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Blood Production Structure Function Anaemia Notes

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Semester 2 Case 7: Giving and Receiving

* What is the normal composition of blood?
Refer to anatomy workbook for general outline. Whole Blood = 46-63% plasma, 37-54% formed elements. Plasma = 92% water, 7% plasma proteins, 1% other solutes. Formed elements = 99.9% RBC, <0.1% WBC, <0.1% platelets. Extended notes:
{1} Plasma Proteins Albumins: Constitute roughly 60% of the plasma proteins. They are major contributors to the osmotic pressure of plasma. They are also important in the transport of fatty acids, thyroid hormones, some steroid hormones, etc. Globulins: Constitute about 35% of the plasma proteins. Antibodies (AKA. Immunoglobulins) attack foreign proteins & pathogens. Transport globulins bind small ions, hormones, &
compounds that might otherwise be lost at the kidneys or that have very low solubility in water. Fibrinogen: Constitutes roughly 4% of plasma proteins. Under certain conditions, fibrinogen molecules interact, forming large, insoluble strands of fibrin. Fibrin provides the basic structure for a blood clot. Other plasma proteins: Make up the remaining 1%. Examples include insulin, prolactin, TSH, FSH, and LH. Formed Elements Hematocrit = The % of whole blood volume contributed by formed elements. Adult males =
46%, and adult females = 42%. The sex difference in Hematocrit primarily reflects the fact that androgens stimulate red blood cell production, whereas oestrogens do not. Hematocrit can increase due to dehydration, or after EPO stimulation. It can decrease as a result of internal bleeding or problems with RBC production.
[2] RBC:Platelet:WBC = 700:40:1.

* Where is blood formed & how does this vary between the foetus, child &
adult?
Stage of Development

Fetus Infant Adult

Age

0-2 months 2-7 months 5-9 months

Site of Haematopoiesis

Yolk sac Liver, spleen Bone marrow Bone marrow of all bones Bone marrow of flat bones mainly, as only 1/2 of bone marrow is red.

In bone marrow failure e.g. leukaemia, haematopoiesis again takes place in other areas of the body. AKA: Extramedullary haematopoiesis. - liver, spleen, thymus, etc. Stromal cells, including yellow bone marrow, provide the microenvironment for haematopoiesis to occur. They, for example, secrete growth factors and express adhesion molecules. The stromal matrix provides physical support for haematopoietic cells. Foetal Hb has 2 alpha chains & 2 gamma chains. There is increasing synthesis of beta chains from 13 weeks of gestation, and at term there is 80% Hb F and 20% Hb A, which contains 2 alpha chains & 2 beta chains. The switch from Hb F to Hb A occurs after birth when the genes for gamma chain production are further suppressed and there is rapid increase in the synthesis of beta chains. Less than 1% of Hb F is produced after 6 months of life. Hb A2, which contains 2 alpha chains and 2 delta chains, comprises about 2% of adult haemoglobin.

* How is blood formed?
[2] Blood

is composed of plasma and formed elements. Plasma The liver synthesises & releases >90% of the plasma proteins, including ALL albumins &
fibrinogen, MOST globulins, and various prohormones. It is for this reason that liver disorders can alter the composition and functional properties of blood. Antibodies are produced by plasma cells, which are derived from lymphocytes. Peptide hormones are produced in a variety of endocrine organs. Formed Elements The formed elements are produced via the process of haematopoiesis. Blood cells have various lifespans, so need to be produced at various rates. Platelets: 9-10 days. RBCs: 120 days. WBCs: A few days to a few years. RBCs and platelets are produced at the same rate. However, RBCs have a much larger lifespan, so there are more present in the blood. Two populations of pluripotent stem cells are responsible for the production of all of the different types

of formed elements. These are myeloid stem cells and lymphoid stem cells. Lymphoid stem cells only give rise to lymphocytes. Myeloid stem cells give rise to every other blood cell type - RBCs, platelets, neutrophils, basophils, & eosinophils. Stem Cell Division Self-renewal (divide
& proliferate) to maintain stem pool.

Multiplication (mitosis) Differentiation into progenitor cells

Maturation

Function

Cell death Haematopoietic Stem Cells All blood cells originate in bone marrow! They are capable of differentiating into any blood cell type. They become specialised and produce more mature cell types from a precursor. Haematopoietic stem cells give rise to different progenitor cells (myeloid & lymphoid stem cells). They look similar to small/medium lymphocytes, and are identified using CFU (Colony Forming Units) In order to identify progenitor cells, cell culture assays are used. CFU are ascribed to cells based on what lineage they give rise to. They are derived on colonies that form on agar culture. Myeloid cells are CFU GEMM, since they give rise to granulocytes, erythrocytes, monocytes, & megakaryocytes. Lymphoid cells are CFU L, since they give rise to T cells and B cells (lymphocytes). immunological testing for CD34+ and DC38+ markers.

Erythropoiesis Proerythroblasts are large cells with cytoplasm that stains dark blue. They give rise to normoblasts, which are smaller cells whose cytoplasm starts to stain lighter blue. Late normoblasts have extruded nucleus (they get ready to rid their nuclei). Normoblasts then become reticulocytes, which contain some ribosomal RNA, and circulate in peripheral blood for 1-2 days. (An increased number of reticulocytes suggest the body is trying to produce more RBCs, for example in anaemia.) In mature RBCs, RNA is lost. 1000million erythrocytes are replaced every day!
Thrombopoiesis

Endomitosis occurs in myeloid cells to produce megakaryoblasts. This is when nuclear content (chromosomes) increases, but cells don't divide. The cells become larger &
polyploid. At a certain point, endomitosis stops, cytoplasm becomes more granular, and megakaryocytes fragment. This process takes 2-3 days. After 9-10 days, they are broken down if they haven't been used. Each megakaryocyte produces roughly 4000 platelets. Monopoiesis A myeloid stem cell differentiates into a monoblast, which then becomes a promonocyte. Promonocytes are large cells with indented nuclei that are only found in bone marrow. These become monocytes. Monocytes have a kidney-shaped nucleus. They are the largest blood cells. Monocytes remain in circulation for 20-40 hours in peripheral blood. They then migrate to tissues & mature into macrophages, which phagocytise bacteria. Granulopoiesis Granulocytes are eosinophils, neutrophils, and basophils. They begin as myeloblasts, which come from myeloid stem cells. Myeloblasts vary in size, have a large nucleus, but no cytoplasmic granules. They form promyelocytes, then myelocytes, and then metamyelocytes. These become more lobulated, the nucleus changes, and the amount of cytoplasm increases as the cells mature. Neutrophils: Most abundant of white blood cells. They constitute 50-70% of WBCs, and have a very distinct nucleus. The nucleus has between 2-5 lobes. <2 lobes could mean that it is an immature cell. >5 lobes indicates Vitamin B12 or folate deficiencies, which inhibit the production of DNA in the bone marrow. It takes about 14 days for myeloblasts to mature & then enter the peripheral blood. They are highly mobile. Their average lifespan in circulation is 5 days, with a further 1-2 days if in tissues. Basophils: Rarest of WBCs (make up 1% of leukocytes). May be the precursors of mast cells, but we are unsure as they are so rare. They have a very granular cytoplasm that stains bright blue on a blood film. They survive for weeks to months. Their lifespan is thought to be about 60-70 hours. Eosinophils: Have larger cytoplasmic granules. They constitute about 1-4% of circulating leukocytes. Tend not to have >3 nuclear lobes. They only survive for 8-10 hours in circulation, but can last a further 8-12 days in tissue. Lymphopoiesis Lymphocytes differentiate from lymphoid stem cells. In infants, B cell differentiation occurs in liver, but happens in bone marrow in adults. Lymphoid stem cells mature into plasma cells, which then differentiate into B cells. Many other lymphoid stem cells migrate from the bone marrow to peripheral lymphoid tissues, including the thymus, spleen, and lymph nodes, so lymphocytes are also produced in these organs. T cells, for example, tend to mature in the thymus. Lymphocytes have a relatively large circular nucleus, surrounded by a thin halo of cytoplasm. They account for 20-30% of the circulating WBCs. They continuously migrate from the bloodstream, through peripheral tissues, and back into the bloodstream. Most of the body's lymphocytes are usually in other connective tissues and lymphatic organs. Their lifespans vary from weeks to years.

* How is blood cell production initiated?
[2] Haematopoiesis

is initiated by stem cell division. This requires adequate supplies of amino acids, iron, and vitamins (including B12, B6, and folic acid) for protein synthesis. B12 is needed for synthesis of some amino acids, and folic acid is needed for synthesis of purines &
pyrimidines (bases). A differentiated cell is formed & self-renewal occurs.

The differentiation of cells is regulated by transcription factors. There are many, many transcription factors. The most well-known are PU.1 (myeloid lineage) and GATA-1 (erythropoietic & megakaryocytic lineages). There are also growth factors that are needed to stimulate haematopoiesis. These are glycoproteins that can increase the production of haemopoietic cell lines when needed by altering transcription factors, and regulating the proliferation & differentiation of progenitor cells by activating genes. They are present in the extracellular environment, where they bind to the extracellular matrix. Growth factors that play a role in haematopoiesis include:
- G-CSF (Granulocyte Colony-Stimulating Factor)
- GM-CSF (Granulocyte Macrophage Colony-Stimulating Factor)
- M-CSF (Macrophage Colony-Stimulating Factor)
- SCF (Stem Cell Factor)
- IL-3
- IL-5
- EPO (Erythropoietin)
- TPO (Thrombopoietin) Erythropoietin
[1] Erythropoiesis is stimulated directly by the peptide hormone EPO (and indirectly by several hormones, including thyroxine, androgens, and GH). EPO is a glycoprotein that appears in the plasma when peripheral tissues, especially the kidneys & liver, are exposed to low oxygen concentrations. This state is called hypoxia. EPO is released:
- During anaemia
- When bloodflow to the kidneys declines
- When the oxygen content of air in the lungs declines, owing to disease or high altitude
- When the respiratory surfaces of the lungs are damaged. Once in the bloodstream, EPO travels to areas of red bone marrow, where it stimulates stem cells & developing RBCs. EPO has two major effects:

* It stimulates increased cell division rates in erythroblasts & in the stem cells that produce erythroblasts

* It speeds up the maturation of RBCs, mainly by accelerating the rate of Hb synthesis. This corrects hypoxia, and then EPO synthesis is switched off. Thrombopoietin TPO is mainly produced in the liver. It stimulates megakaryocytes & platelet production. Stem Cell Factor This synergises with cytokines such as IL-3 and GM-CSF to increase proliferation of stem cells. GM-CSF This is necessary for growth & development of granulocyte & macrophage progenitor cells. They stimulate myeloblasts & monoblasts. M-CSF This plays a role in proliferation & differentiation of haemopoietic stem cells to produce monocytes & macrophages. G-CSF This is similar to M-CSF but acts on precursor cells which give rise to neutrophils. G-CSF can be used in hospital scenarios to artificially culture WBCs.

* What is the structure & function of Red Blood Cells?
The primary function of red blood cells is to transport respiratory gases. Each RBC is a biconcave disc with a thin central region & a thicker outer margin. Due to their shape, they:

* Have a large surface area-to-volume ratio, which allows faster exchange of oxygen.

* Can form stacks that smooth the flow through narrow blood vessels, and then dissociate again without affecting the cells involved.

* Can bend & flex when entering small capillaries & branches. During their differentiation, RBCs lose most of their organelles, so only the cytoskeleton remains. As they have no nuclei or ribosomes, they are unable to perform repairs, so have a relatively short life span. Their energy demands are low, and as they have no mitochondria, they obtain the energy they need through the anaerobic metabolism of glucose absorbed from the surrounding plasma. The absence of mitochondria also ensures that oxygen is carried to peripheral tissues rather than being used in the cell. Haemoglobin Haemoglobin (Hb) accounts for 95% of all intracellular proteins. Haemoglobin content of whole blood is reported in grams of Hb per decilitre of whole blood. Normal ranges are 1418g/dl in males and 12-16g/dl in females. Haemoglobin is responsible for the cell's ability to transport oxygen & carbon dioxide. Structure :

* Complex quaternary structures.

* Each molecule has 2 a chains and 2 b chains of polypeptides. Each chain is a globular protein subunit that resembles the myoglobin in skeletal & cardiac muscle cells.

* Each of the 4 chains contains a single molecule of heme, a pigment complex. Each heme unit holds 1 iron, so Hb has 4 iron ions. These are held in such a way that an oxygen molecule can interact with an iron ion, forming oxyhaemoglobin, HbO2. A haemoglobin molecule that is not bound to oxygen is called deoxyhaemoglobin.

* Each Hb molecule can bind 4 oxygen molecules.

* Blood containing RBCs filled with oxyhaemoglobin is bright red.

* Blood containing RBCs filled with deoxyhaemoglobin is dark red.

* The iron-oxygen interaction is very weak; the two can easily dissociate without damaging the heme unit or the oxygen molecule. Therefore, the binding is completely reversible. The RBCs of an embryo or a foetus contain foetal haemoglobin, which has a higher affinity for oxygen, so that during development it can "steal" oxygen from the maternal bloodstream at the placenta. The conversion to the adult form begins shortly before birth & continues over the next year. Foetal Hb production can be stimulated in adults by drugs such as hydroxyurea or butyrate, which can be used in conditions such as sickle cell anaemia. Function: 1 RBC contains about 280million Hb molecules. 1 Hb has 4 heme units. So, each RBC can potentially carry more than a billion molecules of oxygen at

a time. 98.5% of oxygen carried by the blood travels through the bloodstream bound to Hb molecules inside RBCs. Amount of oxygen bound to haemoglobin depends primarily on the oxygen content of the plasma. When plasma oxygen levels are low, Hb releases oxygen. Under these conditions (which typically occur in peripheral capillaries), the a and b chains of Hb bind to carbon dioxide, forming carbaminohaemoglobin. In the capillaries of the lungs, plasma oxygen levels are high and carbon dioxide levels are low, so RBCs absorb oxygen and release carbon dioxide. Cell Death: RBCs have a lifespan of about 120 days, after which, either its cell membrane ruptures or some other damage is detected by phagocytes, which engulf the RBC. Macrophages of the liver, spleen, and bone marrow monitor the condition of circulating RBCs, generally recognising & engulfing them before they haemolyse, or rupture. These phagocytes also detect & remove Hb molecules and cell fragments from the relatively small proportion of RBCs (10%)in the bloodstream. If the Hb released by haemolysis isn't phagocytised, its components aren't recycled. Haemoglobin only remains intact inside RBCs. When haemolysis occurs, the Hb breaks down, and the a and b chains are filtered by the kidneys and eliminated in urine. Abnormally large numbers of RBCs breaking down in the bloodstream ? Red/brown urine ?
Haemoglobinuria. Also, the presence of intact RBCs in urine is a sign called haematuria, and only occurs after kidney damage or damage to vessels along the urinary tract. RBC is engulfed & broken down by a phagocytic cell, but each component of the Hb molecule has a different fate:

* Globular proteins are disassembled into their component amino acids. The amino acids are then either metabolised by the cell or released into the bloodstream for use by other cells.

* Each heme unit loses its iron & is converted to biliverdin, an organic compound with a green colour. Biliverdin is then converted to bilirubin, an orange-yellow pigment, & released into the bloodstream. Bilirubin then binds to albumin & is transported to the liver for excretion in bile. [If the bile ducts are blocked or the liver cannot absorb or excrete bilirubin, circulating levels of the compound climb rapidly. It then diffuses into peripheral tissues, giving them a yellow colour - jaundice.]
In the large intestine, bacteria convert bilirubin into urobilinogens & stercobilinogens. Some of the urobilinogens are absorbed into the bloodstream & are subsequently excreted into urine. The remaining urobilinogens & the stercobilinogens, on exposure to oxygen, are converted to urobilins & stercobilins. (Urine = yellow because it contains urobilins. Faeces = Yellow-brown or brown because it contains urobilins & stercobilins in varying proportions.)

* The iron that is lost by heme may be bound & stored in a phagocytic cell or released into the bloodstream.

* Large quantities of free iron are toxic to cells, so in the bloodstream it binds to transferrin, a plasma protein. RBCs that are developing in the bone marrow absorb the amino acids & transferrins from the bloodstream and use them to synthesise new Hb molecules. Excess transferrins are removed in the liver & spleen, and the iron is stored in 2 special protein-iron complexes: ferritin & haemosiderin.

* What is the structure & function of White Blood Cells?
[1] Structure:

Unlike RBCs, WBCs have nuclei & other organelles, but they lack haemoglobin. WBCs can be divided into 2 groups on the basis of their appearance after staining with Wright's stain or Giemsa stain: Granulocytes (with abundant stained granules) -

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