ANAEMIAS OF DIMINISHED

ERYTHROPOIESIS
DR SHWE SIN
FMHS
By the end of the lesson, the students should
be able to :
Understand the blood cells and haemopoiesis.
Describe the definition, classifications, clinical
presentations and complications of anaemia.
State the definition of anaemia of diminished
erythropoiesis.
Describe the aetiology, pathogenesis, clinical features,
complications and laboratory findings of common
anaemia of diminished erythropoiesis (e.g Iron Deficiency
Anaemia, Megaloblastic Anaemia, Aplastic Anaemia etc)
Describe the pathogenesis of anaemia formation in
chronic diseases.
Haemoglobin (Hb) molecule (HbA)
7
Hemoglobin biosynthesis
Heme biosynthesis
8

Heme
The prosthetic group of
hemoglobin, myoglobin, &
cytochromes
A complex of iron and
protoporphyrin (a
porphyrin ring)
Most stable compound
Synthesis in all tissue
bone marrow & liver
 Pathway for Heme Biosynthesis
GLYCINE + Succinyl CoA

ALA synthase
Ferrochelatase

ALA dehydratase

9
 Control of Heme Biosynthesis
GLYCINE + SuccinylCoA

ALA synthase
Rate limiting step Ferrocheletase
Heme Inhibit by heavy metal
Iron storage
Drugs
Metabolites
Glucose
Steroid
ALA dehydratase

(PBG synthase)
Inhibit by heavy
metal e.g. Pb++
elevated ALA
brain toxicity

10
 Clinical correlation
Porphyrias
11
1. Acute
Refers as Vampires disease 2. Cutaneous
Can be caused by
Genetic abnormality of enzymes involved in Heme biosynthesis
Lead poisoning
Drug, infections, alcohol and hormone such as estrogen
Clinical presentation:
Extreme sensitivity to sunlight (sun allergy)
Problems with nervous systems and muscles
Constant abdominal pains Does not cause a
craving for blood
Receding gum prominent fang like teeth
Have an averse reaction to garlic
Reddish to purplish urine
Anemia/ Increased hair growth/ high blood pressure/ severe vomiting
and etc
Not a vampires disease
12

Complications:
Coma, Gallstones, Dehydration,
Kidney failure, Liver failure,
Respiratory failure , Permanent skin
damage
Prophyria is a rare, but
frightening condition: hard to
diagnose and has no cure
13
 ANAEMIA
Anaemia is defined as a reduction in the
haemoglobin concentration of the blood below
normal for age and sex.
For adult males- <13.5 g/dl
For adult females- <11.5 g/dl
2 years to puberty- < 11.0 g/dl
Newborn infants - < 14.0 g/dl
Signs and Symptoms
Shortness of breath particularly on exercise (dyspnoea)
Weakness
Lethargy
Palpitation
Headache, confusion
Visual disturbances
Cardiac failure
General Signs: Pallor of mucous membrane
Tachycardia, cardiac murmurs
Features of heart failure
Specific Signs : e.g Koilonychia in IDA
Bone deformities in thalassaemia
Pallor of conjunctival mucosa and nail
bed
Complications:
Cardiac failure
Angina pectoris
Visual disturbances
Retinal haemorrhage
Classification of anaemia according to
red cell morphology

Classification is based on red cell indices

Divided into microcytic, normocytic and
macrocytic anaemias

Red Cell Indices

Mean Cell Volume (MCV)
Mean Cell Haemoglobin (MCH)
Mean Cell Haemoglobin concentration (MCHC)
Anemia Inadequate of RBCs

Inadequate erythropoiesis or haemoglobin synthesis

Kidney failure and insufficient erythropoietin
Iron-deficiency anemia
Pernicious anemia autoimmune attack of stomach tissue leads to inadequate vitamin B12
absorption
Hypoplastic anemiaslowing of erythropoiesis
Aplastic anemiacomplete cessation of erythropoiesis

Haemorrhagic anemias from bleeding

Haemolytic anemias from RBC destruction
I. Hypochromic microcytic anaemia
Causes: Iron deficiency
Thalassaemia
Anaemia of chronic disease (some cases)
Lead poisoning
Sideroblastic anaemia
II. Normocytic normochromic anaemia
Causes: Many haemolytic anaemias
Anaemia of chronic diseases (some cases)
After acute blood loss
Renal disease
Bone marrow failure (e.g. post-chemotherapy,
infiltration by carcinoma etc.)
III. Macrocytic anaemia
Causes: 1. Megaloblastic (Vitamin B12 or folate
deficiency)
2.Non-megaloblastic (alcohol, liver disease,
myelodysplasia, aplastic
anaemia etc.)
ANISOCYTOSIS AND POIKILOCYTOSIS
Classification of anaemia according to
underlying mechanism
I. Blood Loss:
Acute: trauma
Chronic: lesions of GIT, Gynaecologic disturbances
II. Increased Destruction (Haemolytic Anaemias):
A. Intrinsic (intracorpuscular) abnormalities
Hereditary: Membrane abnormalities
Enzyme deficiencies
Disorders of haemoglobin
synthesis
Acquired: Membrane defect (PNH)
 B. Extrinsic (extracorpuscular) abnormalities
Antibody mediated: Alloantibodies
Autoantibodies
Mechanical trauma to red cells: MAHA
Infections

III. Impaired Red Cell Production:

E.g Iron Deficiency anaemia, Megaloblastic anaemia,
Aplastic anaemia
ANAEMIA OF DIMINISHED
ERYTHROPOIESIS
Anaemias result from deficiencies of vital
nutrients necessary for red cell formation (e.g. IDA
& megaloblastic anaemia) or other causes of
decreased erythropoiesis (e.g. anaemia of
chronic diseases, AA) or bone marrow infiltration
by tumours or inflammatory cells (e.g.
myelophthisic anaemia).

1. Iron deficiency anaemia

2. Megaloblastic anaemia
3. Anaemia of chronic diseases
4. Marrow stem cell failure e.g Aplastic anaemia
I. Iron deficiency anaemia
Most common cause of anaemia
Hypochromic microcytic anaemia
Total body iron- 2 gm for women and 6 gm for men
Storage form Haemosiderin and ferritin
Iron transport protein- Transferrin

Causes of IDA:
Chronic blood loss (Most common)
Increased demands (Pregnancy, Infancy etc)
Malabsorption
Poor diet

Pathogenesis:
Deficient formation of Haem synthesis leading to reduced Hb
(Anaemia)
Iron absorption
Clinical features:
Features of anaemia (pallor, weakness, listlessness etc)
Nail changes (Koilonychia or spooning, brittle, thinning & flattening)
Painless glossitis, angular stomatitis, dysphagia (Oesophageal web)
Pica (consume non-foodstuffs)

Peripheral blood film changes:

Hypochromic microcytic anaemia (Reduced MCV, MCH & MCHC)
Anisocytosis, poikilocytosis (target cells, pencil-shaped cells)
Plt count may be increased

Laboratory findings:
Serum iron- Reduced
Serum ferritin- Reduced
Transferrin saturation- Low
Total iron-binding capacity (TIBC)- Increased
Koilonychia
IDA (Peripheral blood film)

IDA Normal Blood Film

II. Megaloblastic anaemia
Caused by deficiencies of folate or vitamin B12
Macrocytic anaemia
Both vitamins are co- enzymes & required for DNA
synthesis (Purine & thymidine)

Vit B12 absorption process:

Dietary Vit B12 bind R-binders or cobalophilins in
saliva then Vit B12 release at duodenum
then bind with intrinsic factor (IF) produced by parietal
cells absorption at ileum
Pathogenesis:
Both Vitamin B12 & folic are coenzymes required for DNA
synthesis deficiency leads to disturbances in
derangement of DNA synthesis delayed nuclear
maturation and cell division enlarged erythroid
precursors (megaloblasts) because of nuclear-
cytoplasmic asychrony abnormal large red cells
(macrocytes)
Other myeloid lineages are affected
hypersegmented neutrophils
Because of all three cell lineages affected
Pancytopenia
 Causes of Vit B12 deficiency:
Pernicious anaemia due to deficiency of intrinsic factor (IF)
Nutritional deficiency
Malabsorption
Strict vegetarians
Following gastrectomy
Excess loss
Drugs

Causes of folate deficiency:

Nutritional deficiency
Malabsorption
Following gastrectomy
Excess loss
Drugs
 Clinical Features:
Glossitis (red tongue)
Angular stomatitis
Mild jaundice
Neuropathy- Demyelinating disorder (Vit B12 only) (Subacute
combine degeneration of spinal cord) leading to symmetric
numbness, tingling and burning in feet or hands, unsteadiness
of gait & loss of position sense

Peripheral blood film changes:

Hypochromic macrocytic anaemia
Hypersegmented neutrophils
Pancytopenia
Glossitis & Angular stomatitis
Megaloblastic anaemia (Peripheral blood film)
III. Anaemia of chronic diseases
It occurs in variety of chronic inflammatory disorders:
- Chronic microbial infections (OM, bacterial
endocarditis & lung abscess)
- Chronic immune disorders (SLE, RA, regional enteritis)
- Neoplasms (Hodgkin lymphoma, Ca breast, Ca lung)

Pathogenesis:
Chronic inflammation pro-inflammatory cytokines
sequestration of iron in mononuclear phagocytes
anaemia (but increased storage iron)
Result in reduced serum iron, reduced total iron binding capacity but
high serum ferritin

Peripheral blood film findings:

Normochromic normocytic anaemia
IV. Anaemia due to marrow failure
Aplastic Anaemia
Multipotent myeloid stem cells are suppressed leading to
bone marrow failure (hypocellularity) and pancytopenia
Associated with reticulocytopenia (decrease reticulocyte
count)

Pathogenesis:
Aplasia of bone marrow due to fault in remaining stem
cells or immune reaction
 Causes of aplastic anaemia:
I. Primary
1) Congenital (e.g. Fanconi type)
2) Idiopathic
II. Secondary
1) Ionizing radiation
2) Chemicals (e.g. Benzene, organophosphates)
3) Drugs (e.g cyclophoshpamide, chloramphenicol,
sulphonamides)
4) Virus (e.g. Viral hepatitis, EBV)
 Peripheral blood film findings:
Anaemia (NNA)
Leucopenia
Thrombocytopenia
Reticulocyte count- low (Normal- 0.5-2.5 %)
No abnormal cells in peripheral blood

Bone marrow findings:

Hypocellular marrow with increased fat
Myelophthisic Anaemia
Extensive replacement of marrow by tumors or other
lesions
Most commonly associated with metastatic Ca breast,
lungs, prostate or advanced TB

Peripheral blood film findings:

Leukoerythroblastic (LE) pictures- immature granulocytic
and erythrocytic precursors seen
Tear-drop rbc can be seen
LABORATORY FINDINGS IN ANAEMIA
Haemoglobin (Hb) concentration Reduced
Red cell indices MCV Reduced or normal or
increased
MCH- Reduced or normal
MCHC- Reduced
WBC count Normal or reduced or increased
Platelet count Normal or reduced or increased
Reticulocyte count Increased or reduced
Blood film examination
It is essential in all cases
Checked for abnormal red cell morphology or red cell
inclusions.
Also assessed for white cell abnormalities and platelet
number and presence or absence of abnormal cells
REFERENCES
Essential Haematology (A.V. Hoffbrand and P.A.H.Moss),
6th Edition
Robbins Basic Pathology, 9th Edition