3.1, 3.3 & 3.4 - Red Blood Cells Flashcards
1
Q
Origin of blood cells - haemopoiesis
A
- blood cells of all types originate in the bone marrow
- derived from pluripotent haemopoietic stem cells (HSCs) throughout life - HSC = hemocytoblast
- HSCs give rise to lymphoid stem cells (give rise to T, B, NK lymphocytes) and myeloid stem cells (give rise to erythrocytes, platelets, granulocytes, monocytes, eosinophils, mast cells, basophils) - common lymphoid and myeloid progenitor
- haemopoiesis - the formation and development of blood cells
2
Q
Functions and life span of blood cells
A
- erythrocyte - 120 days - oxygen transport
- platelet - 10 days - haemostasis
- monocyte - several days - defence against infection by phagocytosis + killing of microorganisms
- neutrophil - 7 to 10 hours - defence against infection by phagocytosis + killing of microorganisms
- eosinophil - little shorter than a neutrophil - defence against parasitic infection
- lymphocyte - variable - humoral and cellular immunity
3
Q
Essential characteristics of HSCs
A
HSCs have the ability to both:
1) self renew
- some daughter cells remain as HSCs
- pool of HSCs not depleted
2) differentiate to mature progeny
- other daughter cells follow a differentiation pathway
4
Q
Sites of haemopoiesis
A
- yolk sac - in embryo within mesoderm
- liver - takes over at 6-8 weeks gestation, is principal source of blood in foetus until shortly before birth
- bone marrow - starts developing haematopoietic activity at 10 weeks gestation
- haemopoiesis in children occurs in almost all bone
- in adults it mainly occurs in the bone marrow, especially the pelvis, femur and sternum
5
Q
Haemopoietic progenitor cells
A
- pluripotent HSC –> common lymphoid progenitor + common myeloid progenitor
- HSCs and progenitor cells are distributed in an ordered fashion within the bone marrow amongst mesenchymal cells, endothelial cells and the vasculature with which the HSCs interact
- haemopoiesis is regulated by a number of genes, transcription factors, growth factors and the microenvironment
- disruption of this regulation can disturb the balance between proliferation and differentiation, and may lead to leukaemia or bone marrow failure
6
Q
Haemopoietic growth factors
A
- glycoprotein hormones which bind to cell surface receptors
- regulate proliferation and differentiation of HSCs
- regulate function of mature blood cells
- erythropoiesis (RBC production) - erythropoietin
- granulocyte and monocyte production - G-CSF, G-M-CSF, cytokines e.g. interleukins
- megakaryocytopiesis and platelet production - thrombopoietin (TPO)
7
Q
Lymphoid differentiation
A
pluripotent HSC –> common lymphoid progenitor –>
- B cell progenitors in bone marrow –> mature B cells (antibody-producing)
- T cell progenitors in thymus -> bone marrow –> mature T cells (cytokine-producing)
- NK cell progenitors in bone marrow –> mature NK cells (cytokine-producing)
8
Q
Myeloid differentiation
A
pluripotent HSC –> common myeloid progenitor –>
- MEP –> erythroid + megakaryocyte
- granulocyte-monocyte
9
Q
Development of RBCs - erythropoiesis
A
- the common myeloid progenitor can give rise to a proerythroblast
- this in turn gives rise to erythroblasts and then erythrocytes (continue to divide and mature, losing nuclei and organelles)
- as the differentiation progresses, self-renewal and lineage plasticity decrease
- polychromatic RBC (young RBC with high RNA content seen using methylene blue stain - reticulocyte) –> RBCs
- erythropoiesis requires iron, folic acid, vitamin b12, erythropoietin (EPO)
10
Q
Development of anaemia
A
low iron / b12 / folic acid –> anaemia
- microcytic (small RBCs) - iron deficiency due to blood loss, reduced intake, increased requirement. Low iron availability leads to anaemia of chronic disease/inflammation
- macrocytic (large RBCs) - b12 / folic acid deficiency - megaloblastic anaemia
11
Q
Erythropoietin (EPO)
A
- normal erythropoiesis requires the presence of the growth factor EPO
- EPO is a glycoprotein that is synthesised in response to hypoxia/anaemia so there is a demand-supply feedback loop
- stimulates bone marrow to produce more RBCs
- EPO is produced in the kidney
12
Q
Development of RBCs - iron
A
Iron has two major functions:
- oxygen transport in haemoglobin
- mitochondrial proteins cytochrome a, b and c - for production of ATP, and cytochrome P450 for hydroxylation reactions (e.g. drug metabolism)
13
Q
Iron absorption
A
- iron is absorbed in the duodenum
- haem iron (animal derived) is in ferrous (Fe2+) form - best absorbed form
- non-haem iron is present in ferric (Fe3+) form in food and requires action of reducing substances (e.g. ascorbic acid, vitamin C) for absorption - sources often contain phytates which reduce absorption
14
Q
Iron homeostasis
A
- excess iron is potentially toxic to organs and there is no physiological mechanism by which iron is excreted, therefore iron absorption is tightly controlled
- absorption in the gut is carefully regulated according to body stores by hepcidin, secreted by the liver in response to high storage iron
- high iron levels stored = increased hepcidin = reduces absorption
- low iron levels stored = decreased hepcidin = increases absorption
- hepcidin synthesis is suppressed by erythropoietic activity - ensures iron supply by increasing ferroportin in the duodenum enterocyte, increasing absorption
15
Q
What does hepcidin do?
A
- decreases Fe absorption
- decreases Fe transport
- decreases Fe availability
- hepcidin binds to ferroportin and induces its internalisation = prevents efflux of iron from duodenal enterocyte
- iron lost when enterocyte dies and is shed into gut lumen
- when iron stores (ferritin) are full, upregulation of hepcidin expression = iron absorption limited
- requirement for increased erythropoiesis (needs iron for Hb) = reduction in hepcidin = increased iron absorption
16
Q
What is transferrin?
A
- the transport protein in plasma that delivers iron to bone marrow for erythropoiesis and for its use in enzymes and muscles
17
Q
What is ferritin?
A
- protein that stores and releases iron
- reduced ferritin –> reduces hepcidin production –> increases iron supply = negative feedback
18
Q
What are vitamin B12 and folic acid required for and where are some sources?
A
Vitamin B12 is required for:
- DNA synthesis
- integrity of the nervous system
Folic acid is required for:
- DNA synthesis
- homocysteine metabolism
- vitamin b12 - animal origins e.g. meat, eggs, fish, milk & fortified cereals
- folate - both animal and plant origins - green leafy vegetables, yeast, fruit
19
Q
How are vitamin B12 and folic acid important in erythropoiesis?
A
- vitamin b12 and folate are needed for dTTP synthesis, necessary for the synthesis of thymidine
- deficiency inhibits DNA synthesis –> megaloblastic erythropoiesis in bone marrow –> macrocytic anaemia
- affects all rapidly dividing cells: bone marrow (cells can grow but are unable to divide), epithelial surfaces of mouth and gut, and gonads
20
Q
Absorption of folate and vitamin B12
A
Folate - absorbed in small intestine, requirements increase during pregnancy and increased RBC production e.g. sickle cell anaemia
Vitamin B12:
- stomach - B12 combines with intrinsic factor (IF) made in the gastric parietal cells
- small intestine - B12-IF binds to receptors in the ileum
- vitamin B12 deficiency may result from inadequate intake (veganism), inadequate secretion of IF (pernicious anaemia, autoimmune), malabsorption, lack of stomach acid
21
Q
RBC destruction
A
- iron released from haem ring and bound to transferrin to return to bone marrow where it is recycled
- erythrocyte circles for around 120 days
- ultimately destroyed by phagocytic cells of the spleen (macrophages)
- haem –> bilirubin - excreted in bile
22
Q
RBC function - essential requirements
A
Erythrocyte function depends on:
- integrity of the membrane
- haemoglobin structure and function
- cellular metabolism
- a defect in any of these results in shortened erythrocyte survival (haemolysis)
23
Q
The RBC membrane
A
- erythrocytes are biconcave - aids manoeuvrability through small blood vessels to deliver oxygen
- membrane is made of a lipid bilayer supported by a protein cytoskeleton and contains transmembrane proteins
- these maintain the integrity, shape and elasticity of the RBC
- disruption to vertical linkages in the membrane causes hereditary spherocytosis (autosomal dominant) –> spherocytes are cells that are approx spherical in shape and lack a central pallor. They result from the loss of cell membrane without the loss of an equivalent amount of cytoplasm so cell is forced to round up. RBCs become less flexible and are removed prematurely by the spleen - haemolysis
- disruption of horizontal linkages in membrane produces hereditary elliptocytosis - elliptocytosis may also occur in iron deficiency
24
Q
RBC metabolism
A
Highly adapted for:
- generation of ATP to meet energy demands
- maintenance of: Hb function, membrane integrity and deformability, RBC volume
25
Glucose-6-phosphate dehydrogenase deficiency
- G6PD - important enzyme in the hexose monophosphate (HMP) shunt, tightly coupled to glutathione metabolism, which protects the cell from oxidant damage - deficiency of G6PD causes RBCs to be vulnerable to oxidant damage
- oxidants generated in bloodstream (e.g. during infection) or exogeneous (e.g. drugs, broad beans)
- X-linked inheritance = usually males affected
- G6PD deficiency usually causes intermittent, severe intravascular haemolysis as a result of oxidant exposure
- episodes of intravascular haemolysis are associated with the appearance of considerable numbers of bite cells - irregular in outline but smaller than normal cells and lost their central pallor, usually resulting from oxidant damage to cell and Hb
- Hb is denatured and forms round inclusions known as Heinz bodies (detected by test)
26
Polycythaemia
- means 'many cells' - too many RBCs in circulation
- Hb, RBC and HCT are all increased compared with normal subjects of the same age and gender
- pseudo: reduced plasma volume
- true causes: blood doping/overtransfusion, appropriate EPO elevation (e.g. hypoxia), inappropriate erythropoietin use, independent of EPO
27
What is polycythaemia vera?
- polycythaemia can result from inappropriately increased erythropoiesis that is independent of EPO
- intrinsic bone marrow disorder - polycythaemia vera
- myeloproliferative disorder
- polycythaemia --> thick blood (hyperviscosity) --> vascular obstruction/thrombosis
- blood can be removed (venesection) to reduce viscosity
- drugs can be given to reduce BM production of RBCs
28
Blood cell parameters
- WBC - white blood cell count in a given volume of blood (x 10^9/l)
- RBC - red blood cell count in a given volume of blood (x 10^12/l)
- Hb - haemoglobin concentration (g/l)
- Hct - haematocrit (l/l) - previously known as PCV and expressed as % - proportion of RBCs in blood
- MCV - mean cell volume (fl) (1 x 10^-15 L)
- MCH - mean cell haemoglobin (pg) (1 x 10^-12 g)
- MCHC - mean cell haemoglobin concentration (g/l)
- platelet count - the number of platelets in a given volume of blood (x 10^9/l)
29
Calculating MCV
- divide total volume of red cells in a sample by the number of red cells in a sample
- MCV (fl) = (Hct x 1000) / RBC
30
Calculating MCH
- the amount of haemoglobin in a given volume of blood divided by the number of red cells in the same volume
- Hb / RBC
31
Calculating MCHC
- the amount of haemoglobin in a given volume of blood divided by the proportion of the sample represented by red blood cells
- Hb / Hct
32
What is anaemia?
- anaemia is a reduction in the amount of Hb in a given volume of blood below what would be expected in comparison with a healthy subject of the same age and gender
- Hb concentration is reduced
- RBC and Hct/PCV also usually reduced
- usually due to the reduction of the absolute amount of Hb in the bloodstream
- looking at other parameters e.g. MCV can help determine the cause of the anaemia
33
Anaemia - mechanism vs cause
- the mechanism might be failure of RBC production
- the cause could be either a condition causing reduced synthesis of haem or reduced synthesis of globin
- sometimes the mechanism nor the cause are immediately apparent - classification on the basis of cell size can help suggest specific causes
- microcytic - usually also hypochromic
- normocytic - usually also normochromic
- macrocytic - usually also normochromic
- normal RBCs have about a third of the diameter that is pale - result of the disc shape, centre has less Hb and is paler
- hypochromia - cells have a larger area of central pallor than normal, resulting from a lower Hb concentration and a flatter cell
34
What are the causes of iron deficiency anaemia?
- increased blood loss - commonest cause in adults, hookworm commonest cause worldwide, gastrointestinal (often silent), menstrual (menorrhagia)
- insufficient intake - dietary (vegetarians), malabsorption (Coeliac disease, H. pylori gastritis)
- increased requirements - physiological e.g. pregnancy, infancy
- treated with iron replacement therapy
35
What are the clinical features of iron deficiency anaemia?
- pallor, fatigue, breathlessness
- failure to thrive, impaired intellectual development in children
- koilonychia, angular cheilitis
36
How do you distinguish between iron deficiency and thalassaemia trait?
- reduced MCH and MCHC = iron deficiency
- reduced MCH, normal MCHC = thalassaemia trait
- iron deficiency vs thalassaemia trait
- Hb: normal vs normal
- MCV: low (in proportion to Hb) vs lower for same Hb
- MCH: low (in proportion to Hb) vs lower for same Hb
- MCHC: low vs relatively preserved
- RBC: low vs increased
- Hb electrophoresis: normal vs Hb A2 raised in B-thal trait
- ferritin: low vs normal
37
What is microcytic anaemia?
- anaemia in which average cell size is decreased
- common causes:
- defect in haem synthesis e.g. iron deficiency, anaemia of chronic disease
- defect in globin synthesis (thalassaemia) - defect in alpha chain synthesis (a-thalassaemia) or defect in beta chain synthesis (B-thalassaemia)
38
What is macrocytic anaemia?
- anaemia in which average cell size is increased
- lack of vitamin B12 / folic acid (megaloblastic anaemia - megaloblast is an abnormal erythroblast in the bone marrow, larger than normal and shows asynchronous nucleocytoplasmic maturation)
- use of drugs interfering with DNA synthesis
- liver disease and ethanol toxicity
- haemolytic anaemia (reticulocytes increased) - shortened erythrocyte survival
39
What is polychromasia?
- polychromasia describes an increased blue tinge to cytoplasm of a red cell
- indicates that the cell is young and reflects increased erythropoiesis in the bone marrow which occurs as a response to haemolysis
- polychromatic cells larger than normal RBCs --> polychromasia is one of the causes of macrocytosis
40
What is normocytic anaemia?
- cells are average sized
Mechanisms:
- recent blood loss - e.g. GI haemorrhage, trauma
- failure of production of RBCs - e.g. bone marrow failure or suppression (e.g. chemotherapy), bone marrow infiltration (e.g. leukaemia), anaemia of chronic disease
- pooling of red cells in the spleen - e.g. hypersplenism (e.g. liver cirrhosis), splenic sequestration in HbSS
41
What is poikilocytosis?
- RBCs show more variation in shape than normal
- target cells
- sickle cells
- fragments
- spherocytes
- elliptocytes
- irregularly contracted cells (hemighosts/bite cells/blister cells)
