Production and Survival of Red blood Cells Flashcards
Describe what a proerythroblast is.
It’s the first recognisable cell in the erythroid series. It is a large cell with loose, lacy chromatin and clearly visible nucleoli with a basophillic cytoplasm
State the stages of the erythroid series
Haemocytoblast -> Proerythroblast -> Early erythroblast -> Late erythroblast -> Normoblast -> Reticulocyte -> Erythrocyte
Early erythroblast stage
Has a much stronger basophilic cytoplasm and much condensed nucleus
Late erythroblast stage
Not as basophilic as the early erythroblast.
Also known as poly-chromatic erythroblast.
Normoblast stage Pt.1
The cell has started to make more Hb so the cell size has decreased and the nucleus has condensed more.
Cytoplasm is more pinkish as more Hb is produced and the cytoplasm becomes more acidophilic compared to the basophilic cytoplasm of the erythroblasts.
Normoblast stage Pt.2
This becomes an auto-chromatic erythroblast which will the differentiate then extrude the nucleus.
What happens when the nucleus is expelled from the auto-chromatic erythroblast?
The expelled nucleus can be engulfed by macrophages.
Reticulocyte stage
After the expulsion of the nucleus the cell still contains some residual RNA which continues to make Hb.
Erythrocyte stage
As the cell matures to an erythrocyte, all the residual RNA is removed and it becomes mature red blood cell with a biconcave shape.
What is the relationship between rbc and ambient oxygen pressure?
Number of rbc is inversely related to ambient oxygen pressure. When ambient oxygen pressure is low, more rbc are produced to be able to carry enough oxygen around the body. This suggests a negative feedback loop.
Name the key regulator of the rbc and oxygen pressure feedback loop.
Erythropoietin (EPO)
Name a stimulus of the feedback loop
Hypoxia due to:
decreased RBC count
decreased hemoglobin
or decreased availability
What is HIF?
Hypoxia inducing transcription factor. It determines EPO gene expression in kidneys and enhances expression of iron-absorbing genes which go on to make iron-absorbing proteins.
What is ferropoietin?
Its a iron-absorbing protein. It carries iron through the blood to the site of rbc production.
The central role of iron in erythropoiesis
When blood oxygen content is low and it goes through the kidney, HIF-2 will then determine the gene expression of EPO to release EPO from the kidney and that goes into the erythroblast for the synthesis of mature red cells and also Hb.
The central role of iron in Hb production
Iron is absorbed from the small intestines into the blood by the help of ferropoietin. The ferropoietin carries rbc to site of rbc production. As red cells are produced, they go in circulation where the red cells are carried in circulation with oxygen bound to the iron in the Hb.
What regulates iron in rbc production?
Hepcidin
HIF can be regulated or degraded by what and why?
Prolyl hydroxylase domain (PHD) - it will degrade HIF if no more EPO is needed
Function of hepcidin
Inhibits intestinal iron absorption and iron release from macrophages, thereby reducing iron availability by binding to ferropoietin and induces its internalisation and degradation
When does hepcidin inhibit ferropoietin?
If iron is not required for the synthesis of Hb.
What’s the purpose of erythroferrone?
Produced by erythroblasts and acts on hepatocytes to suppress hepcidin production.
Apart from ferropoietin, what else regulates iron-absorption?
DMT - 1 (divalent metal transporter 1)
Function of DMT - 1
Helps iron to be transported from the lumen into the enterocytes (cells in the intestines) then into circulation regulated by ferropoietin.
Sources of iron
Meat, eggs, vegetables and dairy foods
Absorption of iron from its sources
5-10% absorbed (1mg) in the duodenum and jejunum.
Gastric secretion (of HCI) and ascorbic acid help absorption from duodenum to jejunum
How much iron does a normal western diet provide?
15mg of iron daily
State 4 causes of iron defiencey
Poor diet
Increased demand
Chronic blood loss
Malnutrition
Poor diet
Inadequate intake
Malabsorption
Malabsorption
Can be any lesion in the small intestines that prevents the GI tract from absorbing the nutrients that are required by the body. E.g. Coelic disease
What is Colic disease?
A disease where absorption is disrupted because the villi has gone through villus atrophy so the is mild absorption.
Increased demand
Pregnancy
Growth spurt
Pregnancy
There is an increase in rbc production so there is an increased iron demand. Iron is needed for the synthesis of Hb in the red cell and for increase in maternal red cell mass of about 35%, transfer of 300mg of iron to fetus.
Chronic blood loss
GI bleed - leads to blood loss
Excess loss in menses
Chronic blood loss
GI bleed - leads to blood loss
Excess loss in menses
Chronic blood loss
GI bleed - leads to blood loss
Excess loss in menses
Chronic blood loss
GI bleed - leads to blood loss
Excess loss in menses
Chronic blood loss
GI bleed - leads to blood loss
Excess loss in menses
Chronic blood loss
GI bleed - leads to blood loss
Excess loss in menses
Symptoms of iron defiency
IDA
Spoon nails
IDA
The red cells are smaller and paler than the normal red cells. They are called hypochromic microcytic anemia in iron deficiency. The mean cell volume will be less than the normal one.
Where can you find B12?
fish
liver
meat
dairy products
fruits
vegetables
How is B12 absorbed?
It binds to IF which transports it from the stomach to the ileum where there is a receptor to allow B12 to be absorbed.
Function of IF
Intrinsic factor (IF) is a protein made by the parietal cells in the stomach and transports B12 to the ileum. No IF means no B12 absorption.
Where is folate absorbed?
Folate is absorbed in the duodenum and jejunum in the form of MTHF (methyltetrahydrofolate)
Roles of folate and B12?
Both are essential for DNA synthesis and RBC maturation. In the absence of one, DNA maturation is delayed.
Both are needed for the formation of thymidine triphosphate which is an essential building block of DNA.
B12 is a coenzyme for what?
Its a coenzyme for methionine synthase in methylation of homocysteine to methionine.
What are the 3 main causes of Vitamin B12 deficiency?
Inadequate intake
Absorption defect
IF defiency
Example of inadeqaute intake
Vegans
Examples of Absorption defect
Tropical sprue
Coeliac dx
IF deficiency examples
Pernicious anaemia
Crohn’s dx
Gastrectomy
what is tropical sprue and what does it cause?
It’s an infectious disease found in tropical areas and affects the villi of the small intestines. By affecting the villi, it will subsequently affect the absorption of B12.
what is tropical sprue and what does it cause?
It’s an infectious disease found in tropical areas and affects the villi of the small intestines. By affecting the villi, it will subsequently affect the absorption of B12.
What is coeliac dx?
When the villi of the small intestine goes through villus atrophy so the small intestine is not able to function properly to help in the absorption of nutrients, particularly B12.
Describe Pernicious anaemia
An autoimmune disease due to gastric atrophy. By affecting the GI tract, the stomach does not have the parietal cells to produce IF.
What happens with Crohn’s dx?
Crohn’s dx can affect every part of the GI tract.
What is gastrectomy?
When the stomach is removed. If the stomach is removed then there is no parietal cells to produce IF that helps transport B12 which also leads to B12 deficiency.
Give the 4 causes of folate deficiency
Inadequate intake
Absorption defect
Demand/loss
Drugs
Demand/loss can be
Pregnancy
Haemolysis
Cancer
Example of Drugs that cause folate deficiency
Anticonvulsants
Anticonvulsants
Some inhibit the absorption of folate.
What are the effects of folate and B12 deficiencies?
Megaloblastic anaemia with macroovalocytes and hypersegmented neutrophil
Describe the effect of folate and B12 on a blood film
Red cells become bigger than normal due to a delay in nuclear maturation and biconcave shape is unseen. Oval macrocytes and reduced wbc and platelets.
What effect does only B12 have?
Demyelination in the CNS
What else can affect RBC production?
Renal dx - due to reduced EPO
Reduced BM erythroid cells - needed to mature to erythrocytes
Give 2 causes of reduced BM erythroid cells
Aplastic anaemia
Marrow infiltration by leukemia or the other malignancies
How do RBCs function and survive without nuclei or cytoplasmic organelles?
Components needed for their function and survival are already present when erythrocytes reach maturity.
What is the role of red cell enzymes in RBC survival?
The ability to survive depend on cytoplasmic enzymes involved in metabolic pathways.
The metabolic pathways provide energy to accomplish several of the cell’s functions. Name the metabolic processes involved.
Glycolytic (Embden-Meyerhof) pathway
Hexose Monophosphate Shunt (or PPP)
Rapoport-Luebering shunt
What is the most significant effect when the cells are not functioning properly?
Enzyme defects
Glycolytic Pathway
Generates ATP
State the role of pyruvate kinase in the glycolytic pathway
It converts phosphoenolpyruvate to pyruvate
State the role of ATP in RBC production
Maintains the red cell shape, deformability and flexiblity
Regulates intracellular cation conc. via cation pumps (3Na out, 2K in) and also water content within the cell
What effects ATP generation
PK - an autosomal recessive disorder results in low intracellular ATP generation affecting membrane structure.
PK (pyruvate kinase deficiency)
ATP is depleted - cells lose large amounts of potassium and water becoming dehydrated and rigid - causes chronic non-spherocytic haemolytic anaemia
Importance of PPP in RBC production
10% of red cell glucose is metabolised via PPP
G6PD is a product of PPP and brings about the generation of NADPH. Why is NADPH so important?
It has a role in protecting the red bllod cell from oxidative stree.
Why do red blood cells need to be protected from oxidative stress?
Oxidative stress can lead to red cell damage or precipitation of Hb within the cell forming Heinz bodies
Give 1 cause and 1 prevention of oxidative stress
GSH acts as an anti-oxidant that prevents oxidative stress to the red cell
Anti-malarial drugs cause oxidative stress
