Lecture 1 Notes - Blood Physiology PDF

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Dr Carol Rea...

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Human Anatomy and Physiology 2 Lecture 1 Blood Physiology Function of Blood  Transport  Exchange of materials between o Blood and cells o Blood and respiratory, digestive and excretory systems  Homeostasis and defence o Immune response, clotting  Only fluid connective tissue Distribution Functions  Delivering O2 and nutrients to body cells o An exception is RBC; they function purely anaerobically as they have no mitochondria – this stops them from using the O2 being transported by the haem groups  Transporting metabolic wastes to lungs and kidneys for elimination  Transporting hormones from endocrine organs to target organs Regulation Functions  Maintaining body temperature by absorbing and distributing heat o Also aids dissipation of heat so we don’t overheat  Maintaining normal pH using buffers; alkaline reserve of bicarbonate ions o Normal pH is 7.35-7.45 (slightly alkaline)  Maintaining adequate fluid volume in circulatory system (determining blood pressure) Protection Functions  Preventing blood loss o Plasma proteins and platelets initiate clot formation o Bleeding time is determined by platelet number and function  Preventing/fighting infection o Antibodies (B lymphocytes) o Complement proteins (membrane attack complex on bacteria/viruses) o WBCs (neutrophils, eosinophils, basophils, lymphocytes, monocytes, dendritic cells) Composition  4-5 litres in average human  Approx. 55% plasma, 45% cells o Red blood cells (erythrocytes) o Platelets (thrombocytes) o While blood cells (leucocytes) Blood Plasma  90% water  Over 100 dissolved solutes o Nutrients, gases, hormones, wastes, proteins, inorganic ions o Electrolytes  Most abundant solutes by number; cations include sodium, potassium, calcium, magnesium; anions include chloride, phosphate, sulphate and bicarbonate  Help to maintain osmotic pressure and normal blood pH

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Plasma proteins most abundant solutes  Remain in blood; not taken up by cells  Proteins produced mostly by liver  60% albumin; 36% globulins; 4% fibrinogen  Albumin – main contributor to osmotic pressure  Globulins o Alpha/beta – most are transport proteins that bind to lipids, metal ions and fat-soluble vitamins o Gamma – antibodies released by plasma cells during immune response  Fibrinogen – forms fibrin threads of blood clot Nitrogenous substances  By-products of cellular metabolism, such as urea, uric acid, creatinine and ammonium salts Nutrients  Materials absorbed from digestive tract and transported for use throughout body; include glucose and other simple carbohydrates, amino acids, fatty acids, glycerol and triglycerides, cholesterol and vitamins Respiratory gases  Oxygen and carbon dioxide; oxygen mostly bound to haemoglobin inside RBCs; carbon dioxide transported dissolved as bicarbonate ion or CO2, or bound to haemoglobin in RBCs Hormones  Steroid and thyroid hormones carried by plasma proteins

Formed Elements  Only WBCs are complete cells  RBCs have no nuclei or other organelles  Platelets are cells fragments  Most formed elements survive in bloodstream only a few days  Most blood cells originate in bone marrow and do not divide Red Blood Cells  Approx. 5 x 10^12/l  Shape – biconcave disc, anucleate (has no nucleus)  Function – carry oxygen bound to haemoglobin o Maximum amount of space achieved by absence of organelles  Formed in the bone marrow by erythropoiesis  Destruction in the reticuloendothelial system – spleen, liver, bone marrow o Can also be produced in the liver in severe situations o Scavenger cells break down RBCs, mostly in the spleen under normal circumstances o Abnormally – spleen enlarges, and swelling in liver and bone marrow  Survive around 120 days Erythrocytes  Diameter is larger than some capillaries o If it can’t squeeze through capillaries properly, it’s an older blood cell and needs to be broken down o 7.5um diameter, 2.5um thick  Filled with haemoglobin (Hb) for gas transport  Contain plasma membrane protein spectrin and other proteins

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o Spectrin provides flexibility to change shape Major factor contributing to blood viscosity o Too many – blood is thicker, more prone to inappropriate clotting  Caused by high altitude

Haemoglobin Structure  Globin composed of 4 polypeptide chains o Two alpha and two beta chains o Makes porphyrin around haem group  Haem pigment bonded to each globin chain o Gives blood red colour  Haem’s central iron atom binds one O2  Each Hb molecule can transport 4 O2  Each RBC contains 250 million Hb molecules Haematopoiesis  Blood cell formation in red bone marrow o Composed of reticular connective tissue and blood sinusoids  In adults, found in axial skeleton, girdles, and proximal epiphyses of humerus and femur  Haematopoietic stem cells (Haemocytoblasts) o Gives rise to all formed elements o Hormones and growth factors push cell towards specific pathway of blood cell development o Committed cells cannot change  New blood cells enter blood sinusoids Erythropoiesis  Formed in the bone marrow by erythropoiesis  Period of cell division, cells differentiate, haemoglobin production increases, specialised membrane proteins synthesised, organelles are lost, starting with the nucleus  Oxygen transport is more efficient – increasing the concentration of haemoglobin, membrane proteins contributing to the deformability, which allows entry to small capillaries, high surface area to volume ratio allows rapid gaseous exchange, no mitochondria to consume oxygen Erythropoiesis: Red Blood Cell Production  Stages o Myeloid stem cell transformed into proerythroblast o In 15 days proerythroblasts develop into basophilic, then polychromatic, the orthochromatic erythroblasts, and then into reticulocytes o Reticulocytes enter bloodstream; in 2 days mature RBC Erythropoiesis  As myeloid stem cell transforms o Ribosomes synthesised o Haemoglobin synthesised; iron accumulates o Ejection of nucleus; formation of reticulocyte (young RBC)  Reticulocyte ribosomes degraded; then become mature erythrocytes  Reticulocyte count indicates rate o RBC formation Regulation of Erythropoiesis

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Too few RBCs leads to tissue hypoxia Too many RBCs increases blood viscosity >2 million RBCs made per second Balance between RBC production and destruction depends on o Hormonal controls o Adequate supplies of iron amino acids, and B vitamins

Fate and Destruction of Erythrocytes  Lifespan: 100-120 days o No protein synthesis, growth, division  Old RBCs become fragile; Hb begins to degenerate  Get trapped in smaller circulatory channels, especially in spleen  Macrophages engulf dying RBCs in spleen  Haemoglobin is split into globin chains and haem  Globin chains are broken down into amino acids  Haem is converted into bilirubin and excreted by the biliary system Blood Groups  Red cells have proteins on their surface called blood group antigens  These determine whether blood from a donor is compatible or not  The major antigens are those of the ABO system 0 giving rise to 4 blood groups A, A, AB and O  Other blood group systems occur such as the Rhesus system ABO     

Enzyme produced by the A gene converts H substance to A substance (or A antigen) making the cells group A N-acetylgalactosamine added as the terminal sugar Enzyme produced by the B gene converts H substance to B substance by the addition of galactose Red cells in a person of AB blood group express both A and B antigens as H substance is randomly converted to A and B in the presence of both enzymes People with blood group O have neither enzymes and express substance H, but not A or B

Rhesus System  Other antigens occur on red cells, e.g. the D protein  Other rhesus antigens: C, c, E, and others  D protein expressed as “Rhesus positive”  D protein absence expressed as “Rhesus negative”  Most people are Rhesus positive (80-90% Caucasians, 95% Black Africans, almost 100% Chinese and Japanese) Other Groups  Red cells express a number of other antigens which can be used for blood grouping  Other blood group antibodies include anti-K (Kell system), anti Fya (Duffy system), anti-Jka (Kidd system) and anti-S (part of the MNSs blood group system) While Blood Cells  Normal range 4-11 x 10^9/l  Function – defence  Granulocytes

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o Neutrophils (60%) – phagocytic cells o Eosinophils (4%) – allergic reactions/kill parasites o Basophils (1%) – produce histamine and heparin Lymphocytes (25-30%) o B-cells – antibody production o T-cells – aid specific immune response Monocytes (5-10%) – phagocytic cells

Neutrophils  Multi-lobed nucleus, cytoplasm stains pale lilac with fine granules  Granules take up both acidic (red) and basic (blue) dyes  Some of the granules are small lysosomes and contain hydrolytic enzymes  Others contain defensins – antibiotic-like proteins  Contribute to the ability to kill bacteria Eosinophils  Bi-lobed nucleus, red stained granules (eosin loving) which are larger and coarser than those in neutrophils o More basic  Granules are lysosome-like, with digestive enzymes. They also contain neurotoxins to immobilise the multicellular parasites they are designed to attack  The digestive enzymes are released from the plasma membrane as the multicellular parasites are too large to be phagocytosed Basophils  Slightly smaller than neutrophils and eosinophils  Cytoplasm stains blue due to the presence of large granules containing histamine which bins basic dyes  Histamine is an inflammatory mediator which dilates blood vessels and attracts other white cells to the site of inflammation  Nucleus U or S shaped  Complement the function of mast cells, which are present in tissues and are important in allergic responses and play a role in protecting mucosal surfaces against pathogens  Mast cells have precursors in peripheral blood which are not well defined Lymphocytes  Smaller cells with a large dark-staining nucleus and little cytoplasm  B and T-lymphocytes cannot be distinguished between by normal microscopy, but by the different cell surface markers  B lymphocytes differentiate in the bone marrow and are present in peripheral blood and lymph nodes. They mature into antibody secreting plasma cells  T cells – present in peripheral blood and lymphoid tissue  Differentiate into effector cells with a number of functions  T helper cells (Th1 and Th2, affect the balance between cell mediated and humoral immunity)  Cytotoxic T cells (kill cells, e.g. infected with intracellular microorganisms)  NK cells are involved in killing cancer cells and cells infected with intracellular pathogens Monocytes  Largest white cell  Abundant cytoplasm, stains pale blue

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Kidney-shaped nucleus Phagocytic, defends against viruses, intracellular parasites and chronic infections – hence the composition of the cytoplasm differs slightly from neutrophils and eosinophils

Dendritic Cells  Specialised to take up antigen, process it and display it for recognition by T lymphocytes  Present in small numbers in peripheral blood, tissues and lymph nodes  Important in the display of self-antigens and tolerance Leukopoiesis  Production of WBCs o Stimulated by 2 types of chemical messengers from red bone marrow and mature WBCs  Interleukins (e.g. IL-3, IL-5_  Colony-stimulating factors (CSFs) named for WBC type they stimulate (e.g. granulocyte-CSF stimulates granulocytes)  All leukocytes originate from haemocytoblasts  Lymphoid stem cells  lymphocytes  Myeloid stem cells  all others  Progression of all granulocytes o Myeloblast  promyelocyte  myelocyte  band cell  mature cell  Granulocytes stored in bone marrow  3 times more WBCs produced than RBCs o Shorter lifespan; die fighting microbes  Progression of agranulocytes differs  Monocytes – live several months o Share common precursor with neutrophils o Monoblast  promonocyte  monocyte  Lymphocytes – live few hours to decades o Lymphoid stem cell  T lymphocyte precursors (travel to thymus) and B lymphocyte precursors Platelets  Cytoplasmic fragments of megakaryocytes  Blue-staining outer region; purple granules  Granules contain serotonin, Ca2+, enzymes, ADP, and platelet-derived growth factor (PDGF) o Acts in clotting process  Normal = 150-400 x 10^9 platelets/L of blood  Form temporary platelet plug that helps seal breaks in blood vessels  Circulating platelets kept inactive and mobile by nitric oxide (NO) and prostacyclin from endothelial cells lining blood vessels  Age quickly; degenerate in about 10 days  Formation regulated by thrombopoietin  Derive from megakaryoblast o Mitosis but no cytokinesis  megakaryocyte – larger cells with multilobed nucleus Haemostasis  Fast series of reactions for stoppage of bleeding  Requires clotting factors and substances released by platelets and injured tissues  Three steps o Vascular spasm

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Platelet plug formation Coagulation (blood clotting)

Haemostasis: Vascular Spasm  Vasoconstriction of damaged blood vessel  Triggers o Direct injury to vascular smooth muscle o Chemicals released by endothelial cells and platelets o Pain reflexes  Most effective in smaller blood vessels Haemostasis: Platelet Plug Formation  Positive feedback cycle  Damaged endothelium exposes collagen fibres o Platelets stick to collagen fibres via plasma protein von Willebrand factor o Swell, become spiked and sticky, and release chemical messengers  ADP causes more platelets to stick and release their contents  Serotonin and thromboxane A2 enhance vascular spasm and platelet aggregation Haemostasis: Coagulation  Reinforces platelet plug with fibrin threads  Blood transformed from liquid to gel  Series of reactions using clotting factors (procoagulants) o I – XIII; most plasma proteins o Vitamin K needed to synthesise 4 of them Coagulation: Overview  Three phases of coagulation o Prothrombin activator formed in both intrinsic and extrinsic pathways o Prothrombin converted to enzyme thrombin o Thrombin catalyses fibrinogen to fibrin (fibrinogen is no longer water soluble)  Amplification pathway Coagulation Phase 1: Two Pathways to Prothrombin Activator  Initiated by either intrinsic or extrinsic pathway (usually both) o Triggered by tissue-damaging events o Involved a series of procoagulants o Each pathway cascades towards factor X  Factor X complexes with Ca2+, PF3, and factor V to form prothrombin activator  Intrinsic pathway o Triggered by negatively charged surfaces (activated platelets, collagen, glass) o Uses factors present within blood (intrinsic)  Extrinsic pathway o Triggered by exposure to tissue factor (TF) or factor III (an extrinsic factor) o Bypasses several steps of intrinsic pathway, so faster Coagulation Phase 2: Pathway to Thrombin  Prothrombin activator catalyses transformation of prothrombin to active enzyme thrombin  Once prothrombin activator formed, clot forms in 10-15 seconds

Coagulation Phase 3: Common Pathway to the Fibrin Mesh  Thrombin converts soluble fibrinogen to fibrin  Fibrin strands form structural basis of clot  Fibrin causes plasma to become a gel-like trap for formed elements  Thrombin (with Ca2+) activates factor XIII which: o Cross-links fibrin o Strengthens and stabilises clot Clot Retraction  Stabilises clot  Actin and myosin in platelets contract within 30-60 minutes  Contraction pulls on fibrin strands, squeezing serum from clot  Draws ruptured blood vessel edges together Vessel Repair  Vessel is healing as clot retraction occurs  Platelet-derived growth factor (PDGF) stimulates division of smooth muscle cells and fibroblasts to rebuild blood vessel wall  Vascular endothelial growth factor (VEGF) stimulates endothelial cells to multiply and restore endothelial lining Fibrinolysis  Removes unneeded clots after healing  Begins within two days; continues for several  Plasminogen on clot is converted to plasmin by tissue plasminogen activator (tPA), factor XII and thrombin  Plasmin is a fibrin-digesting enzyme Summary  The main functions of the blood system are transport, homeostasis and defence  Blood is composed of red cells, white cells, platelets and plasma  Red cells are primarily involved in oxygen transport  White cells are involved in defence against infection  Blood cells are formed in the red bone marrow  Red blood cells have a number of antigens on their surface tat relate to blood grouping  The most important blood group system ins te ABO system...