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Haematology Sem 1 > 3. Haemoglobinopathies + thalasaemias > Flashcards

3. Haemoglobinopathies + thalasaemias Flashcards

1
Q

How many types does normal adult blood contain?

A

3 types: HbA, HbA^2, HbF

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2
Q

What gene is the alpha globin gene carried on?

A

Carried on chromosome 16

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3
Q

Explain the structure of the chromosome that carries the alpha glibin gene

A

Chromosome 16 carries two copies of the alpha globin gene. The alpha chain is duplicated on each globin so there are 4 alpha globin genes in total: two one one chromosome and two on its pair.

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4
Q

What types of globin chains are on HbA?

A

a^2 + b^2

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5
Q

What type of globin chains are on HbA^2?

A

a^2 + o^2

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6
Q

What type of globin chains are on HbF?

A

a^2 + y^2

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7
Q

What chromosome are globin chains B, O and Y found on?

A

Chromosome 11

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8
Q

What type of haemoglobin if foetal haemoglobin?

A

HbF (a2y2)

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9
Q

What haemoglobin type does foetal haemoglobin change into?

A

HbA

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10
Q

How many months post-birth does foetal haemoglobin change?

A

3-6 months

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11
Q

What chains are substituted during the change from F to A haemoglobin?

A

Y2 to B2 but there is residual HbF left

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12
Q

When what haemoglobinopathy mean?

A

Its the damage or abnormality to the structure of haemoglobin on red blood cells

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13
Q

What are the two types of haemoglobinopathy?

A

Structural abnormalities which cause functionally abnormal haemoglobin (qualitive)
Thalassaemia abnormalities: genetic defects causing mutation of the globin gene which either reduces or destroys the synthesis of haemoglobin

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14
Q

What are structural abnormalities of haemoglobin

A

Synthesis of structurally abnormal haemoglobin. Most are rare and clinically insignificant. HbA,C,D,E. Most are point mutations that alter the function of amino acid used in haemoglobin sythesis

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15
Q

What is the most frequent structural variant?

A

Sickle cell

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16
Q

What is sickle cell?

A

Genetic mutation which changes the shape of the red blood cell from biconcave disc to sickle shaped.

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17
Q

What kind of haemoglobin is carried on sickle cell RBC?

A

HbS - 2a and 2b chains

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18
Q

What is the mutation of the haemoglobin chains that is expressed in sickle cell RBCs?

A

Glutamic acid replaced by valine (amino-acid substitution) on one or both B chains on the Hb. Functionally abnormal HbS formed

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19
Q

What is HbS’ affinity for oxygen

A

50 times lower than HbB and therefore 50 times less soluble

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20
Q

What effect does the deoxygenated HbS have on the cell?

A

Deoxygenated HbS polymerises into long fibres, giving the long sickle shape. When oxygenated, the HbS is fully soluble but returns to sickle shape when deoxygenated. Tends to be less oxygenated due to shape and lower affintity for oxygen and therefore is more likely to be in polymerised fibre form (sickle shaped) than fully oxygenated bi-concave

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21
Q

Can sickle cell be reversed?

A

Oxygenating and oxygenating can permentantly reverse sickle cells after many repeated cycles

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22
Q

What conditions can predispose a patient to sickling of the cell

A

hypoxia (lack of oxygen) blood acidosis and increased body temperature

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23
Q

What are the two types of inheritance in terms of sickle cell?

A

Homozygous and heterozygous

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24
Q

What is the genotype is homozygous

A

HbS+ HbS. Afffected with sickle cell

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25
Q

What genotype is heterozygous

A

HbS + HbA. Carrier of sickle cell

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26
Q

What is a sickle cell trait?

A

Carrier of sickle cell allele but not actually being affected by it

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27
Q

During heterozygous inheritance of sickle cell, what would you expect to see in the lab?

A

Normal Hb levels, normal shaped red blood cells in the film.

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28
Q

What symptoms do patients with heterozygous sickling display?

A

Usual asymptotic. Can be haematouria (blood in urine) or renal papillary neucrosis

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29
Q

How much of the haemoglobin molecule does HbS take up during heterozygous sickling?

A

25%-45% Hb. Rest is HbA

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30
Q

When do patients need to take care if they have heterozygous sickling?

A

When exposed to <40% oxygen concentration due to altitude, pregnancy or anaesthesia

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31
Q

What is homozygous sickling?

A

Only HbS being produced. Sickle cell anaemia

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32
Q

What kind of anaemia is sickle cell anaemia

A

severe haemolytic anaemia (breakdown of haemoglobin which body cannot cope with)

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33
Q

What is the symptoms of sickle cell anaemia?

A

Variable but can be janudice or crises (severe pain due to sickle cell blocking vessel due to shape)

34
Q

What is the life expectancy of someone with sickle cell anamia

A

Can be normal life but can also be shortened depending on progression of complications

35
Q

What are the clinical features of someone with sickle cell anaemia?

A

Ulcers of lower leg, dactylitis (sausage fingers) splenomegaly, liver damage, galstones, hypertension, retinopathy kidney infection and sever crises

36
Q

What are the lab findings of someone with sickle cell anaemia

A

60-90 Hb g/L. Sickle cell RBCs. There will be more target cells for Fe and more howell-jolly bodis (DNA reminents). Screening for sickle cell will come out positive. There will be raised HbF.

37
Q

What testing method can be used to deduce HbS from HbA

A

elecrophoresis

38
Q

What is the most common type of crises associated with sickle cell anaemia?

A

Vaso-occlusive crises

39
Q

What is vaso-occlusive crisis?

A

When sickled RBCs block a vessel so tissues are unable to be oxygenised

40
Q

What symptoms occur during vaso-occlusive crises?

A

Severe pain

41
Q

What is vaso-occlusive crisis precipitated by?

A

dehydration, infection and deoxygenation (so tiredness)

42
Q

Where is vaso-occlusive crisis more likely to happen?

A

In the brain, spleen, bone marrow, lungs

43
Q

What is sequestration crisis?

A

Sickling within organs and pooling of blood

44
Q

What causes sequestration crisis?

A

Worsening of anaemia

45
Q

What complication can occur from sequestrian crisis?

A

Sickle chest syndrome (after puberty) or splenic sequestration (infants). Can also be hepatic sequestrian crisis and girdle sequestrian crisis

46
Q

What is aplastic crisis?

A

Crisis that occurs due to infection (parvo virus) or folic acid deficiency.

47
Q

What characterises aplastic crisis?

A

Fall in reticulucytes (treated by transfusion) or sudden drop in Hb

48
Q

What is haemolytic crisis?

A

Rise in Hb breakdown. Decrease in Hb but rise in reticulocytes. Severe pain

49
Q

How is sickle cell screening carried out?

A

Haemoglobin electrophoresis. If single moving band reaches HbS marker alone (so no HbA) then homozygous inheritance. If both HbA and HbS reach marker then heterozygous inheritance

50
Q

What is the treatment for sickle cell? (during crisis, pregnancy etc)

A

Prophalytic: prevention of worsening.
Good nutrition (for Fe for residual target cells and for anaemia treatment. Folic acid). Vacination given and antibiotics to reduce infection rate.
During crisis: rest, rehydration and warmth.
Specialist pregnancy support for monitoring of HbS levels.
Transfusion support - transplants. Transplants if organ damage (kidney for example)
Research drugs coming out - gene therapy and new drugs

51
Q

What is the prognosis of someone with homozygous sickling disease?

A

High mortality rate - 50 years. Increasing with vacination programs and awareness of acute splenic sequestrian syndrome

52
Q

What are the 4 types of crises associated with sickle cell?

A

Aplastic (infection + folic acid), sequestrian (blood pooling in organs) vaso occlusive (blockaging of vessels) and haemolytic (destruction of RBC)

53
Q

What services can be offered to treat patients with sickle cell?

A

Pregnancy and neonatal screening and support: ensures early treatment (decreases mortality rate)
Screening services - screening if have family history or come from a high prevalence area.
Testing partners of affected mothers.
Genetic councilling for high risk parents.
Antenatal screening for better management (folic acid supplementation),
testing of newborns so vacinations and antibiotics can be started early.

54
Q

What geographical locations have a greater prevelance of HbS

A

South mediteranean, Afrocarribean, tropical africa, central india

55
Q

What is thalassemia?

A

Genetic condition resulting in decrease production (or complete omission of) haemoglobin chain productions. (A or B chains)

56
Q

What are the three subcategories used when classifying thalassemia

A

the globin chain affected (is it a or b or both?)
the extent of affected globin synthesis (total reduction or partial reduction)
the genotype of the affected chain (is it homozygous or heterozygous)

57
Q

What is the prevelance of thalassemia?

A

Present in places when malaria is endemic. Most common single-gene disorder in the world.

58
Q

What is Alpha thalassaemia syndrome?

A

Where there are up to 4 A-chains expressed on a haemoglobin. (2 pairs of 2)

59
Q

What chromosone does a thalassaemia occur on?

A

chromosone 16

60
Q

What kind of mutations are common in a-thalassemia

A

deletion of one or both pairs of a globin genes. Point mutations are rare.

61
Q

what is the clinical severity of thalassaemia?

A

Varies - dependant on how many inactive or missing genes

62
Q

What is a silent thalassaemia carrier? Genotype? Symptoms? How is it tested?

A

a+ heterozygote (a-/aa)
deletion of single globin gene
aysymptotic no haematological abnormality
defined with complete and reliable DNA analysis

63
Q

What is is an a thalassemia trait patient? genotype? symptoms?

A

patient with 2 missing globin genes.
a-/a- or aa/– (a+ homozygote or a0 heterozygote)
clinically indistinguishable. usually no significant symptoms but can be mild microcytic, hyper chromatic anaemia (pale red cells).

64
Q

What would you see in the labs with a+homozygote or a0 heterozygote? How would you distingush them?

A

Normal haemoglobin electrophoresis. Identical lab profiles.

Differentiate using DNA analysis. Mean calculated haemoglobin lower in a0 than a+

65
Q

What is haemoglobin H disease? genotype? symptoms? treatment?

A 
deletion of 3 globin genes
a0 a+ double heterozygote (a-/--)  
moderate to severe anaemia (microcytic and hyperchromic) and heptosplenamegaly?
No transfusion required . Hb 80g/l.
Adult blood contains 5-35% HbH (b4)
66
Q

What would the blood film of an HbH patient show?

A

microlytic and hyperchromic RBC (small, pale blood cells with large center of pallor)
abnormal shaped blood cells (poikilocytes)
target cells presents (due to lack of Fe binding to RBC to make ferritin)
polychromasia (high levels of immature red blood cells)
main cause of haemolytic anaemia

67
Q

What is haemoglobin barts hydrops foetails? What does it form? Hb levels? Symptoms + complications? Mortality?

A

Most severe form of thalassaemia: deletion of all four globin genes (–/–) - a0 homozygote.
No normal function of haemoglobin
Forms functionally useless Hb Barts (Y4) and HBH (B4)
Hb concentrations at delivery: 60 Hb g/l
Severe anaemia: complications: oedema, congenative heart failure, severe hepatosplenomegaly
Incompatible with life - termination at pregnancy. Genetic counciling recommended

68
Q

What is B thalassaemia?

A

Point mutation in the B globin chains

69
Q

What are the three subcatergories of thalassaemia

A

B thalassaemia trait, B thalassaemia intermedia, B thalassaemia major

70
Q

What is B thassaemia trait? Genotype? Symptoms?

A

Mildest form of B thalassaemia.
One abnormal B globin gene - heterozygous
No significant signs of disease

71
Q

What are the lab findings of B thalassaemia trait?

A

Mild microcytic hypochromatic anaemia
Increased target cells (die to no Fe binding)
Raised red cell count
Raised HbF and HbA2
Important to differenciate from iron deficiency

72
Q

What is B thalassaemia major? Symptoms?

A

Most severe type. 2 abnormal B globin genes.
Severe anaemia
Major hepatospenamegaly
Failure to thrive
Skeletal deformities - erythroid hyperplasia (enlargement of bone volume)

73
Q

What are the lab findings of B thalassaemia major?

A 
Microcytic and hyperchromic anaemia.
Hyperchromasia (increased DNA content)
Numerous target cells
Nucleated red cells (immature red cells)
Microspherocytes
raised RBC
74
Q

What would bone marrow lab results show in B thalassaemia major?

A

extreme erthyroid hyperplasia
innefective erythropoeisis : clumping (aggregation) of excess a chains promotes intramedullary death of developing erythroblast which reduces life span

75
Q

What would Haemaglobin erythropoeisis lab results show?

A

98% increase in HbF
No HbA
Could also do electrophoresis and DNA anaylsis

76
Q

What is the treatment for B thalassaemia major? Complications of treatment

A 
Regular blood transfusion to keep blood at 100-120g/L. This will suppress erthyropoeisis which prevents skeletal changes (marrow hyperplasia suppressed). Also means there will be less reiculucytes and nucleated RBC in circulation.
Antibiotic therapy
Vitamin C
Splenectomy
Folic acid consumption
Bone marrow transplant

Complications: lifelong transfusions leads to iron build up and toxicity - particularly to liver and heart. Chelation therapy removes heavy metals from body.

77
Q

What is the prognosis for B thalassaemia major sufferers with and without treatment?

A

Without treatment: 5 years
With treatment: with chilation- 50+ years. Without chilation 20-30 years.
Bone marrow transplant is more successful for under 16 year olds who get marrow from relatives/siblings

78
Q

What is B thalassaemia intermedia?

A

Variety of mutations to the B globin genes - not always severe. Encompasses all B thalassamias that are symptomatic but do not require regular blood transfusions to keep Hb above 70 g/l

79
Q

How does B thalassaemia intermedia arise?

A

Milder mutations than B thalassaemia major. Co-inhertiance of gene that increases expression of Y globin synthesis (as they are on same chromosone). Co-inheritance with A-thalassaemia

80
Q

What are the clinical findings of B thalassamia intermedia?

A

Similar to more severe types of thalassamia
No transfusion support necessary although there is still bone changes from erythroctye hyperplasia. Bones break more easily and mild spenomegaly from anaemia.

81
Q

What is the main cause of death in B thalassaemia intermedia?

A

Iron toxicity - although there are no regular transfusion the immature blood cell formation (they still have nucleus’s in the blood film) contributes to the excess absorption or iron.

Haematology Sem 1 (8 decks)

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