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Learning Objective
Understand of the Hematopoesis
Understand the Metabolism of folic acid
Cyanocobalamine in Erythropoesis.
Understand the etiology and the
management of Anemia.
Understand about Thalassemia
Understand about Hemoglobinopathies
Understand the management of
Thalassemia and Hemoglobinopathies.
Hematopoiesis
Factors affecting erythropoiesis:A)-Oxygen supply of tissues:
Decreased oxygen supply (hypoxia) to tissues stimulates
secretion of erythropoietin (EP) hormone.
Hypoxia stimulates kidney to release renal erythropoietic
factor (REF).
Hypoxia stimulates liver to produce a special type of
globulin.
Both REF & globulin unite in plasma and form EP.
EP then stimulates bone marrow to produce RBCs.
Erythropoietin accelerates nearly all stages of RBCs
formation,
i.e. it stimulates proliferation & differentiation of
progenitor stem cells to produce mature RBCs.
Hematopoiesis
Factors affecting erythropoiesis:B) Dietary factors:
i-Proteins: Proteins of high biological value are
needed in the formation of RBCs.
ii-Metal ions:
Hematopoies
is
Factors affecting erythropoiesis:B) Dietary factors:
iii-Vitamins:
Hematopoiesi
s erythropoiesis:Factors affecting
C) Hormonal factors:
i-Androgens: increase erythropoiesis by
stimulating the production of erythropoietin
from kidney.
ii-Thyroid hormones:
Stimulate the metabolism of all body cells
including the bone marrow cells, thus,
increasing erythropoiesis.
Hypothyroidism is associated with anemia
while hyperthyroidism is associated with
polycythaemia.
Hematopoiesis
Factors affecting erythropoiesis:C) Hormonal factors:
iii-Glucocorticoids:
Hematopoiesis
Factors affecting erythropoiesis:C) Hormonal factors:
iv-Pituitary gland: Affects erythropoiesis both
directly and indirectly through the action of
several hormones.
v- Haematopoietic growth factors: Are secreted
by lymphocytes, monocytes & macrophages
to regulate the proliferation and
differentiation of proginator stem cells to
produce blood cells.
Hematopoiesis
Factors affecting erythropoiesis:D)-State of liver & bone marrow:
i-Liver: Healthy liver is essential for
normal erythropoiesis because the
liver is the main site for storage of
vitamin B12 , folic acid, iron & copper.
In chronic liver disease anemia
occurs.
ii-Bone marrow: When bone marrow is
destroyed by ionizing irradiation or
drugs, aplastic anemia occurs.
Anemia
Anemia means a decrease in
hemoglobin content,
or RBCs count,
or both of them below the
normal range.
Anemia leads to a decrease in
blood ability to transport oxygen
to tissue cells.
Anemia
Types & causes of anemia:
I-Blood loss anemia:
A-Acute blood loss anemia:
Due to severe hemorrhage.
Plasma volume is replaced rapidly by the
fluids present in tissue spaces.
This leads to marked dilution of the blood.
RBCs are replaced within 2-3 weeks.
Sufficient iron gives normocytic cells but
insufficient iron will produce microcytic
RBCs.
Anemia
Types & causes of anemia:
I-Blood loss anemia:
B-Chronic blood loss anemia:
Due to repeated loss of small amounts of
blood over a long period e.g.:
-Gastrointestinal bleeding (peptic ulcer)
-Excessive menstruation.
-Hemorrhagic diseases.
Due to depletion in iron stores the newly
formed RBCS are microcytic.
Anemia
Types & causes of anemia:
II-Aplastic anemia:
It results from destructione of bone marrow.
It may result from:
1-Excessive exposure to x-rays or gamma rays.
2-Chemical toxins e.g. cancer therapy & prolonged
exposure to insecticides or benzene.
3-Invasion of bone marrow by cancer cells.
4-Following infection by hepatitis.
Damaged bone marrow dont produce any RBCs, so
in aplastic anemia RBCS are normocytic.
It is associated with decrease in WBCs & platelets.
Anemia
Types & causes of anemia:
III-Hemolytic anemia:
It results from increased rate of destruction of RBCs
inside the cardiovascular system.
Causes of hemolytic anemia:
A-Hereditary:
1-Membrane abnormalities.
2-Enzyme deficiency e.g. G-6-P Dehydrogenase.
3-Hemoglobin abnormalities.
B-Acquired:
1-Incompatible blood transfusion.
2-Parasitic infection e.g. malaria.
3-Toxic agents e.g. snake venom & insect poisons.
4-Thermal e.g. several burns.
Anemia
Types & causes of anemia:
IV-Dyshemopoietic anemia: Which may be due
to:
1-Iron deficiency anemia.
2-Maturation failure (megaloblastic) anemia:a-Vitamin B12 deficiency.
b-Folic acid deficiency.
3-Anemia of endocrine disorders.
4-Nutritional anemia.
5-Anemia of renal failure.
Classification of Anemia
Based on cell size (MCV)
Macrocytic (large) MCV 100+ fl
(femtoliters)
Normocytic (normal) MCV 80-99 fl
Microcytic (small) MCV<80 fl
Based on hemoglobin content (MCH)
Hypochromic (pale color)
Normochromic (normal color)
MEGALOBLASTIC
ANEMIA
By
Liniyanti D.Oswari,
MD,MNS,MSc.
For Block 14
MEGALOBLASTIC (Macrocytic)
ANEMIA
High MCV
High MCH
Normal MCHC
Macrocytic Anemia
Megaloblastic : defective DNA
synthesis
Non-megaloblastic : numerous
mechanisms
Megaloblastic Anemias
A form of anemia characterized by the
presence of large, immature, abnormal
red blood cell progenitors in the bone
marrow
95% of cases are attributable to folic
acid or vitamin B12 deficiency
CH3
CH3
H2NCOCH2CH2
CH2CONH2
H2NCOCH2
N CN
H3 C
H3 C
H
corin nucleus
Co
N
cobalt coordinated
N
H2NCOCH2
H2C
CH2CH2CONH2
CH3
CH3
CH3
CH3
CH2 CH2CONH2
N
O
H3C
O
P
O
OH
CH3
benzylimidazole
N
HO
VITAMIN B 12
CH3
Vitamin B12
Source : food of animal origin
- liver
- muscle
- eggs
- cheese and milk
- Not in plants
- Made by bacteria
B12 Absorption
1. Release from food sources gastric
proteases and acids
2. Binding by salivary cobalophilins
3. Digestion of cobalophilin-B12
complex by pancreatic enzymes
4. Binding to intrinsic factor (IF)
IF is secreted by gastric parietal cells
5. Attachment of B12-IF to receptors
6. Endocytosis and binding to
transcobalamin II
B12 Dependant
Reactions
1. Synthesis of methionine from
homocysteine requires : B12 and
folate
2. Synthesis of succinyl CoA from
methyonyl CoA requires :
methylmalonyl CoA mutase
FOLIC ACID
Sources : synthesized by plants
and microorganisms
Vegetables, fruits, dairy
products
Polyglutamated
Thermo labile
Pernicious Anemia
An Autoimmune Disease
Antibodies against :parietal cells
intrinsic factor
(IF)
Thyroid - myxedema
Melanosomes - vitiligo
Pernicious Anemia
Hematologic features :
anemia
pancytopenia
megaloblastic hematopoiesis
cellular bone marrow
ineffective hematopoiesis
Folate Deficiency
Hematologic features : same as
Pernicious Anemia.
Clinical Picture : no neurologic
findings
Pernicious Anemia
Presenting Complaint
Schilling Test
First stage :
1. Inject B12 IM (1,000 ug) to
saturatetranscobalamin II
2. Administer oral B12 - radiolabeled
3. Collect 24 h urine
4. Measure radioactivity in urine
Second stage :
1. Inject B12 IM (1,000 ug) to saturate
transcobalamin II (Same as 1st stage)
2. Administer oral B12 radiolabeled plus intrinsic
factor (HOG)
3. Collect 24 h urine, (Same as 1st stage)
4. Measure radioactivity in urine,(Same as 1st
stage)
Pernicious Anemia
A macrocytic, megaloblastic anemia caused by a deficiency of vitamin B 12.
Also can be caused by gastric acid secretion, gastric atrophy, Hpylori, gastrectomy, disorders of the small intestine (celiac disease,
regional enteritis, resections), drugs that inhibit B12 absorption
including neomycin, alcohol, colchicine, metformin, pancreatic disease
Symptoms of
Pernicious Anemia
Paresthesia (especially numbness
and tingling in hands and feet)
Poor muscular coordination
Impaired memory and hallucinations
Damage can be permanent
Inadequate ingestion
Inadequate absorption
Inadequate utilization
Increased requirement
Increased excretion
Increased destruction by
antioxidants
Pernicious Anemia
Treatment
B12 by IM injection
Frequent at first
Monthly thereafter life long
Inadequate ingestion
Inadequate absorption
Inadequate utilization
Increased requirement
Increased excretion
Increased destruction
Vitamin B12 deficiency can cause
folate deficiency due to the
methylfolate trap
Methylfolate Trap
In the absence of
B12, folate in the
body exists as 5methyltetrahydrofolate (an inactive
form)
B12 allows the
removal of the 5methyl group to
form THFA
Diagnosis of Folate
Deficiency
Folate stores are depleted after 2-4
months on deficient diet
Megaloblastic anemia, low
leukocytes and platelets
To differentiate from B12, measure
serum folate, RBC folate (more
reflective of body stores) serum
B12
High formiminoglutamic acid
(FIGLU) in the urine also diagnostic
Hemolytic Anemia
Oxidative damage to cellslysis occurs
Vitamin E is an antioxidant that seems to
be protective.
This anemia can occur in newborns,
especially preemies.
Deficiency Glucose 6 Phospat dehidrogenase
in baby boy(X linked)- block 5
Nonnutritional Anemias
Sports anemia (hypochromic
microcytic transient anemia)
Anemia of pregnancy: dilutional
Anemia of inflammation, infection, or
malignancy (anemia of chronic
disease)
Sickle cell anemia
Thalassemias
Sports Anemia
Transientusually in athletes who are
runners; from compression of RBCs in feet
until they burst, releasing hemoglobin
Check lab values
Counsel about a proper diet
THALASSEMIAS AND
HEMOGLOBINOPATHIES
By
Liniyanti D.Oswari,MD,MNS,MSc.
For Block 14
b
Thalassemias and
Hemoblobinopathies: Module
Objectives
At the end of this module you should be
able to
Explain the pathophysiology that causes
thalassemia and hemoglobinopathies.
Explain how thalassemias are
categorized.
Correlate the results of laboratory
testing with specific thalassemias and
hemoglobinopathies.
Thalassemia
Severe inherited anemia affecting mostly
people of Mediterranean extraction
Basic defect is reduced production of
selected globin chains
Defective globin formation in hemoglobin
leads to increased blood volume,
splenomegaly, bone marrow expansion,
facial deformities, osteomalacia, bone
changes
Iron buildup due to transfusions requires
chelation therapy to remove excess iron
Demographics:
Thalassemia
Found most
frequently in the
Mediterranean,
Africa, Western and
Southeast Asia,
India and Burma
Distribution
parallels that of
Plasmodium
falciparum
Terminology
Silent carrier
Minima
Minor
Intermedia
Major
Symbolism Alpha
Thalassemia
Greek letter used to designate globin
chain:
/
Each chromosome 16 carries 2 genes. Therefore
the total complement of genes in an individual
is 4
Normal
/
Silent carrier - /
Minor -/-
--/
Hb H disease --/-
Barts hydrops fetalis
--/--
Symbolism Other
Thalassemia
Greek letter used to designate globin
chain:
+:
by gene:
Superscript
/
/ 0
/ +
0/ +
0/ 0
+/ +
Special Cases
Thalassemia
Hb Lepore: fusion seen in some
types
of thalassemia
Hb Constant Spring
chain with 31 additional amino acids
--/cs
Special Cases:
Thalassemia
Hb Barts & hydrops fetalis
Barts is a 4 tetramer
Associated with --/- Lethal
High concentrations are capable of sickling
Hb H
4 tetramer
Associated with --/- thalassemia
Time of presentation
Untreated thalassemia
Major: Death in first or second decade of life
Intermedia: Usually normal life span
Minor/Minima: Normal life span
Hemoglobine in Human
being
Hb A1a : < 1 %
: Increase in Diabetic Mellitus
HbA1b
: 2% : Increase in Diabetic Mellitus
HbA1c (2(-N-Glucose)2): 4%:Increase in Diabetic
Mellitus
HbF ( 2(-N-Acetyl)2) : < 1% : Increase in
Thalassemia &
Characteristics:
Hemoglobinopathies
Hereditary disorders that can result
in moderate to severe anemia
Basic defect is production of an
abnormal globin chain
The demographics of
hemoglobinopathies are varied.
Hemoglobinopathy
Genetics
Homozygous: Inheritance of two genes
from each parent coding for the same
type of abnormal hemoglobin, e.g., Hb
SS
Heterozygous: Inheritance of genes
from each parent which code for a
different type of abnormal hemoglobin
each, e.g., Hb SC
Terminology
Hemoglobinopathy
Abnormal hemoglobins discovered earlier have been
given letter designations:
Harlem
In South East Asia there is specific
hemoglobinopathies is mutation in codon 26:
Hb E : G- A ( GAG AAG)
6(A3)
6(A3)Glu Val
Classification:
Hemoglobinopathy
Functional Abnormality
Aggregation
Polymerization
Crystallization
Unstable hemoglobins
Methemoglobin
Oxygen affinity
AS
S-Thal
Other hemoglobinopathies, e.g., SC
Hb C
Morphologic Findings
Hb SS vs. Hb SC vs. Hb CC
=
+
Hb S
Hb C
Hb SC
=
Irreversible
Sickle Cell
Sickle Cells
Secondary Laboratory
Investigation
Hemoglobin electrophoresis
Major test for identifying thalassemia
and hemoglobinopathy
Types
Cellulose acetate: Alkaline pH
Citrate agar: Acid ph
Secondary Laboratory
Investigation
Cellulose Acetate Hb
Electrophoresis
- A2/C
S
F
Normal
Hb SS
Hb AS
Hb SC
Hb CC
HB AD
A+
Secondary Laboratory
Investigation
Solubility testing-Dithionite tube test
Alkali denaturation test for
quantification of fetal hemoglobin
Acid elution test for fetal hemoglobin
distribution
Unstable hemoglobin testing for
Heinz bodies
<5
5-15
>15
Sources of error
0.5
1.0
2.0
Alternative treatment
Activation of fetal hemoglobin genes
Bone marrow transplantation