Physiology of Haematopoiesis ✅ Flashcards
What is haematopoiesis?
The process through which all types of mature blood cell are produced
What are haematopoietic stem cells (HSCs)?
Multipotent cells characterised by their ability to ‘self-renew’ (proliferate) and mature into fully differentiated cells of any of the haematopoietic lineages
What is the importance of HSCs?
They sustain blood cell production throughout life
What are the principle haematopoietic lineages?
- Erythroid/megakaryocytic
- Granulocyte/macrophage
- Lymphoid
What does the erythroid/megakaryocytic lineage give rise to?
- RBCs
- Platelets
What does the granulocyte/macrophage lineage give rise to?
Granulocytes and monocytes
What does the lymphoid lineage give rise to?
- B cells
- T cells
- NK cells
What can HSCs be characterised by?
Proteins expressed on the cell membrane
What can the cell markers on the membrane of HSCs be utilised for clinically?
To purify HSC for clinical applications, e.g. haematopoietic stem cell transplant
What are the HSCs and their progeny controlled by?
A network of interactions with haematopoietic growth factors and cellular components of the haematopoietic micro-environment that maintain balanced blood cell production
When does primitive haematopoiesis begin?
In the first few weeks of embryonic life
Where does primitive haematopoiesis begin?
In the yolk sac
What does primitive haematopoiesis give rise to?
Mainly RBCs
What is primitive haematopoiesis replaced by?
Definitive hematopoiesis
When is primitive haematopoiesis replaced by definitive haematopoiesis?
5-6 weeks gestation
What does definitive haematopoiesis produce?
Has the capacity to produce all blood cell cycles
Where do definitive hematopoietic stem cells develop?
In the aorta-gonad-mesonephros (AGM) region of the dorsal aorta
Where do HSCs migrate after developing in the AGM?
To the fetal liver and spleen
When do HSCs migrate from the AGM region to the fetla liver and spleen?
6-7 weeks gestation
What is the primary site of haematopoiesis from 6-7 weeks gestation?
The liver
What happens to the site of haematopoiesis in the third trimester?
It progressively increases in the bone marrow
What is the site of haematopoiesis after birth?
Bone marrow
Where in the bone marrow does haematopoiesis occur?
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
What are RBCs?
Specialised cells that mainly function to deliver oxygen to the tissues and remove carbon dioxide
What shape are RBCs?
Biconcave
What cellular structure do RBCs lack?
Nucleus
What do RBCs have a lot of?
The oxygen-carrying protein haemoglobin
What does each molecule of haemoglobin consist of?
4 globin chains and a central iron containing haem group
What happens to the composition of Hb during fetal development?
It changes in an ordered sequence
What are the first globin chains produced?
Epsilon and zeta
What follows the production of epsilon and zeta globin chains?
Almost immediately followed by gamma
What do the epsilon, zeta, and gamma globin chains give rise to?
2 types of fetal haemaglobin - Hb Gower and Hb Portland
What is Hb Gower made up of?
Epsilon and zeta globin
What is Hb Portland made up of?
Epsilon and gamma globin
What follows the production of gamma globin?
Alpha globin
What does alpha globin allow the production of?
HbF
What is HbF made up of?
Alpha and gamma globin
When does HbF production start?
3-4 weeks of fetal life
What is the predominant fetal Hb?
HbF
What is adult Hb (HbA) made up of?
Alpha and beta globin
When do the levels of HbA remain low until?
30-32 weeks gestation
What are the levels of adult Hb before 30-32 weeks gestation?
10-15%
What happens to haemoglobin production after 30-32 weeks gestation?
The rate of HbA production increases at the same time as HbF production falls
What is the average composition of haemoglobin at birth for most term babies?
- 70-80% HbF
- 25-30% HbA
- Sometimes small levels of HbA2 and sometimes traces of Hb Barts (4 gamma chains)
What happens to HbF after birth?
It falls rapidly
What level should HbF be by 12 months?
2%
What happens to HbF in the first 15 days after birth in term babies?
There is little change
How long after birth does HbF remain at the same level in pre-term babies?
Up to 6 weeks
What is the result of it taking up to 6 weeks for HbF to fall in preterm babies?
Can make diagnosis of some haemoglobinopathies difficult in some neonates
What is the major function of Hb?
Deliver oxygen to tissues
What does the binding and release of oxygen cause in Hb?
Small changes to configuration of globin chains in the Hb molecule
What is the result of small changes to configuration of globin chains in the Hb molecule?
It alters the affinity of Hb for oxygen
What happens to the Hb molecule when oxygen is unloaded?
It opens up, allow 2,3-DPG to enter
What is the result of 2,3-DPG entering when oxygen is unloaded from Hb?
It reduces oxygen affinity and ensures that the Hb molecule does not take up oxygen from the tissues
What is the result of changes in affinity of haemoglobin to the oxygen dissociation curve?
It gives it it’s sigmoid shape
What must red cells be able to do to function effectively?
Generate energy in the form of ATP, and reduce molecules to prevent oxidative damage
What does the Embden-Meyerhof pathway do?
Metabolises glucose to lactate, producing 2 molecules of ATP, NADH, and 2,3-DPG
What is the ATP used for in RBCs?
Maintain red cell shape and osmotic gradient
What is NADH used for?
Reduce iron to active ferrous form
What is an alternative pathway glycolytic pathway?
The pentose phosphate pathway
What does the pentose phosphate pathway produce?
NADPH
What is NADPH important for?
Source of reducing power that maintains iron in active form
What enzyme is key in the pentose phosphate pathway?
G6PD
What does G6PD deficiency result in?
Marked susceptibility to oxidative stress
What is the average RBC lifespan in older children?
120 days
What is the average RBC lifespan in neonates?
About 90 days
What is the importance of the specialist RBC membrane?
Prevents damage and maximises flexibility
What does the RBC membrane consist of?
A complex lipid bilayer containing a number of key scaffolding proteins
What is the most abundant protein in the RBC membrane?
Spectrin
What is the of spectrin in the RBC membrane?
It forms tetramers and attaches to the membrane via the ankyrin protein
What can abnormalities of the proteins in the RBC membrane lead to?
Membrane disorders such as hereditary spherocytosis and hereditary elliptocytosis
What dietary component is vital for erythropoiesis?
Iron
How common is iron deficiency anaemia, compared to other types?
It is the most common cause of anaemia worldwide
What are the broad causes of iron deficiency anaemia?
- Inadequate intake
- Chronic blood loss
What foods are rich in iron?
- Meat (especially liver)
- Nuts
- Pulses
Where does iron absorption occur?
In the duodenum
What cells absorb dietary iron?
Enterocytes
In what form is dietary iron absorbed?
Either in the Fe2+ form, or as haem
How is iron in the Fe2+ iron absorbed by enterocytes?
Via the divalent metal transporter
What happens once dietary iron is absorbed by enterocytes?
The iron transporter protein, ferroportin, transports iron across the basolateral membrane of the enterocyte into the bloodstream
What happens to dietary iron absorbed into the bloodstream?
Iron is bound to transferrin and transported to the tissues
How much can each molecule of transferrin bind?
Two molecules of iron
What cells can iron be delivered to?
Those expressing transferrin receptors, including developing red cells
What receptors are important in the regulation of body iron?
- DMT1
- Transferrin receptor 1 (TfR1)
What controls the synthesis of DMT1 and TfR1?
Iron regulatory proteins
What do iron regulatory proteins (IRP) bind to?
Iron response elements (IREs) on genes
What happens to IRPs when iron levels are accurate?
They do not bind
What is the effect of IRPs not binding to IREs?
It allows production of ferritin, and therefore storage of iron
What happens to IRPs when iron is deficient?
They bind to IREs
What is the effect of IRPs binding to IREs?
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
What do mutations in DMT1 cause?
Congenital anaemia
What are mutations in the ferroportin gene associated with?
Congenital hyperferritinaemia and iron overload
In what forms is iron present in the body?
- Haemoglobin
- Ferritin
- Haemosiderin
- Myoglobin
- Many important enzymes
In what form is the greatest amount of iron in the body?
Haemoglobin
What happens to haemoglobin once the cells reach the end of their lives?
Recycled
What is ferritin?
A water-soluble molecule found in many tissues
What is the clinical use of serum ferritin levels?
It gives a fairly accurate estimation of total body iron levels, and is a useful investigation when iron deficiency is suspected
What is required for serum ferritin levels to give an accurate estimation of total body iron levels?
Absence of inflammation
Is haemosiderin soluble?
No
Where is myoglobin found?
In muscles
What % of dietary iron is usually absorbed?
5-10%
What can happen to dietary iron absorption in times of increased need, e.g. iron deficiency?
Can be increase to up to 30%
At what level is iron availability regulated?
Cellular and systemic levels
What is the key to regulation of iron levels?
Hepcidin
What is hepcidin?
A small peptide hormone produced by the liver
What is the role of hepcidin?
It plays a major role in controlling iron flux to plasma from enterocytes and macrophages
How does hepcidin control iron flux to plasma from enterocytes and macrophages?
By degradation of the cellular iron exporter ferroportin
What happens to hepcidin levels in iron deficiency?
They fall
What happens when there are mutations in the genes which encode proteins of the hepcidin-activating pathway?
Iron overload
What is hepcidin insufficiency and increased iron absorption characteristic of?
Anaemia due to ineffective erythropoiesis
What happens to hepcidin in the situation of anaemia due to ineffective erythropoiesis?
Hepcidin is suppressed by the high erythropoietic activity, despite high total body iron, thereby worsening both the iron overload and the anaemia
What problem with hepcidin can lead to iron refractory iron deficiency?
Hepcidin excess due to mutations in the hepcidin inhibitor, transmembrane protein serine 6 (TMPRSS6)
What happens to hepcidin under steady state conditions?
Levels are normal
What do normal levels of hepcidin do?
Prevent excess iron absorption and iron overload
What is the mechanism for regulating iron excretion if iron levels are too high?
There isn’t one
What is the result of there not being a mechanism for regulating iron excretion if iron levels are too high?
Patients receiving regular blood transfusions, and some patients with severe haemolytic anaemia, can become iron overloaded
What is the result of iron overload?
Iron can be deposited in various organs, including the liver and the heart, which can result in serious damage and organ failure
