Red Blood Cells Flashcards
What is the making of red plaid cells called?
Haemopoiesis
Blood-making
Where where are red blood cells produced?
The bone marrow
What pluripotent cells to RBCs develop from?
Haemopoietic stem cells
HSCs
These are distributed in an ordered fashion in the bone marrow amongs mesenchymal, endothelial cells and the vasculature which they interact with.
HSCs give rise to two types of stem cells?
Lymphoid stem cells
Myeloid stem cells
From which red cells, granulocytes, monocytes and platelets are developed
What is the approximate lifespan of a RBC?
120 days
How many blood cells are produced each day on average?
500 billion
How are HSCs able to regulate the numbers of each type of blood cell? (Two characteristics)
Self renewing:
Some daughter cells remain as HSCs so the pool of HSCs is not depleated
Differentiate into mature progeny:
The other daughter cells are committed to follow the differentiation pathway
This Balances the numbers of each blood cell being made and destroyed
What blood cells come from the common myeloid progenitor?
Slide photo
Where are HSCs derived from in the embryo?
After the first 3 weeks of gestation, the mesoderm in the yolk sac.
After the 3 weeks where does haemopoiesis take place?
The liver
Main source until shortly before birth
When does the bone marrow start developing haemopoietic activity?
Around 10 weeks In to gestation
After birth it becomes the only site of haemopoiesis
What is the difference In the sites of haemopoiesis between children and adults?
Children
Bone marrow of all bones
Adults
Bone marrow of pelvis, sternum, vertebrae, the proximal ends of the femur and humorous
(Although all bones maintain the ability, they just don’t always use it)
How is haemopoiesis regulated?
Genes, transcription factors, growth factors, the microenvironment
What are haemopoietic growth factors?
Glycoprotein hormones which bind to cell surface receptors
Regulate proliferation and differentiation of HSCs
Regulate function of mature blood cells
Which growth factor leads to the proliferation of RBCs?
Erythropoietin
Produced in the kidney, stimulated by reduced oxygen supply
What growth factors lead to the proliferation of granulocytes and monocytes?
Cytokines e.g. interleukins
G-CSF
Granulocyte colony stimulating factors
G-M CSF
Granulocyte macrophage
All produced in the bone marrow
Which growth factor controls megakaryopoiesis and platelet production?
Thrombopoietin
Produced in the bone marrow
Give an overview of where each blood cell differentiates from?
Last slide of RBC part 1
What are the stages of development to an RBC?
Common myeloid progenitor
Erythroblasts
Erythrocytes
The process involves cell division until it reaches the late erythroblast stage when it extrudes it’s nucleus. At this stage it is polychromatic
What is required for erythropoiesis?
Iron
Vitamin B12
Folate
Erythropoietin
How do the different types of anemia affect RBC size?
Iron: microcytic
B12/folate: macrocytic
What are the main functions of iron?
Oxygen transport in harmoglobin
Mitochondrial proteins: Cytochromes a b and c for ATP production Apoptosis Respiration Cell cycle arrest DNA synthesis
Where is iron absorbed?
Duodenum in the small intestine
How much iron is consumed a day, and how much is absorbed?
10-20 mg consumed
1-2mg absorbed
What are the two forms of dietary iron?
Haem
Ferrous FE2+
Best absorbed
Animal derived
Non haem Ferric FE3+ Required vitamin C to be absorbed E.g. soya beans, spinach Often contain ohytates which bind to iron making it harder to absorb
Why is it important that iron levels are regulated?
There is no physiological mechanism for regulating iron excretion
Iron can form free radicals that damage bodily tissues
How is iron transported around the body?
In the plasma
Bound to the protein transferrin
Where is iron stored?
In the liver
As the protein ferritin
What is the role of hepcidin?
When iron stores of ferritin are full more hepcidin is released. This prevents absorption.
A need for more erythropoiesis leads to a reduction in hepcidin, and more iron absorption
Is hepcidin synthesis stimulated or surpresses by erythropoiesis?
Surpressed
When storage iron is high what happens to the synthesis of hepcidin?
It is increased
It then binds and degrades ferroportin
Therefore when the enterocyte dies the iron is lost
In inflammation cytokines such as interferon and interleukins are released. What is the effect of these on erythropoiesis?
Reduction
The interleukin and Thmor necrosis factor increase hepcidin levels
What are folate and vitamin B12 used for?
The synthesis of thymidine (dTTP)
Needed for DNA synthesis
Which rapidly deciding cells are especially effected by vitamin B12 and folate deficiency?
Bone marrow
Epithelial surfaces of mouth and gut
Gonads
Where do we get vitamin B12?
Only animal derived foods:
Meat Fish Oysters Eggs Milk Cheese Fortified cereals
Where do we get folate?
Green leafy veg Cauliflowers Sprouts Liver and kidney Cereals Yeast Fruit
What happens to vitamin B12 once ingested?
Stomach:
Cleaved from food proteins by HCL
Binds to intrinsic factor
Small intestine (duodenum): B12-IF binds to receptors in the ileum and is absorbed
Once absorbed binds to the transport protein transcobalamin
How can vitamin B12 deficiency arise?
Veganism
Lack of HCL (acorhydria)
Inadequate secretion if IF
-pernicious anemia
Malabsorption
E.g. coeliac
Where is folate absorbed?
Small intestine
Duodenum and jejunum
Total body stores are around 10mg and last 3 months
Demand increases during pregnancy
And diseases which involve increased red cell production
What happens to RBCs at the end of their life cycle?
Phagocytosis by reticuloendothelial macrophages one the spleen
The the iron in the haem ring is recycled, bound to transferrin and taken to the bone marrow to produce more RBC
The haem is broken down to bilirubin which is excreted one bile
What does the function of RVCs depend on?
Integrity of membrane
Harmoglobin structure
Cellular metabolism
A defect in any of these results in a shortened lifecycle (haemolysis)
What is the shave of a red blood cell?
Biconcave disc
Helps with manoeuvrability through small blood vessels
What is the membrane of a red blood cell made of and what is it’s function?
Lipid bilayer supported by a protein cyto skeleton and contains transmembrane proteins
Maintain integrity and the elasticity/deformability of the red blood cell
What are some examples of transmembrane and skeletal proteins In RBCs?
Transmembrane:
Rhesus and band 3
Skeletal:
Spectrin
What happens when there is a disruption of vertical linkages in the membrane (spectrin)?
Hereditary sphericytosis
What are some properties of spherocytes?
Smaller Round No central pallor Regular outline Smaller membrane but same cytoplasm
Less flexible so are removed prematurely by the spleen (haemolysis)
What happens when the horizontal linkages across the membrane are disrupted?
Hereditary elliptocytosis
Also happens in iron deficiency
What is the main function of erythrocytes?
To transport oxygen from the lungs to the tissues
Able to do this because of the haem moiety
How many harmoglobin molecules in one RBC?
~300 million
What is the make up if haemoglobin A (adults) ?
4 subunits
Each comprised of a globin chain
2 alpha globin chains
2 beta globin chains
All bound to a haem group
The haem group is comprised of a ferrous iron (2+), held in a porphyrin ring
Each Fe2+ binds to 1 oxygen
So 4 oxygen molecules per RBC
How is foetal haemoglobin F differ from haemoglobin A?
2 alpha globin chains
2 gamma globin chains
As opposed to two alpha and two beta
A small amount of haemoglobin F persists throughout adult life
What is the shape of the oxygen Hb dissociation curve?
Sigmoid
Partial pressure on x
% saturation on right
Sigmoid is due to cooperativity (first oxygen bound creates a conformational change so the next is easier)
What does the position of the haemoglobin depend on?
pH
CO2 in RBCs
Structure
Conc of 2,3-DPG
What is the Bohr effect? How do the shifts work?
Increased CO2 means decreased pH
Shift to the right
Easier unloading of O2
Also with high 2,3-DPG
And sickle haemoglobin
Foetal haemoglobin has a higher oxygen affinity (left shift)
What is the metabolism in a RBC adapted for?
The generation of ATP
Maintainence of Hb function, integrity of the membrane and the RBC volume
What is 2,3-DPG
2,3-diphosphoglycerate
Binds to the beta globin chain,modulates the oxygen affinity of haemoglobin
Plays an important role in the adaptive response to anaemia, hypoxia and high altitude
What is G6PD?
An important enzyme in the hexose monophosphate shunt
Coupled to the metabolism of glutathione, protecting cells from oxidant damage
Oxidants can be generated in the blood, or come from diet (e.g. broad beans)
G6PD deficiency can lead RBCs to become vulnerable to oxidant damage
What is G6PD deficiency?
Most prevalent enzyme disorder
X linked, so infected individuals are usually hemizygous males
Causes intermittent severe intravascular haemolysis as a result of infection or exposure to an exogenous oxidant (e.g. broad beans or drugs)
What are irregularly contracted cells?
They have an irregular outline
Smaller
Have lost their central pallor
Also called hemighosts
Usually result from oxidant damage to cell membrane and haemoglobin
Haemoglobin is denatured and forms Heinz bodies, a specific test detects these
How is the size of RBCs described?
Microcytic
Smaller
Normocytic
Normal
Macrocytic
Bigger
What are some causes of microcytosis
Defects in haem synthesis
Caused by iron deficiency Or anaemia of chronic disease
Defects in globin synthesis (thalassaemia)
Eithe alpha or beta chain synthesis
What are some types of macrocytes?
Round
Oval
Polychromatic (young immature red blood cells )
What are some causes of macrocytosis?
Lack of vitamin B12 or folate
Liver disease and ethanol toxicity
Areas with high amounts Haemolysis of polychromatic cells
Pregnancy
What is hypochromia?
Larger area of central pallor
Less haemoglobin
Often goes with microcytisis
Causes include iron deficiency and thalassemia
What is polychromasia?
A blue tinge to the cytoplasm of a red cell
Indicates the cell is young and immature
Goes with macrocytosis
What is a new methylene blue stain used for?
To look for young cells with reticulocytes that have higher rna content
Reticulocytosis refers to increased numbers of reticulocytes
May occur in areas of bleeding or haemolysis
What is a variation in size of red blood cells called?
Anisocytosis
Eg in patients who have had a transplant
What is poikilocytosis?
Higher variation in shape than usual
What are target cells?
Accumulation of Hb in the area of central pallor
Cause by: Obstructive jaundice Liver disease Haemaglobinopathies Hyposplenism
What are sickle cells?
Crescent shape
Result from the polymerisation of haemoglobin S, which when deoxygenated is much less soluble than haemoglobin A
Occurs when two abnormal copies of the beta globin gene are inherited
In beta globin an charged glutamic acid is replaced by an uncharged valine molecule
What are red cell fragments?
Also know as shistocytes
Fragmented red cells
May result from a shearing process caused by platelet rich blood cells such as in disseminated intravascular coagulation
