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BLOOD Blood • fluid connective tissue • contains specialized cells-formed elements • suspended in matrix-plasma • containing-collagen & elastic fibers –protein fibers are in solution-visible during clotting process Functions • transports & distributes nutrients, gases, hormones & waste products • regulates pH & ion composition of interstitial fluids • restricts fluid loss at injury sites • defends against toxins & pathogens • helps to maintain body temperature Composition • 8% of total body weight –5-6 liters in males –4-5L in females • Temperature-38oC –just above body temperature • Viscosity 5X more viscous than water • pH between 7.35-7.45 Composition • Whole blood = plasma + formed elements • red blood cells (RBCs) • white blood cells (WBCs) • platelets • Centrifuged-separates into three parts • Bottom-erythrocytes (RBCs) • top-plasma • junction of RBC & plasmabuffy coat – contains WBCs & platelets Plasma Composition • • • • 46-63% of blood volume 92% water plasma proteins-made by liver Albumin-60% – major contributor to osmotic pressure – transports fatty acids, steroid & thyroid hormones • Globulins-35% – from smallest to largest in molecular weights-alpha, beta & gamma globulins – used to transport hormones, metal ions, triglycerides and lipids – includes antibodies or immunoglobins • defend against infections and foreign materials • Fibrinogen-4% – blood clotting – fibrinogen is cleaved into fibrin-basic framework of clot Erythrocytes • • • • • most numerous of formed elements number varies with health & altitude – Peruvians who live 18,000 feet above sea level may have as many as 8.3 x 106 RBCs/µl contain hemoblobin (Hb) – red pigment which transports O2 & CO2 – gives blood its color Ratio of RBC/plasma is hematocrit – % of whole blood occupied by cellular elements: 40-45%-women; 37-48%-men – almost entirely due to volume of RBCs – provides estimate of packed cell volume (PCV) – PCV increases with dehydration & with erythropoietin-protein which stimulates RBC production RBCs are a major contributor to blood viscosity – as numbers increaseviscosity increasesblood flow slowsblood thinsflows more rapidly • • • • • • • • • RBC Structure simple-small, biconcave disc plasma membrane-no nucleus & no organelles bag of Hb no nucleuscannot divide or make proteins – can’t repair its self and has a short life span-120 days shape is directly related to function-most important transport of O2 – large surface area, relative to volume – 30% more surface area than spherical cells – larger surface area makes for faster gas exchange shape allows them to stack like dinner plates – allows for smoother flow of blood through vessels Flexible – able to pass through small capillaries Modify shape in response to osmotic changes – Hypotonic solutionswellsforms sphere without disrupting integrity of membrane – Hypertonic solutionshrinksforms spikey surface No mitochondria – generate ATP anaerobically via glycolysis – do not need O2- makes them very efficient O2 transporters Hemoglobin (HB) Structure • red pigment • formed by 4 globular polypeptide chains • 2 & 2 • each chain has a molecule of heme • each heme has iron (Fe) molecule • each Fe can carry one molecule of oxygentherefore each HB molecule can carry 4 molecules of oxygen • Fe binds with O2 oxyhemoglobin bright red • Fe-O2 bond is weak • can separate easily without damage to Fe or O2 • Hb from which O2 has separated is deoxyhemoglobindark red Hemoglobin Functions • Transport gases-O2 & CO2 – there are 280X106 Hb molecules in each RBC – each contain 4 heme groups – gives blood capacity to carry a billion O2 molecules • amount of O2 bound depends on O2 content of plasma Leukocytes-White Blood Cells • • • • • • • less numerous than RBCS 1% of total blood volume provide protection against infections complete cells – typically have lobed nuclei, organelles & no Hb two groups based on appearance after staining Granulocytes – contain cytoplasmic inclusions – Basophils – Eosinophils – Neutrophils Agranulocytes – contain only a very few stained granules – Lymphocytes – Monocytes Neutrophils • • • • • • • • • • • • • • • 60-70% of circulating WBC population live only about 10 hours twice size of RBC Nucleus-polymorphonuclear – varied nuclear shapes – mature have 3-5 lobes connected by slender nuclear strands cytoplasmic granules in cytoplasm are packed with lysosomal enzymes & bacteria killing compounds produced in response to acute body stress – infection, infarction, trauma, emotional distress can double in a few hours highly mobile – first WBC to arrive at injury site specialize in attacking & digesting bacteria when binds to bacteriummetabolic rate increases H2O2 -hydrogen peroxide & O2- superoxide anions are produced which kill bacteria neutrophil + bacterium will fuse with a lysosome which contains digestive enzymes & defensins defensins kill bacteria & lysozymes digest them makes prostaglandins & leukotrienes during this process – restricts spread of infection & attracts other phagocytotic cells cell kills its self in the process Neutrophils + other waste = pus Eosinophils • 2-4% of WBCs • bilobed nuclei • contain deep red granules • population increases sharply during parasitic infections & allergic responses • release histaminases which combat the effects of histamine Basophils • smallest part of WBC population0.5-1% • large, deep purple granules in cytoplasm – hides nucleus • increase in number during infections • leave blood & develop into mast cells • granules contain histamine, serotonin & heparin • histamine increases blood flow to area which dilates blood vessels • heparin prevents blood clotting Monocytes • largest agranulocytes • 3-8% of WBC population • nucleus is large – clearly visible – ovoid or kidney shaped • cytoplasm contains sparse, fine granules • arrive in large numbers at the site of an infection • enlarge & differentiate into wandering macrophages Lymphocytes • second most numerous circulating leukocyte25-33% • Nucleus-large, round or slightly dimpled on one side • continually migrates from blood stream through peripheral tissues & back to blood stream • life span varies from several days to years • B cells or B lymphocytes – bone marrow derived – make antibodies which attack foreign antigens • T lymphocytes or T cells – thymus dependent cells – provide cell mediated immunity – attack foreign cells • Natural Killer Cells – immune surveillance cells – detect &destroy abnormal tissue cells – may help prevent cancer Differential Cell Count • determines number of each type of WBC in a sample • gives valuable information • pathogens, infections, inflammation & allergic reactions change WBC numbers • count of different types can help to diagnose disease and illness • Leukopenia – inadequate number • Leuocytosis – Excessive number Blood Cell Formation • all formed elements arise from a single cell type: pluripotent stem cell • Hemocytoblast • hematopoietic stem cell or hemocytoblast • rare-one in 10,000 bone marrow cells • cell differentiates along maturation path which leads to different kinds of blood cells • each type produced in different numbers in response to needs & regulatory factors-cytokines or hormones • • • • • Hemopoietic Tissues Tissues producing blood cells first-yolk sac – makes stem cells that migrate into embryo populate bone marrow, liver, spleen & thymus stem cells multiply & give rise to blood cells throughout fetal development Liver – primary site of RBC production during 2-5th month neonatally is liver & spleen – stops making blood cells at time of birth Spleen – stops soon after but continues to make white blood cells throughout life red bone marrow produces all formed elements from infancy onward Erythropoiesis • inadequate oxygen (hypoxia)kidney EPO (erythopoietin) stimulates production of RBCs • Hemoblasts myeloid stem cellsproethryoblastearly erythroblasts • early erhtyhroblasts multiply & make hemoglobinlate erythroblast normoblast • once normoblast accoulates 34% Hborganelles are ejected, nucleus degeneratescell collapses inwardreticulocyte • still has ribosomes & rough ER; leaves bone marrow • matures in two daysmature erythrocyte RBC LifeCycle • • • • • • • • • • • • • • RBC is terminally differentiated cannot synthesize proteins, enzymes or renew membranes life span-about 120 days engulfed & destroyed by phagocytotic cells in liver, spleen and bone marrow process is hemolysis once hemolyzed-parts are broken down globular proteins are disassembled into amino acids Heme splits from globin of HB molecule Iron is stripped from hemebiliverdin (green, organic compound)bilirubin (orange/yellow pigment)released into blood binds albumin transported to liver for excretion in bile – If circulating levels cannot be handled by liverhyperbilirubinemia-condition which turns peripheral tissues yellowjaundice Fe salvaged for reuse toxic to body-must be stored & transported bound to a protein Tranferrin used for iron transport hemosiderin for iron storage in bone marrow Fe is taken into the mitochondria of developing RBCs and is used to make heme WBC Production-Leukopoiesis • begins with same pluripotent stem used in erythropoiesishemocytoblast • differentiate into distinct types of CFUs-colony forming units • CFUs go on to produce 3 cell lines committed to a certain outcome • Myleoblasts • Monoblasts • Lymphoblasts Leukopoiesis Platelets-Thrombocytes • not cells in strictest sense – Fragments • • • continuously replaced always present-not active unless damage has occurred Thrombocytosis – too many • Throbocytopenia – Too few • • if numbers drop below 50 X 103/ul there is danger of uncontrolled bleeding Functions – contain chemicals for clotting – form temporary platelet plug needed in clotting – secrete growth factors – secrete chemical to attract neutrophils and monocytes to site of inflammation Thrombocytopoiesis • occurs in bone marrow • thrombopoieten-secreted by liverstimulate growth & maturation of hemocytoblastsrepeated mitosis (up to 7X) without nuclear or cytoplasmic divisionvery large polypoloid cell-megakaryocyte • presses against sinusoid wallruptureplatelet fragments • life span-about 5 – 9 days Hemostasis • • • • • • • • • cut or damaged blood vessels bleed outflow must be stopped before shock & death occur accomplished by solidification of blood or coagulation also called clotting or hemostasis clotting is fast localized carefully controlled three phases – vascular spasm – platelet plug formation – coagulation phase Vascular Spasm Phase • blood vessels vasoconstrict –diameter decreases at injury site • immediate & most effective in small vessels • contraction exposes underlying basement membrane to bloodstream Platelet Plug Formation • endothelial cell membranes become sticky • sticky membranes allow platelets to adhere to injury site forms temporary plug within 1 minute of injury as platelets keep arriving continue sticking to each otherplatelet aggregationplatelet plug plug seals break in vessel as arrive become activatedchange shape become more spherical & develop cytoplasmic processes that extend toward other platelets Release – ADP-adenosine diphosphate • aggregating agent – Serotonin • enhances vascular spasms – Enzymes that help make Thromboxane A2 • recruits & activates more platelets & stimulates vascular spasms – PDGF • platelet derived growth factor • promotes vessel repair – Calcium • required for platelet aggregation • • • • • • Coagulation Phase • occurs in asequence of steps • requires 13 clotting factors called procoagulants • designated by Roman numerals – many circulate as proenzymes- inactive precursors • converted to active forms during clotting process • activated by proteolytic cleavage & active proteases • all but 3 are made & released by the liver (III, IV, VIII) • all but 2 (III & VIII) are always present in blood • activated platelets release 5 during platelet phase (III, IV, V, VIII & XIII) Coagulation Cascade • activation of one proenzymeactivates another proenzyme • chain reaction or reaction cascade • 2 reaction pathways to coagulation: • extrinsic • Intrinsic • Both lead to the formation of prothrombinase • at this point the two unitecommon pathway Extrinsic Pathway • shorter & faster-fewer steps • TF-tissue factor or thromboplastin or clotting factor III is released by damaged blood vessels • leaks into blood (extrinsic to it) • TF binds Ca++ & Factor VII forming an enzyme complex • complex cleaves Factor X (prothrombinase) active factor X • first step in common pathway of coagulation Intrinsic Pathway • more complex & slower • activators are in blood or in direct contact with it (intrinsic to it) • contact with collagen fibers or even glass of a collecting vialactivates Factor XII • Begins a series of reactions • activated factors VIII & IX combine to form enzyme complex which activates Factor X Common Coagulation Pathway • the two paths unite at a common pathwaythrombin synthesis • begins when activated Factor X or prothombinase converts prothombin or Factor IIthrombin • Thrombin cleaves fibrinogen or Factor I (soluble)insoluble fibrin The Clot • fibrin glues platelets together forming intertwined web – structural basis of a clot • thrombin & Ca++ activate Factor XIII-fibrin stabilizing factor • cross linking enzyme • forms covalent bonds between fibrin molecules converting them into insoluble meshwork • stabilizes clot Clot Retraction • further stabilizes clot • occurs minutes after initial clot formation • platelets contain contractile proteins-actin & myosin • these contract pull fibrin strands together • squeezing out serum compacts clot • functions to: • pull torn edges of broken vessel together • reduce size of damaged area Rebuilding • begins with clot formation • PDGFstimulates smooth muscle cells & fibroblast division to rebuild vessel wall – angiogenesis • Thrombin, factors VII & X promote healing by stimulating growth of new blood vessels at site of damage Fibrinolysis • • • • hemostasis is not complete until clot has been dissolved plasminogen is incorporated into clot as it forms nearby cells release TPA-tissue pasminogen activator binds to fibren and activates plasimnogen converting it to plasmin • plasmin digests fibrindissolving clot Control of Clotting • clotting must be carefully regulated • inappropriate formationlife-threatening – too much-thrombus • clotting-restricted by several mechanisms • 1. Platelets do not adhere to normal endothelium – intact endothelial cells convert membrane lipids into prostacyclin • blocks platelet adhesion & aggregation • limits platelet plug to area of damage Control of Clotting • Plasma contains anticoagulants – Antithrombin III inactivates thrombin – Heparin accelerates activation of antithrombin III enhances inhibition of thrombin synthesis Control of Clotting • 3. Endothelial cells release thrombomodulin-binds to thrombin converts it into enzyme that activates protein c • Protein Cinactivates clotting factors & stimulates plasmin formation Thromboembolytic Disorders • Undesirable clottingthrombus – blood clots in unbroken vessels • gets into coronary circulationheart attack • thrombus that breaks away & floats freeembolus • Cerebral embolusstroke • Pulmonary emboluslung • Conditions that roughen endothelium encourage clot formation– Arteriosclerosis Bleeding Disorders • Thrombocytopenia – deficient platelet number – can result in spontaneous bleeding from small vessels • Impaired liver function – liver makes procoagulants & when unable to do so result is severe bleeding • Deficiency of Vitamin K – may be a cause of liver dysfunction – cofactor needed for synthesis of factors II, VII, IX, X & proteins C & S – blocking action of vitamin K helps prevent inappropriate clotting • Warfarin-vitamin K antagonist • Deficiency of clotting factors – – – – – – • not enough produced or mutant version fails to perform properly von Willebrand disease-most common Hemophilia A-classic-factor VIII deficiency antihemophilic factor-hemophilia B factor XI deficiency-hemophilia Cactor XI deficiency-in both sexes Lowered Calcium – affects nearly all clotting pathways – any lowering of Ca impairs blood clotting Hemophilia Inheritance ABO Blood Types • blood type-determined by presence or absence of antigens-A and B • Presence of A-blood type A • Presence of B-blood type B • Presense of both-blood type AB • Absence of both-blood type O ABO Blood Types • antibodies begin to appear in plasma 2 to 8 months after birth • person produces antibodies against antigens that are not present on his or her RBCs • Blood type A-makes antibody B • Blood type B-makes antibody A • Blood type O-makes antibodies A & B • Blood type AB-does not make antibodies Blood Type • Antigens are often referred to as agglutinogens • Antibodies-immunoglobulins are made by immune system in response to foreign material-agglutinins • antibody adheres to foreign material & eliminates it • presence of antigens on cells is a way for immune system to decide whether substance is foreign or not • immune system ignores surface antigens on your RBCs • when blood-type antigen senses foreign antigen has entered system alerts immune system to create antibodies to that antigen – antibodies attach themselves to foreign antigens destroy them • when attack foreign cellsclump together-agglutinatetermed agglutination Agglutination • • • • • • • Antibodies react against A or B antigen except those of one’s own RBCs person with antigen A produces anti-B antibodiesattack type B antigens person with antigen B produces anti-A antibodiesattack type A antigens person with neither A or B antigens produces both anti-A & anti-B antibodies person with both antigens A & B will produce no antibodies When antibody meets specific surface antigenRBCs agglutinate & may hemolyze – Cross reaction or transfusion reaction – can be dangerous to receive wrong blood type during a transfusion Compatibility can be verified with blood typing – mix small sample of blood with anti-A or anti-B antibodies-called antiserum – presence or absence of clumping is determined for each type of antiserum – clumping only with anti-A serum blood type A – clumping only with anti-B serumblood type B – clumping with both antigensblood type AB – Absence of clumping with either antigenblood type O Universal Donor & Recipient • Type O-universal donor –no surface antigensrecipient’s blood can have antibodies but there will be no clumping • Type AB-universal receiver –holds no antibodies to react with antigens Antigen D-Rh Factor • • • • • • • • • • • • rhesus antigen in Rh negative individuals D antigen is missing 84% of humans are Rh positive Blood Type A+ carries A & Rh antigens shouldn't mix A+ with A- blood blood must also be typed for Rh factor Anti-D antibodies are not normally found in blood as anti a and b antibodies are form only in Rh negative individuals who are exposed to Rh positive blood Rh negative person receives Rh positive transfusionrecipient produces anti-d antibodies Anti-d does not appear instantaneously presents little danger if person gets another Rh positive transfusion, his or her anti-D could agglutinate donor’s RBCs