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Yr 2 MCD - Haem > 4 - Haemoglobin Molecule and Thalassaemia > Flashcards

4 - Haemoglobin Molecule and Thalassaemia Flashcards

1
Q

Recall the functions of red blood cells

A

Functions:

  • carry oxygen from lungs to tissues
  • transfer carbon dioxide from tissues to lungs
  • contain Hb
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2
Q

What is the normal concentration (g/l) of haemoglobin in adults?

A

120-165 g/l

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3
Q

What is the molecular weight of haemoglobin?

A

64-64.5 kDa

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4
Q

Where is haemoglobin found?

A

Exclusively in RBCs (unless haemolysis is occurring)

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5
Q

What is the average number (per litre) of red cells in adults?

A

3.5-5x10^12 /l

WBCs and platelets are in 10^9, so RBCs have a 3x log increase

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6
Q

How many molecules of haemoglobin does each red cell contain on average?

A

Each cell contains approximately 640 million molecules of Hb

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7
Q

What organelles do mature red blood cells not have?

A

Nuclei

Mitochondria

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8
Q

How much haemoglobin is produced and destroyed in the body per day?

A

90 mg/kg produced and destroyed

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9
Q

How much iron does each gram of Hb contain?

A

3.4mg of Fe

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10
Q

In what stages of RBC development does haemoglobin synthesis occur?

A

Begins in pro-erythyroblast

  • 65% in erythroblast stage (early, still contain nuclei and mitochondria)
  • 35% in reticulocyte stage
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11
Q

Where is haemoglobin synthesised within red blood cells?

A

HAEM
- synthesised in mitochondria

GLOBIN
- synthesised in ribosomes

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12
Q

Describe the structure of haem

A

Same in all types of Hb

Combination of:

  • protoporphyrin ring
  • central iron atom (ferroprotoporphyrin)

Iron usually in Fe2+ form (ferrous)

Able to combine reversibly with oxygen (iron atom)

Synthesised mainly in mitochondria which contain the enzyme ALAS

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13
Q

What is the name of the ring in haem?

A

Protoporphyrin ring

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14
Q

What is the name of the central iron atom in haem?

A

Ferroprotoporphyrin

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15
Q

What form does iron usually take in haem?

A

Ferrous form (Fe2+)

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16
Q

What enzyme is particularly important for haem synthesis?

A

ALAS (Aminolevulinic Acid Synthase)

Found in mitochondria

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17
Q

Describe the structure of globin

A

Various types which combine with haem to form different haemoglobin molecules

Eight functional globin chains, arranged in two clusters

= β- cluster (β, γ, δ and ε globin genes) on the short arm of chromosome 11

= α- cluster (α and ζ globin genes) on the short arm of chromosome 16

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18
Q

What is the globin cluster that is encoded by genes on the short arm of chromosome 11?

A

β- cluster

β, γ, δ and ε globin genes

On the short arm of chromosome 11

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19
Q

What is the globin cluster that is encoded by genes on the short arm of chromosome 16?

A

α- cluster

α and ζ globin genes

On the short arm of chromosome 16

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20
Q

What is the normal proportions of different adult haemoglobins in the body?

A

Hb A
= 96-98%

Hb A2
= 1.5-3.2%

Hb F
= 0.5-0.8%

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21
Q

What makes up the different forms of normal adult haemoglobins?

A

Hb A
= a2β2

Hb A2
= a2d2

Hb F
= a2γ2

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22
Q

What is the primary structure of globin?

A

α globin
= 141 AA

Non- α globin
= 146 AA

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23
Q

What is the secondary structure of globin?

A

75% α and β chains

= helical arrangement

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24
Q

What is the tertiary structure of globin?

A

Approximate sphere

Hydrophilic surface (charged polar side chains)
- accounts for solubility of haemoglobin

Hydrophobic core

Haem pocket

  • each globin chain has a haem pocket which can carry one oxygen molecule
  • therefore, 4 haem pockets per haemoglobin molecule = 4 oxygen molecule carrying capacity
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25
Q

What does the oxygen-haemoglobin dissociation curve show?

A

O2 carrying capacity of Hb at different pO2

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26
Q

What is the shape of the oxygen-haemoglobin dissociation curve?

A

Sigmoid shape

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27
Q

What does cooperativity refer to in terms of oxygen binding to haemoglobin?

A

Binding of one molecule facilitates the second molecule binding
= COOPERATIVITY

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28
Q

What is P50 in terms of oxygen binding to haemoglobin?

A

P50
= partial pressure of O2 at which Hb is half saturated with 02
= 26.6 mmHg in humans in HbA
= 5.5 kPa in humans in HbA

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29
Q

What factors affect the normal position of the oxygen-haemoglobin dissociation curve?

A

Concentration of 2,3-DPG

H+ ion concentration (pH)

CO2 in red blood cells

Structure of Hb

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30
Q

What do right-shift and left-shift mean in terms of the oxygen-haemoglobin dissociation curve?

A 
RIGHT SHIFT
Easy oxygen delivery
= High 2,3-DPG
= High H+ (Reduced pH)
= High CO2
= HbS
LEFT SHIFT
Gives up oxygen less readily
= Low 2,3-DPG
= HbF
= Low H+ (Raised pH)
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31
Q

What are haemoglobinopathies?

A

Structural variants of haemoglobin
- Abnormal haemoglobin

OR

Defects in globin chain synthesis (thalassaemia)
- Reduced production of haemoglobin

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32
Q

How is thalassaemia characterised?

A

Genetic disorders characterised by a defect of globin chain synthesis.

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33
Q

What is the most common inherited single gene disorder worldwide?

A

Thalassaemia

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34
Q

What is the worldwide distribution of thalassaemia?

A

Most common in countries where malaria is prevalent

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35
Q

How is thalassaemia classified?

A

Globin Type Affected

Clinical Severity

  • minor ‘trait’
  • intermedia
  • major

Now it’s more classified as transfusion-dependent or non transfusion-dependent

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36
Q

Where is Beta (β) thalassaemia most prevalent?

A
  • Mediterranean countries (Greece, Cyprus, Southern Italy)
  • Arabian peninsula
  • Iran
  • Indian subcontinent
  • Africa
  • Southern China
  • South-East Asia
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37
Q

What is the mechanism of Beta (β) thalassaemia?

A

Deletion or mutation in β globin gene(s)

Results in a reduced or absent production of β globin chains

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38
Q

What is the inheritance pattern of Beta (β) thalassaemia?

A

Recessive Mendelian

39
Q

How is thalassaemia diagnosed in a laboratory?

A

FBC
= Microcytic Hypochromic indices
= Increased RBCs relative to Hb

Film
= Target cells, poikilocytosis but no anisocytosis

Hb EPS / HPLC
= α- thal- Normal HbA2 & HbF, +/- HbH (more difficult to diagnose, need DNA analysis to be definitive)
= β- thal- Raised HbA2 & raised HbF

Globin Chain synthesis/ DNA studies
= Genetic analysis for β-thalassaemia mutations and XmnI polymorphism (in β-thalassaemias) and α-thalassaemia genotype (in all cases)

40
Q

What would the blood film of Beta (β) thalassaemia show?

A

Microcytosis

Hypochromia

Occasional cells showing basophilic stippling

41
Q

How is Thalassaemia Major categorised?

A

Carry 2 abnormal copies of the beta globin gene

Severe anaemia, incompatible with life without regular blood transfusions

Clinical presentation usually after 4-6 months of life (at switch between γ chain predominating to β chain predominating)

42
Q

What would a Beta Thalassaemia Major peripheral blood film show?

A

Microcytosis

Extreme hypochromia

Poikilocytosis

Often Howell Jolly bodies and nucleated RBC’s will be present as a result of splenectophy and a hyper plastic bone marrow.

43
Q

What forms of inclusion bodies can be seen in Beta Thalassaemia?

A

Alpha Globin Precipitates

Pappenheimer Bodies

44
Q

How do Pappenheimer bodies stain?

A

Perls Stain

  • inky blue granules
  • these are haemosiderin granules
45
Q

Why do Alpha Globin Precipitates form?

A

Alpha globin chains are unstable and readily precipitate. These cause the cells to become more rigid.

46
Q

What gives Alpha Thalassaemia Major its haemolytic component?

A

Alpha globin chains are unstable and readily precipitate. These cause the cells to become more rigid.

47
Q

What is the clinical presentation of Thalassaemia Major?

A

Severe anaemia
- usually presenting after 4 months

Hepatosplenomegaly

Blood film

  • gross hypochromia
  • poikilocytosis
  • many NRBCs

Bone marrow (not often done)

  • erythroid hyperplasia
  • attempt to address the anaemia
  • frontal bossing
  • thickening of maxillary bones

Extra-medullary haematopoiesis

Haemoglobin electrophoresis

  • little/no HbA
  • increased HbA2
48
Q

What is the clinical presentation of β Thalassaemia?

A
  • Chronic fatigue
  • Failure to thrive
  • Jaundice (due to chronic haemolysis)
  • Delay in growth and puberty
  • Skeletal deformity
  • Splenomegaly
  • Iron overload
49
Q

What can be some further complications of β Thalassaemia?

A 
Cholelithiasis and biliary sepsis
- due to chronic haemolysis
Cardiac failure
- mainly due to iron overload
Endocrinopathies
- mainly due to iron overload
Liver failure
- mainly due to iron overload
50
Q

What are the main causes of death in people with β Thalassaemia?

A
  1. Cardiac Disease
  2. Infections
    - normally due to microorganisms that feed on extra iron
  3. Liver Disease
    - mainly due to iron overload
  4. Other Causes
51
Q

What are the treatments for Thalassaemia Major?

A
  • REGULAR BLOOD TRANSFUSIONS
  • IRON CHELATION THERAPY
  • Splenectomy
  • Supportive medical care
  • Hormone therapy
    Iron deposition can cause hypogonadism and problems with anterior pituitary (e.g. failure to grow due to lack of GH)
  • Hydroxyurea to boost HbF
  • Bone marrow transplant
52
Q

How are blood transfusions carried out for Thalassaemia Major patients?

A

Phenotyped red cells
- to try and prevent rejection

Aim for pre-transfusion Hb 95-100g/L

Regular transfusion 2-4 weekly

If high requirement, consider splenectomy

53
Q

What are the major infection threats to Thalassaemia Major patients?

A
  • Yersinia

- Other Gram Negative species

54
Q

How is infection risk managed in Thalassaemia Major patients who have undergone a splenectomy and are therefore immunocompromised?

A

Prophylaxis in splenectomised patients

  • Immunisation
  • Antibiotics
55
Q

How is iron chelation therapy carried out for Thalassaemia Major patients?

A

Start after 10-12 transfusions or when serum ferritin >1000 mcg/l

Audiology and ophthalmology screening prior to starting

56
Q

How is effective iron chelation therapy achieved, following research and clinical experience?

A
  1. Achievement of continuous chelation coverage is an essential characteristic of effective chelation therapy. Constant, 24-hour control of NTBI/LPI protects against the harmful effects of toxic iron and helps to prevent further tissue damage
  2. Good treatment compliance is important in achieving chelation coverage has been shown to be a key factor in attaining therapeutic efficacy and improving morbidity and survival
57
Q

What different treatments are used in iron chelation therapy?

A

Deferasirox (Exjade)

Desferrioxamine (Desferal)

Deferiprone (Ferriprox)

Combination therapy

58
Q

What is the administration and dose of Deferasirox (Exjade)?

A

Oral

Dose: 20-40mg/kg

59
Q

What is the administration and dose of Desferrioxamine [DFO] (Desferal)?

A

Sc infusion 8-12 hours 5-7 days per week (or IV in cardiac iron overload)

Dose: 20-50 mg/kg/day

60
Q

What is the administration and dose of Deferiprone (Ferriprox)?

A

Oral

Dose: 5-100 mg/kg/day

61
Q

What are the advantages and disadvantages of Deferasirox (Exjade)?

A

ADVANTAGES

  • oral administration
  • once daily
  • control of body iron
  • specific

DISADVANTAGES

  • short clinical experience with drug
  • cardiac protection uncertain
  • toxicity limited but long-term data lacking
  • SEs: GI symptoms, hepatitis, renal impairment
62
Q

What are the advantages and disadvantages of Desferrioxamine (Desferal)?

A

ADVANTAGES

  • 3 decades of experience with drug (long-established)
  • survival benefit
  • heart failure prevented and reversed
  • vitamin C can help with iron removal if taken on same day as treatment
DISADVANTAGES
- parenteral administration
- limits compliance
- toxicity (dose dependent)
= ocular
= auditory
= skeletal
- SEs: vertebral dysplasia, pseudo-rickets, genu valgum, retinopathy, high tone sensorineural hearing loss, increased risk of Klebsiella and Yersinia infection
63
Q

What are the advantages and disadvantages of Deferiprone (Ferriprox)?

A

ADVANTAGES

  • oral administration
  • cardiac protection (effective in reducing myocardial iron)
DISADVANTAGES
- 3 times a day, 7 days a week
- short plasma half-life
- unpredictable control of body iron
- toxicity
= agranulocytosis (~0.5%)
= arthopathy
= zinc deficiency
- SEs: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy
64
Q

How do monitor potential iron overload on iron chelation therapy?

A

Serum ferritin

  • > 2500 associated with significantly increased complications
  • Acute phase protein
  • Check 3 monthy if transfused otherwise annually

Liver biopsy
- Rarely performed

T2* cardiac and hepatic MRI

  • <20ms – increased risk of impaired LF function
  • Check annually or 3-6monthly if cardiac dysfunction

Ferriscan – R2 MRI

  • Non-invasive quantitation of LIC
  • Not affected by inflammation or cirrhosis
  • <3mg/g = normal
  • > 15mg/g = associated with cardic disease/cardiac iron overload
  • Check annually or 6monthly if result >20
65
Q

What would a Sickle β Thalassaemia blood film show?

A

All the features of both sickle and beta thalassaemia

  • sickled cells
  • target cells
  • microcytosis
  • hypochromia

As little or no HbA is being produced in these patients, HbS will be the dominant haemoglobin and will precipitate as it does in homozygote sickle cell patients

66
Q

Where is HbE β Thalassaemia most common?

A

Very common combination in South East Asia.

67
Q

What is HbE β Thalassaemia?

A
  • Clinically variable in expression
  • Can be as severe as β Thalassaemia Major
  • The globin chain of HbE is unstable and hence at a molecular level this can be classed as a mild form of Beta Thalassaemia.
  • Hence coinheritance of Beta Thalassaemia Trait.
  • In terms of clinical severity, it is classed as a Beta Thalassaemia intermedia.
  • However the degree of clinical support required by such individuals varies quiet markedly.
68
Q

What is α Thalassaemia?

A

Deletion or mutation in α globin gene(s)

Reduced or absent production of α globin chains

Excess β and γ chains form tetramers of HbH and Hb Barts respectively

69
Q

What does the severity of α Thalassaemia depend on?

A

Severity depends on number of α globin genes affected

1/2 genes affected = trait
3 = HbH disease
4 = foetus death in utero

70
Q

Who is affected by α Thalassaemia?

A

Can affects both foetuses and adults

71
Q

What is a Thalassaemia carrier?

A

A person who carries a single abnormal copy of the beta globin gene

Usually asymptomatic

Mild anaemia

72
Q

What is a Thalassaemia carrier known as in terms of the severity classification?

A

Thalassaemia minor/trait

73
Q

What is HbH Disease?

A

A form of Alpha (α ) Thalassemia in which moderately severe anemia develops due to reduced formation of alpha globin chains

74
Q

What would a peripheral blood film of a person with HbH Disease look like?

A

Haemolytic element

Microcytosis

Anisoocytosis

Poikilocytosis

“Puddling” of haemoglobin within the RBC.

75
Q

What would HPLC of a person with HbH Disease show?

A

Shows a fast band which is probably more easily seen shortly after the strip has started to run.

HPLC

76
Q

What are the problems associated with thalassaemia treatment in developing countries?

A

Lack of awareness of the problems

Lack of experience of health care providers

Availability of blood

Cost and compliance with iron chelation therapy

Availability of and very high cost of bone marrow transplant

77
Q

What screening and prevention is available for thalassaemia?

A

Counselling and health education for thalassaemics, family members and general public

Extended family screening

Pre-marital screening?

Discourage marriage between relatives?

Antenatal testing

Pre-natal diagnosis (CVS)

78
Q

Describe the full structure of haemoglobin

A

4 globin chains

  • 2 α globin chains
  • 2 β globin chains

Centre of these globin chains is the haem molecule, with iron atom at its centre

79
Q

How is haemoglobin synthesised?

A

HAEM

Iron is transported to cell via transferrin (carrier protein for free iron)

Transferrin complex taken up by endocytosis

Transported to mitochondria

Haem synthesis occurs here due to presence of particular enzymes, especially delta-ALAS

GLOBIN

Occurs in ribosomes

Alpha and beta globin chains produced

COMBINATION

Of Haem and Globin chains

80
Q

In what proteins is haem found?

A

Haemoglobin

Myoglobin

Cytochromes

Peroxidases

Catalases

Tryptophan

Foetal Haemoglobin

81
Q

On what enzyme does haem exert negative feedback?

A

ALAS

82
Q

Which globin genes are important at which stages of human development?

A

Embryonic

  • γ (produced until after birth), ε
  • ζ (produced until approx. 8 weeks into embryogenesis, then α globin takes over)

Post-Natal

  • β, γ, δ
  • α (2 types)
83
Q

Why does β-thalassaemia typically manifest at about 3-6 months to age as opposed to α-thalassaemia being potentially fatal in utero?

A

α-thalassaemia

  • ζ chains produced until approx. 8 weeks into embryogenesis
  • then α globin takes over
  • if there’s a failure/defect of α globin, there would be a massive effect on the embryo in utero

β-thalassaemia

  • in embryogenesis, predominant chain is γ
  • γ globin chain is produced until after 3-4 months after birth
  • gives opportunity to identify problem in baby and take action
84
Q

What is the predominant haemoglobin in adults?

A

HbA

85
Q

In what circumstances does haemoglobin adopt a tighter structure?

A

In its deoxygenated state

86
Q

What is 2,3-DPG?

A

A molecule that aids transfer of oxygen away from haem.

87
Q

What is on the x and y axes of the oxygen-haemoglobin dissociation curve?

A

X-Axis
- Partial pressure of oxygen

Y-Axis
- Hb O2

88
Q

What would HPLC electrophoresis of someone with Beta Thalassemia trait show?

A

Mostly HbA

Raised HbA2

Still have one functioning beta globin chain allowing for HbA

89
Q

What are the 2 forms of iron overload that can occur in β Thalassaemia?

A

Transfusion-dependent

Non Tranfusion dependent
- due to extra iron absorption in GI tract

90
Q

Why is iron chelation therapy important?

A

This is because the primary treat for thalassaemia is blood transfusions.

However, this leads to iron overload which massively increases risk of mortality.

Iron chelation tackles the issue of iron overload.

91
Q

What is iron chelation therapy?

A

The removal of excess iron from the body with special drugs.

92
Q

What forms of iron overload are common in thalassaemia and SCD?

A

Thalassaemia
- cardiac iron overload is more common

SCD
- hepatic iron overload is more common

93
Q

What would you see on the HPLC of a person with α Thalassaemia?

A

You would see fast-exiting bands showing hetromers or dimers of just beta-globin chains

Reduced HbA2

94
Q

What is HPLC?

A

High Performance Liquid Chromatography

A form of column chromatography that pumps a sample mixture or analyte in a solvent (known as the mobile phase) at high pressure through a column with chromatographic packing material (stationary phase).

Yr 2 MCD - Haem (12 decks)

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