BMS2021 - Blood.docx

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Monash University
Biomedical Sciences
Prof.Christina Mitchell

Blood Blood contains many types of cells with different function, all derived from one cell of origin (stem cells) in the bone marrow. Red cell: the main function is to transport oxygen and delivery of 02 to tissues. White cell: fight infection and mediate the immune response. Platelets: responsible for the arrest of bleeding. Granulocytes: 3 types recognised on the basis of morphology and chemistry and function. Neutrophils: Multilobed nucleus – most common the function to phagocytose bacteria. Basophils: Function is to secrete histamine and mediate inflammatory reaction they are the circulating form of tissue mast cells. Eosinophil’s : Mediate allergic inflammatory responses. Lymphoctyes: B cells – make antibodies T cells – Kill virus infected cells and regulate the activity of other cells NK cells – subset of lymphocytes that kill some types of tumour cells and also some virus infected cells. White blood cells circulate within capillaries. Damaged tissues release mediators of inflammation. Chemotaxins towards attractants, released from damages tissues. White blood cells in connective tissue. Bone marrow is the site of blood cell formation from hematopoietic stem cells. Bone marrow transplantation. Bone marrow can be harvested and can be transplanted into recipient without marrow. Expriment done, irradiated mice, halts blood cell production, the mouse will die if no further treatment given. Treatment sia n ijection of bone marrow cells from a healthy donor. The mouse survives, the injected stem cell colonize its hemopoietic tissues and generate a steady supply of new blood cells. Haematopoiesis This is the method of the production of differentiated blood cells. These include red blood cells (erythrocytes) as well as the different white cell types i.e. NK cells, T, cells, B cells etc. The pathway for all of the different cells begins with a single multipotent hemopoietic stem cell. This becomes a multipotent hemopoietic progenitor cell, that is destined to become a blood cell. This differentiates into two progenitors, a common lymphoid progenitor or a common myeloid progenitor. The common lymphoid progenitor differentiates into cells that become NK cells, T cells, B cells and dendritic cells. Common myeloid progenitor cells however become monocytes, neutrophils, eosinophils, basophils, megakaryocytes and erythrocytes. Hematopoietic stem cells are regulated by stromal cells and growth factors in the bone marrow to proliferate, differentiate or die. Granulopoiesis This is the formation of granulocytes, which are neutrophils, basophils and eosinophils. It occurs within the bone marrow as a part of haematopoiesis. Regulation is maintained by a number of factors. GM-CSF stimulates maturation of these granulocytes and enhances neutrophil activity. IL-3 has multilineage mutation and proliferative effects. G-CSF is widely produced in response to inflammatory stimuli and neutrophil maturation and mobilisation. IL-5 supports terminal differentiation of eosinophils and synergises with GM-CSF. Stem cell factor is ligand for c-Kit receptor tyrosine kinase. Supports mast cell differentiation and activation, It also stimulates proliferation of hemopoietic stem cells. CSFs and cytokine signalling. Receptors (IL3 or GMCSF) are bound to the cell membrane. A common beta subunit is present, which binds to the receptor when ligand is bound, causing a signal. The red cell is a round, biconcave disc. It has no nucleus and no organelles. It does possess a complex cytoskeleton which allows it to squeeze though the micro circulation. Its main function it to transport oxygen around the body. It picks up oxygen from within the lungs. Haemoglobin is the functional unit. When leaving the lungs the haemoglobin, now oxy-haemoglobin carries oxygen. It picks up c02 from the tissus, where its travels back to the lungs as deoxy-haemoglobin to release the co2 and pick up 02. Erythropoietin is a glycoprotein hormone. It is synthesised in the peritubular endothelial cells of the kidney and is triggered in response to hypoxia. It binds to receptors on primitive erythroid cells in the bone marrow and stimulates stem cells already commited to becoming rbc. Reticulocytes are immature red blood cells, that mature in the blood stream roughly 24 hours after release from the bone marrow. After erythropoietin release an increase of reticulocytes is seen. Mammalian Red Blood cells. Mammalian red blood cells contain no nucleus, and no endoplasmic reticulum and therefore there is no protein synthesis. No mitochondria and therefore no oxidative metabolism. It is highly specialled cytoskeleton, therefore while this allows for ability to squeeze through microcirculation it results in limited repair capacity. The life span of a RBC is ~120 days. Anaemia is defined as either a reduction in blood cells, concentration of haemoglobin or volume of red blood cells. It could also result from a combination or all of these characteristics. Normal lifespan of a RBC is 120 days, after 100 they experience a low rate of glycolysis, low ATP and have a loss in flexibility. These cells are removed from circulation by macrophages of the spleen and liver. Iron is reused. Protoporphyin of hem is metabolised and excreted in the faeces or urine. Heme is converted to biliverdin, then to bilirubin. Polycythaemia is an increase or excess of RBCs. Anaemia’s result from iron deficiencies, haemoglobin abnormalities or abnormalities in RBC proteins. Polycythaemias can result from chronic hypoxia, erythropoietin excess or leukaemia. An indication of anaemia is an abnormal cell RBC size. Identification of this down a microscope may prompt further investigation. Iron is key nutritional requirement for erythropoiesis. It is lost though urine, feces and bleeding. Low absorption rate requires consumption of 5-20mg/day. B12 and folic acid are required for rapid cell divison and copper are cofactors for enzymes synthesizing RBCs. Haemoglobin While Human haemoglobin a (adult) makes up 97.5% of total adult haemoglobin, there are 5 other normal haemoglobins that are mainly found at other time of development. It is found in tetramers with two alpha or alpha like chains and two beta or beta like chains. Haemoglobin production is characterised by two significant switches in production. After the first 2 months embryonic haemoglobin is switched to fetal. Just before birth it switches to adult. A globin and B globin are encoded by two genetically distinct loci, chromosome 6 and 11 respectively. In both clusters, the genes are arranged 5` to 3` in the order in which they are expressed during development. A thalassemia is an inherited haemoglobin disorder that affects globin synthesis. Can vary from mild to severe and arises from an imbalance between the number of a and b globin chains. Failure to produce a is termed a thalassemia and is fatal. Failure to produce b globin is termed b thalassemia and results in life long transfusion dependence. Beta thalassemia (major) this disease results in underproduction of haemoglobin and ineffective erythroid development. This causes anaemia and and abnormal red blood cells. Anaemia develops within the first few months of life. Haematopoiesis can outside of the bone and result in an enlarged spleen. Expansion of the bone marrow with erythropoiesis results in thin bones and expansion of the marrow into the facial bones. Alpha chain proceeds at normal rate, causing an imbalance and thereby excess of a chains. These for unstable complexes which precipitate in the cell and cause haemolysis. Alpha thalassima Severe homozygous die in utero. Milder forms survive to adult life. Beta tetramers precipitate in the cell and inclusion bodies form with causes cell damage and destruction of the red cell occurs. Hemostasis This involves the prevention and cessation of bleeding from blood vessels by formation of blood clots. These mechanisms are usually effective at stopping bleeding from small vessels, but not usually adequate to stop bleeding from large vessels. This mechanism is tightly regulated, inappropriate clot formation can lead to arterial and venous thrombosis causing heart attacks or strokes. Therefore there exists a balance between the prevention of clotting and promotion of clotting. Haemostasis pathway. in the event of vessel injury. Vasoconstriction of the broken vessel occurs to reduce bleeding. A platelet plug then forms as platelets adhere to exposed collagen fibres of the vessel wall and temporarily seals the break. A blood clot forms as platelets and erythrocytes become enmeshed in fibrin threads. This forms a longer lasting seal and gives the vessel a chance to repair itself. The vascular spasm is the immediate response for protection against blood loss and in maintained long enough for the plug to form. The endothelial lining of blood vessels usually prevents contact between blood compartments and subendothelium. Normally the endothelium contains and secretes anti-coagulant proteins that act to maintain circulating blood in a fluid phase. Damage to the endothelium by trauma exposes the subendothelium. This contains proteins such as collagen ad Von Willebrand factor and ligands for platelet surface receptors. This causes platelet adhesion and activation. Platelets: These are small anucleate cells that bud off from megakaryocytes and exist in circulation for 1-4 days. The accumulate at the sites of trauma by binding to the exposed subendothelium. They adhere, clump, aggregate stopping bleeding. Pathogenic states cause stroke and heart attack. They also secrete procoagulants and clotting factors which promote blood clotting, vasoconstrictors that cause vascular spasm. A fall in platelet count (thrombocytopenia) is associated with significant bleeding tendency. In the event of trauma, bleeding is continual and can occur in the skin or mouth without any obvious trauma. Causes may include bone marrow transplant following leukemia, chemotherapy or various autoimmune diseases. Coagulation: It is important for blood clotting to occur quickly but not inappropriately, therefore it is tightly regulated and involves over 30 specific chemical reaction and must take place on an appropriate surface such as platelets or subendothelium. Blood coagulation proteins circulate as inactive prec
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