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Cardiorespiratory CC > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

Haemoglobin

A

Four globin subunit proteins or ‘chains’

Each with iron-containing haem prosthetic group attached

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2
Q

Haemoglobin subunits

A

Each have slightly differing aa sequences
–> precise folding of each subunit + way the 4 fit together is critical in determining ability of molecules to carry + release O2

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3
Q

Adult Haemoglobin

A

2 alpha

2 beta

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4
Q

Alpha subunit

A

2 genes for subunit on chromosome 16

Therefore overall 4 genes for alpha subunit, 2 maternal + 2 paternal

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5
Q

Beta subunit

A

Five genes for subunit on chromosome 11

  • -> epsilon, gamma A, gamma G, delta and beta
  • -> each produce slightly different forms of beta globin
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6
Q

Different haemoglobins

A

Can be produced from different gene combinations from chromosomes 11 + 16

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7
Q

First form Haemoglobin

A

In Embryonic Yolk Sac (up to about 6wks)
Zeta 2 Epsilon 2 a.k.a Hb Gower-1
V high O2 affinity

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8
Q

After 6 weeks Haemoglobin

A

Haemoglobin F
2 alpha 2 gamma
Higher affinity than maternal haemoglobin, so O2 passed from maternal to foetal Hb

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9
Q

3-6 months after birth

A 
HbA replaces foetal haemoglobin
Some HbA2 (alpha 2 gamma 2) also present in adult
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10
Q

Thalassaemia

A

Genetic defect resulting in inadequate quantities of one or other of subunits that make up haemoglobin
Can be alpha or beta

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11
Q

Alpha thalassaemia

A

One or more of alpha genes on chromosome 16 deleted or faulty

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12
Q

Beta thalassaemia

A

Point mutation on chromosome 11

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13
Q

Thalassaemia genetic defect

A

Mutation in non-coding introns of gene –> inefficient RNA splicing to produce mRNA –> decreased mRNA production
Partial or total deletion of globin gene
Mutation in promoter –> decreased expression
Mutation in termination site –> production of longer, unstable mRNA
Nonsense mutation

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14
Q

Alpha thalassaemia epidemiology

A

Manifests immediately at birth

Severity depends on number of gene alleles defective or missing

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15
Q

Alpha thalassaemia- 1 alpha gene defective

A 
Alpha thalassaemia minima
Minimal effect on haemoglobin synthesis
Individuals called silent carriers
May have slightly reduced MCV and MCH
3 alpha globin genes enough to permit normal Hb production 
No clinical symptoms
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16
Q

Alpha thalassaemia- 2 alpha genes defective

A

Alpha thalassaemia minor
2 alpha globin genes permit normal RBC production, but mild microcytic hypochromic anaemia
Can be mistaken for iron deficiency anaemia –> inappropriately treated with iron

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17
Q

Alpha thalassaemia- 3 alpha genes defective

A

Haemoglobin H disease
2 unstable haemoglobins in blood
–> Haemoglobin Barts (4 gamma) and Haemoglobin H (4 beta)
Both unstable
Both have higher O2 affinity than Hb –> poor release of O2 in tissues
Microcytic hypochromic anaemia

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18
Q

Alpha thalassaemia- 4 alpha genes defective

A

Foetus can’t survive outside uterus
May not survive gestation
Most infants stillborm with hydrops fetalis
Oedematous
Little circulating Hb
–> all tetrameric gamma chains (Haemoglobin Barts)

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19
Q

Beta thalassaemia

A

Mutations in Haemoglobin beta gene on Chromosome 11
Autosomal recessive
Heterozygous, homozygous or intermedia

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20
Q

Beta thalassaemia- heterozygous

A 
Thalassaemia trait
Beta thalassaemia minor
Decreased MCV, MCH
Normal HbA and HbF
Increased HbA2
21
Q

Beta thalassaemia- homozygous

A

Beta thalassaemia major
No beta chains
Body’s inability to construct beta-globin leads to underproduction of Haemoglobin A
–> microcytic anaemia

22
Q

Beta thalassaemia- intermedia

A

Both beta globin genes mutated

But still able to make some beta chains

23
Q

Beta thalassaemia manifestation

A

When switch from gamma to B chain synthesis occurs several months after birth
May be a compensatory increase in g and d chain synthesis –> increased levels of Hb F and A2

24
Q

Pathological effects B thalassaemia

A

Excess alpha globins produced in developing erythroblasts in marrow
–> alpha tetramers unstable + precipitate on erythrocyte membrane
Causes intra-medullary destruction of developing erythroblasts, erythroid hyperplasia + ineffective erythropoiesis
–> SEVERE HYPOCHROMIC MICROCYTIC ANAEMIA

25
Q

Untreated B Thalassaemia Minor

A 
Hypochromic Microcytic Anaemia
Bone marrow expansion, Splenomegaly
Bone deformity, extramedullary erythropoietic masses
Failure to thrive 6 months
HF and death age 3-4
26
Q

Beta thalassaemia facial bone abnormalities

A

Bossing of skull
Hypertrophy of maxilla- exposed upper teeth
Depression of nasal bridge
Periorbital puffiness

27
Q

Thalassaemia Major treatment

A

Regular transfusions
Iron chelation therapy
Splenectomy
Allogeneic BM transplant

28
Q

Thalassaemia vs Iron deficiency

A

In Thalassaemia, although red cells are microcytic, serum iron and ferritin are normal

29
Q

Iron overload

A

Excess haemolysis –> free iron released –> free iron in blood
If hydrogen peroxide present, Fenton reaction can occur
–> hydroxyl radicals produces –> oxidise and damage all biological tissues

30
Q

Fenton reaction

A

Hydroxyl radicals oxidise + damage all biological tissues

Cirrhosis, diabetes, glandular dysfunction (GH deficiency)

31
Q

Iron Chelating compounds

A

Bind to free iron

Prevent Fenton reaction

32
Q

Desferoxamine

‘Desferal’

A 
Iron Chelation therapy
8-12 hour s.c. infusion
5-7 days/week
Chelation enhanced with ascorbate
Toxicity with higher doses - diarrhoea, vom, fever
33
Q

Deferiprone

Exjade

A

Oral iron chelator
75-100mg/kg/day
Agranulocytosis/neutropenia may occur
Not suited for pregnancy

34
Q

Deferasirox

Exjade

A

Once daily iron chelator
GI bleeding
Kidney or liver failure

35
Q

Sickle cell

A

Mutant form of one of beta haemoglobin subunits
Red cells sickles
Obstruct capillaries + restrict blood flow to organ
–> ischemia, pain + organ damage

36
Q

Sickle cell signs

A

Haemolytic anaemia- Hb 6-8g/dL
Microvascular occlusion- rigid sickle cells adhere to endothelium, interact with WBC + vessel wall, cause NO depletion
Large vessel wall damage

37
Q

Sickle cell Hb

A

Glutamic acid –> Valine (GAG-GTG)
Codon 6 of beta globin chain
Beta S produced
Produced abnormal Hb S- (2 alpha 2 BetaS)

38
Q

HbS

A

May precipitate or crystallise

Distorts RBCs–> fragile + easily destroyed

39
Q

Sickled RBCs

A

Decreased survival time
Occlude capillaries
Lead to ischaemia + infarction of organs downstream of blockage

40
Q

Clinical consequence Sickle Cell

A

Anaemia
Increased susceptibility to infection
Vaso-occlusive crises
Chronic tissue damage

41
Q

SCD management

A 
Infection prophylaxis
Analgesics for crises
Education
Transfusions
Hydroxyurea (increases HbF, reduced painful crises)
Bone marrow transplant
42
Q

Carrier detection screening

A

Simple blood analysis

43
Q

Newborn screening

A

Cord blood

Heel-prick sample

44
Q

HbC

A

Mutation where abnormal beta subunit
Reduced plasticity + flexibility of erythrocytes
Red cell destruction

45
Q

HbC homozygous

A

Mild haemolytic anaemia

46
Q

HbC heterozygous

A

No anaemia

47
Q

HbE

A

Single point mutation in Beta chain
Get from both parents
Increases after 3-6 months –> mild beta thalassaemia

48
Q

G6PD deficiency

A

X linked recessive
Causes haemolysis + jaundice
Mediterranean
Triggers e.g. Fava beans, oxidative drugs like aspirin or infection

Cardiorespiratory CC (34 decks)

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