ANEMIA

Prepared by : Mark jayson Barcelona

 Anemia is defined as a reduction of the total

circulating red cell mass below normal limits
usually diagnosed based on a reduction in the
Hematocrit (the ratio of packed red cells to total blood
volume)
hemoglobin concentration of the blood to levels that are
below the normal range

Anemia
Classification:
according to underlying mechanism
1.
2.
3.

Blood loss
Increased Red cell destruction
Decrease Red cell production

 according to alterations in red cell morphology

Morphologic characteristics providing etiologic clues
red cell size (normocytic, microcytic, or macrocytic);
degree of hemoglobinization, reflected in the color of
red cells (normochromic or hypochromic);
shape.

most useful red cell indices are as follows:

Mean cell volume: the average volume of a red
cell expressed in femtoliters (fL)
Mean cell hemoglobin: the average content
(mass) of hemoglobin per red cell, expressed in
picograms

 Mean cell hemoglobin concentration:

the average concentration of
hemoglobin in a given volume of packed
red cells, expressed in g/DL
Red cell distribution width: the
coefficient of variation of red cell
volume

Clinical findings
common complaints
Patients appear pale. Weakness, malaise, and easy
fatigability are

The lowered oxygen content of the circulating

blood leads to dyspnea on mild exertion.
Hypoxia can cause fatty change in the liver,
myocardium, and kidney.

Anemias of Blood Loss

ACUTE BLOOD LOSS
CHRONIC BLOOD LOSS

Acute Blood loss

due to the loss of intravascular volume,
which if massive can lead to
cardiovascular collapse,
shock,
death

Intravascular
shift

It takes about 5 days for

the progeny of these
CFU-Es to mature and
appear as newly released
red cells (reticulocytes)
in the peripheral blood

Rapidly restored by the intravascular shift

of water from the interstitial fluid
compartment.

hemodilution

hemodilution and a lowering

of the hematocrit.

reduction in
oxygenation

increased secretion of
erythropoietin from the
kidney

proliferation

proliferation of
committed
erythroid
progenitors (CFUE) in the marrow

 Significant bleeding results in predictable changes in the blood

involving not only red cells, but also white cells and platelets.
If the bleeding is sufficiently massive >> leukocytosis

 Initially, red cells appear normal in size and color

(normocytic, normochromic).
as marrow production increases increase in the
reticulocyte count (reticulocytosis), which reaches 10%
to 15% after 7 days.
larger in size than normal red cells (macrocytes)
blue-red polychromatophilic cytoplasm.

 Early recovery from blood loss is also often accompanied by

thrombocytosis, which results from an increase in platelet
production.

CHRONIC BLOOD LOSS

anemia only when the rate of
loss exceeds the regenerative capacity of the
marrow
iron reserves are depleted
EX. Gastrointestinal tract lesions, gynecologic
disturbances

Hemolytic Anemias
Features:
A shortened red cell life span below 120 days
Elevated erythropoietin levels and a compensatory
increase in erythropoiesis
Accumulation of hemoglobin degradation products that
recreated as part of the process of red cell hemolysis

Hemolytic anemia
extravascular hemolysis,- premature destruction of red cells also
occurs within phagocytes,

If persistent, extravascular hemolysis leads to a hyperplasia of phagocytes

manifested by varying degrees of splenomegaly.

Extravascular hemolysis is generally

caused by alterations that render the red
cell less deformable.
principal clinical features of extravascular
hemolysis:
anemia, splenomegaly, and jaundice

intravascular hemolysis predominates Intravascular hemolysis of red

cells may be caused by:
mechanical injury,
Manifested by:
Complement fixation,
anemia,
intracellular parasites
hemoglobinemia,
hemoglobinuria,
Exogenous toxic factor
hemosiderinuria, and
Jaundice
Unlike in extravascular hemolysis,
splenomegaly is not seen.

free hemoglobin
released from lysed
red cells

heme groups
-catabolized to bilirubin
within mononuclear
phagocytes

bound by haptoglobin

free hemoglobin
oxidizes to
methemoglobin,

reabsorb and
catabolize hemoglobin
and methemoglobin

some passes out in the

urine, imparting a redbrown color

Iron released from

hemoglobin
>>renal
hemosiderosis.

Jaundice.

MORPHOLOGY
increased numbers of erythroid precursors (normoblasts) in
the marrow
Compensatory increases in erythropoiesis result in a prominent
reticulocytosis in the peripheral blood.
The phagocytosis of red cells leads to the accumulation of the
iron containing pigment hemosiderin
If the anemia is severe, extramedullary hematopoiesis can
appear in the liver, spleen, and lymph nodes.

Hereditary Spherocytosis
Hereditary spherocytosis (HS) is an inherited disorder
caused by intrinsic defects in the red cell membrane
skeleton that render red cells spheroid, less
deformable, and vulnerable to splenic sequestration
and destruction

pathogenesis
HS is caused by diverse mutations that lead to an insuf ciency of
membrane skeletal components.
life span of RBC- 10 to 20 days
The pathogenic mutations most commonly affect

ankyrin,
band 3,
spectrin, or
band 4.2,

this complex is particularly

important in stabilizing the lipid
bilayer.

 An autosomal dominant inheritance pattern

is seen in about 75% of cases.
The prevalence of HS is highest in northern
Europe,
1 in 5000 are reported

mutations cause
frameshifts or
introduce
premature stop
codons,

mutated allele fails

to produce any
protein

Deficiency of the
affected protein
reduces the
assembly of the
skeleton as a whole

Young HS red cells are normal in shape, but the destabilized lipid bilayer sheds membrane fragments

destabilizing the
overlying plasma
membrane.

Morphology
The most specific morphologic finding is
spherocytosis, apparent on smears as small, darkstaining (hyperchromic) red cells lacking the central
zone of pallor
Spherocytosis is distinctive but not pathognomonic
Cholelithiasis (pigment stones) occurs in 40% to 50%
of affected adult
Moderate splenomegaly is char chracteristic (5001000 gm)

Clinical feature
The diagnosis is based on family history, hematologic ndings, and
laboratory evidence.
2/3 of the patients the red cells are abnormally sensitive to
osmotic lysis
HS red cells also have an increased mean cell hemoglobin
concentration,

 The characteristic clinical features:

anemia,
splenomegaly
jaundice.
HS presents at birth with marked jaundice and requires exchange
transfusions
In 20% to 30% of patients the disease is so mild as to be virtually
asymptomatic
The generally stable clinical course is sometimes punctuated by
aplastic crises, >> acute parvovirus infection
Hemolytic crises are produced by intercurrent events leading to

 Splenectomy treats the anemia and its

complications, but brings with it an increased risk
of sepsis

Glucose-6-Phosphate Dehydrogenase
Deciency
Abnormalities in the hexose monophosphate shunt or
glutathione metabolism
hereditary deficiency of glucose-6-phosphate dehydrogenase
(G6PD) activity
Reduce ability of RBC to protect themselves against
oxidative injuries and lead to hemolysis

 Two variants with most significant hemolytic

anemia
G6PD (Present in about 10% of American black)
G6PD Mediterranean, (prevalent in the Middle East)

 The episodic hemolysis that is characteristic of

G6PD deficiency is caused by exposures that
generate oxidant stress
Trigger :
Infection- most common
viral hepatitis,
pneumonia,
typhoid fever

Drugs
Antimalarials (e.g., primaquine and
chloroquine),
sulfonamides,
nitrofurantoins,

Oxidant

cross linking of
reactive
sulfhydryl groups
on globin chain

Heinz bodies can

damage the membrane
suficiently to cause
intravascular
hemolysis.

become
denatured and
precipitate

As inclusion-bearing
red cells pass through
the splenic cords,
macrophages pluck out
the Heinz bodies.

formation of
Heinz bodies

Some cells retain an

abnormal shape,
appearing to have a
bite taken out of
them

 Acute intravascular hemolysis, marked by anemia,

hemoglobinemia, and hemoglobinuria, usually begins 2 to 3 days
following exposure of G6PD-deficient individuals to oxidants
The hemolysis is greater in individuals with the highly unstable
G6PD Mediterranean variant.
Because hemolytic episodes related to G6PD deficiency occur
intermittently, features related to chronic hemolysis (e.g.,
splenomegaly, cholelithiasis) are absent.

Sickle cell anemia

a common hereditary hemoglobinopathy caused by a point
mutation in -globin
promotes the polymerization of deoxygenated hemoglobin,
leading to red cell distortion, hemolytic anemia, microvascular
obstruction, and ischemic tissue damage

 Hemoglobin is a tetrameric protein

composed of two pairs of globin
chains, each with its own heme
group
Normal adult red cells contain
mainly HbA (22), along with
small amounts of HbA2 (22),
fetal hemoglobin (HbF; 22).

 Sickle cell disease is caused by a point mutation in the sixth codon

of -globin that leads to the replacement of a glutamate residue
with a valine residue

roughly 2 million individuals, are

heterozygous for HbS, a largely
asymptomatic condition known as
sickle cell trait.
The off- spring of two
heterozygotes has a 1 in 4 chance
of being homozygous for the sickle
mutation, a state that produces
symptomatic sickle cell disease. In
such individuals, almost all the
hemoglobin in the red cell is HbS
(2S2)

Pathogenesis
The major pathologic manifestations
chronic hemolysis,
microvascular occlusions, and
tissue damage

stem from the tendency of HbS

molecules to stack into polymers
when deoxygenated

 Initially, this process converts the red cell cytosol from a

freely owing liquid into a viscous gel.
With continued deoxygenation HbS molecules assemble
into long needle-like fibers within red cells, producing a
distorted sickle or holly-leaf shape.

Several variables affect the rate and degree of sickling:

Interaction of HbS with the other types of hemoglobin in the

cell.
Mean cell hemoglobin concentration (MCHC).
Higher HbS concentrations increase the probability that aggregation and
polymerization will occur during any given period of deoxygenation.

Intracellular pH. A decrease in pH

reduces the oxygen af nity of hemoglobin, thereby increasing the fraction of deoxygenated
HbS at any given oxygen tension and augmenting the tendency for sickling

Mechanism of red cell damage

As HbS polymers grow, they herniate through the membrane skeleton and
project from the cell ensheathed by only the lipid bilayer
This severe derangement in membrane structure causes the in ux of Ca2+
ions, which induce the cross-linking of membrane proteins
With repeated episodes of sickling, red cells become increasingly
dehydrated, dense, and rigid
Eventually, the most severely damaged cells are converted to end-stage,
nondeformable, irreversibly sickled cells, which retain a sickle shape even
when fully oxygen- ated

 Most serious clinical feature- microvascular occlusions

sickle red cells express higher than normal levels of adhesion
molecules and are sticky.
Microvascular occlusions are not related to the number of
irreversibly sickled cells in the blood, but instead may be
dependent upon more subtle red cell membrane damage and local
factors,
such as inflammation or vasoconstriction, that tend to slow or arrest the
movement of red cells through microvascular beds

Morphology
In sickle cell anemia, the peripheral blood demonstrates variable
numbers of irreversibly sickled cells, reticulocytosis, and
target cells, which result from red cell dehydration
Howell-Jolly bodies (small nuclear remnants) are also present in
some red cells due to the asplenia
The bone marrow is hyperplastic as a result of a compensatory
erythroid hyperplasia.

Morphology
expansion of the marrow leads to bone resorption and
secondary new bone formation, resulting in
prominent cheekbones and changes in the skull that
resemble a crewcut on x-ray studies
Extramedullary hematopoiesis can also appear. The
increased breakdown of hemoglobin can cause
pigment gallstones and hyperbilirubinemia.

Morphology
In early childhood, the spleen is enlarged up to 500 gm by
red pulp congestion

 Infarctions caused by vascular occlusions can occur

in many other tissues as well,
bones,
brain,
kidney,
liver, retina, and pulmonary vessels, the latter sometimes
producing cor pulmonale.

In adult patients, vascular stagnation in subcutaneous

tissues often leads to leg ulcers; this complication is
rare in children.

Clinical Features
Sickle cell disease causes a moderately severe
hemolytic anemia (hematocrit 18% to 30%)
Associated with reticulocytosis,
hyperbilirubinemia, and the presence of
irreversibly sickled cells.
Its course is punctuated by a variety of crises.
Vasoocclusive crises, also called pain crises
The most common sites -bones, lungs, liver, brain,
spleen, and penis

 In children- painful bone crises are extremely

common and often difFIcult to distinguish from
acute osteomyelitis.
frequently manifest as the hand-foot syndrome or
dactylitis of the bones of the hands or feet, or
both

 Acute chest syndrome is a particularly dangerous type of

vaso-occlusive crisis involving the lungs,
typically presents with fever, cough, chest pain, and pulmonary
infilltrates.

Priapism affects up to 45% of males after puberty and may lead

to hypoxic damage and erectile dysfunction

Other disorders related to vascular obstruction, - stroke and

retinopathy leading to loss of visual acuity and even blindness,

 Sequestration crises. -massive entrapment of sickle red cells leads

to rapid splenic enlargement, hypovolemia, and sometimes shock.
Both sequestration crises and the acute chest syndrome may be
fatal and sometimes require prompt treatment with exchange
transfusions.
Aplastic crises -stem from the infection of red cell progenitors by
parvovirus B19

 chronic hypoxia is responsible for a generalized

impairment of growth and development, as well
as organ damage affecting the spleen, heart,
kidneys, and lung
Sickling provoked by hypertonicity in the renal
medulla causes damage that eventually leads to
hyposthenuria

Diagnosis
The diagnosis is suggested by the clinical findings and
the presence of irreversibly sickled red cells
confirmed by various tests for sickle hemoglobin
involve mixing a blood sample with an oxygen- consuming
reagent, such as metabisulfate, which induces sickling of red
cells if HbS is present
Hemoglobin electro- phoresis is also used to demonstrate the
presence of HbS and exclude other sickle syndromes, such as
HbSC disease.
Prenatal diagnosis is possible by analysis of fetal DNA obtained
by amniocentesis or chorionic biopsy.

Prognosis
The outlook for patients with sickle cell disease
has improved considerably over the past 10 to 20
years.
About 90% of patients survive to age 20, and close to
50% survive beyond the fth decade