Red Blood Cells Flashcards
What do all blood cells originate from?
pluripotent haemopoietic stem cells in the bone marrow
What is haemopoiesis?
the formation and development of blood cells
Where does foetal haematopoeisis start?
The yolk sac
Which bones in children does haematopoiesis occur in?
All bones
Which bones in adults does haematopoiesis occur in?
Long bones - femur, pelvis, sternum
What are the two characteristics of haematopoietic stem cells?
They can self renew
- some daughter cells remain as HSCs
- therefore the pool of HSCs are not depleted
They can differentiate to mature progeny
- other daughter cells follow a differentiation pathway
What are the two cells that HSC differentiate into?
Common Lymphoid Progenitor and Common Myeloid Progenitor
What does the common myeloid progenitor cell differentiate into?
Megakaryocyte
erythrocyte
Mast cell
Myeloblast
What do megakaryocytes break into?
platelets
What do myeloblast differentiate into?
Granulocytes= basophils, neutrophils, eosinophils
Monocytes
What do monocytes become?
macrophages
What do common lymphoid progenitor cells differentiate into?
Natural killer cells (large granular lymphocyte)
Small lymphocyte
What do small lymphocytes differentiate into?
T lymphocytes
B lymphocytes
Do you understand/ remember the diagram of the stem cell hierarchy?
What are the sites of haemopoiesis from zygote (you know what I mean) to birth?
Yolk sac
- generation of HSC (mesoderm)
- 3 weeks
- primitive
Liver
- HSC maintenance
- HSC expansion
- Liver takes over at 6-8 weeks gestation
- It becomes the principle source of blood in foetus until shortly before birth
Bone marrow
- Haemopoiesis in children occurs in almost all bone
- In adults it mainly occurs in the bone marrow, especially the pelvis, femur and sternum
- Bone marrow starts developing haematopoietic activity at roughly 10 weeks gestation
What is the intravascular life span of red blood cells and what is their major function?
120 days
oxygen transport
What is the intravascular life span of platelets and what is their major function?
10 days
haemostasis
What is the intravascular life span of monocytes and what is their major function?
several days
defence against infection by phagocytosis and killing of micro-organisms
What is the intravascular life span of neutrophils and what is their major function?
7-10 hours
defence against infection by phagocytosis and killing of micro-organisms
What is the intravascular life span of eosinophils and what is their major function?
a little shorter than neutrophils
defence against parasitic infection
What is the intravascular life span of lymphocytes and what is their major function?
very variable lifespan
Humoral and cellular immunity
How are haematopoietic stem cells and progenitor cells distributed?
Haemopoietic stem cells and progenitor cells are distributed in an ordered fashion within the bone marrow amongst mesenchymal cells, endothelial cells and the vasculature with which the HSCs interact
What regulates haemopoiesis?
A number of genes, transcription factors, growth factors and the microenvironment
- disruption of this regulation can disturb the balance between proliferation and differentiation, and may lead to leukaemia or bone marrow failure
what are haemopoietic growth factors?
Glycoprotein hormones which bind to cell surface receptor
- they regulate proliferation and differentiation of HSCs
- regulate function of mature blood cells
Give examples of haemopoietic growth factors.
Erythropoiesis (red cell production): ERYTHROPOIETIN
Granulocyte and monocyte production: G-CSF, G-M CSF, cytokines e.g. interleukins
Megakaryocytopoiesis and platelet production: THROMBOPOIETIN (TPO)
Describe Lymphoid differentiation.
Describe Myeloid differentiation.
What are erythroids.
Cells concerning RBCs/ erythrocytes.
Where does erythropoiesis occur?
Bone Marrow
What are the overall major cells made from haemopoiesis: differentiation from stem cells?
What is erythropoeisis?
Development of RBCs
How is a red blood cell formed, starting from the common myeloid progenitor?
The common myeloid progenitor can give rise to pro-erythroblasts
This in turn gives rise to erythroblasts
Then erythrocytes
What happens as differentiation progresses?
Self renewal and lineage plasticity decreases
What stains RNA content?
New methylene blue
What are the types of erythroblasts?
early–> intermediate–> late erythroblasts
What stage of a RBC is higher RNA content seen in the peripheral blood?
reticulocytes
What are reticulocytes?
immature young RBC, that circulate in the blood for 1-4 days before maturing into erythrocytes
- Reticulocytes have no nucleus, but lots of RNA to complete the production of haemoglobin (as they mature in the blood)
What is needed for erythropoiesis?
iron
Folic acid
Vitamin b23
Erythropoietin
What is erythropoietin?
a growth factor
glycoprotein synthesised in response to hypoxia- so there is a demand supply feedback loop
erythropoietin stimulates the bone marrow to produce more RBCs
What is HAEM iron also known as?
Ferrous iron - fe2+= animal derived, best absorbed form
What is non-HAEM iron also known as?
Ferric iron - fe3+= in food and requires action of reducing substances (e.g., ascorbic acid, vitamin C) for absorption
What affect do phytates have on iron absorption?
They reduce it
What organs is excess iron toxic to?
Heart and liver
Iron absorption is tightly controlled because it can be toxic, how much is absorbed from the diet a day?
1-2mg
How is absorption of iron carefully regulated?
Absorption of iron from the gut and release of storage iron is blocked by hepcidin (secreted by liver in response to high storage iron)
Where is ferroportin found?
In duodenum enterocytes
How do we lose iron if it is high?
Higher iron leads to HEPCIDIN release, which blocks ferroportin, so iron cannot leave the enterocytes. Therefore when the enterocyte is destroyed so is the iron stored within it
What does inflammation do to Hepcidin?
Increases hepcidin, and therefore can lead to anaemia of inflammation as there is not enough iron in the blood as it is all being kept within the enterocytes
What are the pro-inflammatory cytokines?
IL-1, TNFa, IL-6, IFNy
Why do we need vitamin B12?
They are needed for dTTP synthesis - thymidine, needed for DNA synthesis
Integrity of the nervous system
Why do we need folic acid?
They are needed for dTTP synthesis - thymidine, needed for DNA synthesis
Homocysteine metabolism
Due to them affecting DNA synthesis, vitamin B12 and folic acid deficiency affects all rapidly dividing cells, which are?
Bone marrow: cells can grow but are unable to divide normally
Epithelial surfaces of mouth and gut
Gonads
What can a Vitamin B12 and Folate deficiency cause?
Megaloblastic erythropoiesis - this is because the cells keep dividing but lack the DNA
Macrocytic (RBCs large size)
Where is folic acid absorbed?
in the small intestine
Name three sources of Folate
Green leafy vegetables, cauliflower and Brussels sprouts
When do requirements of folate increase?
pregnancy
increased red cell production e.g., sickle cell anaemia, other haemolytic anaemias
Name three sources of B12
Meat, fish, clams
What does B12 combine with so it can be absorbed?
Intrinsic factor which is made in the gastric parietal cells
What is the order of absorption of vitamin B12?
1) Stomach
- B12 combines with intrinsic factor (IF) made in the gastric parietal cells
2) Small intestine
- B12-IF binds to receptors in the ileum
3) Vitamin B12 deficiency may result from:
- Inadequate intake e.g. veganism
- Inadequate secretion of IF: pernicious anaemia (autoimmune disorder)
- Malabsorption e.g. coeliac disease, surgery
Lack of acid in stomach (achlorhydria)
What causes vitamin B12 deficiency
Inadequate intake, pernicious anaemia and malabsorption
What does iron deficiency cause?
microcytic (RBCs small size)
anaemia of chronic disease/ inflammation
What can cause iron deficiency?
increased loss (blood loss)
Reduced intake
Increased requirement
What is pernicious anaemia?
This is where your body does not make IF therefore the B12 cannot bind and therefore cannot be absorbed
Why do red blood cells have a life span of 120 days?
When they move through capillaries and blood vessels, the walls bend and stretch meaning they get damaged
Where are the red blood cells destroyed?
Spleen
What are the RBCs broken down into?
HAEM and globin
What does the HAEM part of the RBC after it is destroyed?
Gets broken down into bilirubin
How is bilirubin excreted
In bile
Why is bile important
Contains bile salts which are needed for the emulsification of fats so they can be absorbed
What are the three types of granulocytes
Neutrophil, basophils and eosinophil
What does hypochromia mean?
Too little haemoglobin so pale
What is a polychromatic RBC?
One that is too red due to too much haemoglobin
What are target cells?
When you have an accumulation of haemoglobin in the area of central pallor
What causes the presence of target cells?
Jaundice, liver disease, hyposplenism
What does anisocytosis mean
Variation in size
What does poikilocytosis mean
Variation in shape
What causes sickle cells?
Due to the polymerisation of HbS which forms tachtoids that distort the shape of the RBC
What is the mutation that causes sickle cell disease? SICKLE CELL SIX GIVES ME A CRISIS
Charged glutamic acid residue at positive 6 in beta Hb gene is replaced by uncharged valine
“Normal” Hb is determined by many things like..
Gender and physiological status eg altitude
What type of distribution fo Hb concentrations show?
Gaussian distribution
An infant with sickle cell anaemia (HbSS) develops symptoms of fatigue and pain. Blood tests reveal anaemia with thrombocytopenia. Examination reveals a mass on the left-hand side of his abdomen. Given this information, what could be the most likely explanation for his symptoms?
Pooling of blood in the spleen - spleenic sequestration
What is Crohn’s Disease?
inflammatory bowel disease which often involves ulcer formation in the mucosal layer of the intestines.
How can Crohn’s disease lead to iron-deficiency anaemia?
Crohn’s disease can lead ulcer formation in the stomach, meaning internal bleeding can occur. This may result in iron-deficiency anaemia due to blood loss
What regulates the proliferation and differentiation of Haematopoietic stem cells?
Haematopoietic growth factors
A 28-year old female has some tests carried out following a full blood count that subsequently reveal that she is folate deficient. What changes in the red blood cells would you expect to see.
Macrocytic cells
What are haematopoietic growth factors?
Glycoprotein hormones which bind to cell surface receptors
Regulate proliferation and differentiation of HSCs
Regulate function of mature blood cells
What is the haematopoietic growth factor which influences red cell production?
Erythropoietin
What are the haematopoietic growth factors which influence granulocyte and monocyte production?
G-CSF, G-M CSF, cytokines e.g. interleukins
What are three causes of microcytic anaemia?
Iron deficiency
Pregnancy
Childhood
What are three causes of macrocytic anaemia?
(B12/folate deficiency)- alcohol excess, pregnancy, vegan diet
What are the two main functions of iron?
Oxygen transport in haemoglobin
Mitochondrial proteins
- cytochromes a, b and c: for production of ATP
- cytochrome P450 for hydroxylation reactions (e.g., drug metabolism)
What are side effects of iron deficiency?
Hypochromic (pale), microcytic (small), red cells
Spoon shaped nails: koilonychia
Glossitis and angular stomatitis (shiny tongue)
How much iron does the normal western diet contain?
10-20mg per day
Why is ferric iron not as easily absorbed?
and requires action of reducing substances (e.g. vitamin C) for absorption
How does anaemia of chronic disease/inflammation occur?
Pro-inflammatory cytokines such as IL-1, TNF-alpha, IL-6 and IFN-gamma work to decrease EPO production, and increase hepcidin - increased hepcidin means less iron absoprtion in the gut as hepcidin binds to ferroportin, meaning iron is unable to leave theenterocytes and therefore is destroyed when the entoercytes die
When is hepcidin released?
Released from the liver in response to high storage iron
What can cause a deficiency in B12?
inadequate intake e.g. veganism
- inadequate secretion of IF: pernicious anaemia (an autoimmune disorder)
Malabsorption e.g. coeliac disease
lack of acid in stomach (achlorhydria)
During what situations do the requirements for folic acid increase?
During pregnancy and during red cell production
What three things does erythrocyte function depend on?
Integrity of the membrane
Haemoglobin structure and function
Cellular metabolism
a defect in any of these results in shortened erythrocyte survival (haemolysis)
What structures helps to maintain the integrity and shape of the red cell?
The red cell membrane - made of lipid bilayers which is supported by proteins and contains transmembrane proteins
What is special about the red cell membrane (3 things)?
- Erythrocytes are biconcave in shape, aiding manoeuvrability through small blood vessels to deliver oxygen
- The membrane is made up of a lipid bilayer supported by protein cytoskeleton and contains transmembrane proteins
*These maintain the integrity, shape and elasticity/ deformability of the red cell
What are the transmembrane proteins found in red cell membrane?
Band 3 and rhesus
What are the skeletal proteins found in red blood cells membrane?
Spectrin and junctional
What does a disruption to vertical linkages in the red blood cell membrane cause?
Hereditary Spherocytosis
What are the vertical linkages usually disrupted in spherocytosis?
ankyrin/ spectrin
How is spherocytosis passed on?
autosomal dominant
Describe spherocytes.
Spherocytes are cells that are approximately spherical in shape
They therefore have a round, regular outline and lack central palor
They result from the loss of cell membrane without the loss of an equivalent amount of cytoplasm
So the cell is forced to round up
RBC become less flexible and are removed prematurely by the spleen
Disruption of horizontal linkages in red cell membrane produces…
Hereditary elliptocytosis
- it may also occur in iron deficiency
How does deficiency in G6PD affect red cells?
- G6PD is an important enzyme in the HMP shunt
- The HMP shunt is involved in metabolism of glutathione which protects the red cell from oxidant damage
- Therefore deficiency of G6PD causes red cells to be vulnerable to oxidant damage
What protects the red cells from oxidant damage?
Glutathione
What does G6PD deficiency cause?
G6PD deficiency usually causes intermittent, severe intravascular haemolysis as a result of infection or exposure to an exogenous oxidant
What are examples of extrinsic oxidants?
foodstuff, e.g., broad beans, chemicals, drugs
What are episodes of intravascular haemolysis associated with the appearance of?
considerable numbers of Irregularly contracted cells/ ‘bite cells’
What are bite cells?
- These irregular in outline but are smaller than normal cells and have lost their central pallor
- They usually result from oxidant damage to the cell membrane and to the haemoglobin
Haemoglobin is denatured and forms round inclusions known as Heinz bodies, which can be detected by a specific test
Explain more of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- X-linked inheritance: the gene for G6PD is on the X chromosome so affected individuals are usually hemizygous males (occasionally homozygous females)
- Distribution parallels malaria: selective advantage, resistance to falciparum malaria
What is polycythaemia?
High concentration of RBCs in blood
- blood is therefore thicker
- less able to travel through vessels
- and towards organs
What is increased with polycythaemia?
Hb, RBC, and Hct increased compared with normal subjects of the same age and gender
What is pseudo polycythaemia?
reduced plasma volume
What is true polycythaemia?
increase in total volume of red cells in the circulation
What are the 4 causes of polycythaemia?
Blood doping or overtransfusion
Appropriately increased erythropoietin
Inappropriate erythropoietin synthesis or use
Independent of erythropoietin
What is an example of appropriately increased erythropoietin?
polycythaemia can result from the action of erythropoietin that is appropriately elevated
e.g., as a result of hypoxia
- in some situations such as at altitude this may be beneficial
When might there be inappropriate erythropoietin synthesis or use?
Renal or other tumour inappropriately secretes erythropoietin
- this is not surprising since this is a major site of erythropoietin production
When is there polycythaemia independent of erythropoietin?
This condition is an intrinsic bone marrow disorder called polycythaemia vera
It is classified as a myeloproliferative disorder
Polycythaemia can lead to ‘thick blood’– more technically known as hyperviscosity, which can lead to vascular obstruction/ thrombosis
Blood can be removed (venesection) to reduce the viscosity
Drugs can be given to reduce bone marrow production of red cells
