PHS 3342 Lecture Notes PDF

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PHS 3342 Lecture NotesBloodLecture 1:Slide 1: Introduction  Only bodily connective tissue  Formed from erythrocytes, leukocytes, platelets  Suspended in plasmaPhysical Characteristics  Scarlet o O2 Rich  Dark Red o O2 Poor  Higher Viscosity than H2O  pH range between 7-7. o Lower than 7 = 7 a...

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PHS 3342 Lecture Notes

Blood Lecture 1: Slide 1: Introduction  Only bodily connective tissue  Formed from erythrocytes, leukocytes, platelets  Suspended in plasma Physical Characteristics  Scarlet o O2 Rich  Dark Red o O2 Poor  Higher Viscosity than H2O  pH range between 7.35-7.45 o Lower than 7.35 = 7.35 acidosis o Higher than 7.45 = 7.45 alkalosis  Far more red blood cells than platelets and white blood cells Slide 2: Functions  Transportation o Nutrients from GI tract to cells o O2 from lungs o Hormones to target organs o Metabolic waste from cells to kidneys o CO2 from cells to lungs  Regulation o Temperature  Conservation of heat by reducing the amount of blood going to the edges of the body  Dissipation of heat by increasing amount of blood going to the edges of the body  Distribution o pH in body tissues  Bicarbonate reaction 

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Adequate fluid volume  Holds enough water in the blood to maintain blood pressure Protection o Against blood loss  Platelets, Plasma Proteins

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Blood clotting factors Immune components  Antibodies, complement, white blood cells

Slide 3: Blood Plasma  Straw Coloured  91.5% water, 8.5% solute  Plasma Proteins o Synthesized by liver o Confined to the blood o

Albumins

Nonspecific carrier of hydrophobic molecules Blood buffer Major osmotic protein Important factor in how much water is being held within the blood Major osmotic Cation is Sodium Alpha, beta, gamma

Fibrinogen 

Key plasma protein involved in blood coagulation

Other Solutes o Electrolytes o Nutrients o Enzymes o Hormones o Gases and waste

Slide 4: Difference between Plasma and Serum  Plasma o Contains fibrinogen o Contains clotting factors  Serum o No fibrinogen o No clotting factors Slide 5: Formed Elements  Erythrocytes, Leucocytes, Platelets  Most are short lived and disposable  Only Leukocytes are complete cells o Platelets and Erythrocytes do not contain nuclei  Formed in the bone marrow  Hematocrit o Total percent of blood volume occupied by red blood cells o 42% in females, 45% in males

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Testosterone stimulates erythropoietin synthesis which stimulates the production of RBCs Anaemia o Loss of red blood cells o Less than 40% of blood volume Polycythemia o Increase in red blood cells o Epoetin alfa  Synthetic form of erythropoietin to stimulate the production of red blood cells

Slide 6: Visual Diagram of Components of Blood

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Never Let Monkeys Eat Bananas Neutrophils Lymphocytes Monocytes Eosinophils Basophils

Slide 7: Table Describing Typical Human Blood Cell Counts

Slide 8: Erythrocytes  Biconcave shape  8um in diameter and 1-2um thick  Anucleic cells (do not contain a nucleus)  Spectrin o Maintain biconcave shape o Found within the plasma membrane o Allows deformity for travel through capillaries  Hemoglobin o Binds to  OXYGEN  Carbon dioxide  H+  CARBON MONOXIDE  Can be fatal  Binds to same site as oxygen  Replaces oxygen  Nitric Oxide  Promotes vasodilation  Improves blood delivery to tissues  Maximize oxygen delivery Slide 9: Haemoglobin  Protein globin bound to red heme pigment  Four Polypeptide chains o 2 alpha 2 beta o Within each chain is a central heme group

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Iron within each heme group is where oxygen associates

Slide 10: Specialized RBC characteristics that Optimize Function  Small Size and Biconcave Shape o Shorter diffusion distance for oxygen  280 million Hb molecules/RBC o 4 binding sites/hemeoglobin molecules  Generation of ATP anaerobically Slide 11: Hb in Erythrocytes  Not lost through capillary membranes  Doesn't contribute directly to osmotic pressure and blood viscosity  O2 combines with the Heme  CO2 binds with globin Slide 12: Erythropoiesis  Erythropoiesis: Production of red blood cells  Haematopoiesis: production of blood cells

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Stem Cells

Hemocytoblast - In bone marrow

Committed Cell

Proerythroblast

Ejection of Nucleus

Reticulocyte Contains left over synthetic machinery compared to erythrocyte Stage where new RBCs are released into the circulation

Final Product

Erythrocyte

Occurs within the red bone marrow Haematopoietic stem cell are formed for all elements Higher than 0.5-1.5% of reticulocytes would indicate stimulation of production of new RBC

Slide 13: Regulation of Erythropoiesis  Rate of Production vs. Destruction

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Too Many RBCs - Polycythemia Too Few RBCs - Anemia Production Rate o >2 million/second if sufficient iron and B vitamins are present. Pernicious Anemia o Too little Vitamin B12 within body o Too little Vitamin B12 from diet or due to Intrinsic Factor Deficiency Aplastic Anemia o Ionizing Radiation

Slide 14: Erythropoietin (EPO)  Glycoprotein produced in the kidneys (majority) and liver (minority)  Respond to poor oxygen delivery (hypoxia) o Hemorrhage/excess RBC destruction o High altitude or pneumonia o Increased demand (aerobic exercise)  Increase rate of production and release of EPO  Excess RBCs reduce EPO production  Level of oxygen delivery to the kidneys is being measured  Takes a few days for a measurable EPO response to occur Slide 15: Summary of Erythropoietin Diagram  Renal Failure Patients o Additional problem is lack of EPO o RBC counts can be around 50% of normal levels o Helped by using recombinant EPO  Athletes and EPO Abuse o Increase hematocrit (45% to 65%) o Increases viscosity and dehydration o Increased clotting, stroke, heart failure Slide 16: Life Cycle of RBC

1. Dying Red blood cells (approximately 120 days) in spleen (RBC graveyard) 2. Heme portions cannot be recycled a. Removal of bullirubin b. Mostly by GI tract c. Some by kidneys 2. Iron bound to transferrin for transport a. Ferritin and hemosiderin keep iron from having toxic effects within cells 2. Proteins are recycled a. Converted into globin b. Amino acids are reused for protein synthesis

Lecture 2: Slide 1: Erythrocyte Disorders  Most are anemias or polycythemias  Anemias o Individuals are;  Tired  Pale  Short of breath  Chilly o Lack of haemoglobin or RBCs results in lack of oxygen being delivered to tissues o Nutritional  Iron deficiency, insufficient dietary B-12 o Pernicious  Lack of intrinsic factor/vitamin B12 o Aplastic  Bone marrow has what it needs but cannot produce enough RBCs

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Low on stem cells (damaged) Causes  Chemotherapy, exposure to toxic chemicals, irradiation

Renal 

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Diseased kidneys are deficient in EPO production Haemorrhagic  Brief  Usually reversed fairly quickly Haemolytic  RBCs being destroyed earlier than normal  Harder to maintain adequate levels of RBCs in the circulatory system  Sickle Cell Disease, Malaria  Rupture of RBCs prematurely

Slide 2: Sickle Cell Anemia  Genetic point mutation disease o Affects single amino acid o Glutamine at position 6 replaced by Valine  Conversion from biconcave disc to sickle shaped  Harder to travel and more prone to being tagged for degradation  Why does this gene persist in certain areas of the world o Increased resistance to malaria o Due to sickle shape of some RBCs and the quicker degradation, makes it harder for malaria microorganism to establish itself o Africa it is an evolutionary advantage Slide 3: Gene Map of Sickle Cell Disease Hereditary

Slide 4: Polycythemia  Elevated level of RBCs  Blood is more viscous and harder to circulate  Increased risk of blood clotting in smaller blood vessels

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Primary Polycythemia o Polycythemia Vera o Usually cancer in the bone marrow causes elevated levels of one or more subtypes of RBCs Secondary Polycythemia o Not direct complication of the bone marrow o Outside source is triggering the elevated production within the bone marrow of RBCs o Example is high altitudes, respiratory diseases such as pneumonia Artificial Polycythemia o Induced polycythemia o Blood Doping Hematocrit o During dehydration there is a reduced amount of plasma o Known as relative polycythemia o Number of RBCs is not increased but the amount of plasma present is decreased

Slide 5: Diagram of 4 Situations of Blood

Slide 6: Leukocytes  Only formed elements which are complete cells o Only cells which are nucleated and have all required components  50% o 2 types of granules (both basic and acidic) o Hydrolytic Enzymes o Antibiotic like proteins (defensins) o Phagocytes  Clean up scavengers  Ingest and destroy bacteria  Eosinophils

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1-4% One nucleus often with 2 lobes Coarse red cytoplasmic granules Most important against parasitic worms; surround & release enzymes  Much smaller therefore more are required o Reduce severity of allergies by phagocytosis of immune complexes Basophils o [Anticoagulation Factors]  Anticoagulants o Nitric Oxide/Prostacyclin  Released by healthy endothelial cells  Inhibit platelet aggregation Slide 3: Controlling Size of Blood Clot  Tissue Factor Pathway Inhibitor o Associated with the extrinsic pathway o Healthy endothelial cells secrete TFPI o Keeps clots from forming in locations where endothelial cells are healthy and no clot formation is needed Slide 4: Thrombin  Thrombomodulin receptor found on endothelial cells o Leads to regulation or modulation of the activity of thrombin o Binding of thrombin to thrombomodulin results in the activation of protein C  Protein C inhibits Factor VIIIa and Factor Va  Antithrombin III o Plasma protein which inactivates thrombin and other clotting factors Slide 5: Intravascular Clotting  Thrombus o Clot that forms in an unbroken blood vessel o Stasis: Slow blood flow  Airplane o Critical concentration of procoagulants in an area of the vessel which promotes the formation of a blood clot o Causes exposure to collagen due to slight peeling of endothelial cells  Platelets will begin to adhere to exposed collagen forming clots even though there is no broken vessel  Embolus o A thrombus that has broken free

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o Can be free air/fat bubble, piece of debris What might promote thrombus formation in an unbroken blood vessel o A person sitting on an airplane o Hypertension  Peeling of some endothelial cells exposing underlying collagen o Person with liver issues not producing enough anticoagulants

Slide 6: Anticoagulant Medications  Aspirin o Blocks thromboxane A2 production  Heparin o Hemodialysis  Increased risk of blood clot formation as blood is leaving blood vessels and circulating through tubing o Open Heart Surgery  Circulation of blood outside the body o Activates Antithrombin III  Warfarin (coumadin) o Antagonist to Vitamin K o Slower than Heparin  Calcium Chelator o Donated blood o Calcium is very important cofactor in blood clotting cascade o Citrate Phosphate Dextrose (CPD) is an example Thrombolytic Agents  Dissolve Clots o Directly or indirectly activate plasminogen  Streptokinase o Derived from streptococcal bacteria o 1982 o Able to directly dissolve clots  Tissue Plasminogen Activator (t-PA) o Genetically engineered o Can be useful to help dissolve clots associated with myocardial infarction or strokes Slide 7: Blood Groups and Types  

Antigens (agglutinogens) o Genetically determined assortment of cell surface glycoproteins and glycolipids ABO Blood Group System o Based on 2 glycolipid antigens  A and B (creating blood types A,B, AB, O)  Plasma contains antibodies (anti-A, anti-B)  Will have the antibodies to the opposite antigen.  Person with type B will have anti-A

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Slide 8: QUESTIONS ABOUT BLOOD TYPES  Why is type O the universal donor o Neither A nor B antigens are contained on the red blood cells o Will not induce antibodies to A or B when entering the body  Why is type AB the universal recipient o Contains both the A and B antigens on their red blood cells o Therefore no antibodies are present  Which blood type is most common/least common

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Slide 10: Newborns  Newborn blood has no ABO factor antibodies o Antibodies begin appearing around 2 months  Although no antibodies are present, giving the wrong blood can be fatal  Agglutination o Antibodies cause foreign red blood cells to stick together and form clots  Only A,B antigen and Rh factor are prevalent when dealing with transfusions Slide 11: Rh Blood Group  First discovered in the Rhesus Monkey  Rh antigens are not spontaneously formed in blood of Rh- individuals o Antibodies will be produced to Rh factor if exposed o Ex.  Rh- woman carrying an Rh+ fetus  First pregnancy will be fine since circulatory systems do not mix  Production of antibodies to Rh factor will be stimulated upon delivery of placenta which will cause production of Rh antibodies

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If during second pregnancy the fetus is Rh+, antibodies can cross harming the fetus Hemolytic disease of newborn Treatment of RhoGAM

Slide 12: Transfusion Reactions  Issues arise due to recipient's antibodies rather than the donors o Upregulation of antibody production against the incorrect blood type o Results in agglutination of foreign red blood cells  Clogging of small blood vessels o Clumped RBCs rupture  Release of Hb  Autologous transfusions o Donation of blood prior to a surgery to be used in the event a transfusion is needed Blood Typing  Serum containing anti-A or Anti-B agglutinins o Adding a person's blood will cause reactions to the serum o Adding AB blood will cause both to react o Adding A blood will cause anti-A to react o Adding B blood will cause anti-B to react o Adding O blood will cause neither to react  Similar procedure for Rh factor Slide 13: The Immune System  Innate Defenses o Protect against foreign substances/abnormal cells without having to specifically identify them o More generalized cell surface markers which bind to toll-like receptors on phagocytic cells  Adaptive Defenses o Acquired immunity o Subpopulations of lymphocytes which recognize and attack specific targets Slide 14: Innate Defenses (Nonspecific)  External Defenses (Skin and Mucous Membranes) o Effective but can be breached o Physical barrier of skin and mucosal membranes o Acidity of Skin  Secretions are a lower pH than normal deterring bacteria o Flow of urine  Outward flow tends to carry bacteria trying to enter out of the body o Vaginal Secretions  Secretions are somewhat acidic  Deter growth of bacteria o Sebum  Contain bactericidal chemicals

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Gastric HCl  Destruction of bacteria within the food or drink Saliva and Lacrimal Fluid  Contain lysozyme  Lysozyme break down bacterial cell walls Mucus in Respiratory  Mucus elevator  Mucus is constantly being propelled upwards and away from the lungs by cilia  It traps dust, debris, bacteria and other things not healthy for the lungs

Slide 15: Immune Protective Functions of Skin  Significant Physical barrier  SALT o Skin Associated Lymphoid Tissue o Langerhans Cells  Dendritic Cells  Phagocytic cells which are antigen presenters  Inform other cell types (T-Cells) of the intrusion found  Sebum o Released into the hair follicles o Broad-spectrum antibacterial chemicals  Sweat o Contains dermicidin o Acidic pH Slide 16: Dendritic Cells

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Dendritic cells come from lymphoid or myeloid precursor

Slide 17: Inflammation  Response to any type of injury o Take steps to keep response under control

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Four Key Signs o Redness o Heat o Swelling o Pain isolates area and prevents spread of damaging agents to nearby tissues disposes of cell debris & pathogens sets the stage for repair processes Occurs as part of nonspecific defenses o Amplified by specific immune system responses o Cross-Talk Inflammatory Chemicals o Released by injured cells, macrophages and lymphocytes

Slide 18: Figure Depicting Inflammation Response

Slide 19: Diagram depicting Inflammation Response

Slide 20: Interferon  Effective against viruses  Secreted by virus infected cells o These diffuse to nearby non-infected cells and block protein synthesis at the level of ribosomes  Part of the innate system o Does not identify the subtype of virus  interferons also activate macrophages & mobilize natural killer cells, allowing for some anticancer effects as well Slide 21: Interferon Mechanism

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Interferes with viral replication o Breakdown of viral mRNA and inhibition of viral protein synthesis

Slide 22: Complement System  Main goal is the formation of the membrane attack complex  Refers to a group of ~30 plasma proteins circulating in an inactive state  Once activated, various components amplify all aspects of inflammation  On its own, can also kill bacteria & certain other cell types o extracellular killing o 2 pathways to C3  common terminal pathway causing cell lysis  Opsonin o Makes bacteria more visible to phagocytic cells Slide 23: Activation pathways of C3  Innate System o Carbohydrate complexes on microbes o Different than the carbohydrate complexes found on our own cells  Adaptive System o Antibodies produced against the invader o Antibodies activate C3  C3b o Opsonization

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C3a o o o

Activate the release of histamine by mast cells Part of the chemical trail supporting positive chemotaxis Amplification of inflammation response

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Activate histamine release Part of chemical trail Amplification of inflammation response

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Continues on to form membrane attack complex

C5a

C5b Ca2+ o

Enters the bacterium through the hole created by the membrane attack complex

Slide 24: Functions of Complement Proteins

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37 degrees Celsius is body's normal temperature Pyrogens o Can increase body temperature o Released by leukocytes and macrophages exposed to bacteria and other foreign substances High Fever o Can lead to protein denaturation and loss of normal cell function o Neurons very sensitive to high temperatures Moderate Fever o Speeds metabolic rate o Causes liver and sleep to sequester iron and zinc  Reduce availability of iron and zinc which are used in bacterial replication

Lecture 4: Slide 1: Innate Defences vs Adaptive Defences Innate Defences  Able to work without having to specifically identify what they are fighting against  Not recruiting specific subtypes of cells which are genetically programmed to fight a particular type

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Primarily carbohydrates/lipid groups which are signals to alert the innate immune system that something is wrong Recognize abnormality and remove it before it can cause problems How does it work o Triggered by microorganisms entering the body from outside or tissue damage PAMPS o Pathogen Associated Molecular Patterns o Molecular patterns associated with molecules not normally present in the body DAMPs o Damage Associated Molecular Patterns o Patterns of molecules in the wrong place within the body PAMPs and DAMPs notify the innate immune system that something is wrong o No need to recognize a specific organism

Slide 2: PAMPs and DAMPs  Interact with pattern recognition receptors associated with cells responsible for innate immune responses o Can be found on cell surface or inside the cell  PAMPs o Toll-Like Receptors  On surface of phagocytic cells  Enhances phagocytic activity of microorganisms  Triggers inflammatory res...