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TAS Haematology > Physiology of Haematopoiesis ✅ > Flashcards

Physiology of Haematopoiesis ✅ Flashcards

1
Q

What is haematopoiesis?

A

The process through which all types of mature blood cell are produced

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2
Q

What are haematopoietic stem cells (HSCs)?

A

Multipotent cells characterised by their ability to ‘self-renew’ (proliferate) and mature into fully differentiated cells of any of the haematopoietic lineages

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3
Q

What is the importance of HSCs?

A

They sustain blood cell production throughout life

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4
Q

What are the principle haematopoietic lineages?

A
  • Erythroid/megakaryocytic
  • Granulocyte/macrophage
  • Lymphoid
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5
Q

What does the erythroid/megakaryocytic lineage give rise to?

A
  • RBCs

- Platelets

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6
Q

What does the granulocyte/macrophage lineage give rise to?

A

Granulocytes and monocytes

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7
Q

What does the lymphoid lineage give rise to?

A
  • B cells
  • T cells
  • NK cells
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8
Q

What can HSCs be characterised by?

A

Proteins expressed on the cell membrane

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9
Q

What can the cell markers on the membrane of HSCs be utilised for clinically?

A

To purify HSC for clinical applications, e.g. haematopoietic stem cell transplant

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10
Q

What are the HSCs and their progeny controlled by?

A

A network of interactions with haematopoietic growth factors and cellular components of the haematopoietic micro-environment that maintain balanced blood cell production

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11
Q

When does primitive haematopoiesis begin?

A

In the first few weeks of embryonic life

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12
Q

Where does primitive haematopoiesis begin?

A

In the yolk sac

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13
Q

What does primitive haematopoiesis give rise to?

A

Mainly RBCs

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14
Q

What is primitive haematopoiesis replaced by?

A

Definitive hematopoiesis

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15
Q

When is primitive haematopoiesis replaced by definitive haematopoiesis?

A

5-6 weeks gestation

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16
Q

What does definitive haematopoiesis produce?

A

Has the capacity to produce all blood cell cycles

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17
Q

Where do definitive hematopoietic stem cells develop?

A

In the aorta-gonad-mesonephros (AGM) region of the dorsal aorta

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18
Q

Where do HSCs migrate after developing in the AGM?

A

To the fetal liver and spleen

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19
Q

When do HSCs migrate from the AGM region to the fetla liver and spleen?

A

6-7 weeks gestation

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20
Q

What is the primary site of haematopoiesis from 6-7 weeks gestation?

A

The liver

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21
Q

What happens to the site of haematopoiesis in the third trimester?

A

It progressively increases in the bone marrow

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22
Q

What is the site of haematopoiesis after birth?

A

Bone marrow

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23
Q

Where in the bone marrow does haematopoiesis occur?

A

Initially it occurs in all areas of the bone marrow, but becomes restricted to axial skeleton and proximal ends of long bones later in childhood

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24
Q

What are RBCs?

A

Specialised cells that mainly function to deliver oxygen to the tissues and remove carbon dioxide

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25
Q

What shape are RBCs?

A

Biconcave

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26
Q

What cellular structure do RBCs lack?

A

Nucleus

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27
Q

What do RBCs have a lot of?

A

The oxygen-carrying protein haemoglobin

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28
Q

What does each molecule of haemoglobin consist of?

A

4 globin chains and a central iron containing haem group

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29
Q

What happens to the composition of Hb during fetal development?

A

It changes in an ordered sequence

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30
Q

What are the first globin chains produced?

A

Epsilon and zeta

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31
Q

What follows the production of epsilon and zeta globin chains?

A

Almost immediately followed by gamma

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32
Q

What do the epsilon, zeta, and gamma globin chains give rise to?

A

2 types of fetal haemaglobin - Hb Gower and Hb Portland

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33
Q

What is Hb Gower made up of?

A

Epsilon and zeta globin

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34
Q

What is Hb Portland made up of?

A

Epsilon and gamma globin

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35
Q

What follows the production of gamma globin?

A

Alpha globin

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36
Q

What does alpha globin allow the production of?

A

HbF

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37
Q

What is HbF made up of?

A

Alpha and gamma globin

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38
Q

When does HbF production start?

A

3-4 weeks of fetal life

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39
Q

What is the predominant fetal Hb?

A

HbF

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40
Q

What is adult Hb (HbA) made up of?

A

Alpha and beta globin

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41
Q

When do the levels of HbA remain low until?

A

30-32 weeks gestation

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42
Q

What are the levels of adult Hb before 30-32 weeks gestation?

A

10-15%

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43
Q

What happens to haemoglobin production after 30-32 weeks gestation?

A

The rate of HbA production increases at the same time as HbF production falls

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44
Q

What is the average composition of haemoglobin at birth for most term babies?

A
  • 70-80% HbF
  • 25-30% HbA
  • Sometimes small levels of HbA2 and sometimes traces of Hb Barts (4 gamma chains)
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45
Q

What happens to HbF after birth?

A

It falls rapidly

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46
Q

What level should HbF be by 12 months?

A

2%

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47
Q

What happens to HbF in the first 15 days after birth in term babies?

A

There is little change

48
Q

How long after birth does HbF remain at the same level in pre-term babies?

A

Up to 6 weeks

49
Q

What is the result of it taking up to 6 weeks for HbF to fall in preterm babies?

A

Can make diagnosis of some haemoglobinopathies difficult in some neonates

50
Q

What is the major function of Hb?

A

Deliver oxygen to tissues

51
Q

What does the binding and release of oxygen cause in Hb?

A

Small changes to configuration of globin chains in the Hb molecule

52
Q

What is the result of small changes to configuration of globin chains in the Hb molecule?

A

It alters the affinity of Hb for oxygen

53
Q

What happens to the Hb molecule when oxygen is unloaded?

A

It opens up, allow 2,3-DPG to enter

54
Q

What is the result of 2,3-DPG entering when oxygen is unloaded from Hb?

A

It reduces oxygen affinity and ensures that the Hb molecule does not take up oxygen from the tissues

55
Q

What is the result of changes in affinity of haemoglobin to the oxygen dissociation curve?

A

It gives it it’s sigmoid shape

56
Q

What must red cells be able to do to function effectively?

A

Generate energy in the form of ATP, and reduce molecules to prevent oxidative damage

57
Q

What does the Embden-Meyerhof pathway do?

A

Metabolises glucose to lactate, producing 2 molecules of ATP, NADH, and 2,3-DPG

58
Q

What is the ATP used for in RBCs?

A

Maintain red cell shape and osmotic gradient

59
Q

What is NADH used for?

A

Reduce iron to active ferrous form

60
Q

What is an alternative pathway glycolytic pathway?

A

The pentose phosphate pathway

61
Q

What does the pentose phosphate pathway produce?

A

NADPH

62
Q

What is NADPH important for?

A

Source of reducing power that maintains iron in active form

63
Q

What enzyme is key in the pentose phosphate pathway?

A

G6PD

64
Q

What does G6PD deficiency result in?

A

Marked susceptibility to oxidative stress

65
Q

What is the average RBC lifespan in older children?

A

120 days

66
Q

What is the average RBC lifespan in neonates?

A

About 90 days

67
Q

What is the importance of the specialist RBC membrane?

A

Prevents damage and maximises flexibility

68
Q

What does the RBC membrane consist of?

A

A complex lipid bilayer containing a number of key scaffolding proteins

69
Q

What is the most abundant protein in the RBC membrane?

A

Spectrin

70
Q

What is the of spectrin in the RBC membrane?

A

It forms tetramers and attaches to the membrane via the ankyrin protein

71
Q

What can abnormalities of the proteins in the RBC membrane lead to?

A

Membrane disorders such as hereditary spherocytosis and hereditary elliptocytosis

72
Q

What dietary component is vital for erythropoiesis?

A

Iron

73
Q

How common is iron deficiency anaemia, compared to other types?

A

It is the most common cause of anaemia worldwide

74
Q

What are the broad causes of iron deficiency anaemia?

A
  • Inadequate intake

- Chronic blood loss

75
Q

What foods are rich in iron?

A
  • Meat (especially liver)
  • Nuts
  • Pulses
76
Q

Where does iron absorption occur?

A

In the duodenum

77
Q

What cells absorb dietary iron?

A

Enterocytes

78
Q

In what form is dietary iron absorbed?

A

Either in the Fe2+ form, or as haem

79
Q

How is iron in the Fe2+ iron absorbed by enterocytes?

A

Via the divalent metal transporter

80
Q

What happens once dietary iron is absorbed by enterocytes?

A

The iron transporter protein, ferroportin, transports iron across the basolateral membrane of the enterocyte into the bloodstream

81
Q

What happens to dietary iron absorbed into the bloodstream?

A

Iron is bound to transferrin and transported to the tissues

82
Q

How much can each molecule of transferrin bind?

A

Two molecules of iron

83
Q

What cells can iron be delivered to?

A

Those expressing transferrin receptors, including developing red cells

84
Q

What receptors are important in the regulation of body iron?

A
  • DMT1

- Transferrin receptor 1 (TfR1)

85
Q

What controls the synthesis of DMT1 and TfR1?

A

Iron regulatory proteins

86
Q

What do iron regulatory proteins (IRP) bind to?

A

Iron response elements (IREs) on genes

87
Q

What happens to IRPs when iron levels are accurate?

A

They do not bind

88
Q

What is the effect of IRPs not binding to IREs?

A

It allows production of ferritin, and therefore storage of iron

89
Q

What happens to IRPs when iron is deficient?

A

They bind to IREs

90
Q

What is the effect of IRPs binding to IREs?

A

It blocks the production of ferritin and enhances the synthesis of DMT1 and TfR1, which encourages increased iron absorption in the gut and uptake by the tissues

91
Q

What do mutations in DMT1 cause?

A

Congenital anaemia

92
Q

What are mutations in the ferroportin gene associated with?

A

Congenital hyperferritinaemia and iron overload

93
Q

In what forms is iron present in the body?

A
  • Haemoglobin
  • Ferritin
  • Haemosiderin
  • Myoglobin
  • Many important enzymes
94
Q

In what form is the greatest amount of iron in the body?

A

Haemoglobin

95
Q

What happens to haemoglobin once the cells reach the end of their lives?

A

Recycled

96
Q

What is ferritin?

A

A water-soluble molecule found in many tissues

97
Q

What is the clinical use of serum ferritin levels?

A

It gives a fairly accurate estimation of total body iron levels, and is a useful investigation when iron deficiency is suspected

98
Q

What is required for serum ferritin levels to give an accurate estimation of total body iron levels?

A

Absence of inflammation

99
Q

Is haemosiderin soluble?

A

No

100
Q

Where is myoglobin found?

A

In muscles

101
Q

What % of dietary iron is usually absorbed?

A

5-10%

102
Q

What can happen to dietary iron absorption in times of increased need, e.g. iron deficiency?

A

Can be increase to up to 30%

103
Q

At what level is iron availability regulated?

A

Cellular and systemic levels

104
Q

What is the key to regulation of iron levels?

A

Hepcidin

105
Q

What is hepcidin?

A

A small peptide hormone produced by the liver

106
Q

What is the role of hepcidin?

A

It plays a major role in controlling iron flux to plasma from enterocytes and macrophages

107
Q

How does hepcidin control iron flux to plasma from enterocytes and macrophages?

A

By degradation of the cellular iron exporter ferroportin

108
Q

What happens to hepcidin levels in iron deficiency?

A

They fall

109
Q

What happens when there are mutations in the genes which encode proteins of the hepcidin-activating pathway?

A

Iron overload

110
Q

What is hepcidin insufficiency and increased iron absorption characteristic of?

A

Anaemia due to ineffective erythropoiesis

111
Q

What happens to hepcidin in the situation of anaemia due to ineffective erythropoiesis?

A

Hepcidin is suppressed by the high erythropoietic activity, despite high total body iron, thereby worsening both the iron overload and the anaemia

112
Q

What problem with hepcidin can lead to iron refractory iron deficiency?

A

Hepcidin excess due to mutations in the hepcidin inhibitor, transmembrane protein serine 6 (TMPRSS6)

113
Q

What happens to hepcidin under steady state conditions?

A

Levels are normal

114
Q

What do normal levels of hepcidin do?

A

Prevent excess iron absorption and iron overload

115
Q

What is the mechanism for regulating iron excretion if iron levels are too high?

A

There isn’t one

116
Q

What is the result of there not being a mechanism for regulating iron excretion if iron levels are too high?

A

Patients receiving regular blood transfusions, and some patients with severe haemolytic anaemia, can become iron overloaded

117
Q

What is the result of iron overload?

A

Iron can be deposited in various organs, including the liver and the heart, which can result in serious damage and organ failure

TAS Haematology (7 decks)

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