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Anaemia Summary:
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Anaemia – a Low Haemoglobin (Hb) Concentration for the specific Age and Sex of a given patient
o

Always causes by an underlying disease

Reticulocyte:
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Red Blood Cell Precursor which has no Nucleus but still contains Residual RNA (Stains Deep Blue Colour)
Increased Reticulocyte Count:
o Indicates Bone Marrow responding to Anaemia
▪ E
...
Haemorrhage or Haemolysis
Decreased Reticulocyte Count:
o Red Blood Cell Production Defect
o Bone Marrow unresponsive
▪ Bone Marrow Disease, Iron/Folate/B12 Deficiency
o Lack of Erythropoietin

Classification of Anaemia:
•

•

Morphological Classification:
o Microcytic Anaemia (<80 fL)
o Normocytic Anaemia (80 – 95 fL)
o Macrocytic Anaemia (>95 fL)
Aetiological Anaemia:
o Increased Red Blood Cell Loss
▪ Haemolytic Anaemia
o Increased Red Blood Cell Destruction
▪ Destruction of Stem Cells
• E
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Aplastic Anaemia
▪ Defective DNA Synthesis
• E
...
Leukaemia, Metastatic Tumour or Fibrosis
▪ Defective Haemoglobin Synthesis
• E
...
Iron Deficiency or Thalassaemia

Hypochromic Anaemias Includes:
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Hypochromic Anaemia – Decreased Haemoglobin

•

Iron Deficiency Anaemia (IDA)
o
o
o

o

Most Common cause of Anaemia
Depletion of Body Stores and Iron-deficient erythropoiesis before frank Iron Deficiency Anaemia and
tissue effects occur
Iron is needed for Haemoglobin synthesis, when Iron is deficient this leads to decreased synthesis
of Haemoglobin and consequently a Decrease in Red Blood Cells being filled with Haemoglobin and
therefore resulting in Small Red blood Cells → therefore, Iron Deficiency Anaemia causes Microcytic
Anaemia
Causes:
▪ Poor Dietary Intake
• Poverty
▪ Increased Requirements:
• Infancy
• Pregnancy
• Females in general (Menstruation)
▪ Blood Loss

o

o

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Anaemia of Chronic Disorders/Inflammation:
o
o

o

•

Genetic Disorders in the Mutations of the Alpha & Beta Globin Genes
This results in Reduced Synthesis of Alpha & Beta Globin Chains

Lead Poisoning:
o
o
o

•

Anaemia due to a state of Chronic Illness which may be Infective, Inflammatory or Malignant in
Origin
This includes:
▪ Impaired Iron Uptake
▪ Impaired Release of Iron from Macrophages
▪ Blunted Erythropoietin (EPO) Response
▪ Decreases Responsiveness of EPO
Hepcidin:
▪ Hepcidin is a contributor to Anaemia of Inflammation
▪ Hepcidin is a Hepatocyte derived hormone increased in inflammation
• Released due to IL-6
▪ Fucntion:
• Impairs Macrophage and Enterocyte Release of Iron due to its effects on Ferroportin
• Therefore, Decreases Iron Absorption & Release

Thalassaemia:
o
o

•

• GIT Bleed
• Haemorrhage
▪ Malabsorption
• Gastrectomy
Lab Findings:
▪ Hypochromic Microcytic Red Blood Cells
▪ Decreased Reticulocyte Count
▪ Decreased Bone Marrow Iron (Not Routinely Done)
▪ Iron Studies:
• Serum Iron Decreased
• TIBC Increased
• Ferritin Decreased
Management:
▪ Iron Replacement

Rare cause
Lead is an Inhibitor of Haem and Globin Synthesis
Lead Impairs RNA Breakdown which results in Basophilic stippling appearance on Blood Smear

Sideroblastic Anaemia:
o

Sideroblastic Anaemia – finding >15% Ring Sideroblasts in the Bone Marrow Erythroblasts
▪ Sideroblasts – Pathological Erythroblasts with a Ring of Iron Granules around the Nucleus
instead of being scattered throughout the erythroblast cytoplasm
▪ Due to Defective Haem Synthesis:
• Hereditary:
o SLS-S Gene Mutation
o Pearson’s Syndrome
• Acquired:
o Primary:
▪ Refractory Anaemia with Ring Sideroblasts
▪ Subtype of Myelodysplastic Syndrome
o Secondary:
▪ Bone Marrow Pathologies
▪ Nutritional Deficiencies
▪ Drugs:

•

• Alcohol
• Lead
▪ Benign Conditions
• Haemolytic Anaemia
• Megaloblastic Anaemia
Iron Refractory Iron Deficiency Anaemia (IRID)

Megaloblastic Anaemia:
•

•

Megaloblastic Anaemia is due to an Abnormality in DNA Synthesis which results in:
o Delayed maturation of Nucleus
o Skipped Cell Divisions, therefore Large Cells (MCV >100 fL)
o Neutrophils show hypersegmentation of Nuclei (a neutrophil with 6 lobes or 5% of neutrophils with
5 Lobes)
o Megakaryocytes affected leading to Peripheral Thrombocytopaenia
▪ Thrombocytopenia – Low Platelet Count
Causes of Megaloblastic Anaemias:
o B12 Deficiency
o Folate Deficiency
o Drugs affecting Vitamin B12 & Folate Metabolism

Vitamin B12:
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•

•

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Vitamin B12 is a Naturally occurring Cobalamin
Absorption:
o In the stomach B12/Cobalamin is taken up by Haptocorrin (HC)
o The Cobalamin HC Complex then enters the Duodenum after Haptocorrin (Transcobalamine I) is
Digested and releases the Cobalamin into the Interstitial lumen
o Cobalamin is then taken up by Intrinsic Factor (IF) secreted by Gastric Parietal Cells
o Cobalamin-Intrinsic Factor Complex is absorbed into the Ileum through receptor mediated
endocytosis, involving cubilin and other proteins
o The Cobalamin is released within lysozymes and transported to the Blood stream where is Circulates
bound to Transcobalamin II (TC)
o Passive absorption through the Duodenum and Ileum (Terminal Ileum is main site of Absorption)
exists
Biochemical Function of Vitamin B12:
o Cobalamin/B12 required for
▪ Intramitochondrial conversion of methylmalonyl conenzyme A to succinyl coenzyme A
▪ Cytosolic conversion of Homocystine to Methionine

Vitamin B12 Deficiency:
o

Causes
▪ B12 deficiency takes 2 – 3 years to develop and may present with Severe Anaemia
• Nutritional
o Lank of Animal Products in Diet
• Malabsorption:
o No Production of Intrinsic Factor
o Unable to release Vitamin B12 from proteins
• Mechanical:
o Gastric causes:
▪ Gastrectomy – Removal of part of the Stomach
o Intestinal causes
▪ Crohn’s Disease
• Damage to the Distal Ileum

▪
o

o

Removal of part of the Distal Ileum

Clinical Features:
▪ Tends to occur in Elderly
▪ Jaundice
• Unconjugated bilirubin released due to Increased Destruction of Red Blood Cells in
Bone marrow
▪ Glossitis
▪ Vitamin B12 Neuropathy:
• Dementia
• Loss of touch & Proprioception
Lab Findings:
▪ Pancytopaenia
• Decreased Blood Cell Count
▪ Oval Macrocytes and Hypersegmented Neutrophils
▪ Decreased Reticulocyte
▪ Biochemical:
• Increased Unconjugated Bilirubin
• Increased LDH breakdown
• Decreased Heptoglobin
• Increased Serum Iron
• Increased Ferritin

Folate Deficiency:
•
•
•
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Daily requirement is 200ug
Total body store is 10 – 12 mg
Deficiency is usually due to poor intake of vegetables in combination with increased demand or
malabsorption
Causes of Folate Deficiency:
o Nutritional:
▪ Old Age
▪ Special Diets
o Mechanical:
▪ Coeliac Disease
o Increased Utilisation:
▪ Physiological:
• Pregnancy
o Increased Demand by the Foetus
o Many births over a short period of time
o Breast Feeding
• Premature Neonates
▪ Pathological:
• Haemolysis
• Malignancy
▪ Drugs:
• Anticonvulsants
▪ Multiple Factors:
• Liver Disease
• Alcoholism

Treatment of Megaloblastic Anaemia:
•
•
•

Treatment with either Folate or Vitamin B12 depending on deficiency
Vitamin B12/Cobalamin Deficiency should be excluded first
Folate will correct Haematological abnormalities of Vitamin B12 deficiency, but Neurological manifestations
will still progress
...
Therefore, the Serum Haptoglobin Levels drop below
the normal Range when there is Increased Haemoglobin in the Blood
▪ Plasma LDH Levels:
• Red Blood Cells are rich in LDH 1 Isoenzyme and it would therefore be raised in
serum during increased Red Blood Cell Damage or Destruction
▪ Haemosiderinuria:
• Excessive breakdown of Haem which can be found in the Urine when Stained
o Evidence of Compensatory Increase in Bone Marrow Activity:
▪ ↑ Reticulocyte Count & Normoblasts
▪ Bone Marrow Hyperplasia
▪ Skeletal Radiological Abnormalities
• If Haemolysis is sufficiently prolonged and intense, cortical bone may expand which
can be seen on x-ray
o Evidence of Red blood Cell Damage:
▪ Spherocytosis:
• Due to Inherited or Acquired Abnormality of the Cytoskeleton, the membranes are
less compressible and when forced through the microcirculation of the spleen, there
is loss of Surface Membrane which exceeds the loss of intracellular contents
...

▪ Fragmentation:
• Red Cells may be Damaged under certain conditions:
o Microvascular Thrombosis
o Mechanical Damage due to Turbulent flow
o Compression stress
▪ Heinz Bodies:
• Aggregates of Oxidised Denatured Haemoglobin seen typically in G6PD Deficiency
• These appear as round inclusions within red blood cells

•

Removal of these inclusions by the spleen results in Red Blood Cell Membrane
Damage and Reduction in Red Blood Cell Survival

Inherited Haemolytic Anaemias:
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Enzyme Deficiencies:

o Glucose 6-Phosphate Dehydrogenase Deficiency:
▪
▪
▪
▪
▪

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Affects the Pentose Phosphate Pathway
G6PD is a enzyme required for the production of NADPH which is essential for maintaining
the Glutathione of Red Blood Cell Membrane in the reduced state
Deficiency in reduced Glutathione causes susceptibility of Red Cell to Oxidative Stress
• Therefore taken out of Circulation as they are easily Damaged
Most Common Haemolytic Disorder
X-linked Disorder
• Full Expression in Males
• Females are carriers with 50% reduction in G6PD Levels
Diagnosis:
• Low G6PD Levels
Treatment:
• Avoidance of Oxidant Drugs and prompt management of infection

o Pyruvate Kinase Deficiency:
▪
▪
▪
▪

▪

▪

Pyruvate Kinase catalysis the final step in the Glycolytic pathway
Pyruvate Kinase Deficiency leads to Chronic non-spherocytic Haemolytic Anaemia with
Extravascular Haemolysis
Autosomal Recessive Disorder
Clinical Features:
• Neonatal Jaundice & Anaemia
• Chronic non-spherocytic haemolytic Anaemia (CNSHA)
• Compensated Haemolysis
Lab Diagnosis:
• Normochromic Anaemia with reticulocytosis, acinocytosis and poikilocytosis
• Increase in MCHC due to Dehydration Brought by ATP deficiency
Management:
• Splenectomy in patients with severe haemolysis

o Hereditary Spherocytosis:
▪
▪
▪
▪

▪

Haemolytic Disorder due to defects in the proteins which connect the underlying
Cytoskeleton to the lipid bilayer if the membrane
These Cell’s membranes become more rigid and are unable to pass through the spleen and
therefore have a Decreased Lifespan
Autosomal Dominant Condition
Clinical Presentation:
• Anaemia with episodes of Haemolysis presenting with Jaundice
• Jaundice may lead to Gallstones in long-term
• Folate deficiency due to Chronic Haemolysis
• Splenomegaly → Splenectomy reverses mechanisms of Cell destruction and
alleviates Anaemia
Lab Findings:
• Spherical shaped Red Blood Cells
• Peripheral Blood Smear:
o Microspherocytes with polychromasia
• Negative Coombs Test
• MCHC is Increased

Acquired Haemolytic Disorders:
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•
•

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Chronic Haemolysis is most frequently mediated through immune mechanisms as Red Blood Cell Survival is
shortened due to Antibody response directed at Antigens within the Red Blood Cell Membrane
...

Anaemia develops when the rate of Haemolysis is greater than the rate of Haematopoiesis
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Secondary Cold Agglutination Disease:
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▪

▪

▪

▪

▪

Associated with monoclonal or polyclonal cold-reacting autoantibodies
predominantly caused by Infection and lymphoproliferative disorders
Pathology:
• Natural cold Antibodies occur at low Titres and measured at 4 OC
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g
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g
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Result of an Acquired Mutation in the Gene on the X-chromosome
This results in the cell lacking GPI protein on their surface and therefore results in
Haemolysis
Clinical Findings:
• Passage of Dark Urine after waking due to Haemolysis
• Jaundice
• Thrombosis
• Cytopenias
Lab Findings:
• Anaemia and Thrombocytopenia
• Increased LDH and Unconjugated Bilirubin
• Decreased Haptoglobin
• Haemosiderinuria

o Microangiopathic Haemolytic Anaemia: (MAHA)
▪

Collectively a group of conditions which fall under the Microangiopathic Haemolytic
Anaemias constitute the most frequent causes of Haemolysis:
• Disseminated Intravascular Coagulopathy (DIC)
• Thrombotic Thrombocytopenic Purpura (TTP)
o Clotting in Small Blood Vessels resulting in Low Platelet Count
• Haemolytic Uraemic Syndrome (HUS)
• Vasculitis
• Pre-eclampsia
• Mechanical Heart Valves
• Disseminated Malignancy
• Glomerulonephritis
• Malignant Hypertension

Disorders of Haemoglobin
•

Haemoglobin Abnormalities:
o Synthesis of Abnormal Haemoglobin – most commonly due to Amino Acid Substitution
o Reduced Rate of Synthesis of Normal Alpha or Beta Globin Chains – a heterozygous group of
Disorders (Thalassamias)

Sickle Cell Disease:
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•
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Inherited Chronic Haemolytic Anaemia
o Autosomal Recessive
Arises due to the deficiency of the Sickle Haemoglobin (HbS) to polymerise and deform Red Cells to Sickle
Shaped
This is due to an inheritance mutation which produces an abnormality of the Beta Globin Chain

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The Sickle Cell Trait allows protection in areas endemic for Falciparum Malaria as the cells containing HbS
inhibit the proliferation of the parasite as they are more likely to become deformed with resultant removal
by the spleen from the circulation
...

o This Chronic process will result in Anaemia that required transfusion
...
This leads to ineffective
Erythropoiesis and Haemolysis

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