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Topic 1 - Overview + Blood Diseases
There are 20-30 trillion RBCs in body, lifespan of 120 days, 180 million produced per hour.
Haematopoiesis [Production of Blood Cells]
The Haematopoietic Stem Cell is the starting point (multipotent).
These determine lineage and are self-renewable.
Their numbers and rate of divisions is kept few to reduce cancer, they are also restricted to the 'stem cell niche'.
The Haematopoietic Stem Cell then divide up to 20x, forming committed precursor cells that can no longer self-renew. They are initially highly proliferative but as they gain functional characteristics they become less so. Cell death is essential at this stage as a mechanism to control their numbers, depending upon need (40%
Erythropoietin (EPO) controls RBC production in response to demand on oxygen delivery, it is controlled by sensors the kidney.
G-CSF determines Neutrophil production, dependent on how many are needed to fight infection. It is released and acts as a signal from endothelial cells during infection/inflammation.
Thrombopoietin (TPO) controls platelet production by acting on Megakaryocytes, like G-CSF it is produced in response to inflammation. It is controlled by negative feedback (depending on level of circulating platelets).
Types of Blood Cells 1)
Erythrocytes (RBC) - Involved in Oxygen Carriage.
Platelets - Involved in the platelet plug formation and prevention of bleeding.
Lymphocytes - Mainly involved in antibody production and the killing of virus infected cells.
Granulocytes (Eosinophils, Neutrophils and Basophils) which directly kill the invading organisms.
Monocytes - Kill organisms directly and help stimulate Lymphocytes.
The Erythrocyte [RBC]
RBC has given up: Nucleus, Mitochondria, Ribosomes.
It has done this to remain efficient, stable and to provide additional room for Haemoglobin (toxic).
However, it also cannot undergo Apoptosis or repair because of this, and is vulnerable to disease.
The RBC has Vertical anchors and Horizontal linkers and is very flexible.
It is a biconcave disc to maintain an optimal surface area to volume ratio.
Its Cytoskeleton can prevent haemoglobin release through fibrin stands and forming a Spherocyte (removed in Spleen).
Haem = Oxygen binding element. Globin = Protein element.
Haemoglobin has a sigmoidal curve for oxygen release, regulating the distribution of O 2 to the areas that need it most. Globin 1 keeps the haem contained.
Has a porphyrin structure that holds the iron flat with 2 interaction sites above and below the plane, one of these fix the molecule to the globin molecule and one binds O 2.
Haemoglobin has a 4-chain structure - 2 alpha chains and 2 beta chains.
A change to one of these chains will cause a change to all others - so once one oxygen is released, structure becomes tighter and further release is easier, this is influences by pH, CO 2 and metabolic products. Malaria
Parasite carried by mosquitoes able to infect RBCs and uses haemoglobin for energy and replication.
Estimated to have killed half of human life.
The RBC can fight this by 'becoming less perfect', such as acquiring the Haemoglobin S, the heterozygous sickle cell trait, Beta Thalassaemia and G6PD.
G6PD is a red cell enzyme that generates reducing power (NADPH) and protects haemoglobin from oxidative damage.
When G6PD is deficient the pentose phosphate shunt cannot function and the appropriate level of reducing power is not reached, damaging the haemoglobin.
Deficiency of GPPD means that oxidative stress is high, and the haemoglobin is damaged.
It is believed that during a malarial infection oxidative stress is high and malarial cells are destroyed as a result, providing some protection.
This is X-linked and is associated with Heinz bodies, which results in premature RBC destruction in the spleen
This gene is prevalent in Africa, some Arab states and some Mediterranean areas.
Sickle Cell Disease
Sickle Cell Disease arises because of a single gene mutation substituting one amino acid in the β
When deoxygenated the sickle haemoglobin forms long polymers that dramatically alter the red cell shape,
and these are prematurely destroyed in the spleen.
Heterozygotes are generally healthy and unaffected by the mutation; however, homozygotes have a greatly reduced lifespan.
Sickle Haemaglobin (HbS) replaces the Hbβ, and this gives up its oxygen to the tissues and then forms the sickle shape, causing blockages and severe anaemia as well as crises (aplastic, visceral, haemolytic and vaso-occluive)
There must be 2x copies of the HbS gene carried by the individual for it to be expressed (chromosome 11).
There are many preventative measures for this (Folic Acid and Vaccinations) and transfusions but no ultimate cure, CRISPR-cas9 in the future could provide this.
The Beta Haemoglobin chain has a reduced or absent function, so the alpha/beta haemoglobin molecule is not fully formed, and cells are deficient in haemoglobin.
This low haemoglobin environment is inhospitable to malarial parasites and so it cannot develop here.
Thalassemia - The affected red cell cannot make haemoglobin efficiently and the cells and therefore small and pale as a result.
Severe Thalassemia - The red cells here look almost blue with a thin ring of haemoglobin.
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