Production and Survival of Red blood Cells Flashcards by Abigail Kusi

Q

Describe what a proerythroblast is.

A

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

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Q

State the stages of the erythroid series

A

Haemocytoblast -> Proerythroblast -> Early erythroblast -> Late erythroblast -> Normoblast -> Reticulocyte -> Erythrocyte

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Q

Early erythroblast stage

A

Has a much stronger basophilic cytoplasm and much condensed nucleus

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Q

Late erythroblast stage

A

Not as basophilic as the early erythroblast.
Also known as poly-chromatic erythroblast.

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Q

Normoblast stage Pt.1

A

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.

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Q

Normoblast stage Pt.2

A

This becomes an auto-chromatic erythroblast which will the differentiate then extrude the nucleus.

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Q

What happens when the nucleus is expelled from the auto-chromatic erythroblast?

A

The expelled nucleus can be engulfed by macrophages.

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Q

Reticulocyte stage

A

After the expulsion of the nucleus the cell still contains some residual RNA which continues to make Hb.

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Q

Erythrocyte stage

A

As the cell matures to an erythrocyte, all the residual RNA is removed and it becomes mature red blood cell with a biconcave shape.

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Q

What is the relationship between rbc and ambient oxygen pressure?

A

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.

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Q

Name the key regulator of the rbc and oxygen pressure feedback loop.

A

Erythropoietin (EPO)

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Q

Name a stimulus of the feedback loop

A

Hypoxia due to:
decreased RBC count
decreased hemoglobin
or decreased availability

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Q

What is HIF?

A

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.

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Q

What is ferropoietin?

A

Its a iron-absorbing protein. It carries iron through the blood to the site of rbc production.

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Q

The central role of iron in erythropoiesis

A

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.

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Q

The central role of iron in Hb production

A

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.

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Q

What regulates iron in rbc production?

A

Hepcidin

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Q

HIF can be regulated or degraded by what and why?

A

Prolyl hydroxylase domain (PHD) - it will degrade HIF if no more EPO is needed

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Q

Function of hepcidin

A

Inhibits intestinal iron absorption and iron release from macrophages, thereby reducing iron availability by binding to ferropoietin and induces its internalisation and degradation

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Q

When does hepcidin inhibit ferropoietin?

A

If iron is not required for the synthesis of Hb.

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Q

What’s the purpose of erythroferrone?

A

Produced by erythroblasts and acts on hepatocytes to suppress hepcidin production.

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Q

Apart from ferropoietin, what else regulates iron-absorption?

A

DMT - 1 (divalent metal transporter 1)

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Q

Function of DMT - 1

A

Helps iron to be transported from the lumen into the enterocytes (cells in the intestines) then into circulation regulated by ferropoietin.

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Q

Sources of iron

A

Meat, eggs, vegetables and dairy foods

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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