3.1 Red Blood Cells Flashcards
What do all blood cells originate from?
Haematopoetic stem cells
Where does foetal haematopoeisis start?
The yolk sac in the first 3 weeks of gestation
When does the liver take over as the main site of haemopoiesis?
6-8 weeks of gestation
How does the site of haemopoiesis change at 10 weeks gestation?
Bone marrow becomes main site
Especially in the pelvis, femur and sternum
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 HSC and what does this allow?
The can self renew and differentiate
Maintains adequate population of mature blood cells and controls population of each blood cell type
What are the two cells that HSC differentiate into?
Common Lymphoid Progenitor and Common Myeloid Progenitor
What is the intravascular life span of red blood cells?
120 days
What is the intravascular life span of neutrophils?
7-10 hours
What is the intravascular life span of monocytes?
Several days
What is the intravascular life span of eosinophils?
Slightly shorter than neutrophils (7-10 hrs)
What is the intravascular life span of lymphocytes?
Very variable
What is the intravascular life span of platelets?
10 days
Where does erythropoiesis occur?
Bone marrow
Outline the timeline of erythropoiesis
Proerythroblast
Early → intermediate → late erythroblast
Polychromatic RBC
RBC
How do erythroblasts become mature erythrocytes?
Lose their nucleus
What does seeing nucleated RBCs in blood mean?
High demand for RBCs, thus immature RBCs are released prematurely into circulation
Why do polychromatic RBCs have a blue tinge?
Due to high RNA content on new methylene blue stain
They are still reticulocytes (immature RBCs) that lose their ribosomes after a few days
What happens to RBCs as differentiation progresses?
Self renewal and lineage plasticity decrease
What are the 4 essentials of erythropoiesis?
Erythropoietin
Iron
Vitamin B12
Folic acid
What is haem iron also known as?
Ferrous iron – Fe2+
What is non-haem iron also known as?
Ferric iron – Fe3+
What is erythropoietin?
Glycoprotein growth factor made in the kidneys
When is erythropoietin made and what does this create?
In response to hypoxia and anaemia
Creates a demand-supply feedback loop
How does EPO work?
Interacts with EPO receptors on RBC progenitors in bone marrow to increase RBC production
What affect do phytates have on iron absorption?
They bind to iron and reduce its absorption
What organs is excess iron toxic to?
Heart and liver
Where is ferroportin found?
In duodenum enterocytes
How do we lose iron if it is high?
High iron leads to release of hepcidin which binds to and blocks ferroportin so iron cannot leave duodenum enterocytes
Iron in the enterocytes is bound to ferritin and is lost from the body when the enterocyte dies
What does inflammation do to hepcidin?
Increases hepcidin and reduces iron supply, leading to anaemia of chronic disease
Why do we need Folate and Vitamin B12?
Both are involved in dTTP synthesis thus DNA synthesis
B12 – integrity of nervous system
Folate – homocysteine metabolism
What can a Vitamin B12 and folate deficiency cause?
Megaloblastic erythropoiesis
This is because the cells keep dividing but lack the DNA, thus the cell matures and cytoplasm grows while the nucleus hasn’t matured
Name three sources of folate
Green vegetables, yeast, fruits
Name four sources of B12
Meat, fish, eggs, milk
What does B12 combine with so it can be absorbed?
Intrinsic factor which is made in the gastric parietal cells
What does B12-IF bind to for absorption?
Receptors in the ileum of the small intestine
What are 4 causes of vitamin B12 deficiency?
Inadequate intake
Pernicious anaemia (inadequate IF seretion)
Achlorydria (lack of stomach acid)
Malabsorption (coeliac disease)
What is pernicious anaemia?
Inadequeate intrinsic factor production
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 and how?
In the spleen by reticular endothelial macrophages which phagocytose them
What are the RBCs broken down into?
Haem and globin
What happens to the haem part of the RBC after it is destroyed?
Gets broken down into bilirubin
What happens to the iron that is released from the haem ring when an RBC is destroyed?
Bound to transferritin and sent to bone marrow for recyclin
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?
Cells are flatter and have larger central pallor due to lower Hb content
What is hypochromia associated with?
Microcytosis since iron deficiency and thalassaemia are common causes
What is polychromasia?
Blue tinge to RBC cytoplasm indicating that the cell is young
Thus the cell is also larger than normal
What can polychromasia cause?
Macrocytosis
What are reticulocytes?
Young developing RBCs that may be present due to bleeding or haemolysis
How do we detect reticulocytes?
Stain with new methylene blue for higher RNA content
What are target cells?
When you have an accumulation of haemoglobin in the area of central pallor
What causes the presence of target cells?
Obstructive jaundice, liver disease, hyposplenism, haemoglobinopathies
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)
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 - splenic 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
Which cells do myeloid stem cells give rise to?
Red blood cells, granulocytes, monocytes, mast cells and basophils
What is the function of a platelet?
Haemostasis
What is the function of a monocyte?
Defense against infection by phagocytosis
What is the function of a neutrophil?
Defense against infection by phagocytosis and killing of micro-organisms
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
Which common progenitor do megakaryocytes derive from?
Myeloid
What causes microcytic anaemia?
Defects in haem synthesis (iron deficiency and anaemia of chronic disease)
Defects in globin synthesis (alpha and beta thalassaemia)
What are microcytic cells?
Smaller than normal with areas of central pallor
What can cause lack of iron leading to microcytic anaemia?
Blood loss
Reduced intake
Increased iron requirement
Anaemia of chronic disease
What anaemia does B12/folate deficiency cause?
Macrocytic anaemia
What are macrocytic cells?
Larger than normal with areas of central pallor
Apart from B12 and folate deficiency, what can cause macrocytic anaemia?
Liver disease and ethanol toxicity
Haemolysis (polychromasia)
Pregnancy and drugs that affect DNA synthesis
How does B12/folate deficiency cause macrocytic anaemia?
Inhibits DNA synthesis, causing megaloblastic erythropoiesis
This affects all rapidly dividing cells in the bone marrow and epithelial surfaces in the mouth, gut and gonads
What is normocytic anaemia?
RBCs are of a normal size but still have anaemia
What can cause normocytic anaemia?
Recent blood loss
Failure of RBC production
Pooling of RBCs in spleen
What is iron deficiency anaemia?
Ferritin is reduced, reflecting low body iron stores
What can cause iron deficiency anaemia?
Increased blood loss (e.g. hookworm, menorrhagia)
Insufficient intake and malabsorption
Increased iron requirements due to pregnancy or infancy
What are some clinical features of iron deficiency anaemia?
Pallor, fatigue, breathlessness
Impaired intellectual development in children
Features of underlying causes of deficiency
What are other clinical features of iron deficiency anaemia?
Koilonychia – concave nails
Angular cheilitis – inflammation of both corners of mouth
What is reduced in anaemia?
Hb concentration
RBC
Hct/PCV
Due to a decrease in the absolute amount of Hb in blood
What are the two main functions of iron?
Oxygen transport in haemoglobin
Mitochondrial proteins
What mitochondrial proteins is iron used for?
Cytochromes a, b, c for ATP production
Cytochrome P450 for hydroxylation reactions
Why is ferric (Fe3+) iron not as easily absorbed?
Requires action of reducing substances (e.g. ascorbic acid, vitamin C) for absorption
How does anaemia of chronic disease/inflammation occur?
Pro-inflammatory cytokines (IL-1, TNF-a, IL-6, IFN-gamma) increase EPO which increases hepcidin which binds ferroportin
This decreases iron absorption in the gut as iron is trapped in enterocytes and lost when they die
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
What structures help to maintain the integrity, shape and elasticity of RBCs?
The membrane is a lipid bilayer supported by a protein cytoskeleton with transmembrane proteins
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 causes hereditary spherocytosis?
Disruption to ankyrin/spectrin vertical linkages
What happens to spherocytes?
Premature removal and haemolysis by the spleen due to less flexibility
What would be seen on a blood film of a patient with hereditary spherocytosis?
Rounded, with a regular outline and lacking central pallor
What causes hereditary elliptocytosis?
Disruption of ankyrin/spectrin horizontal linkages
Can also occur in iron deficiency
How does deficiency in glucose-6-phosphate dehydrogenase affect RBCs?
G6PD is an important enzyme in the hexose monophosphate shunt which is responsible for glutathione metabolism
Glutathione normally protects RBCs from oxidant damage during infection or drug use
What protects the red cells from oxidant damage?
Glutathione
What does G6PD deficiency cause?
G6PD deficiency usually causes intermittent, severe intravascular haemolysis (RBC breakdown in blood vessels) as a result of infection or exposure to an exogenous oxidant
What are episodes of intravascular haemolysis in G6PD deficiency associated with the appearance of?
Irregularly contracted cells (bite cells) with no central pallor
Hb is denatured and forms round inclusions called Heinz bodies
What molecule modulates Hb O2 affinity and how?
2,3-DPG
By competing with O2 for Hb binding
What causes a right shift in the O2 dissociation curve?
Decreased pH
Increased CO2
Increased 2,3-DPG
Increased temperature
Thus more O2 unloading due to decreased affinity
What causes a left shift in the O2 dissociation curve?
Increased pH
Decreased 2,3-DPG and temperature
Increase in CO and HbF
Thus more O2 loading due to increased affinity
What is polycythaemia?
Too many RBCs in circulation
What can cause polycythaemia?
Blood doping or overtransfusion
Appropriately increased EPO due to hypoxia
Inappropriate EPO use or renal tumour secreting EPO
Causes independent of EPO
What is polycythaemia vera?
Myeloproliferative disorder of the bone marrow
What does polycythaemia vera cause?
Hyperviscosity leading to thrombosis requiring venesection
How can polycythaemia vera be treated?
Drugs can be given to reduce bone marrow RBC production
What is MCV and its formula?
Average volume of each RBC
What is MCH and its formula?
Average mass of Hb in each RBC
What is MCHC and its formula?
Average concentration of Hb in each RBC
Compare iron deficiency anaemia and thalasseamia in terms of Hb
Iron deficiency – normal or decreased
Thalassaemia – normal or mildly decreased
Compare iron deficiency anaemia and thalasseamia in terms of MCV
Iron def – low in proportion to Hb
Thal – lower for same Hb
Compare iron deficiency anaemia and thalasseamia in terms of MCH
Iron def – low in proportion to Hb
Thal – low for same Hb
Compare iron deficiency anaemia and thalasseamia in terms of MCHC
Iron def – low
Thal – relatively preserved
Compare iron deficiency anaemia and thalasseamia in terms of RBC count
Iron def – low
Thal – increased
Compare iron deficiency anaemia and thalasseamia in terms of Hb electrophoresis
Iron def – normal
B-thal – Hb A2 is raised
a-thal – normal
Compare iron deficiency anaemia and thalasseamia in terms of ferritin
Iron def – low
Thal – normal
