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Aims and objectives

• Why is haematology so difficult?

• Classification of anaemias

• Duration: 70 mins

• Slides and recordings: app.bitemedicine.com

History and examination

A 20-year-old lady presents to the GP with lethargy.

She is a medical student and complains of intense

fatigue, struggling to stay awake during lectures. As

soon as she gets home, she goes straight to bed.

She reveals that she often has heavy periods.

Observations

HR 80, BP 118/77, RR 18, SpO2 98%, Temp 37.0

3

Case-based discussion: 1

4

A 20-year-old lady presents to the GP with lethargy. She is a medical student and

complains of intense fatigue, struggling to stay awake during lectures. As soon

as she gets home, she goes straight to bed.


Observations: HR 80, BP 118/77, RR 18, SpO2 98%, Temp 37.0

Which of the following is the most likely type of anaemia?

Question 1

Microcytic

Normocytic

Macrocytic

Megaloblastic

Aplastic

app.bitemedicine.com

Q3 Q4 Q5Q1 Q2

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Explanations


Which of the following is the most likely type of anaemia?

Microcytic

Chronic blood loss, e.g. menstrual bleeding, leads to iron deficiency and is the commonest cause

of anaemia worldwide

Normocytic

Iron deficiency is microcytic

Macrocytic

Iron deficiency is microcytic

Megaloblastic

This is a subtype of macrocytic anaemia

Aplastic

This is a cause of a normocytic anaemia and may occur secondary to infection e.g. parvovirus B19

Q3 Q4 Q5Q1 Q2

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Introduction: Anaemia

Structure of haemoglobin• 4 polypeptide ‘globin’ chains

• Each chain is complexed to a haem molecule

• Haem is an iron containing compound

Anaemia: reduction of haem and/or globin

Normal Hb variants Structure Proportion in adults

HbA α2β2 90%

HbA2 α2δ2 <2%

HbF α2γ2 <2-5%

7

Introduction: Anaemia

Anaemia• Men: Hb <130g/L

• Women: Hb <120g/L

• Classified based on mean corpuscular volume (MCV)

Microcytic (MCV < 80fL) Normocytic (MCV 80-95fL) Macrocytic (MCV >95fL)

Iron deficiency Acute blood loss B12 deficiency

Thalassaemia Haemolytic anaemia Folate deficiency

Anaemia of chronic disease Anaemia of chronic disease Alcohol

Sideroblastic anaemia Chronic kidney disease Liver disease

Aplastic anaemia Hypothyroidism

8

Clinical features: General principles

Symptoms Signs

Fatigue Tachycardia

SOB on exertion Tachypnoea

Chest pain Hypotension

Palpitations Pallor

9

History taking: General principles

History of presenting complaint

• Symptoms of anaemia e.g. SOB

• Screen for areas of blood loss: GI, resp, urinary tract, menstrual

• Alarm symptoms: weight loss, loss of appetite, night sweats, lymphadenopathy

• Dietary habit

Past medical history

• Chronic disease

• Trauma

Family history

• Inherited disorders e.g. haemoglobinopathies

Drug history, social history

10

Investigations: General principles

Bedside• Full set of observations

Bloods• FBC: reduced Hb. Assess MCV

• Blood film

• Iron studies

• B12 and folate levels

• Haemolysis screen: bilirubin, haptoglobin, Coombs test

• U&Es: CKD

• TFTs: hypothyroidism

• LFTs: chronic liver disease

Imaging• Assess for site of blood loss

Special tests• Bone marrow biopsy

Iron deficiency anaemia

Microcytic anaemia

Iron deficiency

Thalassaemia

Anaemia of chronic disease

Sideroblastic anaemia

Definition: reduced intake, increased requirement, or increased

loss of iron, leading to anaemia

Epidemiology:

• Most common cause of anaemia and affects ~ 500 million

people worldwide (NICE)

• 3% of men and 8% of women in the UK

Pathophysiology: Iron deficiency anaemia

Aetiology: Iron deficiency anaemia

Age group Cause

Infants • Malnutrition

• Breast feeding

Children • Malnutrition

• Malabsorption

• E.g. Coeliac disease

Adults • Peptic ulcer disease

• Menorrhagia

• Malabsorption

• E.g. Coeliac disease

Elderly • Colon cancer

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You confirm a microcytic anaemia. Which of the following tests should be conducted next if you

suspect iron deficiency?

Question 2

Serum iron

Transferrin

Ferritin

Total iron binding capacity

Urinary iron


Q3 Q4 Q5Q2Q1






15

Explanations


You confirm a microcytic anaemia. Which of the following tests should be

conducted next if you suspect iron deficiency?

Serum iron

Can be unreliable due to diurnal variation and can vary between labs

Transferrin

NICE advise measuring ferritin

Ferritin

NICE advises measuring this first-line. Low in iron deficiency

Total iron binding capacity

NICE advise measuring ferritin

Urinary iron

This is not measured

Q3 Q4 Q5Q2Q1

Aetiology: Iron deficiency anaemia

Cause

Reduced intake • Malnutrition

• Breastfeeding

• Malabsorption

• Coeliac disease

Increased requirement • Pregnancy

Increased loss • Chronic bleeding

• Colon cancer

• Menorrhagia

• Peptic ulcer disease

Clinical features: Iron deficiency anaemia

Features

Glossitis

Angular stomatitis/chelitis

Koilonychia

Pica

(1)

(2)

18

Q2

Which of the following is true for a patient with iron deficiency anaemia?

Question 3

Treat with blood transfusion

Treat with intravenous iron

Arrange urgent upper GI endoscopy if ≥50

Arrange urgent colonoscopy if ≥60



Q3Q1 Q4 Q5






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Explanations


Which of the following is true for a patient with iron deficiency anaemia?

Treat with blood transfusion

Oral iron is first line

Treat with intravenous iron

Oral iron is first line. IV iron can be used if oral therapy not tolerated

Arrange urgent upper GI endoscopy if ≥50

Not indicated unless suspecting an upper GI bleed in any age group


As per NICE guidelines


NICE suggest ≥60

Q2 Q3Q1 Q4 Q5

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Investigations: Iron deficiency anaemia

Bloods• FBC: microcytic anaemia (MCV <80fL)

• Blood film: hypochromic red cells, target cells

• Iron studies

• Ferritin: reduced

• Serum iron: reduced

• TIBC: increased

• Transferrin saturation: decreased

Imaging • Endoscopy

• Suspecting upper GI bleed

• ≥60 years old with iron deficiency anaemia

Special tests• Coeliac serology

21

Management: Iron deficiency anaemia

Address the underlying cause

Oral iron replacement

• Ferrous sulphate or ferrous fumarate

• Monitor Hb 2-4 weeks after starting and then at 2-4 months

• Treatment should continue for 3 months after anaemia corrected

Intravenous iron replacement

• Not responding or intolerant to oral therapy

• Malabsorption

• Renal failure

Blood transfusion

• Hb <70g/L or

• Hb <80g/L and cardiac co-morbidity

History and examination

A 1-year-old child is brought to the GP as his mother

is concerned he is not gaining weight. He is dropping

off the centiles on his growth chart.

On examination he appears pale and has evidence of

hepatosplenomegaly. His forehead looks prominent.

Further investigations reveal a diagnosis of beta

thalassaemia major.

22

Case-based discussion: 2

(3)

23

Which of the following would you expect to see on haemoglobin electrophoresis in this

patient?

Question 1

Raised HbH

Raised HbA

Raised HbA2

Reduced HbF

HbS


A 1-year-old child is brought to the GP as his mother is concerned he is not

gaining weight. He is dropping off the centiles on his growth chart.

On examination he appears pale and has evidence of hepatosplenomegaly. His

forehead looks prominent.

Further investigations reveal a diagnosis of beta Thalassaemia major.

Q1 Q2

24

Question 1


Which of the following would you expect to see on haemoglobin electrophoresis?

Raised HbH

Associated with alpha thalassaemia

Raised HbA

Reduced in beta thalassaemia

Raised HbA2

Raised along with HbF

Reduced HbF

Should be raised

HbS

Associated with sickle cell disease

Q1 Q2

Introduction: Thalassaemia

Microcytic anaemia

Iron deficiency

Thalassaemia



Definition: autosomal recessive haemoglobinopathy

• Impaired globin chain synthesis

Epidemiology:

• Prevalent in areas of malaria

• Alpha thalassaemia: Asian and African

• Beta thalassaemia: Asian, Mediterranean and Middle Eastern

Pathophysiology: Thalassaemia

Normal Hb Structure Proportion in adults

HbA α2β2 90%

HbA2 α2δ2 <2%

HbF α2γ2<2-5%

Alpha thalassaemia Beta thalassaemia

Reduced Reduced

Reduced Increased

Reduced Increased

Pathophysiology: Alpha Thalassaemia

Impaired synthesis of alpha globin

• 4 alleles on chromosome 16 are responsible for alpha globin production

• Gene deletions

Disease No. of

deletions

HbA

(α2β2)

HbA2

(α2δ2)

HbF

(α2γ2)

Features

Silent

carrier

1 N N N Asymptomatic

Trait 2 ↓ ↓ ↓ Mild anaemia

HbH 3↓↓ ↓↓ ↓↓

Beta chains form tetramers

Marked anaemia

Hb Barts 4

Absent Absent Absent

Gamma chains form tetramers

Hydrops fetalis

Death in utero

Pathophysiology: Beta Thalassaemia

Impaired synthesis of beta globin

• 2 alleles on chromosome 11 are responsible for beta globin production

• Gene mutations

• Reduced production (β+)

• Absent production (β0)

Disease Genetics HbA

(α2β2)

HbA2

(α2δ2)

HbF

(α2γ2)

Features

Trait β/β+ ↓ ↑ ↑Asymptomatic or mild symptoms

Intermedia β+/β+

β+/β0

Variable Variable Variable

Variable

Major β0/β0 Absent ↑↑ ↑↑Marked anaemia

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Which of the following is the cause of his prominent forehead?

Question 2

Trauma

Cortical thickening

Normal variant

Bone marrow expansion

Osteomyelitis


A 1-year-old child is brought to the GP as his mother is concerned he is not

gaining weight. He is dropping off the centiles on his growth chart.

On examination he appears pale and has evidence of hepatosplenomegaly. His

forehead looks prominent.

Further investigations reveal a diagnosis of beta Thalassaemia major.

Q2Q1

30

Explanations


Which of the following is the cause of his prominent forehead?

Trauma

No evidence of trauma

Cortical thickening

It’s an issue with the marrow, not the cortex

Normal variant

Not normal as the patient has thalassaemia

Bone marrow expansion

Compensatory bone marrow expansion in sites away from the long bones occurs, causing

frontal bossing and prominent zygomatic bones

Osteomyelitis

We would not expect this in thalassaemia, nor would we expect it to occur in the frontal bone

Q2Q1

31

Clinical features: Thalassaemia

Signs

Neonatal jaundice

Hepatosplenomegaly

Failure to thrive

Chipmunk facies

(3)

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Investigations: Thalassaemia

Bloods• FBC: microcytic anaemia (MCV <80fL)

• Blood film: hypochromic red cells, target cells, Howell Jolly bodies

• Hb electrophoresis

Imaging • Skull X-ray: hair-on-end appearance

(4) (5)

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Management: Thalassaemia

Alpha and Beta thalassaemia trait

• No intervention required

HbH and beta thalassaemia major

• Regular blood transfusions

• Folate supplementation: haemolysis leads to folate deficiency

• Iron chelation: desferrioxamine reduces the risk of iron overload

• Splenectomy

• Patients develop splenomegaly due to extramedullary haematopoiesis

• Leads to hypersplenism and increased haemolysis

• Stem cell transplant: only curative option

Introduction: Anaemia of chronic disease

Microcytic anaemia

Iron deficiency

Thalassaemia



Definition: anaemia due to inflammation mediated reduction in

RBC production

• Microcytic or normocytic anaemia

Epidemiology:

• Second most common anaemia worldwide

• Multiple causes

• E.g. prevalence of ACD in rheumatoid arthritis ~ 30-40%

Introduction: Anaemia of chronic disease

Aetiology

• Autoimmune disorders e.g. rheumatoid arthritis

• Chronic infection

• Chronic disease e.g. CKD, heart failure

• Malignancy

• Major trauma

Pathophysiology: Anaemia of chronic disease

Functional iron

deficiency

Investigations: Anaemia of chronic disease

Bloods

• Iron studies

• Ferritin: raised

• Serum iron: reduced

• Transferrin saturation: reduced

• TIBC: reduced

• Inflammatory markers: raised

Chronic disease Iron deficiency

Hb Reduced Reduced

Serum Fe Reduced Reduced

Ferritin Raised Reduced

Transferrin saturation Reduced Reduced

TIBC Reduced Raised

Inflammatory markers Raised Reduced

Management: Anaemia of chronic disease

Treat the underlying cause• Anaemia is frequently mild and the below is may not be required

Iron supplementation• Oral or intravenous

Erythropoietin

Blood transfusion• Not usually required

Introduction: Sideroblastic anaemia

Microcytic anaemia

Iron-deficiency

Thalassaemia



Definition: Anaemia due to defective haem synthesis within the

mitochondria

Aetiology:

• Congenital: X-linked recessive enzyme deficiency

• Vitamin B6 deficiency

• Lead poisoning

• Chronic alcoholism

Pathophysiology: Sideroblastic anaemia

Glycine + succinal CoA

δ-aminolevulinic acid Porphobilinogen

Hydroxymethylbilane

Uroporphyrinogen III

Coproporphyrinogen IIIProtoporphyrin + Fe

Haem

ALA synthase

ALA dehydrogenase

Ferrochelatase

• Congenital: ALA synthetase

• Lead: ALA dehydrogenase and

ferrochelatase

• Vitamin B6: cofactor for ALA synthase

• Alcohol: mitochondrial poison MITOCHONDRIA

Pathophysiology: Sideroblastic anaemia

• Iron becomes trapped in the mitochondria and forms a ring around the nucleus of the

erythroblast

• Ringed sideroblast

(6)

Investigations: Sideroblastic anaemia

Bloods

• FBC: microcytic anaemia (MCV <80fL)

• Blood film: ringed sideroblasts

• Iron studies

• Ferrtin: increased

• Serum iron: increased

• Transferrin saturation: increased

• TIBC: reduced

43

Top-decile question

44

Explanations


Which of the following is most associated with choriocarcinoma?

Iron deficiency

Not associated


Not associated


Not associated

Alpha thalassaemia

Increased spontaneous abortion in Hb Barts disease

Beta thalassaemia

Not associated

45

Recap

• Microcytic

• Iron deficiency: most common

• Chronic disease: second most common

• Thalassaemia

• Sideroblastic anaemia

Microcytic (MCV < 80fL) Normocytic (MCV 80-95fL) Macrocytic (MCV >95fL)

Iron deficiency Acute blood loss B12 deficiency

Thalassaemia Haemolytic anaemia Folate deficiency

Anaemia of chronic disease Anaemia of chronic disease Alcohol

Sideroblastic anaemia Chronic kidney disease Liver disease

Aplastic anaemia Hypothyroidism

48

References

1. Matthew Ferguson 57 / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0)

2. CHeitz / CC BY (https://creativecommons.org/licenses/by/2.0)3. US Federal Government / Public domain4. Paulo Henrique Orlandi Mourao and Mikael Häggström / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0)5. Dr Graham Beards / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0)6. Paulo Henrique Orlandi Mourao / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0)

All other images were made by BiteMedicine or under basic license from Shutterstock and not suitable for

redistribution.

https://creativecommons.org/licenses/by-sa/3.0

https://creativecommons.org/licenses/by/2.0



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