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Essential Haematology > 4. Inherited Haemolytic Anemias- Haemoglobinopathies > Flashcards

4. Inherited Haemolytic Anemias- Haemoglobinopathies Flashcards

1
Q

List two main types of factors that affect red blood cell survival

A

Intrinsic

Extrinsic

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2
Q

What are three intrinsic factors affecting red blood cell survival

A

Enzymes for glucose metabolism
Normal phospholipid membrane
Normal hemoglobin

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3
Q

What are the three types of hemoglobin that normal adult blood contains

A 
Hemoglobin A  (α2β2)
Hemoglobin F   (α2γ2)
Hemoglobin A2 (α2δ2)
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4
Q

What percentage of adults hemoglobin does Hemoglobin A (a2β2) account for

A

98%

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5
Q

Describe a qualitative haemoglobin disorder

A

Structural defect of Alpha or Beta Globin Chain

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6
Q

Describe a quantitative haemoglobin disorder

A

Deficiency of alpha or beta globin chain

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7
Q

What is the diagnosis for:
A 2yr old boy that presents with
- Failure to thrive and progressive pallor
- Was well up to age 4 months
- Physical examination shows prominent maxillae
- Moderate splenomegaly noted

A

Beta Thalassemia

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8
Q

What is the definition of Thalassemia

A

A decrease in the production of either alpha or beta subunits

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9
Q

Which chromosome is affected in Beta Thalassemia

A

Chromosome 11

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10
Q

Which population is Beta Thalassemia most common in

A

Mediterranean
Middle Eastern
Asia

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11
Q

What type of mutation causes severe anemia in Beta Thalassemia?

A

Point mutation, where a stop codin is introduced early in the coding sequence and therefore terminates the protein sequence ( in this case Beta Globin sequence is terminated)

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12
Q

Is Beta Thalassemia Heterozygous or Homozygous

A

Both

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13
Q

What are the three types of Beta Thalassemia

A

Thalassemia Major (β0/β0)
Minor
Intermedia

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14
Q

Is Beta Thalassemia Major Heterozygous or Homozygous

A

Homozygous

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15
Q

Is Beta Thalassemia Intermedia Heterozygous or Homozygous

A

Heterozygous

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16
Q

Is Beta Thalassemia minor Heterozygous or Homozygous

A

Homozygous

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17
Q

What is the level of Microcytic RBCs in Beta Thalassemia minor

A

Increased Microcytic RBCs

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18
Q

What are the symptoms of Beta Thalassemia Minor

A

Asymptomatic or Mild Anemia

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19
Q

What are the changes in Adult Haemoglobin seen in Beta Thalassemia Minor

A 
Haemoglobin A (α2 β2) decreases
Haemoglobin A2 (α2 δ2) increases
Haemoglobin F (α2 γ2) increases
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20
Q

Which test shows an increase in HbA2 and HbF in Beta Thalassemia Minor

A

Haemoglobin Electrophoresis

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21
Q

What is another name for Beta Thalassemia Major

A

“Cooley’s Anemia”

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22
Q

Which Anemia is known as “Cooley’s Anemia”

A

Beta Thalassemia Major

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23
Q

Is there Beta Globin production in Beta Thalassemia Major

A

Nope, None

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24
Q

What is the major Haemoglobin formed in Beta Thalassemia Major (β0/β0)

A

Haemoglobin F

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25
Q

What condition of the Spleen and Liver is evident in β Thalassemia Major (β0/β0)

A

Splenomegaly

Enlargement of Liver

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26
Q

Why is the liver and spleen enlarged in β Thalassemia Major

A

It is as a result of excessive red cell destruction

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27
Q

If both parents are the carrier of the β-Thalassemia trait, what is the chance of a β- Thalassemia Major offspring

A

1 in 4

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28
Q

What is the effect of the excessive α-chain precipitation in β-Thalassemia Major

A

The α - chains precipitate in erythroblasts and in mature red cells causing the severe ineffective erythropoiesis and hemolysis

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29
Q

What is the relationship between α-chain excess and anemia

A

Greater the α-chain excess the more severe the anemia

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30
Q

The production of which globin chain helps to “mop up” the excess α-chains in β- Thalassemia major?

A

γ-chains (gamma chains found in Haemoglobin F)

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31
Q

True or False

Thalassemia Major is often the result of inheritance of two different mutations, each involving β-globin synthesis

A

True

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32
Q

What are six clinical features of β-Thalassemia Major

A 
Severe Anemia
Enlargement of Liver and Spleen
Expansion of Bones
Iron overload (for patients sustained by blood transfusion)
Increased susceptibility to infection
Osteoporosis
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33
Q

Severe anemia in a β-Thalassemia Major patient becomes apparent at which age

A

3-6mths after birth

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34
Q

Why does β-Thalassemia Major become apparent at 3-6 mnths

A

Because this is when the switch from γ- to β-chain production should take place

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35
Q

One Clinical Feature of β-Thalassemia Major is splenomegaly, how does this affect the blood requirements

A

It increases blood requirements by increasing red cell destruction and pooling and by causing expansion of the plasma volume

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36
Q

What causes the expansion of bones in β- Thalassemia Major

A

Caused by intense marrow Hyperplasia (in an attempt to correct the anemia)
Leading to Thalassemic Facies

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37
Q

Expansion of bones is a clinical feature of β-Thalassemia Major

What effect does it have on bone structure, and bones like the maxilla and skull

A

Thins the bone cortex (increasing susceptibility to fracture)

Protruding Maxilla

Bossing of skull with hair- on - end appearance on X-ray

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38
Q

Which therapy is administered to β- Thalassemia Major patients along with their sustained blood transfusions to prevent iron overload

A

Chelation Therapy

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39
Q

What is the effect of iron overload

A 
Failure of growth
Delayed or absent puberty
Diabetes 
Hypothyroidism 
Hypoparathyroidism
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40
Q

What changes in skin pigmentation are seen in an early stage of iron overload

A

Slately grey

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41
Q

What causes the Slate Grey appearance in an early stage or iron overload

A

Excess melanin and haemosiderin

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42
Q

Which test can be done to observe Iron overload in Liver or heart

A

T2 Magnetic Resonance Images

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43
Q

What is the reticulocyte percentage in β-Thalassemia

A

Raised

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44
Q

What type of anemia is seen in β- Thalassemia Major

A

Hypochromic

Microcytic anemia

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45
Q

Which iron test is used to assess iron overload

A

Serum Ferritin

46
Q

For patients with Thalassemia Major you should attempt to keep the iron level in what range

A

1000 - 1500 ug/L

Normal is 30-620 ug/L in males
20-220 ug/L in premenopausalfemales

47
Q

List eight treatment options for Thalassemia Major

A

1) Blood Transfusions
2) Regular Folic acid
3) Iron Chelation therapy
4) Vitamin C
5) Splenectomy
6) Endocrine Therapy
7) Immunization against Hep B
8) Allogenic bone marrow transplantation

48
Q

How many units of blood and how often are these units administered to β- Thalassemic Major patients

A

2-3 units every 4-6 weeks

49
Q

What type of blood is used in the Blood Transfusion for Beta Thalassemic Major patients

A

Fresh blood

No WBCs

50
Q

If the Beta Thalassemic Major Pt has a folic acid poor diet what is the amount prescribed per day

A

5mg/day

51
Q

List three options for Iron Chelators

A

Deferasirox ( oral ) - best option
Deferiprone (oral)
Deferoxamine (iv)

52
Q

Why is Vitamin C apart of the treatment for Beta Thalassemia Major

A

It increases the excretion of iron by Deferoxamine

[It is believed that vitamin C can reduce both ferric (Fe(3+)) and ferrous (Fe(2+)) ions, and also facilitate the accessibility of iron to chelators through increase of iron release from the reticuloendothelial system.]

53
Q

Splenectomy is a form of treatment for Beta Thalassemia Major, however this should not be performed in children until after what age

A

Age 6

54
Q

Why is splenectomy an option for treatment in patients with Beta Thalassemia Major

A

To reduce blood requirements

(Remember the spleen destroys rbcs and releases the blood requirements back into the plasma, this is excessive in Beta Thalassemia Major)

55
Q

Why is Endocrine Therapy an option for Beta Thalassemia Major pts

A

It is given either as replacement because of end organ failure

OR

To stimulate the pituitary if puberty is delayed

56
Q

What is the blood picture of Beta Thalassemia minor

A

Hypochromic

Microcytic

57
Q 
What are the relative values for 
Mean Cell Volume MCV
Mean Cell Haemoglobin MCH
Red Cell Count RBC
Haemoglobin

in Beta Thalassemia Minor

A

MCV is low
MCH is low
RBC is high
Haemoglobin is a bit low

58
Q

A raised level in what type of Haemoglobin confirms the diagnosis for Beta Thalassemia Minor

A

Hb A2 (>3.5%)

59
Q

Describe Thalassemia intermedia

A

Thalassemia of moderate severity who do not need regular transfusions

60
Q

In β-Thalassemia Major Management the Haemoglobin is maintained at what level

A

12g/dl

61
Q

True or False

All Beta Thalassemic Intermedia patients are transfusion dependent

A

False

Not all are

62
Q

Diagnose this patient

Results
> Hb 8.0g/dl
> MCV 65fl ; MCH 18pg
> Blood film: hypochromic, microcytic with occasional nucleated RBCs
> Serum iron, TIBC normal (total iron binding capacity)
> Electrophoresis: Hb H

A

α-thalassemia

63
Q

What is the genetic cause of α-thalassemia

A

All are due to gene deletion

64
Q

What are Thalassemias

A

These are heterogenous group of genetic disorders that result from a reduced rate of synthesis of α or β chains

65
Q

What is the effect of the loss of all four α globin genes on α-chain synthesis

A

Completely suppresses α-chain synthesis

Leads to death in utero (hydrops fetalis)

66
Q

What is the result of 3 α gene deletions

A

Leads to a moderately severe microcytic, hypochromic anemia

67
Q

What is the condition associated with Four gene deletion α-Thalassemia

A

Hydrops fetalis

68
Q

What type of Haemoglobin is observed in α-Thalassemia

A

Hb H

[H (β4) - four β globulin chains]

69
Q

What type of Haemoglobin is observed in α-Thalassemia of the fetus

[loss of all 4 α globin chains]

A 
Hb Barts (γ4)
(Hydrops fetalis)

Four gamma chains

70
Q

Describe what causes α-Thalassemia trait

A

Caused by loss of one or two genes and are not usually associated with anemia

71
Q

True or False MCV and MCH are low in α- Thalassemia trait

A

True

72
Q

What is the cause of in utero death of fetuses with α-Thalassemia

A 
Severe hypoxia due to 
Hb Barts (γ4) that has High oxygen affinity
73
Q

Describe α+ trait thalassemia

A

1 α globulin gene deleted

74
Q

Describe homozygous α+ trait

A

2 α globulin genes deleted

1 from opposite chromosomes

75
Q

Describe heterozygous α0 thalassemia trait

A

2 α genes deleted

Both deleted genes from same chromosome

76
Q

Describe Hb H disease

A

3 alpha globulin genes deleted

77
Q

Diagnose this patient

Hb 7.5g/dl; sickled cells on film
Wbc 28.6 x 10^9/L
Plats 295 x 10^9/L
Retic 18%
Sickle solubility test positive 
Hb electrophoresis S and A2
A

Sickle Cell Disease

78
Q

Define Sickle Cell Anemia

A

It is a group of hemoglobin disorders in which the sickle β-globin gene is inherited

79
Q

What is the most common type of sickle cell anemia

A 
Hb SS (homozygous sickle cell)
(i.e. Hb α2β2 s)
80
Q

What happens to Hb S when exposed to low oxygen tension

A

Forms crystals

81
Q

Substitution of which amino acid causes the sickle β-globin abnormality

A

Substitution of Valine for Glutamic Acid in position 6 in the β chain

82
Q

What percentage of West Africans have Sickle Cell Anemia

A

25%

83
Q

Why is the 25% occurrence of sickle cell disease in West Africa maintained

A

Because of the protection against malaria that is afforded by the carrier state

84
Q

Which Haemoglobin type gives up O2 more readily to tissues Hb S or Hb A

A

Hb S

O2 dissociation curve shifted to the right

85
Q

List four clinical features of Sickle Cell Anemia

A

Painful Vaso-occlusive crises
Visceral sequestration crises
Aplastic Crises
Haemolytic Crises

86
Q

What is vaso-occlusive crisis

A

When the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and resultant pain

87
Q

Painful vaso occlusive crises of the sickle cell anemic patient are often precipitated by what factors

A

Infection
Acidosis
Dehydration
Deoxygenation

88
Q

What are some states of deoxygenation that can cause vaso occlusive crises in the sickle cell anemic patient

A 
Altitude
Operations
Obstetric delivery
Stasis of the circulation
Exposure to cold
Violent exercise
89
Q

What are the most serious sites of vaso occlusive crises

A

Brain

Spinal cord

90
Q

Which test can be used to detect abnormal blood flow that is indicative of arterial stenosis

A

Doppler Ultrasonography

91
Q

What is typically the first presentation of sickle cell disease HbSS

A

‘Hand-foot’ Syndrome

92
Q

What causes dactylitis in HbSS pts

A

Infarcts of the small bones

93
Q

What causes sequestration crises

A

Sickling within organs and pooling of blood, often with severe exacerbation of anemia

94
Q

What is the most common cause of death from Homozygous Sickle cell disease after puberty

A

Acute Sickle Chest Syndrome

95
Q

What is the clinical presentation of Acute sickle chest syndrome

A

Dyspnoea
Falling arterial Po2
Chest pain
Pulmonary infiltrates on chest X ray

96
Q

What is the treatment for Acute Sickle Chest Syndrome

A

Analgesia
Oxygen
Exchange transfusion and ventilatory support

97
Q

What is Aplastic Crises

A

An aplastic crisis is when the body does not make enough new red blood cells to replace the ones that are already in the blood.

[These occur as a result of infection with parvovirus or from folate deficiencies]

98
Q

How is Aplastic Crises characterized

A

Fall in reticulocytes

Fall in Haemoglobin

99
Q

What is a Haemolytic crises

A

Increased rate of haemolysis with a fall in Haemoglobin but rise in reticulocytes

100
Q

List four Laboratory Findings of Homozygous Sickle cell Disease HbSS

A

Haemoglobin is usually low (6-9g/dL)
Sickle cells and Target cells present in blood
Screening test for sickling positive when the blood is dehydrated
Haemoglobin Electrophoresis: in HbSS, no HbA detected
Moderate to severe normochromic anemia
Polychromasia and nucleated red cells
Leucocytosis
Thrombocytosis

101
Q

List four prophylactic treatments for Homozygous Sickle Cell Anemia

A

Avoid factors known to precipitate crises
Folic acid
Good general nutrition and hygiene
Pneumococcal, haemophilus and meningococcal vaccine, also hep b

102
Q

What are four simple treatments for HbSS crises

A

Rest
Warmth
Rehydration by oral fluids/ intravenous normal saline
Antibiotics if infection is present

103
Q

Analgesics is administered to pts with HbSS crises, which drugs are suitable

A

Paracetamol

Non-steroidal anti-inflammatory agent and opiates

104
Q

What is the role of Hydroxyurea treatment in HbSS treatment

A

Can increase Hb F levels and has been shown to improve the clinical course of children or adults who are having three or more painful crises each year

NB// hydroxyurea should NOT be used during pregnancy

105
Q

Which treatment is know to cure HbSS

A

Stem Cell Transplantation

106
Q

What is the mortality rate of stem cell transplantation

A

Less than 10%

107
Q

What is the most common symptom of Sickle cell trait

A

Haematuria

Caused by minor infarcts of the renal papillae

108
Q

List four varieties of Sickle Cell Disease

A

Sickle Cell Anemia (HbSS)
Sickle -Hb C disease
Sickle β 0 Thalassemia (S β0)
Sickle β+ Thalassemia (S β+)

109
Q

List five reasons why Sickle Cell disease is clinically silent until age 6mths

A 
Chronic hemolytic anemia of variable severity
Ischemic strokes 
Pulmonary infection and infarction 
Chronic leg ulcers
Impaired growth and development
110
Q

What are the symptoms of Hand Foot Syndrome in HbSS crises

A

Sudden pain and swelling of extremities

Results in shortened digits in later life

Essential Haematology (14 decks)

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