt to compensate for
the loss of red cells
 Hemolytic Anemias

INTRAVASCULAR
HEMOLYSIS
 Intravascular hemolysis
Normal erythrocytes are damaged by
1. Mechanical injury
Trauma to red cells may be caused by mechanical
cardiac valves or by thrombi within the
microcirculation
2. Complement fixation to red cells, or
Complement fixation may occur on antibody-coated
cells during transfusion of mismatched blood
3. Exogenous toxic factors.
Toxic injury is exemplified by falciparum malaria
and clostridial sepsis
Manifestation of Intravascular H.A.
(1) hemoglobinemia,
(2) hemoglobinuria,
(3) methemalbuminemia,
(4) jaundice, and
(5) hemosiderinuria.

Hgb in plasma bound to Haptoglobin To

prevent renal clearance of iron Result to a
decrease in Haptoglobin
 A decrease in serum haptoglobin level is
characteristically seen in all cases of
intravascular hemolysis

Hence the unbound or free hemoglobin is in part

rapidly oxidized to methemoglobin Excreted
through the kidneys, imparting a red-brown color
to the urine--hemoglobinuria and
methemoglobinuria.
 Within the tubular cells iron released from the
hemoglobin accumulate hemosiderosis

The heme groups derived from the Hgb-Hapto

complexes are catabolized within the
mononuclear phagocytic system leading
ultimately to jaundice.
 In hemolytic anemias, the serum bilirubin
depends on:
FUNCTIONAL CAPACITY OF LIVER
& RATE OF HEMOLYSIS
RARELY SEVERE WITH NORMAL LIVER

Excessive bilirubin excreted by the liver into the

gastrointestinal tract Increased formation and
fecal excretion of urobilin
HEMOLYTIC ANEMIA

EXTRAVASCULAR
HEMOLYSIS
Extravascular hemolysis
Takes place whenever red cells are
injured, are rendered "foreign," or
become less deformable
In hereditary spherocytosis abnormal
membrane cytoskeleton decreases the
deformability of the red cell.
Extravascular hemolysis
In sickle cell anemia, the abnormal
hemoglobin
"gels" or "crystallizes" within the
erythrocyte, = deforming it and reducing its
plasticity.
reduced deformability makes the
passage difficult to splenic sinusoids
sequestration within the cords followed
by phagocytosis
 EXTRAVASCULAR HEMOLYTIC
NO hemoglobinemia,
hemoglobinuria, and the related
intravascular changes
However, the catabolism of
erythrocytes in the phagocytic cells
induces anemia and jaundice
Plasma haptoglobin levels are invariably
reduced when some Hgb escape
phagocytes
 EXTRAVASCULAR HEMOLYTIC
The morphologic changes that follow
are identical to those in intravascular
hemolysis,
Except that the erythrophagocytosis
generally causes hypertrophy of the
mononuclear phagocyte system of cells,
and this may lead to splenomegaly.
 MORPHOLOGY

Standard morphologic changes in the

hemolytic anemias ( BOTH types ):
1. Marked increase in the numbers of normoblasts in
the marrow
2. May lead to extramedullary hematopoiesis.
3. The accelerated compensatory erythropoiesis
leads to a prominent reticulocytosis in the
peripheral blood.
4. The elevated levels of bilirubin, when it is
excreted through the liver = pigment gallstones
(cholelithiasis).
5. With chronicity hemosiderosis, usually
confined to the mononuclear phagocyte system.
PATHOGENETIC CLASSIFICATION OF
HEMOLYSIS
1. Based on whether the underlying cause of red
cell destruction is extrinsic
(extracorpuscular mechanism) or a defect
inherent in the red cell (intracorpuscular
defect).
2. These anemias can also be divided into
hereditary and acquired disorders.
3. In general, hereditary disorders are due to
intracorpuscular defects and the acquired
disorders to extrinsic factors such as
autoantibodies.
HEREDITARY SPHEROCYTOSIS (HS)
 HEREDITARY SPHEROCYTOSIS (HS)
Inherited disorder
European extraction
Approximately 75% of cases, the inheritance

follows an autosomal dominant pattern.

Intrinsic defect in the red cell membrane
Renders erythrocytes spheroidal,
Less deformable,
Vulnerable to splenic sequestration and
destruction
Molecular Pathology
A deficiency of spectrin seems to be
the most common biochemical
abnormality in patients with all
forms of HS.
The spectrin content of these cells
varies from 60% to 90% of normal
and correlates closely with the
severity of spherocytosis.
Molecular Pathology
Mutations diminish "vertical"
interactions that serve to connect the
membrane cytoskeleton to the
overlying lipid bilayer
Resulting in Reduction in cell
surface to volume ratio
Spherocyte.
Loss of membrane
fragments during
exposure to shear stress in
the circulation
MORPHOLOGY

Spheroidal shape of the red cells, apparent on

smears
abnormally small cells lacking their central zone of
pallor (Fig. 14-6) .
Spherocytosis, although distinctive, is not
pathognomonic, since it is also seen in
autoimmune hemolytic anemias.
Moderate splenic enlargement is characteristic of
HS (500 to 1000 gm);
Typically present are the associated changes
found in all hemolytic anemias.
Clinical Course
1. Anemia
2. Splenomegaly
3. Jaundice
Most patient have a Chronic Hemolytic
Anemia, usually of mild to moderate severity.
May be punctuated by an aplastic crisis
(triggered usually by a parvovirus infection
of the marrow red cell precursors
Sudden Worsening of Anemia due to
temporary suppression of red cell
production
 Some show Hemolytic Crisis" resulting from
accelerated red cell destruction, but clinically it is
less significant than the aplastic crisis

Diagnosis of HS is based on family history,

hematologic findings, and laboratory evidence of
spherocytosis manifested by osmotic fragility
since there is little margin for expansion of red cell
volume without rupture.
 Laboratory
Similar to Chronic Extravascular
Hemolysis
Direct Antiglobulin test is Negative
Increased Osmotic Fragility test
Spherocytes in the Smear
Decreased or Absent central Pallor
MCV normal (Normocytic Anemia)
MCHC Often Increased reflecting a
Decrease in Cell Surface
Osmotic Fragility Test
RBC are suspended in a series of tubes contaning
hypotonic soln of NaCl varting from 0.9% -
0.0%
Then incubated at room temp for 30 mins
Then centrifuged % Hemolysis in the
supernatant soln is measured
Osmotic Fragility Test
Cells that are more spherical, have limited
capacity to expand in Hypotonic Solutions
Lyze at a higher conc of NaCl than biconcave
RBC
Test is NOT specific for HS
It may occur in Acquired Spherocytic anemias
Autoimmune Hemolysis
GLUCOSE -6PD DEFICIENCY
Features :
Normally G6PD is highest in young rbc and
Decreases as it ages in person with G6PD
deficiency
The Hemolytic susceptibility Increase Greatly
during :
1. Intercurrent Illness
2. Exposure to Various Drugs that have oxidant
properties
SULFAMETHOXAZOLE
NITROFURANTOIN
PRIMAQUINE
2 Forms :
In Black the variant A is prevalent with normal
activity
BUT 11% 0f Blacks have type A with only 5-15% of
normal enzyme activity More susceptible to
HEMOLYSIS after ingestion Oxidant drugs/ Infection
In White- most common is G6PD Mediterranean
Middle East
Protects against Malaria
The level of activity in affected males is LOW (<1%)
USUALLY ARE NOT ANEMIC
BUT MAY HAVE A MORE SEVERE AND NON-SELF
LIMITED HEMOLYTIC ANEMIA WITH INFECTIONS &
WIDER VARIETY OF DRUGS
 GLUCOSE-6-PHOSPHATE DEHYDROGENASE
DEFICIENCY
The erythrocyte and its membrane are
vulnerable to injury by exogenous and
endogenous oxidants.
Abnormalities in the hexose
monophosphate shunt or in glutathione
metabolism resulting from deficient or
impaired enzyme function
reduce the ability of red cells to protect
themselves against oxidative injuries
and lead to hemolytic disease
 GLUCOSE-6-PHOSPHATE DEHYDROGENASE
DEFICIENCY

Glucose-6-phosphate dehydrogenase (G6PD)

activity is affected
G6PD reduces NADP to NADPH while oxidizing
glucose-6-phosphate.
NADPH then provides the reducing power that
converts oxidized glutathione to reduced
glutathione.
The reduced glutathione so generated protects
against oxidant injury by catalyzing the
breakdown of oxidant compounds like H2 O2 .
 The hemolysis in G6PD deficiency is both
intravascular and extravascular.
Infection or exposure to oxidants
oxidation of the sulfhydryl groups of the
globin chains leads to denaturation of
hemoglobin formation of precipitates
(Heinz bodies) that can be seen within the
red cells as dark inclusions when they are
stained with crystal violet
 Heinz bodies decrease erythrocyte deformability.
pass through the splenic cords pluck out the
Heinz bodies appear to have a bite of
cytoplasm removed
The resultant loss of membrane more
membrane damage induces the formation of
spherocytes.
All these changes predispose the red cells to
become trapped in splenic cords and destroyed by
erythrophagocytosis.
CLINICAL FEATURES
Hemolysis present upon exposure to the oxidant
injuries 2-3 days lag period Intravascular
Hemolysis
Since only senescent red cells are lysed, the
episode is self-limited and hemolysis stops when
only the younger red cells remain in the
circulation (despite continued administration of
the oxidant drug).
Because patients with the Mediterranean variant
have much lower levels of G6PD, their anemia is
more severe.
LABORATORY FINDINGS
ACTIVE HEMOLYSIS
SIMILAR TO HEMOLYTIC ANEMIA
HEINZ BODIES- methyl violet stain
Often attach to rbc membrane
QUANTITATIVE ASSAY OF G6PD
RECOVERY G6PD Deficiency
The recovery phase is heralded by
reticulocytosis, as in the case of other hemolytic
anemias.
Since hemolytic episodes related to deficiencies
of G6PD occur in most patients only when there
is oxidant injury, the morphologic changes
encountered in most chronic hemolytic anemias
are rarely present.
SICKLE CELL DISEASE
PROTOTYPE OF HEREDITARY
HEMOGLOBINOPATHIES
DESCRIPTION :
Characterized by the production of a
structurally abnormal (defective) Hgb
Hemoglobin, as you recall, is a tetramer of
four globin chains comprising two pairs of
similar chains, each with its own heme group.
The hemoglobin in the adult is composed of
96% HbA ( 2 ), 3% HbA2 (2 ), and 1%
fetal hemoglobin ( ).
Incidence:
About 8% of black Americans are heterozygous
for HbS.
In the heterozygote, only about 40% is HbS, the
remainder being normal hemoglobins. Where
malaria is endemic, as many as 30% of black
Africans are heterozygous. This frequency may
be related in part to the slight protection against
falciparum malaria afforded by HbS.
If an individual is homozygous for the sickle
mutation, almost all the hemoglobin in the
erythrocyte is HbS.
FEATURES:
In Homozygous HbS disease
A Serious Chronic Hemolytic Anemia
Early childhood
Often fatal before 30y/o
PATHOGENESIS:
Sickle cell anemia results from a point
mutation substitution of valine for
glutamic acid at the sixth position of the
beta-globin chain.
The resultant hemoglobin, HbS, has
abnormal physiochemical properties
that lead to sickle cell disease.
PATHOGENESIS:
On deoxygenation, the HbS molecules
undergo aggregation and
polymerization.
This change converts hemoglobin from a
freely flowing liquid to a viscous gel,
Leading ultimately to formation of HbS
fibers and resultant distortion of the red
cells, which acquire a sickle or holly-leaf
shape
FEATURES:
If an individual is homozygous for the sickle
mutation almost all the hemoglobin in the
erythrocyte is HbS.
In the heterozygote only about 40% is
HbS & the remainder being normal
hemoglobins.
Where malaria is endemic, as many as 30%
of black Africans are heterozygous.
This frequency may be related in part to the
slight protection against falciparum malaria
afforded by HbS.
FEATURES:
Sickling of red cells is initially a reversible
phenomenon; with oxygenation, HbS returns to
the depolymerized state.
However, with repeated episodes of sickling and
unsickling, membrane damage ensues and the
cells become irreversibly sickled.
These deformed cells retain their abnormal
shape even when they are fully oxygenated and
despite deaggregation of HbS
The precipitation of HbS fibers also has
deleterious effects on the red cell membrane.
Damage both sickled & normal rbc
With membrane injury, the red blood cells
Rbc loaded w/ Ca++
Ca++ Activates K ion channel
Efflux of potassium and water and at the same time
gain calcium
Rbc Dehydrated with increased MCHC
More dense
Renders cell more sticky Microvascular
occlusion
 Membrane phosphorylation and
Detachment of the cell membrane from the
underlying membrane skeleton.
Factors that Affect Sickling
The rate of HbS polymerization is also
significantly affected by the hemoglobin
concentration per cell, that is, the mean
corpuscular hemoglobin concentration
The higher the HbS concentration within the
cell, the greater are the chances of contact and
interaction between HbS molecules. Thus,
dehydration, which increases the MCHC, greatly
facilitates sickling and vascular occlusion
Factors that Affect Sickling
In Heterozygous 40% of the hemoglobin is HbS,
the rest being HbA, which interacts only weakly
with HbS during the processes of gelation.
Therefore, the heterozygote has little tendency to
sickle, except under conditions of severe hypoxia.
In contrast, the homozygote, with virtually
undiluted hemoglobin of the S type, has full-
blown sickle cell anemia.
Factors that Affect Sickling
Finally, a fall in pH, by reducing the oxygen
affinity of hemoglobin, can increase sickling
because it enhances the amount of deoxygenated
HbS.
Hemolysis Occurs Extravascularly & some
Intravascularly due to increased mechanical
fragility
CLINICAL MANIFESTATION
Severe Anemia
Bone changes due to BM hyperplasia
Expansion of marrow space
Thinning of the Cortex
Radial Striations in Skull ( x-ray )
Leg Ulcers
Chronic Hyperbilirubinemia
CLINICAL MANIFESTATION
Vasoocclusive Complications
Painful crises,
Episodes of hypoxic injury and infarction
associated with severe pain in the affected region.
No predisposing causes can usually be identified,
although an association with infection,
dehydration, and acidosis (all of which favor
sickling) has been noted
CLINICAL MANIFESTATION
Increased Susceptibility to infection
(1) splenic function is impaired because
erythrophagocytosis interferes with the ability of the
spleen to clear bacteria;
(2) in later stages, total splenic fibrosis removes an
important filter of blood-borne microorganisms; and
(3) defects in the alternative complement pathway
impair opsonization of encapsulated bacteria such as
pneumococci and Haemophilus influenzae.
Septicemia and meningitis caused by these two
organisms are the most common causes of death in
children with sickle cell anemia.
COMPLICATIONS:
HAND-FOOT SYNDROME
Bilateral painful swelling of the hands due to
capillary stasis
SEQUESTRATION CRISIS
Sudden pooling of Blood and Rapid Splenomegaly
Result to Hypovolemic Shock
May occur in Early childhood
COMPLICATIONS:
FUNCTIONAL ASPLENIA
Inadequate Antibody Responses
Impaired Ability of the RES to Clear Bacteria
Increase risk to Infection
acute chest syndrome
VASO-OCCLUSIVE EPISODES
Progressive Infarction Fibrosis Contraction of Spleen
( AutoSplenectomy )
Bone Necrosis
APLASTIC CRISIS
Temporary cessation of bone marrow activity, usually triggered
by parvovirus infection of erythroid progenitor cells.
Reticulocytes disappear from the peripheral blood, and there is
sudden and rapid worsening of anemia.
BLOOD PICTURE
Normochromic & Normocytic Anemia
Numerous target cells
Howell-Jolly bodies
Sickled rbc
Hematocrit is Unreliable estimate of anemia
Due to Air Trapping
Osmotic Fragility is Decreased
Neutrophilia & Thrombocytosis
BM Hyperplasia
THALASSEMIA
SYNDROMES
Heterogenous group of Inherited D/O
Genetic Lesions
Decreased Synthesis of either orglobin
chain of HbA (
FEATURES:
Beta Thalassemia
Deficient synthesis of beta chain
Fress alpha chains tend to aggregate INSOLUBLE
INCLUSIONS
Alpha Thalassemia
Deificient alpha chain
As a consequence, free chains tend to
aggregate into insoluble inclusions within
erythrocytes
Premature destruction of maturing erythroblasts

within the marrow (ineffective erythropoiesis)

Insoluble Inclusions rigid rbc Lysis of mature

red cells in the spleen (hemolysis).

BETA-THALASSEMIAS
Total lack or Reduction in the synthesis of
structurally normal beta -globin chains
with unimpaired synthesis of alpha chains
Types :

(1) beta0 -thalassemia, associated with

total absence of beta-globin chains in the
homozygous state; and
(2) beta+ -thalassemia, characterized by
reduced (but detectable) beta-globin
synthesis in the homozygous state.
TYPES:
Beta Thalassemia Major
Homozygous for beta-thalassemia
genes
Beta+/beta+ or beta 0/beta 0
Have Severe Transfusion Dependent
Anemia
CLINCAL MANIFESTATION :
Beta- thalassemia minor or
beta- thalassemia trait.
The presence of one normal gene in
the heterozygotes (beta+ /beta or
beta0 /beta) usually leads to enough
normal beta-globin chain synthesis
so that the affected individuals are
usually asymptomatic with only a
mild anemia
CLINICAL MANIFESTATION:
Beta- thalassemia
intermedia.
Intermediate degree of severity
Patients have severe anemia, but
not enough to require regular
blood transfusions.
BETA THALLASEMIA - ABSENCE OF BETA 1. MODERATE
(HOMOZYGOUS ) Hgb CHAINS SEVERE
MICROCYTIC
HYPOCHROMIC
ANEMIA
2. TARGET CELLS
3. BASOPHILIC
STIPPLING
BETA THALLASEMIA - ABSENCE OF SINGLE 1. MILD MICROCYTIC
HETEROZYGOUS BETA Hgb CHAIN ANEMIA
2. TARGET CELLS
3. BASOPHILIC
STIPPLING
ALPHA THALLASEMIA - ONE GENE 1. NORMAL
SILENT CARRIER DELETED 2. AYMPTOMATIC
PATHOGENESIS:
Pointmutation Impaired beta-globin
synthesis
Anemia by two mechanisms .
1. Lack of adequate HbA formation,
(MCHC) is lower
Cells are hypochromic

2.Decreased survival of red cells and their

precursors
 PATHOGENESIS
DECREASED SURVIVAL OF RBC
Damage to the RBC
InclusionDamage
a) Reduces its plasticity Sequestered by spleen
( Hemolytic Component )
Apoptotic death of red cell precursors within the
bone marrow, a phenomenon called ineffective
erythropoiesis
THALASSEMIA MAJOR
Thalassemia major

Manifest 6 to 9 months after birth

When hemoglobin synthesis switches from HbF
to HbA.
Anisocytosis (variation in size) with many
small and virtually colorless (microcytic,
hypochromic) red cells.
Thalassemia major

Growth retardation and die at an early age

from the profound effects of anemia unless
transfused
Blood transfusions not only improve the
anemia but also suppress secondary features
related to excessive erythropoiesis.
Thalassemia major

Cardiac disease resulting from

progressive iron overload and secondary
hemochromatosis is an important cause of
death even in patients who can otherwise
be supported by blood transfusions
Thalassemia major
Enormous expansion of BM Thinning of Cortex
a) Frontal & Maxillary Bossing - thinning of
the cortical bone with new bone formation on
the external aspect, giving rise to the "crew- cut"
appearance on x-rays
Marked hepatosplenomegaly
Hemosiderosis or hemochromatosis a)
compensartory increased dietary iron uptake
( Tx iron chelators )
Bossing- New bone formation
Crew cut xray
Perpendicular
Radiations On Outer
Table
Thalassemia major
Management

Iron chelators. & Transfusion

With transfusions and iron chelation, many patients
survive into the third decade, but the overall outlook
continues to be grim.
Bone marrow transplantation from an HLA-identical
sibling is currently the only therapy that offers a
cure.
Prenatal diagnosis is possible by molecular analysis
of DNA.
Prognosis poor No known Cure
Thalassemia major

Low Hemoglobin
Increased RBC
Low MCV & MCHC Microcytic Hypochromic
Anisocytosis with N-rbc
Target cells
Basophilic Stipplings
Thalassemia
 Basophilic stippling- Precipitation of ribosomes

Mutations in the promoter affect transcription. Mutations in

the coding regions, splice sites, or termination codons affect
RNA processing and translation.
Thalassemia major

Retic count is LOW <10%

Reticulocyte count is lower than would be predicted
from the severity of anemia.

Electrophoresis
High HgF & HgA2
Limited amount of HgA
The excess a-chains combine with other available globin chains (d
or g) to form increased amounts of Hgb A2 (a2 d2) and Hgb F ( a2
g 2) or Hgb Barts (g4).
Hydrops Fetalis.
 Most severe form of alpha-thalassemia,
Deletion of all four alpha-globin genes.
Excess gamma-globin chains form tetramers
(hemoglobin Bart)
Extremely high oxygen affinity but are unable
to deliver the oxygen to tissues.
With intrauterine transfusion, many
such infants can be saved.
The fetus shows severe pallor,
generalized edema, and massive
hepatosplenomegaly similar to that
seen in erythroblastosis fetalis
PAROXYSMAL NOCTURNAL
HEMOGLOBINURIA
GPI Linked Membrane Proteins
GPI-linked proteins that regulate
complement activity
1. Decay-accelerating factor, or
CD55;
2. Membrane inhibitor of reactive
lysis, or CD59;
3. C8 binding protein
CD59 is the most important
because it limits spontaneous in
vivo activation of the alternative
complement pathway by rapid
inactivation of C3 convertase.
PATHOLOGY : REVIEW
Because several GPI-linked proteins
inactivate complement, their
absence renders blood cells
unusually sensitive to lysis by
endogenous complement.
FEATURES: PNH
Acquired Abnormality of Multipotential
Stem Cell
Mutation of Phosphatidylinositol glycan-class
A gene
Chromosome Xp22.1
Leads to DISRUPTION OF PROTEIN ANCHORING
on RBC Membrane
Deficient in : 1. Decay
Accelerator Factor CD55 2. Membrane
Inhibitor of Reactive Lysis CD59 3. C8
Binding Protein
Leads to EPISODIC COMPLEMENT
MEDIATED INTRAVASCULAR HEMOLYSIS
FEATURES: LABORATORY
Episodic Normocytic or Macrocytic
Anemia
Reticulocytosis
Often Leukopenia &
Thrombocytopenia
- Platelets and Granulocytes are also more sensitive
to lysis by complement.
Hemoglobinuria 20 to Intravenous
hemolysis
Flow Cytometry
CLINICAL:
25% ( Intermittent )Paroxysmal & Nocturnal
Intravascuar Hemolysis
75% chronic hemolysis without dramatic
hemoglobinuria
Hemosiderinuria with loss of iron eventually
leads to iron deficiency.
Increased risk for Thrombosis & Bleeding
- Fatal in 50%
May progress to Leukemia and Aplastic
anemia
IMMUNOHEMOLYTIC
ANEMIA
Caused by Extracorpuscular
Mechanisms
Classification:
Warm Antibody type
Cold Agglutinin type
Cold Hemolysins
(Paroxysmal Cold
Hemoglobinuria)
WARM
ANTIBODY TYPE
The antibody is of the IgG type, does
not usually fix complement, and is
active at 37C.
Primary or idiopathic
Secondary to
Lymphomas and leukemias
Other neoplastic diseases
Autoimmune disorder (SLE)
Drugs
Warm Antibody Hemolytic
Anemia.
Most common 40-70% Immune
hemolytic anemia
About 50% are Idiopathic or primary
Most of the autoantibodies are of the
immunoglobulin (Ig) G class
Mostly Extravascular Hemolysis-
Recognized by Fc receptors on Splenic
Macrophages
Producing Spherocytes
Moderate Splenomegaly
Warm Antibody Hemolytic
Anemia.
Common in Women
Drug Induced Theory:
1. Hapten model( penicillin &
cephalosphorin )
Induce antibody directed against the
cell-bound drug
2. Autoantibody model ( methyldopa )
Initiates the prodn. of Ab that are
directed against intrinsic red cell
antigens, in particular the Rh
Blood Picture & Tx:
Normocytic or Macrocytic Anemia
Spherocytes
(+) Direct Coombs test
Patients rbc + Anti-human globulin
serum
Incubated Agglutination
Corticosteroids
Refractorycases : -
With Splenectomy or Transfusion
 COLD AGGLUTININ TYPE- IGM

The antibodies are IgM and are most

active in vitro at 0 to 4C.
Agglutinate rbc & Fix Complement at low
temp).
Antibodies dissociate Rapidly at 30C
or above.
Agglutination of cells by IgM and
complement occurs only in the peripheral
cool parts of the body.
Theantibody fixes complement at
warmer temperatures
Features
15% - 32 % of Immune
Hemolytic anemia
Causes
Infection
Mycoplasma pneumonia, IM
Lymphoid Neoplasm
Idiopathic
 Cold Agglutinins: IgM type

COLD
TEMPERATURE

Pallor,
Cyanosis
( fingers, toes,
ears )
Raynauds
Phenomeno
n WARM
TEMPERATURE

Destructio
n in the
Spleen
 Cold Hemolysin Hemolytic
Anemia.
Paroxysmal cold hemoglobinuria,
Least common
Hx of infections such as
mycoplasmal pneumonia, measles,
mumps, and some ill-defined viral
and "flu" syndromes
Cold Hemolysin Hemolytic
Anemia.
Acute intermittent massive
hemolysis, frequently with
hemoglobinuria, after exposure
of the affected patient to cold
Lysis is clearly complement
dependent.
AutoAb are IgG type
Unknown Autoantibodies prodn.
Cold Hemolysin Hemolytic
Anemia.
Complement mediated
intravascular hemolysis does not
occur until the rbc recirculate to
warm central regions as
complements enzymes are
more efficient at 37 degrees.
Pathophysiology
HEMOLYTIC ANEMIA
RESULTING FROM TRAUMA
TO RED CELLS
Pathogenesis:
1. Cardiac valve
prosthesis ( Traumatic)
Rbc shear stresses 20
Turbulent blood flow and
Abnormal pressure
gradients caused by the
valves.
Pathogenesis:
2. Narrowing or Obstruction
of vasculature
Mechanical damage to the red
cells
a) Most often caused by
widespread deposition of fibrin
in the small vessels in
association with disseminated
intravascular coagulation
Pathogenesis:
b) Other causes of
microangiopathic hemolytic
anemia -Malignant
hypertension, - SLE
-Thrombotic
Thrombocytopenic
purpura (TTP) -
Hemolytic-Uremic Syndrome (HUS) -
Disseminated Cancer.