PhysioLec_-_BloodPhysioEditted

Blood Physiology: Castillo, Calderon, Aquino

July 20,2009

Blood functions: 1. Primary function: Homeostatic function (constancy of internal environment) 2. Respiratory function: Transport of O2 from lung to tissues and elimination of CO2 from lungs 3. Nutritive function: Transport of nutritive materials from intestines to all other body parts 4. Excretory function: Transport of tissue waste products to the kidneys for elimination 5. Transport of internal secretions from secretory  effector cells 6. Maintain acid-base balance: Via buffers and proteins in blood 7. Maintenance of water-electrolyte balance: Regulation of colloid and total osmotic pressure. 8. Immunity 9. Thermoregulation: Distribution of heat from the muscles Normal Blood volume: Weight Normal healthy adult male Healthy adult female

70 kg.

Total blood volume 5L

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4.5 L

Composition 3.0 – 3.2 L plasma [60%] 1.8 – 2.0 L formed elements [40% - 45%]

*estimation of blood volume may be based on about 78 ml/kg body weight or 3L/m2 body surface area.

Relationship of Blood Volume to Fat

Blood Volume Determination 1. Dye Method • Known amount of number of marked plasma blood cells are injected into the circulation and their proportion is compared • Injection of a known amount of harmless dye

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 Evans Blue: T-1824 • Blood volume can be calculated using the formula, Plasma Volume = Amount of Dye Injected Concentration of Dye after Equilibrium TOTAL Blood Volume = Plasma Volume 100 - Hematocrit  Hematocrit: Percentage of the volume of a blood sample occupied by cells. Radiotracer Method • Known amount of number of marked plasma blood cells are injected into the circulation and their proportion is compared • Radio iodinated plasma proteins are injected Marked Red Blood Cell Methods • Measurement of marked blood volume • RBC are tagged with radioactive substance Fe55, Fe59, p32c51 and KA2 • Extent of dilution is measured to deduce the total blood volume Ashby’s technique • Measurement of marked blood volume • A different but compatible RBC group is injected • Proportion is determined by their agglutination Electrical Impedence Methods

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Blood Physiology: Castillo, Calderon, Aquino •

July 20,2009

Estimation of blood volume from alterations in conductivity of the blood brought by the injection of hypertonic solutions • Degree of dilution of the injected material is determine • Advantage: Measures changes in whole blood, so errors brought by the hematocrit values are eliminated 6. Based on Height Page | 2 • Requirement: Individual must be healthy • Total Blood volume = 5720 + 60 (Height [cm] – 174) Regulation of blood volume  Plasma Volume is the result of the dynamic equilibrium of • Capillary Hydrostatic Pressure •

 Force that pushes plasma out of the capillaries Oncotic/Osmotic Pressure

 Force that retains fluids inside capillaries  Attracts fluids from tissue space  Function of proteins, e.g. Albumin  Formed/Cellular Elements (WBC, RBC, Platelets) depends on the dynamic equilibrium of • Rate of Production of the bone marrow • Rate of Destruction Factors in normal blood volume maintenance: 1. Vascular capacity 2. Capillary fluid shift mechanism 3. Renal mechanism of water and electrolyte retention and elimination 4. Bone marrow activity 5. Plasma protein Genesis of Blood Cells: • Pluropotential hematopoietic stem cells  Committed cells Different blood cell types o Pluripotential Hemapoietic stem cell  Parent cell of Blood cells  Numbers diminish by age • Commited stem cells: committed to a particular line of cells o Colony forming unit – erythrocyte (CFU-E): Erythrocytes o Colony forming unit – Granulocyte, Macrophages: Granulocyte and Monocyte • Growth Inducers o Proteins that control growth and reproduction of the different stem cells o Major Growth Inducers  Interleukin-3: Committed stem cells • Differentiation inducers: promote differentiation of cells (stem cell  mature cell) Composition of Blood 1. Formed Elements A. Red Blood Cells/ Erythrocytes • Anucleated Biconcave discs: 2μm-thick, 7.5-8.0μ in diameter, 1μm-center (thinnest part) • Deformable  Prostaglandin (PGE) increases RBC deformability  PGE2 decreases RBC deformability • Hemoglobin Carrier  1 liter of blood carries only 3mL dissolved O2


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 Hemoglobin can carry 70x such amount Normal Values of RBC RBC Count (SI Units) Hemoglobin Hematocrit (Hct.) --relative red cell content of blood

Men 5.0-6.0 x 1012 /L blood 140-170 g/L 0.40-0.50

Women 4.0-5.0 x 1012 /L blood 120-150 g/L 0.38-0.48

Infants 6.5 x 1012 /L blood Page | 3

Red Cell Production

**Even for membranous bones, RBC production declines with age (Chart 1) ***Except for proximal portions of humeri and tibiae, marrows of long bones become fatty and do not produce RBC beyond 20 years of age. (Chart 1)

Erythropoeisis: • Steps in Erythropoiesis 1. Accumulation of hemoglobin (up of  Basophil erythroblast: very little hemoglobin 2. Condensation and extrusion of the 3. Reabsorption of endoplasmic reticulum  Reticulocyte • Have remnants of the mitochondria, reticulum other organelles • Youngest erythrocyte circulate o Diapedesis: squeezing through the pore of the capillary membrane • Duration: 1- 2 days (3 days based on our Histology class) RBC Feedback control: • Inhibited by the rise of RBC to supernormal values • Stimulated by Hypoxia (Low O2) o High altitude  Low O2, High RBC Production Rate o Increase Erythropoietin at kidney, and Increase Globulin production at liver • Increase in RBC results to: o Increase in hematocrit o Increase in Total blood volume o Increase Oxygen o Increase Hemoglobin Production

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Blood Physiology: Castillo, Calderon, Aquino Regulation of RBC • Total mass of RBC regulation: 1. Adequate amount for sufficient transport of O2 from the lungs to the tissues 2. Not numerous, that they impede blood flow Destruction of RBC • Lifespan: 120 days • Function of RBC Cytoplasmic enzymes o Maintain pliability of cell membrane o Maintain membrane transport ions o Keep the Fe of the cells hemoglobin is Ferrous form rather than ferric form o Prevents Oxidation of the proteins in the RBC • Spleen: RBC self-destruction site • Fragile cell membrane rupture during diapedesis

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Erythropoietin • Circulating hormone, principal stimulus for RBC production during hypoxia • Stimulates proerythroblast from hematopoietic stem cells in the bone marrow • Increase speed of maturation of RBCs • In its absence, hypoxia have little or no effect in blood production • Negative feedback: Many RBCs or Many O2 • Origin: 1. Kidney [90%]  Renal tubular epithelium secrete erythropoietin  There is a possibility of having a non renal sensor 2. Liver [10%] • Noepinephrine and Epinephrine, and several of the protaglandins stimulate erythropoietin production In the absence of erythropoietin: few RBCs are formed In the abundance of erythropoietin • Plenty of Fe and other required nutrient • 10x faster RBC production

Hemoglobin Formation • Function: Combine and Release Oxygen • Coordination bond: Fe atom + Oxygen molecule • Begins in the proerythroblasts and ends into the reticulocyte stage • Steps: • 2 succinyl-COA + 2 glycine  pyrrole • 4 pyrrole  protoporphyrin IX • Protophyrin IX + Fe2+  hemoglobin chain ( α or ß) • 2 α chains + 2 ß chains  hemoglobin A (This step varies) • 4 different types of chains • Alpha chains • Beta chains • Delta chains • Gamma chains • Hemoglobin A • Most common typeform of hemoglobin


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• 2 alpha chains + 2 beta chains Prosthetic group: Heme contains Fe • Each Hema can bind with 1 Oxygen molecule (2 Oxygen atom) Destruction • Hemoglobin is released during phagocytosis by macrophages (most especially the Kupffer cells of the liver)

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Iron Metabolism • Essential element, important for the formation of hemoglobin • Absorption Site: Small Intestine [slow process] • Regulatted by: Rate of Fe Absorption (Slows down and Speeds up depending on Fe concentration) • Storage: Liver hepatocyte and reticuloendothial cells of the bone marrow • Transferrin o Apotransferrin [beta globulin] + Fe  Apotransferrin is secreted by the liver, into the bile o Location: Plasma o Binds strongly with receptor cells in membranes of the erythroblast • Ferritin o Apoferritin [Protein] + Fe o Storage Fe o Location: Cell cytoplasm • Hemosiderin o Smaller insoluble storage form o Present, when apoferritin is unable accomodate Fe • Hemoglobin is released from cells ingested monocyte-macrophages o Transported to the bone marrow (production of new RBC) or to the liver/other tissues for storage o Porphyrin portion of hemoglobin converts to the bile pigment, bilirubin by the macrophages • Excretes 0.6 mg Fe in feces Iron Absorption

Liver secretes apotransferrin into bile (bile duct) Duodenum (Apotransferrin binds with Fe+ [myoglobin from meat] and hemoglobin to form transferrin)

Binds with intestinal epithelial cell membrane Pinocytosi s Released into blood capillaries as PLASMA TRANSFERRIN Note: Fe absorption at intestines is extremely slow

the cell

to by the


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Anemias • ↓RBC or ↓ Hemoglobin • Effects of anemia on function of circulatory system o ↑ cardiac output, ↑ pumping workload of heart and due to ↓ viscosity → ↓ resistance to blood flow → ↑ venous return  Acute cardiac failure: when person with anemia exercises because blood/ cardiac output can’t |6 supply oxygen (due to low Hgb)Page to hypoxic tissues Vitamin B12 and Folic Acid • Megaloblastic Anemia o RBC cannot proliferate rapidly enough to Important for the final maturation of RBC form normal numbers of RBC Essential for DNA synthesis o Megaloblast/Macrocytes: Large oval Required for thymidine triphosphate (building shaped RBC with flimsy membrane block of DNA) formation o Pernicious Anemia Deficiency Results to:  Due to atrophic gastric mucosa Abnormal and diminished DNA abnormality Failure to secrete Failure of nuclear maturation and cellular normal gastric secretion division • Parietal cells of gastric glands fail to produce intrinsic factor, which binds to Vit. B12 for absorption by gut • Steps: 1. Binding of intrinsic factors to Vit. B12  coating of Vit. B12 (protection from digestion) 2. Binding to brush borders of ileum 3. Vit. B12 transported to blood via pinocytosis 4. Stored in liver, then released to marrow as needed • Min. Amount of B12 to maintain normal RBC: 1-3 μg • 3-4 years of deficiency is needed before it can cause pernicious anemia o Sprue  Failure to absorb B12 and folic acid in the small intestine • Folic Acid: found in green vegetables, fruits and meat (especially liver) • Aplastic Anemia/Bone marrow Aplasia o Lack of functioning bone marrow o Caused by:  Gamma ray radiation  Excessive x-ray treatment  Certain industrial chemicals • Hemolytic Anemia o Fragile cells that rupture quickly  Shorter Lifespan of RBC o Hereditary Spherocytosis  Spherical RBC rather than biconcave discs  Cannot withstand compression forces o Sickle Cell Anemia  Cells have Hemoglobin S • Valine is substituted for Glutamic acid at one point in each of the two beta chain  If exposed to ↓concentration of O2


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• Hemoglobin precipitates into a crystal chain • Therefore, ↓O2 tension causes sickling Erythroblastosis Fetalis • Rh-positive blood cells of fetus are attacked by Rh-negative blood cells of mother • Rh-positive blood cells are fragile Blood Loass Anemia Page | 7 • 1st hemorrhage, RBC replacement duration: 1-3 days • 2nd hemorrhage , RBC replacement duration: 3-6 weeks • Chronic blood loss: frequently cannot absorb enough Fe from intestines to form hemoglobin • Microcytic/Hypochromic Anemia o ↓ Hemoglobin o Small RBC

Polycythemia o Excessive RBC production (counterpart of Leukemia in WBC) o Very ↑ blood viscosity and ↑ total blood volume 1. Secondary Polycythemia  hypoxia-induced  6-7 million/ mm3 (30% above normal)  Ex. Physiologic Polycythemia: for those who live at high altitudes (a physiologic adaptation to poor oxygen supply in the atmosphere) 2. Polycythemia vera/ Erythremia  Caused by genetic aberration in hemocytoblastic cells  No negative feedback for RBC, hematocrit, WBC and platelet production o Effects of Polycythemia    

Due to ↑ blood viscosity, blood flow is sluggish (↓venous return from viscous blood cancels out with ↑venous return from elevated blood volume) No marked effect on cardiac output Generally, normal arterial pressure [pressure: regulating mechanisms offset increased blood velocity] Cyanotic skin due to large volumes of blood, most of which are deoxygenated

Blood Physiology: Castillo, Calderon, Aquino B. White Blood Cells (WBC) - Function: Prevention of diseases by 1. Phagocytosis/ actual destruction of invaders 2. Antibodies and sensitized lymphocytes - Leukocytes: mobile units of immunity o Granulocytes, monocytes, and lymphocytes (few)  Bone marrow

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Lymphocytes and plasma cells and granulocytes (baso-, neutro-, eosino-)  lymphogenous tissues [lymph glands, spleen, thymus, tonsils, Payer’s patches (underneath epithelium of gut wall)] Granulocytes: “polys,” multinucleated, polymorphonuclear Granulocytes + monocytes = phagocytotic Lymphocytes + plasma cells = related to immune system Platelets: blood-clotting mechanism (fragments of cells) Concentrations of WBC in blood: o Adult human: 7,000 WBC/ μL o Neutrophils: largest number in population Basophils: smallest number in population o Recall: 5 million RBC 300,000 platelets Genesis of WBC o

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CFU-B (CFU-blast)

Pluripotential Hematopoietic Stem Cell (PHSC)

PHSC

Colony Forming Unit (CFU) in spleen

Lymphoid Stem Cell (LSC) T-Lymphocyte BLymphocyte

CFU-E (CFU-erythrocyte)

CFU-GM (Granulocyte, Monocyte)

Erythrocyt e Granulocyte (Baso-, Neutro-, Eosino-) Monocyte


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3 major lineages of WBC: 1. Committed stem cell that also produces the RBC 2. Myelocytic 3. Lymphocytic * 6-day supply of bone marrow produces WBC: mostly stored in marrow o Lifespan  

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Granulocytes: 4- hours lifespan after release from bone marrow to blood Monocyte: 10-20 hours in blood • Once in tissue, monocytes  tissue macrophages, which can live for months

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 Lymphocytes: diapedesis (squeezing through) – goes in and out of capillary pores  Platelets: replaced every 10 days Functions

 Neutrophils: destroy invading bacteria, viruses and other agents even in circulating blood  Monocytes: have little immunity significance until it transformation to macrophage Note: Neutrophils and monocytes can diapedesis too, and can also move via amoeboid motion Chemotaxis o Movement or migration of cells in response to chemicals; can either be attraction (positive chemotaxis) or repulsion (negative chemotaxis) o Transport of or attraction of neutrophils and macrophages to inflamed areas o Can be caused by: 1. Bacterial/ viral toxins 2. Degenerative products of inflamed tissues 3. Reaction production of complement complex 4. Reaction production of plasma clotting o Chemotaxis depends on concentration gradient of chemotactic substance  Effective up to 100 μm away from inflamed tissue 3 precedents of neutrophilic/macrophagic phagocy: 1. Rough surface of substance [because normal tissues are smooth] 2. Substances without protective coats  dead/infectious 3. Opsonisation: antibody combines with C3 product of complement cascade, attaches self to bacterial membrane; C3 attaches to receptors of phagocyte membrane to initiate phagocytosis Neutrophilic phagocytosis (3 to 20 bacteria at a time) o Amoeboid pseudopodia o Chamber invagination o Creation of phagosome/ phagocytic vesicles o Dies with bacteria Macrophagic phagocytosis (100 bacteria at a time) o Extrude particles bigger than bacteria and outlives them Phagosome (phagocytic vesicles) o Digestive vesicles once inside, with enzymes to digest phagocytosed substance Macrophages and neutrophils have many lysosomes with proleolytic enzymes; neutrophils have lipases for thick bacterial membranes (i.e. tuberculosis bacillus) Both have bacterial agents o Oxidizing agents from enzymes of membrane and peroxisome  O2-, H2O, OHo Hypochlorite from H2O2 and Cl catalyzed by myelopectinase (a lysosomal enzyme) Monocyte-macrophage cell system  reticuloendothelial system o Macrophages attached to tissue Reticulocytes: monocytes + mobile macrophages + fixed tissue macrophage + specialized endothelial cells of marrow, spleen, and lymph nodes


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Note: Monocyte-macrophage cell system and reticulocytes have the same origin (monocytic stem cell) [ see Lymph nodes at p. 433 of Guyton] - Inflammation o “walling off” to prevent spread of bacteria to other areas o Characterized by: 1. Vasodilation increased local blood flow Page | 10 2. Increased permeability of capillaries to allow leakage of fluid into interstitial area 3. Due to excess fibrinogen, clotting of fluid in tissue interstitial area 4. Chemotaxis of granulocytes and monocytes 5. Swelling (edema) o Causes: histamines, bradykinin, serotonin, prostaglandin, reaction products of complement system reaction, reaction proliferation of blood clotting system and lymphokines o Lines of defence: 1st line: Macrophage 2nd line: Neutrophils 3rd line: Second macrophage invasion of inflamed tissue  antibody formation affected by macrophage 4th line: Increased production of granulocytes and monocytes by bone marrow  from stimulation of granulocytic and monocytic progenitor cells of the marrow (can continue for months and even years) o Reactions caused by inflammation: 1. Alter endothelial tissue  neutrophil aderes to it (capillary walls)  marginalization 2. Diapedesis from blood to tissue spaces caused by loosening of endothelial wall of capillaries and smalle venules 3. Chemotaxis caused by other products of inflammation o

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Neutrophilia

 Increase of neutrophils in blood due to inflammation  Caused by products of inflammation that enter blood stream and transported to bone marrow Feedback control of macrophage and neutrophil responses (from activated macrophage cells in inflamed tissue) 1. Tumor necrosis factor (TNF) 2. Interleukin-I (IL-I) 3. Granulocyte-monocyte colony-stimulating factor (GmCSF) 4. Granulocyte colony SF (G-CSF) 5. Monocyte CSF (M-CSF) GM-CSF stimulate granulocyte and monocyte production TNF and IL-I + CSFs  powerful feedback mechanisms that help remove cause of inflammation - Pus o Dead necrotic tissue, macrophages and tissue fluid o Autolyze over a period of days o End products are eventually absorbed into surrounding tissue and lymph - Eosinophils


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2% of blood leukocytes Weak phagocytes Exhibit chemotaxis but are considerably weaker/ less effective than neutrophils Parasite defense (veriforms) Ex. Schistosomiasis – eosinophils attach themselves to juvenile forms of these parasites via 1. Release of hydrolytic enzymes from their granules, which are modified lysosomes Page | 11 2. Release of highly reactive forms of oxygen lethal to parasites 3. Release of major basic protein  highly larvacidal polypeptide (kills larvae) o Eosinophilia caused by: 1. Trichinosis by Trichinella parasite (“pork worm”) 2. Mast cells and basophils release eosinophil chemotactic factor • Proliferate at areas of allergies • Believed to detoxify some of inflammation-inducing substances released by mast cells and basophils and destroy allergen-antibody complexes • Prevent spread of local inflammatory process Basophils, like mast cells: heparin (anticoagulant); histamines; bradykinin, serotonin o Allergic reaction o o o o

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o Immunoglobin E (IgE)  propensity to attach to basophils and mast cells

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 Rupture basophil and mast cells when they lyse (due to antigen-antibody attachment)  Contents are poured out, causing local vascular and tissue reactions Leukopenia o Bone marrow produces very few WBC o Less protected o Due to radiation of gamma rays or x-rays, drugs and chemicals with benzene and arthracene nuclei  aplasia (defective development due to absence of all or part of an organ) of bone marrow o Drugs that induce leukopenia   

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Chloramphenicol (antibiotic) Thiouracil (treats thyrotoxicosis) Barbiturate (hypnotics)

Leukemia o Increased number of abnormal or dysfunctional WBC Lyphatic: cancerous products of lymphoid cell usually beginning at lymph nodes Myelogenous: cancerous products of myelogenous cells in bone marrow then spreads around the body, especially in spleen, liver, and lymph nodes. • Neutrophilic, eosinphilic leukemia, basophilic or monocytic leukemia  production of partially differentiated cells, but most of the time, undifferentiated and not identical to any normal WBC. o ↑ chronic: more differentiated o ↑ acute: undifferentiated o Effects of leukemia on the body  

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Metastatic growth of leukemic cells in abnormal areas of the body • Can cause pain to surrounding tissues as to bones from marrow

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Almost all leukemias affect spleen, liver, and lymph nodes regardless of origin Common effects (result from displacement of normal bone marrow and lymphoid cells by nonfunctional leukocytic cells): • Severe anemia • Thrombocytopenia (lack of platelets) – induced bleeding • Infections


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Excessive use of metabolic substrate by growing cancerous cells

Depletion of energy, fast utilization of amino acids  rapid deterioration of normal protein tissues of ody  Chronic metabolic starvation leads to death Immunity and Allergy o

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Page | 12 o o o o o o o o o o o o o o o o Immunity – ability to resist almost all types of organisms o 2 types of immunity: A. Innate immunity (General process) 1. Phagocytosis by tissue macrophage system 2. Destruction of swallowed organism by gastric and intestinal secretions 3. Resistance of skin to invaders 4. Lysozyme: mucolytic polysaccharide that attacks bacteria Basic polypeptides: react with certain gram (+) bacteria Complement Complex: system of 20 proteins for destruction of bacteria Natural killer lymphocytes: destroy foreign cells, tumors, and infected cells B. Acquired Immunity (Adaptive Immunity)  Extremely powerful specific immunity against individual invading agents  Caused by special immune system that forms antibodies and/or activated lymphocytes that attack and destroy specific invading organisms or toxins -

Immunization Acquired immunity A. Antibodies (Humoral/ B-cell immunity)  Globulin molecule in blood plasma capable of attacking invading agent  B-lymphocytes produce them B. Cell-mediated/ T-cell immunity  Activated by T-lymphocytes o Both types of acquired immunity are initiated by antigens 

Antigens: proteins/ large polysaccharides that initiate acquired immunity : must have 8,000 molecular weight or more antigenicity, depends on epitopes [regularly occurring molecular groups] of large molecules

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Proteins and large polysaccharides are almost always antigenic Acquired immunity are produced by your lymphocytes Destruction of lymphocytes (at lymph nodes) = no immunity Areas and other lymphoid organs: spleen, submucosa, GIT, thymus and bone marrow

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PHS C TLymphocyte

Bursa of Fabricus of birds

BLymphocyte Liver (at mid fetal life) + bone marrow (late fetal to after birth

Activated Tlymphocytes

Antibodies

   Lymphocyte: committed stem cell of embryo o T-lymphocytes: bone marrow  thymus to where: 1. Specific reactivity to one antigen is developed 2. Division into many copies  thousands with differential sensitivities/ reactivities 3. Leave thymus (preprocessed T-lymph) and spread via blood and lodge in lymphoid tissue everywhere 4. Where T-lymphocytes that do not auto-attack are formed  Mainly responsible for rejection of transplanted organs  Most of preprocessing occurs shortly before birth and a few months after • Removal of thymus diminishes but not eliminate cell-mediated immunity o Liver and bone marrow preprocess B-lymphocytes @ liver = midfetal @ bone marrow = late fetal and after birth o T-lymphocyte  whole cell is reactive o B-lymphocyte

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 only secretions (antibodies) are reactive  more/ greater diversity  have more antibodies o clone of lymphocytes  only one kind (specificity)that replicates Origin of many clones of lymphocytes o Only gene segments are present in the original stem cells; they mix and match Explains how millions of T and B lymphocytes can be coded from only a few thousand gene codes Mechanism for activating a clone of lymphocytes: o T-lymphocytes: you have T-cell markers/ T-surface receptor proteins at the membrane o B-lymphocytes: T-cell markers have a B-lymphocyte counterpart, which is the antibody at membrane o Once activated, T or B lymphocytes reproduce wildly Macrophages are also present at lymph nodes and other lymphoid tissues. They phagocytose antigens first, then they pass the partially digested substance cell-to-cell to (directly to) lymphocytes, activating cloning. 

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o Macrophages also secrete Interleucin-I, which promotes further growth and reproduction of specific lymphocytes o T-cells [the helper-T cell in particular] secrete lymphokines that activate B-lymphocytes -

 Without the helper cells, the B-lymphocytes produced will be very few Humoral Immunity (B-lymphocyte system)

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Antigen Attack

Macrophage will phagocytose, then present antigen to B-lymphocytes

Triggers T-lymphocyte, helper T-cell will further enhance Blymphocyte production

B-lymphocyte enlarges [Lymphoblast]

Memory cells

Differentiate into Plasma cell

Plasmablasts precursor

Plasm a produce Antibodies are secreted into lymph and carried to circulatory blood

Gamma globulin antibodies [300 molecules/sec/plasma cell]

Note: It

takes several weeks or months before process stops [until exhaustion or death of plasma cells] o Memory cells circulate around the body and populate all lymphoid tissue  Primary Response Slow onset Transient antibody Not so potent attack

Remain dormant until the next attack, but more vicious the 2 nd time  immunization Secondary Response Fast onset Effects of antibodies last long Potent attack -

Nature of antibodies o Immunoglobulins (Ig)     

Antibodies/ γ Globulins Molecular weight: 16,000 – 970,000 Comprise 20% of plasma proteins Combination of light and heavy polypeptide chains 2-10 pairs of light and heavy chains parallel to each other


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Structure of antibodies: o Constant portion: determines diffusability, adherence of antibody to Page | 15 different structures, conductance of membranes to antibody, and attachment to complement complex o Variable portion: different for each specificity of antibody; is the attachment point for antigens Specificity of antibodies: o Caused by unique amino acid structures at the variable portion o Bonds that hold antibody-antigen coupling:  Hydrophobic bonding  Hydrogen bonding  Ionic bonding  Vander Waals forces

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Ka (affinity constant) = Concentration of bound antibody-antigen

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[conc. of antibody][conc. of antigen] Affinity constant: measure of how tightly bound th An-Ab are Ex: bivalent (has 2 varibale binding sites) 5 general classes of antibodies Immunoglobulins (Ig): 1.IgG: 75% of antibodies; bivalent 2.IgE: few (relatively) but potent in allergies 3.IgM: 10 binding sites; few but potent against invaders; primary response 4.IgA 5.IgD Mechanisms for antibody action 1.Direct attack of invader 2.Activation of complement system A. Direct action of antibodies on invaders (not as potent as complement system) 1. Agglutination: clumping of multiple large particles with antigen 2.Precipitation: molecular complex of soluble antigens (ex. Tetanus toxin) and antibody becomes large and insoluble  precipitates (they can’t travel and are deposited) 3.Neutralization: antibodies cover toxic sites of antigenic agent 4.Lysis: rupture of agent by direct attack on membrane B. Complement system for antibody action o System of 20 proteins, most of which are enzyme precursors o Usually present in plasma proteins and proteins that leak from capillary to tissue space o Classic Pathway 

Activated by antigen-antibody reaction (variable portion)  constant portion binds with C1 molecule of complement system  C1 molecules activates cascade of enzyme production


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Effects: 1. Opsonization and phagocytosis: C3b activates phagocy by both neutrophil and macrophages; enhances bacteria engulfment/destruction by a hundredfold 2. Lysis: lytic complex  combination of multiple complement actors and designted C5b,6,7,8,9 (ruptures membranes of invaders) 3. Agglutination: cause complement products to adhere to one another Page | 16 4. Neutralization of viruses 5. Chemotaxis: fragment of C5a initiates neutrophil and macrophage chemotaxis 6. Mast cell and basophil activation: C3a, C4a, an C5a; histamine, heparin, ect. release to local fluids • Histamine increases blood flow and leakage of fluid and plasma protein into tissue to hep immobilize antigenic agent; major role in inflammation 7. Inflammatory effects: • increased blood flow • increased capillary leakage of protein • coagulation of interstitial fluids in tissue spaces o Special attributes of T-lymphocyte system activated T=cells and Cell-mediated immunity 

Same mechanism as with B-lymphocyte system – only difference is instead of secretions (antibodies), it is the entire T-lymphocyte is released into circulation o Recall that antigen-antibody reaction causes proliferation of clones, some of which will remain plasmoblasts, which will be your T-lymphocyte memory cells. o T-lymphocytes only respond to antigens bound to MHC proteins on surface of antigen-presenting cells in lymphoid tissues 3 types of antigen-presenting cells (only function is to present) 1. Macrophage 2. B-lymphocytes 3. Dendritic cells – most potent 

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Cell-adhesion proteins: allow T-cells to bind to antigen-presenting cells long enough to become activated o MHC proteins: encoded by Major Histocompatibility Complex (MHC) o There can be 100,000 receptors on a single T-lymphocyte o Types: 1.MHC I Proteins – present antigen to cytotoxic T-cells 2.MHC II Proteins – present antigens to T-helper cells o Antigens on their surfaces bind with receptor molecules of T-lymphocytes (which also have a variable portion, but stem is bound to T-lymphocyte membrane) T-Cells  Helper T-cells  Cytotoxic T-cells  Suppressor T-cells 1. Helper T-cells  The most numerous (>3/4 of all T-cells)  Major regulator of all immune functions through lymphokines, which are protein mediators that act on other cells of immune system and bone marrow cells  Important lymphokines:  Interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-6, Granulocyte-monocyte colony stimulating factors, Interferon-γ Note: AIDS destroy or deactivate lymphokines o Functions:

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Stimulation of growth and proliferation of cytotoxic T-cells and suppressor T-cells (by Interleukin2) Stimulation of B-cell growth and differentiation to form plasma cells and antibodies (IL-4, IL-5, and IL-6 are especially involved  cell-stimulating/ B-cell growth factors) Activation of Macrophage System Page | 17 • Activate macrophage  more phagocytosis •

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Slow/stop migration of macrophagic cells after chemotaxis  accumulation of macrophages  Feedback stimulatory effect on the helper cells themselves (IL-2)  amplifying effect Cytotoxic T-cells  Killer cell because it directly attacks organisms sometimes, even own cells of the body  Secrete perforins (hole-forming proteins) after binding to antigen • Holes: where interstitial fluids flood in, in addition to cytotoxic secretions • Swollen antigen that will eventually dissolve They withdraw from attacked cell after perforin and cytotoxic secretions and move on to kill others! (Winky: “for more mercenary tendencies” Rox: *LOL*) o Especially potent to: 

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 Viral attacks (entrapped in tissue membranes)  Cancer cells  Heart transplant cells  Foreign cells Suppressor T-cells o Like helper T-cell, is a regulatory T-cell because it regulates cytotoxic T-cell activity o Also suppresses Helper-T-cell Immune tolerance o As in ABO blood typing, you develop antigens for your own tissues so the antibodies will attack everything else instead o Most tolerance results from clone selection during processing o Failure of tolerance mechanism causes auto-immune diseases Ex. Rheumatic fever  Exposure to specific streptococcal toxin with epitope in molecular structure similar to body’s own antigens  immunization against tissues of joints and heart Glomerulonephritis  Immunity against own bastment membrane of glomeruli Myasthenia gravis  Against Ach receptor of NMJ  paralysis Lupus erythematosus  Against many different body tissues at the same time  rapid death or extensive damage Immunization by injection of Antigens (Active) o Injection of dead organisms with some of their antigens still intact, as in typhoid fever, whooping cough, diaptheria, and other bacterial diseases o Toxins whose toxicity had been destroyed as in tetanus, botulism, and other toxic diseases o Attenuated live organisms (cultured so they won’t be disease-causing) as in poliomyelitis, yellow fever (effect on liver caused by mosquitos [the vector]), measles, small po, and other viral diseases Active immunity: body develops its own immunity to such substances Passive immunity: infusion of antibodies, activated T-cells, or both from someone else that had been actively immunized


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o Antibodies last for 2-3 weeks (in recipient’s body), activated T-cells for 1 week (if from another person, but only a few hours to few days if transfused from an animal) Allergy and Hypersensitivity o Side-effect of immunity o Delayed-reaction allergy: caused by activated T-cells (ex. Poison ivy infection) Poison/ toxin of person ivy itself is not harmful, but T-cell mediated immunity causes releasePage of | 18 harmful toxins and macrophage crowding at tissues  tissue damage after repeated exposure o Atropic allergies: caused by non-ordinary immune system response : inheritable : increases amounts of IgE antibodies in blood o IgE : reagins/ sensitizing antibodies; has strong propensity to attach to basophils and mast cells o Allergen: antigen that reacts specifically with specific IgE regain antibody 

o When allergens bind to antibodies, IgE already attached to mast cells or basophils  the antigen-antibody complex membranes contort and ruptures mast cells and basophils, leading to the release of: 1. Histamine** 2. Protease** 3. Slow-reacting substance of anaphylaxis (mixture of toxic leukotrienes)** 4. Eosinophil chemotactic substance** 5. Neutrophil chemotactic substance** 6. Heparin** 7. Platelet activating factors ** cause blood vessel dilation, attraction of eosino and neutrophil, increased permeability of capillaries and loss of fluid into tissues, contraction of local and smooth muscles Examples:  Anaphylaxis: • If allergen is injected directly into circulation; if basophils and mast cells were sensitized

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by binding to IgE  widespread allergic reaction in vascular system and associated tissues • Histamine is released into circulation cause vasodilation and increased capillary permeability and loss o plasma • A person may die within minutes of circulatory shock if not treated with epinephrine • Also, death by suffocation due to slow reacting substances of anaphylaxis which causes bronchiole smooth muscle spasms (asthma-like effect) Urticaria • Antigen enter special skin areas  localized anaphylactictoid reactions • Histamine (local) causes 1. Vasodilation: red flare 2. Swelling due to increased permeability of capillaries (hives)  prevented by antihistamine before exposure Hay Fever • At nose • •

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Histamine causes local intranasal vascular dilation  increased capillary pressure and permeability Rapid fluid leakage (swollen nasal linings)

Asthma • At bronchioles • Slow-reacting substances of anaphylaxis • Anti-histamines are not very effective


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Blood types: Transfusion, Tissue and Organ transplantation Blood Type O and A are most frequent • Titer of agglutinins at different ages: Peaks at 8-10 years of age, declines gradually thereafter • Agglutinins (antibodies) are from plasma as all other antibodies  Most are IgM and IgG

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Why agglutinins are for agglutinogens not present in the body explained via acquired immunity • Agglutinin formation occurs after birth Agglutination process in transfusion reactions  Possible because agglutinins (IgG and IgM) have two binding sites  Clumping plugs small blood vessels throughout the circulatory system  Hemolysis of RBC: when membranes of agglutinated cells release haemoglobin into plasma (destruction due to WBC or distortion of membrane)  Acute hemolysis: when there’s a mismatch between recipients and donors’ bloods : Antibodies lyse RBC by activating complementary system, which releases the lytic complex : Less frequent than delayed hemolysis following agglutination because large titer (volume) of antibodies are needed (especially IgM, which is hemolysin) Blood typing/matching: whatever reacts with agglutinin corresponds to the blood type Rh blood types  ABO blood system: plasma agglutinins responsible causing transfusion reaction develop spontaneously  Rh: needs massive exposure to agglutinogens first before delayed transfusion reaction happens (Rh+ or Rh-)  Rh factors: C,D,E, c ,d, e  Rh +: has antigen D  Rh -: Has no D-antigen Rh immune response  Delayed; takes about 2 to 4 months later for transfusion reactions to occur Characteristics of Rh Transfusion delayed transfusion reactions  First contact: mild reactions only, but the transfusion reactions get progressively worse with subsequent exposure Erythroblastosis fetalis (Hemolytic Disease of the newborn)  Agglutination and phagocytosis of fetus’ RBC  Mostly, mother is Rh- and father is RH+ and baby is Rh+; mother, due to exposure to fetus’ Rh antigen, develop Rh agglutinin  Agglutinin from the other diffuse through placenta into fetus and cause RBC agglutinogens


July 20,2009

Incidence of diseases  subsequent pregnancies have higher/ more potent agglutination Effects of mother’s antibodies on fetus Anti-Rh from mother diffuse through placenta ↓ Agglutination of fetus’ blood ↓ Hemolysis ↓ Release of haemoglobin into blood ↓ Macrophage of fetus converts haemoglobin to bilirubin •

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skin becomes yellow (jaundiced) *antibodies can also attack and damage other cells in body

Clinical picture of Erythroblastosis 1. Jaundice 2. Anaemic anti-Rh agglutinin circulates in blood for one to two months after birth. Therefore, there’s more blood destruction 3. Nucleated blastic forms of RBC pass from baby’s bone marrow into circulatory system (thus, the name) 4. Permanent mental impairment/ damage to motor areas of the brain because of bilirubin precipitation in neuronal cells kernicterus Treatment of erythroblastotic neonate:  replace blood with Rh-negative blood  400 mL of Rh-negative blood infused over a period of 1.5 or more hours while neonate’s own Rh+ blood is being removed  To keep bilirubin level low prevention of kernicterus  By the time the transfused Rh- cells are replaced with infants’ own Rh+, (6 or more weeks) the anti-Rh would have been destroyed Prevention of Erythroblastosis fetalis  During 1970’s: Rh immunoglobulin globin, an antibody administered to mother starting 28-30 weeks of gestation  Also for Rh- women who deliver Rh+ babies to prevent sensitization (heightened reaction) of mothers to Dantigen Transfusion reactions resulting from mismatched blood types  Small amount of infused blood does not significantly dilute the agglutinins in the recipient’s plasma  Therefore, the recipient’s agglutinins can still agglutinate the mismatched donor cells *just remember that your donor’s blood (and its properties) is insignificant, by virtue of its titer, in transfusions

Transfusion reactions cause 1. Hemolysis, due to hemolysin (can be acute or otherwise) 2. Jaundice


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Release of haemoglobin bilirubin excreted in bile by liver jaundice Acute kidney shutdown after transfusion reactions  Kidney failure: one of most lethal effects of transfusion Three causes: Page | 21 1.) renal vasoconstriction due to toxic substances released induced by antigen-antibody reaction 2.) loss of circulating red cells in recipient, production of toxic substances from hemolyzed cells and from immune reactions, which causes circulatory shock ↓arterial blood pressure=decreased renal blood and urine output circulatory shock 3.) if the free haemoglobin> haptaglobin (plasma protein that binds small amounts of haemoglobin) excess leaks though glomerulus membranes into kidney tubules RENAL TUBULAR BLOCKAGE *all three cause acute renal shutdown: can cause death within a week to 12 days if unresolved, unless treated with an artificial kidney Transplantation of tissues and organs  Autograft: transplant of a tissue/ whole organ from one part of same animal to another part  Isograft: from one identical twin to another  Allograft: one human to another/ any animal to another animal of same species  Xenograft: lower animal to human one species to a different species Transplantation of cellular tissues  Autograft and Isograft: since almost same antigens, normal  Xenograft: immune reaction almost always occurs, causing death of cells in graft in a day to five weeks after transplantation  Allograft: ex. Skin, kidney, heart, liver, glandular tissue between persons Attempts to overcome tissue reactions in transplanted tissue 1. tissue- typing: HLA complex of antigens 2. Prevention of graft rejection by suppressing immune system, especially T-lyphocytes Examples of therapeutic agents: a. glucocorticoid hormones from adrenal cortex glands suppress growth of all lymphoid tissue. Thus, decreased antibody and T-cell formation b. Various drugs that have toxic effects on lymphoid system ex. Azathioprine c. cyclosporine: has specific inhibitory effect on helper-T cell formation Thus, blocking T-cell rejection reaction *One of most valuable of all drugs because it does not depress some other portions of immune system Hemostasis (prevention of blood loss) and blood coagulation Mechanisms: 1. Vascular constriction 2. Platelet plug 3. Blood clot due to blood coagulation 4. Eventual growth of fibrous tissue into blood clot to close the hole in vessel permanently Vascular constriction  Contraction of vessel wall smooth muscles results from 1. Local myogenic spasmdue to direct damage to vessel wall and action of thromboxane A, a vasoconstrictor (↑severe damage ↑spasm) 2. Local autocoid factors from automized tissue and blood platelets 3. Nervous reflexes due to pain receptors


July 20,2009

Formation of platelet plug  If cut in blood vessel is very small, platelet plug instead of blood clot Physical and chemical characteristic of platelets: -thrombocytosis -platelets are minute discs (1-4 micrometer in diameter) Page | 22 -formed from megakaryocytes (extremely large cells of hematopoietic series in marrow) in bone marrow  150000 to 300000/microliter  Anucleic and unable to reproduce  Found at the cytoplasm are  Actin and myosin molecules  Thrombostenin  Residues of ER and golgi apparatus that synthesize various enzymes and store large quantities of calcium ions  Mitochondria and enzyme systems that form ATP and ADP  Enzyme systems that synthesize prostaglandin local hormones that cause many vascular and other local tissue reactions  Fibrin-stabilizing factor  Growth factor: cellular growth due to vascular endothelial, vascular, smooth muscle cells and fibroblasts to multiply and grow Platelet cell membrane --has glycoprotein that repulse adherence to normal endothelium o Platelets stick to injured areas of vessel wall only, especially to exposed collagen from deep within vessel wall o Has phospholipids that activate multiple stages in blood clotting o Thus, platelet is an active structure o Has a half-life of 8-12 days o Eliminated via macrophage system Mechanism in platelet plug Platelets swell up contact with damaged vascular wall ↓ Assume several forms with numerous irradiating pseudopods ↓ Contraction of contractile proteins cause granules that contain active factors to be released ↓ They become sticky (to wall and to von Wille brand factor, a protein that leaks into traumatized tissue and secrete ADP and their enzymes form thromboxane A) ↓ ADP+ thromboxane A activate other nearby platelet cells ↓ Fibrin threads form and attach to platelets (blood coagulation later on) Importance of platelet mechanism for closing vascular holes  For minute ruptures in very small blood vessels that happen thousands of times everyday Blood coagulation in ruptured vessel  after trauma: 15-20 seconds if severe; 1-2 minutes if not coagulation  triggers: --activator substances from severed vessel --platelet --blood proteins adhering to traumatized vascular wall •

3-6 minutes after rupture: whole vessel’s filled with clot


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After 20 minutes to one hour: retraction of clot, which closes the vessel further

Fibrous organization or dissolution of blood clot 2 fates of clot: 1. Dissolution 2. More common: become invaded by fibroblasts, which form connective tissue all over the clot (promoted by growth factors) organization of clot into fibrous tissue in about 1 or 2 weeks

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Mechanism of blood coagulation:  Blood coagulation tendencies are a factor of the balance between procoagulants and anti-coagulants present in the blood  In circulation, anticoagulants dominate  Thus, not much clotting in circulation  In damaged vessels, procoagulants dominate clotting General mechanisms of clotting: 3 steps: 1. Prothrombin activator is produced by cascade of chemical reactions involving blood coagulation factors 2. Prothrombin, with help of Prothrombin activator, becomes thrombin 3. Thrombin helps the conversion of fibrinogen to fibrin fibers •

Fibrin fibers enmesh platelets, blood cells and plasma to form clot


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Conversion of Prothrombin to thrombin:  Rate-limiting factor of coagulation is the formation of Prothrombin activator VESSEL DAMAGE

Synthesis of Prothrombin activator

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With sufficient Ca++, Prothrombin is converted to thrombin

Thrombin causes polymerization of fibrinogen molecule to fibrin fibers Platelets --much of Prothrombin first attaches to Prothrombin receptors on platelets already bound to damaged tissue Prothrombin: plasma protein; 15 mg/dL : Alpha-2-globulin with molecular weight of 68700 : Unstable, thus, splits into fragments (ex. Thrombin is almost exactly one half of Prothrombin) : formed continually by liver and used by whole body for clotting : Vit. K is required by the liver for normal Prothrombin and for other factors’ formation **bleeding tendencies can arise from Vit. K deficiency or liver problem Conversion of fibrinogen to fibrin formation of the clot Fibrinogen: High molecular weight (340000) in plasma : produced by the liver : Can’t easily leak out into interstitial fluids. Therefore, there’s not much clotting of interstitial fluids unless there’s a pathological increase in capillaries’ membranes’ permeability Action of thrombin on Fibrinogen to form Fibrin Thrombin: protein enzyme with weak proteolytic capabilities : Acts on fibrinogen by removing four low-molecular weight peptides from each molecule of fibrinogen creation of a fibrin monomer, which has automatic ability to polymerize with other fibrin monomer molecules to form fibrin fibers, which make up the reticulum of blood clot : The same thrombin also activates the fibrin-stabilizing factor, which converts the former non-covalent Hbond among fibrin fibers into covalent bonds, which are stronger Blood clot  

Meshwork of fibrin fibers that entrap blood cells, platelets and plasma Fibrin fibers also adhere to blood vessel damages

Blood retraction Serum: fluid expressed/extracted from clot 20-60 minutes after a clot : can’t clot : Fibrinogen and most of the clotting factors are removed : Platelets determine clot retraction  Attach to fibrin fibers, binding different fibers together  Entrapped in clot, but still releasing procoagulants especially fibrin-stabilizing factor  Also contribute to clot contraction by activating platelet Thrombostenin, Actin and myosin molecules, whose contraction helps compress fibrin meshwork into smaller mass


July 20,2009

 The contraction is activated and accelerated by thrombin and calcium ions (from mitochondria. ER and Golgi apparatus of platelets) **as clot retracts, edges of broken blood vessels are pulled together for hemostasis Clot formation cycle Clot is a positive feedback for more clotting due to extensive reach of thrombin’s proteolytic action (can interact with Page | 25 other clot factors while acting on fibrinogen)

Prothrombin activator formation Triggers of Prothrombin activator formation: 1. Trauma to vascular wall/ adjacent structures 2. Trauma to blood 3. Contact of blood with damaged endothelial cells or with collagen and other tissue elements outside the blood vessel Extrinsic pathway for initiating clotting: Intrinsic Pathway Triggers 1 and 3 Trigger 2 *Extrinsic pathway is very explosive: once initiated, the only limiting factor will be the amount of clot factors, especially 10,7 and 5.

Usually responds to severe trauma (only 15 seconds)  intrinsic pathway is much slower (1 to 6 minutes) **Calcium is needed in promotion of all blood clotting reactions, except for first two steps of intrinsic pathway, so much so that deficiency/absence of it will impede both pathway actions *** it is very seldom that calcium actually falls below threshold for clotting, unless you remove blood and deionize the calcium via citrate ion or by precipitating it with oxalate ion


July 20,2009

Intravascular anti-coagulants I. Endothelial surface factors 1. Smoothness of endothelial cell surface 2. Glycocalyx layer on endothelium—repels clotting factors and platelets 3. Thrombomodulin—a protein bound with endothelial membrane; binds with thrombin *thrombomodulin-thrombin complex activates protein C that inactivates Factors 5 ad 7 Page | 26 ** When endothelial wall gets damaged, it loses 1 and 2, which activate Factors 12 and platelets  Intrinsic Pathway *** More powerful activation if Factor 12 and platelets come in contact with subendothelial collagen II. Antithrombin III and fibrin Remove thrombin in the blood: 1.Fibrin fibers absorb almost 85-90% thrombin during formation 2.Antithrombin III/ Antithrombin-heparin cofactor **remaining thrombin (not used up by fibrin) binds with Antithrombin III, which blocks effects of thrombin on fibrinogen and deactivates thrombin in 12-20 minutes thereafter III. Heparin  Has a low concentration in blood  For prevention of intravascular clotting  Highly negatively-charged conjugated polysaccharide that acts as anticoagulant by enhancing the effects of Antithrombin III  With heparin, removal of free thrombin from circulating blood by Antithrombin iii is almost instantaneous  Also removes Factors 12,11,10 and 9  Produced by basophils and mast cells (prolific at tissues surrounding capillaries of lungs and to a lesser extent, liver, because there are many embolic clots there)

Lysis of blood clots Plasminogen/profibrinolysinfibrinolysin Plasmin: proteolytic (breaks down protein by hydrolysis of peptide chains) : digests fibrin fibers and fibrinogen, Factors 5, 8. 12 and Prothrombin **may cause hypocoagulation Tissue plasminogen activator (t-PA): converts plasminogen to plasmin, which removes unnecessary blood clot a few days after **important in removing minute clots from millions of tiny peripheral vessels that would otherwise become occluded Conditions that cause excessive bleeding in humans: I. Vitamin K deficiency II. Hemophilia III. Thrombocytopenia (Platelet deficiency) *Note that the liver produces almost all of the blood clotting factors ***Hepatitis, cirrhosis and acute yellow atrophy may cause depression of clotting system  Vitamin K is responsible for formation of Prothrombin, Factor 7, 9, 10 and protein C ♦ Produced by bacteria at the intestinal tract ♦ Vit K deficiency often results from poor absorption of fats from GIT (failure of liver to secrete bile into GIT) or liver diseases


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 Vit. K is fat soluble and absorbed into blood along with fats  Hemophiliaoccurs exclusively in males, women are just carriers  Classic haemophilia/ Hemophila A (more common) is caused by Factor 8 (specifically of the smaller component of factor 8) deficiency  Von Willebranck’s disease: bleeding disease caused by Factor 8 (smaller component, whichPage is | 27 important in intrinsic pathway) *almost same with classic haemophilia (?)  Treatment for prolonged bleeding classic haemophilia is therapy/injection of Factor 8 (very expensive)  Thrombocytopenia bleeding from small venules and capillaries and not from larger vessels as with hemophilics  Small punctuate hemorrhage=small purplish blotches (thrombocytopenic purpura)

Recall: Platelets are for repair of minute breaks in capillaries and other small vessels  Platelet levels < 50,000 bleeding  Below 10,000 per microliter death  Signs of deficiency: inability to retract clot **idiopathic thrombocytopenia: platelets are destroyed by own antibodies; unknown cause  Treatments: fresh whole blood transfusion (relief for one to four days) or splenectomy (as spleen removes a lot of platelets from blood)  Thrombus: Abnormal clot in blood vessel  Emboli: Free floating clot  Emboli from large arteries (left side of the heart) can flow peripherally and plug arteries/arterioles in kidney, brain, etc.  Emboli from venous system (right side of the heart) flow into lungs pulmonary arterial embolism  Causes of thromboembolic conditions: 1. Roughened endothelial surface of vessels (initiates clotting) 2. Very slow flow of blood through vessels where thrombin and procoagulants are formed  Tissue plasminogen activator (t-PA): effective in activating plasminogen conversion to plasmin, which dissolves intravascular clot (but only for relatively fresh clot)  Massive pulmonary embolism starts with femoral venous thrombosis (where emboli are formed from leg veins; caused by stasis for hours); goes with venous flow (right side of the heart) and causes blockage of pulmonary arteries  Can cause immediate death if pulmonary arteries are both blocked  Treatment: t-PA  Disseminate intravascular coagulation: widespread coagulation (small but plenty) due to dying or traumatized tissues that release clotting factors  In patients with septicaemia, where edotoxins (bacterial toxins) activate clotting  Leads to low oxygen and nutrient supply, which may lead to circulatory shock  Patient bleeds occasionally because so many factors are removed due to widespread clotting (few procoagulants are left) Anticoagulants for clinical use: I. Heparin: Heparinase (enzyme that breaks it down) : prolongs clotting time (from 6 30 mins. or longer) by slowing thromboembolic conditions II. Coumarin (ex. Warfarin) : has depressant effect on liver compounds (Prothrombin, Factors 8, 9 and 10)


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: competes with Vit. K for reactive sites in enzymatic process for Prothrombin and other clotting factors’ formation Prevention of coagulation outside the body: I. Silicon container prevents contact activation of platelets and Factor 12 II. Heparin: Used in surgical procedure where blood passes through heart-lung machine or through kidney machine and back to the person Page | 28 III. Oxalate: decreases ionic calcium IV. Citrate ion: can be injected intravenously because it can be removed by the liver and turned into glucose **can cause tetany or convulsive death if liver’s damaged Blood coagulation tests: I. Bleeding time: piercing of lobe or finger (normal: 1-6 minutes) II. Clotting time: collect blood in chemically clean test tube and rock back and forth every 30 minutes until clotting happens : no longer used : normal: 6 to 10 minutes III. Prothrombin time: Measure of thrombin concentration in blood

PhysioLec_-_BloodPhysioEditted

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