Haemoglobinopathies Flashcards

1
Q

Describe structure of Hb [2]

A

Tetramer: 4 subunits (of two identical dimers) [1]

Each subunit contains a haem and globin protein chain

Has just the right pocket size containing iron to allow oxygen to fit and form a partial bond with the valence electron on iron

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2
Q

What are the two products of the alpha globin gene? [2]

What are the products of beta globin genes? [4]

How do the above interact? [1]

A

Alpha globin gene:
* Alpha globin chain
* Zeta globin chain

Beta globin genes [4]
* Epsilon (e) globin
* Gamma globin
* Delta globin
* Beta globin

To form Hb: need interaction of one component of alpha globin chain and beta chain (could be alpha and delta etc)

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3
Q

What are the 3 functional genes found on a-Globin gene? [3]

When are each expressed? [1]

A

Embryonic: zeta [1] HbZ gene

Fetal / Adult: Alpha 1 / 2 [2] HbA1 and HbA2

α-globin gene expression begins in early fetal life and is predominant throughout fetal and adult life

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4
Q

What are the 5 functional genes found on beta-Globin gene? [3]

When are each expressed? [1]

A

Embryonic:
- HBE gene / e-globin gene

Fetal:
- HBG2 and HBG1 genes Gy and Ay globin gene (The γ-globin genes (Gγ and Aγ) are the major β-like genes expressed in most of fetal life)

Adult:
- HBD and HBB genes delta and B-globin

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5
Q

Name the different places that haematopoiesis occurs in from embryo to neotate [4]

A

Embryo (3 weeks): Yolk sac

Fetus (6 weeks): Liver

Fetus (8 weeks): Spleen

Neonate: Bone marrow

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6
Q

Label the type of Hb that are dominant in each stage of life [3]

A

Yolk Sac / A: Z2, E2

Fetal liver / B: A2, γ2

Bone marrow / C: A2, B2

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7
Q

What are the normal variants of Hb? [3]

A
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8
Q

Haemoglobinopathies arised from mutations or deletions in which gene? [1]

A

Globin gene

Abnormal structure or Abnormal production

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9
Q

What is the inheritance patten of thalassaemias? [1]

A

Both alpha and beta conditions are autosomal recessive

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10
Q

Describe how the phenotypes and genotypes relate with Beta-thalassaemia [3]

A

Affected patients will either have homozygous or heterozygous expression of the mutated gene:
* Heterozygous (one affected gene): beta-thalassaemia trait
* Homozygous (two affected genes): beta-thalassemia intermedia or major

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11
Q

Describe the two types of thalassaemias [2]

A

Alpha-thalassaemia:
- deficiency of alpha chains in haemoglobin

Beta-thalassaemia:
- Defects in beta-globin chains
- Three types: Thalassaemia minor, intermedia & major

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12
Q

Describe the different types of alpha thalassaemias [4]

A

Alpha thalassemia minima:
- 1 defective alpha subunit
- Silent carriers: slightly reduced / normal MCV but no clinical symptoms
- Hypochromic and microcytic anaemia

Alpha thalassemia minor:
- 2 defective alpha subunits
- Hypochromic and microcyticnaemia
- The remaining two alpha genes produce nearly normal levels of RBCs

HbH disease:
- 3 defective alpha subunits
- Excess beta chains causes RBC membrane damage and intramedullary haemolysis AND does not release oxygen to tissues, causing increased RBC production

Hydrops fetalis, Bart’s hydrops (γ4):
- 4 defective alpha subunits
- Extreme affinity to O2: incompatible with life

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13
Q

Describe the pathophysiology of the different forms of beta thalassamias [3]

A

The gene defects can either consist of abnormal copies (that retain some function) or deletion genes (with no function in the beta-globin)

Beta Thalassaemia minor:
- Mutation in one gene
- Reduced or no production of beta chains from one gene
- Other gene still functional
- Forms HbA
- Asymptomatic

Beta Thalassaemia intermedia
- Have two defective genes OR one defective gene and one deletion gene
- Causes more significant microcytic anaemia.

Beta Thalassaemia major
- homozygous for the deletion genes
- presents with severe anaemia and failure to thrive in early childhood
.

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14
Q

Describe the clinical presentation of a patient with thalassemia major [4]

A

The bone marrow is under so much strain to produce extra red blood cells to compensate for the chronic anaemia that it expands enough to increase the risk of fractures and change the patient’s appearance. Abnormal features relating to bone changes include:

  • Frontal bossing (prominent forehead)
  • Enlarged maxilla (prominent cheekbones)
  • Depressed nasal bridge (flat nose)
  • Protruding upper teeth
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15
Q

What is the management of thallassemia major? [4]

A

Management involves;
- regular transfusions
- iron chelation
- splenectomy
- A bone marrow transplant can be curative.

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16
Q

Write down the genotype of Beta thalassaemia minor, intermedia and major [3]

A

Minor: (b+/b OR b0/b)
Intermedia: (b+/b+)
Major: (b+/b0 OR b0/b0)

Mutation leading to absent production (0)
Mutation leading to reduced production (+)

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17
Q

Describe when beta thal. major typically presents [1]

A

Beta thalassaemia major typically presents after 6 months of age when there is a change from fetal haemoglobin (HbF) to normal adult haemoglobin (HbA).

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18
Q

How do patients with beta thalassaemia usually present?

A

Jaundice
- unconjugated hyperbilirubinaemia and gallstones

Symptoms due to extramedullary haematopoiesis (haematopoiesis occurring outside the medulla of long bones):
- Spleen
- Liver
-

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19
Q

Describe the difference in anaemia between B.T. minor and major [2]

A

Anaemia:
- Minor: usually asymptomatic with mild microcytic anaemia with haemoglobin counts > 100 g/L.
- Major: severe transfusion-dependent anaemia. Features of pallor, dyspnoea, dizziness, lethargy. Untreated, haemoglobin may be as low as 30-40 g/L.

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20
Q

Describe the bone deformities that can occur in B.T major [4]

A

Unusual bone formation:
* Facial deformities: frontal bossing, maxilla overgrowth, prominence of upper incisors, ‘chipmunk’ facies, dental malocculsion.
* Body habitus changes: typically short limbs due to early fusion of epiphyses. Skull, pelvis, ribs and spinal changes may be seen
* Osteopaenia/osteoporosis
* Bone pain

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21
Q

Describe how beta thalassaemia interacts with Fe levels in the body [2]

A

Ineffective erythropoiesis leads to an increase in iron absorption from the gastrointestinal tract that is compounded by regular blood transfusions.

22
Q

How do you counteract iron overload in BT patients? [1]

A

Iron chelation therapy is needed from an early age to prevent complications.

23
Q

Describe three further abnormalities associated with beta thal. [3]

A
  • Pulmonary: at risk of obstructive and restrictive defects. Some patients may develop pulmonary hypertension
  • Thrombotic: beta thalassaemia intermedia and major are associated with a hypercoagulable state.
  • Leg ulcers
24
Q

Describe the diagnostic testing used to confirm the presence of beta thalassaemia [2]

A

Haemoglobin analysis:
- completed using haemoglobin electrophoresis or high-performance liquid chromatography (HPLC). Electrophoresis causes different types of haemoglobin to separate into bands. HPLC is an alternative method of determining the types of haemoglobin in blood.
- Patients with beta thalassaemia will have an increased proportion of HbA2 and HbF due to the absence of beta globin chains. Even in beta thalassaemia minor, there will be an elevation in HbA2.

Genetic testing:
- DNA testing provides a definite and precise diagnosis of beta thalassaemia. It is able to determine the type of mutation present.

Compared to alpha thal: just genetic testing

25
Q

When does screening for beta thalassaemia occur? [1]

What result would indicate B.T? [1]

A

Antenatal screening is offered to all pregnant women within the UK. It involves concurrent assessment of different haemoglobinopathies (i.e. thalassaemia and haemoglobin variants) at 10 weeks gestation.

In beta thalassaemia, the level of HbA2 is quantified. Levels of HbA2 >3.5% is suggestive of being a beta thalassaemia carrier and further analysis of the father is required to determine the risk of beta thalassaemia in the fetus.

26
Q

How does screening for A.T. work? [1]

A

Screening for alpha thalassaemia is more difficult. This is because detection of alpha thalassaemia minima (aa/a-) or alpha thalassaemia trait (a-/a-) can only be completed by DNA testing

Therefore, in pregnant mothers if the mean corpuscular haemoglobin is < 25 pg and they are from a high risk area (e.g. China, Southeast asian, etc) then testing of the biological father should be offered. If the biological father is also suspected of having alpha thalassaemia then both the mother and biological father should undergo DNA analysis

27
Q

Describe the managment of beta thalassaemia trait [1]

A

Genetic counselling + iron advice

Genetic testing may be necessary if the person is planning a family with a partner who also has the trait, or if there is a high suspicion that the partner is a silent carrier.

Patients who have beta-thalassaemia trait are generally asymptomatic and do not require transfusions. They should be advised to avoid iron supplementation for their anaemia unless they are actually iron deficient.

BMJ BP

28
Q

Describe the managment of beta-thalassaemia intermedia: non-transfusion-dependent [3]

A

1ST LINE:
- Transfusions at times of symptomatic anaemia
Patients with beta-thalassaemia intermedia do not usually require regular transfusions (non-transfusion-dependent thalassaemia). They are able to grow and develop at a nearly normal rate despite the moderate anaemia.
Occasionally, patients become severely anaemic and develop symptoms as a result. This usually occurs at times of major stress to the body, such as perioperatively, or during a serious illness or infection.

CONSIDER
- iron monitoring + chelation with desferrioxamine or deferasirox

PLUS
- genetic counselling

29
Q

Describe the managment of beta-thalassaemia intermedia: transfusion-dependent AND beta-thalassaemia major [4]

A

1ST LINE:
- Regular transfusions

PLUS
- iron monitoring + chelation with desferrioxamine or deferasirox

PLUS
- genetic counselling

CONSIDER
- Splenectomy

CONSIDER
- Assessment for stem cell transplantation

30
Q

Describe the impact of increased Fe in B.T patients [2]

How is this managed? [2]

Why such an issue? [1]

A

Iron overload is inevitable:
- Iron levels need to be monitored regularly using ferritin +/- formal iron studies and magnetic resonance imaging can be used to quantify the amount of iron deposition in organs.
- This is particularly important for hepatic and cardiac tissue.

31
Q

Which drugs are used to manage iron overload? [3]
What is their MoA? [1]

A

Typical agents include Deferasirox, Deferoxamine and Deferiprone.

These chelators bind iron and increase excretion through urine and/or faeces.

32
Q

Describe the implications of having a splenectomy [1]

A

Increases your risk of blood clots and infections

33
Q

Vaccinations agaisnt with pathogens are recommended in splenectomy patients? [4]

A

Vaccinations against S. pneumoniae, N. meningitidis, H. influenzae type b and influenza virus are strongly recommended.

34
Q

Describe the management of hyposplenism [2]

A

In summary, the management can be considered to be two-fold:

Immunisations
- S. pneumoniae, N. meningitidis, H. influenzae type b and influenza virus

Antibiotic prophylaxis recommended in patients at high risk of pneumococcal infections
- oral phenoxymethylpenicillin or macrolides
- infection risk is highest in the initial years after splenectomy, all splenectomised patients are recommended to take daily antibiotic prophylaxis for the initial few years.

35
Q

Name some pathologies that cause hyposplenism [5]

A

sickle cell anaemia (chronic damage to the spleen results in atrophy)
coeliac disease
dermatitis herpetiformis
essential thrombocythaemia
ulcerative colitis.

36
Q

What are 4 blood film findings of hyposplenism [4]

A

Blood film: features of hyposplenism include Howell-Jolly bodies, Pappenheimer bodies, target cells and irregular contracted red blood cells.

37
Q

According to NICE guidelines, which diagnostic test is recommended for confirming the diagnosis of alpha thalassemia trait?
a) Hemoglobin electrophoresis
b) Molecular genetic testing
c) Complete Blood Count (CBC)
d) Serum Ferritin

A
38
Q

Alpha thalassemia can result from the deletion of alpha-globin genes. What is the most common alpha thalassemia genotype associated with clinical manifestations?
a) αα/αα
b) –/αα
c) –/–
d) α-/α-

A

Alpha thalassemia can result from the deletion of alpha-globin genes. What is the most common alpha thalassemia genotype associated with clinical manifestations?
a) αα/αα
b) –/αα
c) –/–
d) α-/α-

39
Q

In alpha thalassemia, the Hemoglobin H (HbH) disease results from the deletion of three alpha-globin genes. What is the recommended treatment for patients with HbH disease, according to NICE?

a) Blood transfusion
b) Hydroxyurea
c) Folic Acid supplementation
d) Hematopoietic stem cell transplantation

A

c) Folic Acid supplementation

40
Q

Individuals with alpha thalassemia trait (silent carrier) typically have two affected alpha-globin genes. How does NICE recommend managing asymptomatic individuals with alpha thalassemia trait during pregnancy?

a) Iron supplementation
b) Genetic counseling
c) Folate supplementation
d) Regular blood transfusions

A

Individuals with alpha thalassemia trait (silent carrier) typically have two affected alpha-globin genes. How does NICE recommend managing asymptomatic individuals with alpha thalassemia trait during pregnancy?

a) Iron supplementation
b) Genetic counseling
c) Folate supplementation
d) Regular blood transfusions

41
Q

For couples at risk of having a child with alpha thalassemia, what is the primary method of prenatal diagnosis recommended by NICE?

a) Amniocentesis
b) Chorionic villus sampling (CVS)
c) Non-invasive prenatal testing (NIPT)
d) Ultrasound

A

b) Chorionic villus sampling (CVS)

42
Q

NICE recommends screening for alpha thalassemia in newborns. What is the primary screening test used for this purpose?

a) Hemoglobin electrophoresis
b) Complete Blood Count (CBC)
c) DNA analysis
d) Serum Ferritin

A

NICE recommends screening for alpha thalassemia in newborns. What is the primary screening test used for this purpose?

a) Hemoglobin electrophoresis
b) Complete Blood Count (CBC)
c) DNA analysis
d) Serum Ferritin

43
Q

After the diagnosis of alpha thalassemia, what is the recommended frequency of follow-up monitoring for individuals with alpha thalassemia trait, according to NICE?

a) Every 6 months
b) Annually
c) Biennially
d) Only as needed based on symptoms

A

After the diagnosis of alpha thalassemia, what is the recommended frequency of follow-up monitoring for individuals with alpha thalassemia trait, according to NICE?

a) Every 6 months
b) Annually
c) Biennially
d) Only as needed based on symptoms

44
Q

According to NICE guidelines, which diagnostic test is recommended for confirming the diagnosis of beta thalassemia major?
a) Complete Blood Count (CBC)
b) Hemoglobin electrophoresis
c) Serum Ferritin
d) Molecular genetic testing

A

d) Molecular genetic testing

45
Q

In beta thalassemia major, NICE recommends regular blood transfusions to maintain hemoglobin levels. What is the target pre-transfusion hemoglobin level, according to NICE?
a) 8-9 g/dL
b) 9-10 g/dL
c) 10-11 g/dL
d) 11-12 g/dL

A

In beta thalassemia major, NICE recommends regular blood transfusions to maintain hemoglobin levels. What is the target pre-transfusion hemoglobin level, according to NICE?
a) 8-9 g/dL
b) 9-10 g/dL
c) 10-11 g/dL
d) 11-12 g/dL

46
Q

Individuals with beta thalassemia major are at risk of iron overload due to frequent transfusions. How often does NICE recommend monitoring serum ferritin levels for these patients?
a) Every 3 months
b) Every 6 months
c) Annually
d) Biennially

A

Individuals with beta thalassemia major are at risk of iron overload due to frequent transfusions. How often does NICE recommend monitoring serum ferritin levels for these patients?
a) Every 3 months
b) Every 6 months
c) Annually
d) Biennially

47
Q

To manage iron overload in beta thalassemia major, NICE recommends chelation therapy. Which chelator is commonly used in this setting?
a) Deferoxamine
b) Deferiprone
c) Desferrioxamine
d) Deferasirox

A

To manage iron overload in beta thalassemia major, NICE recommends chelation therapy. Which chelator is commonly used in this setting?
a) Deferoxamine
b) Deferiprone
c) Desferrioxamine
d) Deferasirox

48
Q

NICE recommends folate supplementation in beta thalassemia major. What is the purpose of folate supplementation in these patients?
a) Stimulate erythropoiesis
b) Prevent neural tube defects
c) Enhance iron chelation
d) Reduce oxidative stress

A

NICE recommends folate supplementation in beta thalassemia major. What is the purpose of folate supplementation in these patients?
a) Stimulate erythropoiesis
b) Prevent neural tube defects
c) Enhance iron chelation
d) Reduce oxidative stress

49
Q

In beta thalassemia major, allogeneic bone marrow transplantation is considered a curative option. What is a key requirement for a successful bone marrow transplant?
a) Age over 50 years
b) HLA-matched sibling donor
c) Presence of iron overload
d) Chronic liver disease

A

In beta thalassemia major, allogeneic bone marrow transplantation is considered a curative option. What is a key requirement for a successful bone marrow transplant?
a) Age over 50 years
b) HLA-matched sibling donor
c) Presence of iron overload
d) Chronic liver disease

50
Q

NICE suggests the use of hydroxyurea in beta thalassemia intermedia to reduce transfusion requirements. What is the mechanism of action of hydroxyurea in this context?
a) Stimulation of fetal hemoglobin
b) Inhibition of iron absorption
c) Prevention of bone marrow suppression
d) Induction of erythropoiesis

A

NICE suggests the use of hydroxyurea in beta thalassemia intermedia to reduce transfusion requirements. What is the mechanism of action of hydroxyurea in this context?
a) Stimulation of fetal hemoglobin
b) Inhibition of iron absorption
c) Prevention of bone marrow suppression
d) Induction of erythropoiesis

51
Q

Beta thalassemia major can lead to complications such as endocrine dysfunction. Which endocrine complication is commonly associated with beta thalassemia major, according to NICE?
a) Thyroid dysfunction
b) Diabetes mellitus
c) Growth hormone deficiency
d) Adrenal insufficiency

A

Beta thalassemia major can lead to complications such as endocrine dysfunction. Which endocrine complication is commonly associated with beta thalassemia major, according to NICE?
a) Thyroid dysfunction
b) Diabetes mellitus
c) Growth hormone deficiency
d) Adrenal insufficiency

52
Q

Beta thalassemia major can lead to cardiac complications. How often does NICE recommend cardiac monitoring, including echocardiography, for these patients?

a) Every 2 years
b) Every 5 years
c) Annually
d) Only when symptoms arise

A

Beta thalassemia major can lead to cardiac complications. How often does NICE recommend cardiac monitoring, including echocardiography, for these patients?
a) Every 2 years
b) Every 5 years
c) Annually
d) Only when symptoms arise