APLASTIC AND HYPOPLASTIC

ANEMIAS (Hypoproliferative
Disorder)
What happens when the bone marrow shuts down?
L (8)
 APLASTIC ANEMIA
• Aplastic anemia is a severe, life threatening
syndrome in which production of erythrocytes,
WBCs, and platelets has failed.
• Aplastic anemia may occur in all age groups and
both genders.
• The disease is characterized by peripheral
pancytopenia and accompanied by a
hypocellular bone marrow.
HYPOCELLULAR BONE MARROW IN
APLASTIC ANEMIA
 APLASTIC ANEMIA
• Pathophysiology:
• The primary defect is a reduction in or depletion of
hematopoietic precursor stem cells with decreased
production of all cell lines. This is what leads to the
peripheral pancytopenia.
• This may be due to quantitative or qualitative
damage to the pluripotential stem cell.
• In rare instances it is the result of abnormal
hormonal stimulation of stem cell proliferation
• or the result of a defective bone marrow
microenvironment
• or from cellular or humoral immunosuppression of
hematopoiesis.
 APLASTIC ANEMIA
• Etiology
• (A) Acquired
• (1) Idiopathic - some cases of aplastic anemia are
idiopathic and there is no history of exposure to
substances known to be causative agents of the disease
• (2) Exposure to ionizing radiation – hematopoietic
cells are especially susceptible to ionizing radiation.
Whole body radiation of 300-500 rads can completely
wipe out the bone marrow.
• (3) Chemical agents – include chemical agents with a
benzene ring, chemotherapeutic agents.
• (4) Drugs - some commonly used drugs such as
chloramphenicol or quinacrine.
 APLASTIC ANEMIA
• (5) Infections – viral and bacterial infections
such as infectious mononucleosis, infectious
hepatitis, cytomegalovirus infections, and
military tuberculosis occasionally lead to
aplastic anemia
• (6) Paroxysmal nocturnal hemoglobinuria
(PNH)– this is a stem cell disease in which the
membranes of RBCs, WBCs and platelets have
an abnormality making them susceptible to
complement mediated lysis.
 APLASTIC ANEMIA
• (B) Congenital disorders
• Fanconi’s anemia – the disorder usually becomes
symptomatic ~ 5 years of progressive bone marrow
hypoplasia. Congenital defects such as skin
hyperpigmage and is associated with entation and small
stature (dwarf) are also seen in affected individuals.
• Clinical manifestations
• Fatigue
• Heart palpitations
• Pallor
• Infections
• Petechiae
• Mucosal bleeding
 APLASTIC ANEMIA
• Lab findings
• Severe pancytopenia with relative lymphocytosis
(lymphocytes live a long time)
• Normochromic, normocytic RBCs (may be slightly
macrocytic)
• Mild to moderate anisocytosis and poikilocytosis
• Decreased reticulocyte count
• Hypocellular bone marrow with > 70% yellow marrow
• Treatment – in untreated cases the prognosis is poor
• Remove causative agent, if known
• Multiple transfusions
• Bone marrow transplant
 RELATED DISORDERS
• Disorders in which there is peripheral
pancytopenia same as AA, but the bone marrow
is normocellular, hypercellular, or infiltrated
with abnormal cellular elements
• (1) Myelopathic anemia – replacement of
bone marrow by fibrotic, granulomatous, or
neoplastic cells
 PURE RED CELL APLASIA
• (2) Pure red cell aplasia (PRCA) is
characterized by a selective decrease in
erythroid precursor cells in the bone marrow.
WBCs and platelets are unaffected. 3 Types
• Acquired: absence of red cell
precursors(reticulocytes)and low RBCs count-
rare condition
• Transitory: with viral or bacterial infections
(when the virus clears, or the responsible
drugs are eliminated, the PRCA will
disappear.)
 PURE RED CELL APLASIA
• Congenital
• Diamond-Blackfan anemia is a genetic
condition usually diagnosed during the first
two years of life. About half of patients also
have physical malformations or mental
retardation. Only several hundred cases
have been reported worldwide. The severity
of the disease varies by patient..
HEMOLYTIC ANEMIA
Introduction
INTRODUCTION
Hemolysis:
Is the destruction or removal of red blood cells from the
circulation before their normal life span of 120 days.
Hemolytic anemias (H.A):
Are a group of anemias in which red-cell lifespan is
shortened.
INTRODUCTION
- Normally, about 1% of human red blood cells
break down each day.
- When the rate of breakdown increases, the body
compensates by producing more RBCs
(compensated hemolytic disease).
- If compensation is inadequate clinical problems
can appear.
- Breakdown of RBCs can exceed the rate that the
body can make RBCs and so anemia can
develop.
CLASSIFICATION OF HEMOLYTIC
ANEMIA
A- Hereditary hemolytic anemias:
Usually are the result of ‘intrinsic’ red cells defects:
1. Hemoglobin defect: (hemoglobinopathies)
-Sickle cell disease.
-Thalassemia
-Hb-C, Hb-D, Hb-E….etc.

2. Membrane defect:
- Hereditary spherocytosis.
- Hereditary elliptocytosis.
- Hereditary Stomatocytosis
CLASSIFICATION OF HEMOLYTIC
ANEMIA
3. Enzyme defects:
- Glucose-6-phosphate dehydrogenase (G6PD)
deficiency.
- Pyruvate kinase (PK) deficiency.
B- Acquired hemolytic anemias:
Usually are the result of ‘extracorpuscular’ or
‘environmental’ change.
1. Immune mediated H.A:
- Autoimmune H.A.
- Alloimmune H.A.
- Drug induced mediated H.A.
CLASSIFICATION OF HEMOLYTIC
ANEMIA
2. Non-immune mediated HA:
- Drugs
- Toxins
- Infections
HEMOLYTIC ANEMIA
HEMOGLOBIN DEFECT
HEMOGLOBINOPATHIES
(1) Sickle Cell Anemia
 INTRODUCTION
• Qualitative abnormality. Abnormality in
amino acid of globin chain, but not in
amount of globin produced
 WHAT IS SICKLE CELL ANEMIA?
• A serious condition in which red blood cells can
become sickle-shaped hemggy.is
• Normal red blood cells are smooth and round. They move easily
through blood vessels to carry oxygen to all parts of the body.
• Sickle-shaped cells don’t move easily through blood. They’re stiff
and sticky and tend to form clumps and get stuck in blood vessels.
• The clumps of sickle cell block blood flow in the blood vessels that
lead to the limbs and organs. Blocked blood vessel can cause pain,
serious infection, and organ damage.
 NORMAL AND SICKLED RED BLOOD CELLS
IN BLOOD VESSELS
Figure B shows abnormal, sickled red blood cells clumping and
blocking the blood flow in a blood vessel. The inset image shows a
cross-section of a sickled red blood cell with abnormal strands of
hemoglobin.

Figure A shows normal red blood cells flowing freely in a

blood vessel. The inset image shows a cross-section of a
normal red blood cell with normal hemoglobin.
 5 ED
6 6 6
VASO-OCCLUSION
mar
• Vaso-occlusion phenomena and
hemolysis are the clinical hallmarks
of Sickle Cell Disease (SCD)
• Inherited disorder due to
homozygosity for the abnormal
hemoglobin, hemoglobin S (HbS)
• Consider normocytic normochromic
anemia
 SICKLE CELL ANEMIA
• HbS results from substitution of valine for
glutamic acid at sixth amino acid of the
beta globin chain, which produces a
hemoglobin tetramer that is poorly soluble
when deoxygenated.
• Polymer assumes elongated rope-like fiber
form in the classic sickle shape
AMINO ACID SUBSTITUTION IN HBS
 SICKLE CELL ANEMIA VS. SICKLE
CELL TRAIT
• People who have sickle cell anemia are born with
it; means inherited, lifelong condition.
• They inherit two copies of sickle cell gene, one
from each parent.
• Sickle cell trait is different from sickle cell anemia.
People with sickle cell trait don’t have the
condition, but they have one of the genes that
cause the condition.
• People with sickle cell anemia and sickle cell trait
can pass the gene on when they have children.
INHERITANCE OF SICKLE CELL
ANEMIA
• If one parent has sickle
cell anemia (HbSS) and
the other is completely
unaffected (HbAA) then
all the children will have
sickle cell trait.
• None will have sickle cell
anemia.
• The parent who has sickle
cell anemia (HbSS) can
only pass the sickle
hemoglobin gene to each
of their children.
 INHERITANCE OF SICKLE CELL
ANEMIA
• If both parents have sickle
cell trait (HbAS) there is a
one in four (25%) chance
that any given child could be
born with sickle cell anemia.
• There is also a one in four
chance that any given child
could be completely
unaffected.
• There is a one in two (50%)
chance that any given child
will get the sickle cell trait.

HE tapering
 WHY ANEMIA?
• In sickle cell anemia, a lower-than-normal number of red blood
cells occurs because sickle cells don’t last very long. Sickle cells die
faster than normal red blood cells, usually after only about
10 to 20 days. The bone marrow can’t make new red
blood cells fast enough to replace the dying ones. The
result is anemia.
SIGNS AND SYMPTOMS
 LABORATORY FINDING
• Moderate anemia • Peripheral smear
shows sickle cells
• Reticulocytosis 3-15% • Polychromasia
• hyperbilirubinemia • Howell-jolly bodies
• Elevated LDH • Elevated WBC
• Low haptoglobin • Elevated Platelets
• Folate & iron deficit

a
 SICKLE SOLUBILITY TEST
• A sickle cell test is a blood test done to screen for sickle cell trait or
sickle cell disease.
• The presences of HbS or HbC are indicated by the turbid solutions.
The normal HbA under these same conditions results in a clear non-
turbid solutions.
• Sickle Solubility Test conceder rapid test
• HGB ELECTROPHORESIS: confirmatory t.
• HGB SS: > 80%
• HGB F : 1-20%
• Sickle cell Trait:
• HGB A: 55-65%
• HGB S: 35-45%
HGB ELECTROPHORESIS
 COMPLICATION OF SICKLE CELL
ANEMIA
• Hand-Food Syndrome
(Swallow) •Gallstone
• Splenic Crisis •Ulcerson the legs
• Infections •Pulmonary Arterial
• Acute Chest Syndrome Hypertension
• Delayed growth and •Multiple Organ Failure
puberty in children
• Stroke
• Eye problem
 TREATMENT
• Effective treatments are available to help relieve the
symptoms and complications of sickle cell anemia, but in
most cases there’s no cure.
• The goal is to relieve the pain; prevent infections, eye
damage, strokes and control complications if they occur.
• Pain medicine: acetaminophen, non-steroidal anti-
inflammatory drugs (NSAIDs), and narcotics such as
meperidine, morphine, oxycodone, and etc.
• Heating pads
• Hydroxyurea, Folic Acid
• Blood Transfusions
 HYDROXYUREA
• Increases production of hemoglobin F.
• Reduces median crisis rate by 50%, decreased
acute chest syndrome and transfusion.
• 40% reduction in mortality.
 THE FEATURE
• Gene therapy
• Increase expression of Hb F
• RNA repair
• Hematopoietic cell transplantation
HEMOLYTIC ANEMIA
HEMOGLOBIN DEFECT
HEMOGLOBINOPATHIES
(2) Thalassemia
 INTRODUCTION
• Quantitative abnormality. Amino acid
sequence of globin chains is normal, but there
is underproduction of one or more globin
chains
 INTRODUCTION
• Result of defective production of globin portion
of hemoglobin molecule.
• May be either homozygous defect or
heterozygous defect.
• Defect results from abnormal rate of synthesis in
one of the globin chains.
• Globin chains structurally normal (is how
differentiated from hemoglobinopathy), but
have imbalance in production of two different
types of chains.
 INTRODUCTION
• Results in overall decrease in amount of
hemoglobin produced and may induce
hemolysis.
• Two major types of thalassemia:
• Alpha (α) - Caused by defect in rate of
synthesis of alpha chains.
• Beta (β) - Caused by defect in rate of
synthesis in beta chains.
• May contribute protection against malaria.
 GENETICS OF THALASSEMIA
• Adult hemoglobin composed two alpha
and two beta chains.
• Alpha thalassemia usually caused by
gene deletion; Beta thalassemia usually
caused by gene mutation.
• Results in microcytic, hypochromic
anemias of varying severity.
 CLASSICAL SYNDROMES OF
BETA THALASSEMIA
• a) Silent carrier state – the mildest form of beta
thalassemia.
• b) Beta thalassemia minor - heterozygous disorder
resulting in mild hypochromic, microcytic hemolytic
anemia.
• c) Beta thalassemia intermedia - Severity lies between
the minor and major.
• d) Beta thalassemia major - homozygous disorder
resulting in severe transfusion-dependent hemolytic
anemia.
 SILENT CARRIER STATE FOR Β
THALASSEMIA
• Are various heterogenous beta
mutations that produce only small
decrease in production of beta
chains.
• Patients have nearly normal
beta/alpha chain ratio and no
hematologic abnormalities.
• Have normal levels of Hb A2.
BETA THALASSEMIA MINOR
 BETA THALASSEMIA MINOR
• Anemia usually hypochromic and microcytic
with slight aniso and poik, including target cells
and elliptocytes; May see basophilic stippling.
• Rarely see hepatomegaly or splenomegaly.
• Have high Hb A2 levels (3.5-8.0%) and
normal to slightly elevated Hb F levels.
• Are different variations of this form depending
upon which gene has mutated.
• Normally require no treatment.
• Make sure are not diagnosed with iron deficiency
anemia.
 BETA THALASSEMIA INTERMEDIA
• Patients able to maintain minimum hemoglobin
(7 g/dL or greater) without transfusions.
• Expression of disorder falls between thalassemia
minor and thalassemia major. May be either
heterozygous for mutations causing mild
decrease in beta chain production, or may be
homozygous causing a more serious reduction in
beta chain production.
• See increase in both Hb A2 production and
Hb F production.
• Peripheral blood smear picture similar to
thalassemia minor.
 BETA THALASSEMIA MAJOR
• Characterized by severe microcytic,
hypochromic anemia.
• Detected early in childhood:
• Infants fail to thrive.
• Have pallor, variable degree of jaundice, abdominal
enlargement, and hepatosplenomegaly.
• Hemoglobin level between 4 and 8 gm/dL.
• Severe anemia causes marked bone changes
due to expansion of marrow space for increased
erythropoiesis.
• See characteristic changes in skull, long bones,
 BETA THALASSEMIA MAJOR
• Have protrusion upper teeth and Mongoloid
facial features.
• Physical growth and development delayed.
• Peripheral blood shows markedly hypochromic,
microcytic erythrocytes with extreme
poikilocytosis, such as target cells, teardrop cells
and elliptocytes. See marked basophilic
stippling and numerous NRBCs.
• MCV in range of 50 to 60 fL.
• Low retic count seen (2-8%).
• Most of hemoglobin present is Hb F with
slight increase in Hb A2.
COMPARISON OF BETA
THALASSEMIA'S
Alpha Thalassemia
 ALPHA THALASSEMIA
• Absence of alpha chains will result in increase
of gamma chains during fetal life and excess
beta chains later in life; Causes molecules
like Bart's Hemoglobin (γ4) or Hemoglobin H
(β4), which are stable molecules but
physiologically useless.
 ALPHA THALASSEMIA
• Predominant cause of alpha thalassemia is large
number of gene deletions in the alpha-globin
gene.
• Are four clinical syndromes present in alpha
thalassemia:
• a) Silent Carrier State
• b) Alpha Thalassemia Trait (Alpha
Thalassemia Minor)
• c) Hemoglobin H Disease (4 beta chains)
• d) Bart's Hydrops Fetalis Syndrome (4
Gamma chains)
 A) SILENT CARRIER STATE
• Deletion of one alpha gene, leaving three
functional alpha genes.
• Alpha/Beta chain ratio nearly normal.
• No hematologic abnormalities present.
• No reliable way to diagnose silent carriers by
hematologic methods; Must be done by genetic
mapping.
• May see borderline low MCV (78-80fL).
B) ALPHA THALASSEMIA TRAIT
(ALPHA THALASSEMIA MINOR)
 C) HEMOGLOBIN H DISEASE
• Second most severe form alpha thalassemia.
• Usually caused by presence of only one gene
producing alpha chains (--/-a).
• Results in accumulation of excess unpaired
gamma or beta chains. Born with 10-40% Bart's
hemoglobin (γ4). Gradually replaced with
Hemoglobin H (β4). In adult, have about 30-
50% Hb H.
γ4 β4
D) BART’S HYDROPS FETALIS
SYNDROME
COMPARISON OF ALPHA
THALASSEMIA
CLINICAL FEATURE
CBC WITH DIFFERENTIAL
CBC WITH DIFFERENTIAL
 RETICULOCYTE COUNT
• Usually elevated. Degree of elevation depends upon
severity of thalassemia
 HEMOGLOBIN ELECTROPHORESIS
• Important role in diagnosing and differentiating
various forms of thalassemia.
• Can differentiate among Hb A, Hb A2, and Hb F,
as well as detect presence of abnormal
hemoglobin such as Hemoglobin Lepore,
hemoglobin Bart's, or Hemoglobin Constant
Spring.
• Also aids in detecting combinations of
thalassemia and hemoglobinopathies.
MICROCYTIC, HYPOCHROMIC
ANEMIAS
COMPARISON BETWEEN HGB% IN
DIFFERENT TYPES OF ANEMIA