NURS 8022 Advanced Pathophysiology Exam 2 Study Guide, Exams of Pathophysiology

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NURS 8022 Advanced Pathophysiology Exam 2 Study Guide MODULE 3: Hematology Readings: Ch. 27-29; article – interpretation of iron studies Blood NOT ON STUDY GUIDE  Volume: 6 quarts or 5.5 L  Consists of fluid, cells, and protein o Electrolytes and proteins maintain the osmolarity and acid-base balance of the blood  Functions: o Provide nutrition to cells; provide O2 for cellular metabolism; removes by-products of cellular metabolism; carries cells that protect the body against infection and invading organisms  Plasma o Solution of protein and inorganic materials o 92% water, 8% dissolved solutes – 50-55% of blood volume o Contains plasma proteins which are mainly synthesized in the liver – primary element of plasma  Albumins: function as carriers; control plasma oncotic pressure in blood/capillaries; “protein pressure”; regulate fluids and solutes through circulation; very large – not easily passed through microvasculature which is how the maintain oncotic pressure  Globulins will discuss in immunity lecture  Clotting factors: mainly fibrinogen – precursor to fibrin clot  Lipoproteins: triglycerides; cholesterol; and fatty acids o Also contains several charged ions that regulate cell function, osmotic pressure, and blood pH  Serum o Plasma that has been allowed to clot in the lab in order to remove fibrinogen and other clotting factors  May interfere with some diagnostic tests Pluripotent cells NOT ON STUDY GUIDE  “precursor cells” - in the bone marrow that differentiate into major blood cells o Red cells: erythrocytes o White cells: leukocytes o Platelets: thrombocytes  Erythrocytes o Most abundant cells of the blood o Responsible for tissue oxygenation o Contain hemoglobin; carry gases and electrolytes o Have limited life span – 120-day life cycle  No mitotic division  Can be removed from circulation by spleen and replaced with new o Biconcavity: function/efficient shape that allows gas diffusion and ability to change shape o Reversible deformity: enables torpedo shape to squeeze through microcirculation & return to normal  Leukocytes o Defend the body against infection and remove debris (dead and damaged cells) o Classified by structure and function  Granulocytes and agranulocytes – will discuss in immune lecture  Thrombocytes o 150,000-400,000/mm3 = normal o Irregularly shaped cytoplasmic fragments; formed by fragmentation of megakaryocytes o Essential for blood coagulation and the control of bleeding o Incapable of mitotic division – no nucleus or DNA; limited life span – 5-9 days & removed by spleen o Granules are proinflammatory – released when there is vessel injury – ATP, ADP, calcium, serotonin, histamine o Produced in bone marrow – stored in spleen – slowly released Lymphoid Organs NOT ON STUDY GUIDE  Sites of residence, proliferation, differentiation, and function of lymphocytes and mononuclear phagocytes  Link to hematologic and immune systems  Primary lymphoid organs: o Thymus, bone marrow  Secondary lymphoid organs: spleen, lymph nodes, tonsils, peyer patches of the small intestine  Spleen o Largest secondary lymphoid organ o Functions: fetal hematopoiesis, filters and cleanses the blood, mounts an immune response to bloodborne microorganisms, serves as a blood reservoir  Lymph nodes o Site of the development or activity of lymphocytes, monocytes, and macrophages o Structurally part of lymphatic system o Functionally part of the immune and hematologic systems Understand the basic physiology of hematopoiesis, erythropoiesis, and what erythropoietin is and what it does  Hematopoiesis: process of blood cell production in adult bone marrow or the liver and/or spleen of the fetus o Two stages  Mitosis (proliferation)  Maturation (differentiation) o Act on pluripotent cells o Bone marrow: “myeloid tissue” - primary site of hematopoietic stem cells  Red marrow (produces RBCs) yellow marrow (does not produce RBCs)  Active bone marrow sites: pelvic bones, vertebrae, cranium, mandible, sternum, ribs, humerus, femur o Process  STEM CELL POOL contains: hematopoietic stem cell – progenitor cell  BONE MARROW POOL contains: proliferating and maturing cells and storage for those cells as they prepare for release o Syncope, angina, compensatory tachycardia, organ dysfunction o CLASSIC: fatigue, weakness, dyspnea, tachycardia, pallor  Labs: o Normal: RBC 4.2-6.1; hgb 12-18; hct 35-50% o MCV: 78-100 – related to size o MCH: 27-34 – related to hgb content o Reticulocytes: new RBC formation – low suggest issues in production Microcytic-hypochromic (small size, decreased amt of hgb)  Causes: disorders of iron metabolism, porphyrin and heme synthesis, and globin synthesis  Iron deficient anemia o Most common type of anemia o Highest risk: older adults, women, infants, poverty o Associated with cognitive impairment in children o Causes: inadequate dietary intake; excessive blood loss (GI bleed most common pathophysiologic cause); chronic parasite infestations; metabolic or functional iron deficiency; menorrhagia (most common physiologic cause) o Good sign of malignancy for postmenopausal women and men o Iron:  Ferritin: protein that stores iron; produced in the intestines  Most found in liver, spleen, and bone, small amt in blood  Most sensitive test for IDA  Transferrin: transports iron in the blood  Delivers iron from absorption centers (duodenum, macrophages) to tissues  Saturation is typically measured indirectly by assessing the total iron binding capacity (TIBC)  TIBC: measure of available transferrin that is left unbound to iron  Low transferrin that is actually saturated with iron = high TIBC = more capacity to bind or high total iron binding capacity o Diagnostic manifestations:  Low MCV, low MCH  High RDW  Low initial reticulocyte count – elevated once treatment and iron supplementation begin  Ferritin low - #1 test for IDA  Low serum iron; TIBC high – not enough iron to bind transferrin o Clinical manifestations:  Symptoms vary depending on severity  Mild (hgb 10-12): likely no symptoms  Moderate (hgb 7-11): palpitations, dyspnea, exercise intolerance, angular stomatitis, glossitis, pallor, koilonychia (pitting nails), pica  Severe (hgb <7): postural hypotension, dizziness, weakness, gastritis, paresthesias, lethargy  Elderly: lethargy and confusion  Sideroblastic anemia o Caused by a defect in mitochondrial heme synthesis  Altered mitochondrial metabolism causes ineffective iron uptake and results in dysfunctional hemoglobin synthesis – intracellular iron accumulates – can be due to alcohol abuse, lead poisoning  Ringed sideroblasts in the bone marrow are diagnostic – erythroblasts contain iron granules that have not been synthesized into hemoglobin o Diagnostic manifestations:  Moderate – hct 20-30%  MCV usually normal; serum iron is elevated; transferrin saturation is high = TIBC is low o Clinical manifestations:  Iron overload (hemochromatosis)  Enlarged spleen and liver o Refer to hematologist o Acquired or hereditary  Thalassemia o Autosomal recessive o Diagnostic test is hemoglobin electrophoresis o Characterized by abnormal formation of hemoglobin resulting from mutation that causes loss of one or both alpha globin chains or one or both of beta globin chains o Abnormal hgb formed results in improper oxygen transport and destructing of RBCs results in anemia o Diagnostic manifestations:  Low MCV, low MCH  Ferritin normal to high  Serum iron normal to high  TIBC normal o “target cells” may be seen o Can cause complications: iron overload, bone deformities, CV illness o May confer a degree of protection against malaria Macrocytic-normochromic (large size, normal amt of hgb) - “megaloblastic anemias”  Structurally abnormal – immature RBCs  Causes: defective DNA synthesis, vitamin B12 or folate deficiencies, premature release of RBCs  Vitamin B12 deficiency o All vitamin B12 comes from diet – animal products – commonly seen in strict vegans o Functions:  Keeps nervous system functioning properly  Necessary in the formation of blood  Involved in metabolism of every cell but especially affecting DNA synthesis and regulation  Liver stores up to 3 years' worth – unusual to develop B12 deficiency due to diet o Lab findings:  ↓MCV, ↓Ferritin, ↓serum iron, ↑ TIBC, ↓MCH, ↑RDW (>15), ↓reticulocyte count, possible pancytopenia if severe, abnormally low serum B12 (also use antibody and MMA urine tests)  Pernicious anemia o Most common macrocytic anemia o B12 deficiency anemia d/t autoimmune destruction of parietal cells of the stomach that make intrinsic factor needed for B12 absorption o Congenital or autoimmune o Increased risk: past infection with H. pylori bacteria, gastrectomy, PPI’s o S/S: weakness, fatigue, paresthesia, loss of appetite, abdominal pains, weight loss, beefy red tongue – atrophic glossitis, lemon yellow skin (pallor and icterus), neuro symptoms from nerve demyelination – ataxia, decreased DTR’s o Not reversible – even with treatment o Testing:  Schilling test: localized site of pathology of the B12 deficiency  Give IM B12, PO radioactive B12 – normal pt’s with extrinsic factor should absorb radioactive B12 and excrete in urine because the receptors would be saturated with IM B12; if there is a problem with the intrinsic factor then it will not be present in the urine; test is repeated and exogenous intrinsic factor is given  Folate deficiency anemia o Folate is essential for RNA and DNA synthesis o Found in plant products and fortified foods; deficient in alcoholics and chronic malnutrition; associated with neural tube defects in fetus o Most common cause of deficiency: DIET – alcoholics, anorexics, overcooked food, diets excluding veg o S/S: severe cheilosis (scales and fissures of lips and corners of mouth), stomatitis, dysphagia, ulcerations of mouth and tongue – no neuro symptoms o Lab findings: ↑MCV, ↓ serum folic acid, normal MCH, Blood smear: hyper segmented neutrophils, anisocytosis, poikilocytosis; megaloblastic RBCs; pancytopenia if severe; BM: marked erythroid hyperplasia, megaloblastic changes  Decreased folic acid is diagnostic difference between folic acid and B12 deficiency  Alcohol induced – Macrocytic megaloblastic anemia (large, immature RBCs) o Alcohol interferes with absorption of folic acid (megaloblastic); hbg synthesis (sideroblastic anemia); erythropoiesis (macrocytosis) o Anemia reverses with abstinence from alcohol within with weeks – self limiting Normocytic-normochromic (normal size, normal amt of hgb) - insufficient # of RBCs  No common cause, pathologic mechanisms, morphologic characteristics, less frequent than all other anemias  Aplastic anemia o Red bone marrow is replaced with fat; results in pancytopenia because there are less hematopoietic cells o Most often caused by autoimmune  Other causes: chemical exposure or genetic cause (Fanconi anemia which is a defect in DNA repair o S&S: hypoxemia, pallor, weakness, dyspnea, fever o Diagnose via bone marrow biopsy  Post hemorrhagic anemia o Acute blood loss from vascular space o S/S: depend on severity of blood loss  Hemolytic anemia o Accelerated destruction of RBCs o Congenital or acquired o Intrinsic (d/t components of the cell – usually hereditary) or extrinsic (immune, infection, drugs, hyperactive spleen, intravascular trauma) o Autoimmune  Warm reactive antibody type; cold agglutinin type; cold hemolysin type  Based on the optimal temperature at which the antibody binds to the erythrocytes  S/S: may be asymptomatic, jaundice, splenomegaly o Drug-induced  Form of immune hemolytic anemia that is usually the result of an allergic reaction against foreign antigens – penicillin, cephalosporins  S/S: may be asymptomatic, jaundice, splenomegaly o G6PD deficiency  X-linked recessive – most common enzyme related hemolytic anemia  Inability to produce NADPH which protects against oxidative stress. There is episodic hemolytic anemia when exposed to oxidative stress. Stressors include fava beans, illness, medications (anti-malarial).  When exposed to oxidative stress the hgb denatures and forms Heinz bodies which damage the cell membrane and destroy the RBC  Findings: Normal between episodes. During episode: ↑reticulocyte count, ↑indirect bilirubin, Blood smear may show Heinz bodies  G6PD assay: may be low but misleading at or directly after episode; should be repeated  No treatment – avoid triggers o Sickle cell – see below  Paroxysmal nocturnal hematuria o Acquired stem cell disorder o RBCs become sensitive to complement which causes lysis o S/S: episodic hematuria particularly in am – brown tinged urine; prone to thrombosis o Manifestations:  Often asymptomatic  Often occurs in tandem with inflammatory disease  Can occur with polycythemia vera  Immune (idiopathic) thrombocytopenic purpura (ITP) o IgG antibody that targets platelet glycoproteins o Antibody-coated platelets are sequestered and removed from circulation by macrophages within spleen or immune-like cells in the liver o Acute form often develops after viral infection – most common childhood bleeding disorder o Manifestations:  Petechiae (small red dots) and purpura (purple blood spots or skin hemorrhages) progressing to major hemorrhage o Labs:  Decreased platelets with normal bone marrow in absence of other causes  Disseminated intravascular coagulation (DIC) o Acquired disorder in which clotting and hemorrhage simultaneously occur o Causes:  Infections, massive trauma or surgery, neoplastic disease, chronic inflammatory diseases, complication of childbirth  Significant endothelial damage o Result of increased protease activity in the blood caused by unregulated release of thrombin with subsequent fibrin formation and accelerated fibrinolysis – clotting factors become depleted o Activation of fibrinolytic system (plasmin) results in fibrin degradation production – D dimer levels will increase o Amount of activated thrombin exceeds the body’s antithrombins and the thrombin does not remain localized – widespread thrombosis occurs – widespread ischemia, infarction, and organ hypoperfusion o High mortality rate o Signs and symptoms:  Bleeding from venipuncture sites, arterial lines  Purpura, petechia, hematomas  Symmetric cyanosis of fingers and toes  Signs of multisystem and/or end organ failure Sickle cell pathophysiology  Classified as hemolytic anemia  Autosomal recessive; mutation of beta globin chain of hgb resulting in defective hgb o Homozygous = sickle cell anemia o Heterozygous = sickle cell trait  AA: 1/10 have trait; 1/500 have anemia  Hispanics: 1/100 have trait: 1/36,000 have anemia  Sickle-shaped cell o Unstable and when exposed to acidosis or oxidative stress (hypoxia) the cell sickles permanently o Cells cannot change shape which prevents them from passing through narrow capillaries resulting in occlusion of small blood vessels and tissue ischemia o Sickled cells life span: 10-20 days  Lab findings: o Hemoglobin electrophoresis confirms diagnosis o Hct 20-30%; hgb 8-10 o Peripheral smear: sickled cells, target cells, howell-jolly bodies (spleen) o Elevated reticulocytes o Nucleated RBC’s o Elevated WBC’s (12-15K)  Signs and symptoms o Painful episodic attacks brought on by infection, dehydration, hypoxia  Episodes last hours to days o Vaso-occlustion  CVA, organ damage (heart, lung, liver), osteonecrosis, renal tubular defect (hematuria), retinopathy leading to blindness, pulmonary HTN (poor prognosis), acute chest crisis (bones of chest) o Jaundice caused by hemolysis o Pigment gallstones o Splenomegaly/infarcted spleen  Splenic sequestration crisis  Sudden pooling of blood in spleen – hypovolemia – distended abdomen – circulatory collapse – surgical emergency o Poorly healing ulcers over lower tibia o Severe anemia o Hemolysis – aplastic crisis Calcium and platelet function  Platelets: o Functions:  Synthesize enzymes, ATP, ADP, prostaglandins, store calcium ions  Help regulate blood flow into a damaged site by inducing vasoconstriction  Initiate platelet-platelet interactions, resulting in the formation of a platelet plug  Activate the coagulation cascade to stabilize the platelet plug  Initiate repair processes including clot retraction and clot dissolution (fibrinolysis) o Normal: 150,000-400,000 – less than 100,000 thrombocytopenia – less than 50,000 s/s develop and risk of hemorrhage increases – less than 20,000 spontaneous bleeding may occur – elevated spontaneous thrombosis may occur o Cell membrane of platelets:  Have glycoproteins on surface that repulse adherence to normal endothelium and promote adherence to injured endothelium – react with extracellular matrix of injured cell wall  Contains phospholipids that activate several stages in the blood clotting cascade  Calcium o Required in multiple steps in the process of clotting cascade for activating clotting factors o Prothrombin activator causing prothrombin to be converted to thrombin is completely dependent on adequate calcium Life cycles of erythrocytes and platelets  Erythrocyte life cycle o Created within bone marrow or myeloid tissue o Start as erythroid progenitor cells (erythroblasts) o Follow steps of erythropoiesis – see earlier in study guide o Life expectancy: 100-120 days o Erythrocytes are replaced more slowly with aging – iron depletion and/or decreased total serum iron, iron binding capacity and intestine iron absorption o Destruction of old (senescent) erythrocytes  Changes on outer surface of old erythrocyte attract macrophages  Tissue macrophages digest erythrocyte – heme and globin dissociate  Globin broken down into amino acids  Iron is liberated from heme, oxidized and recycled (transferrin to ferritin)  Porphyrin of heme is metabolized to bilirubin – transported to liver and conjugated – excreted as bile into intestine – transformed to urobilinogen – excreted with feces, some through feces  Platelet life cycle o Irregularly-shaped cytoplasmic fragments formed by the fragmentation of megakaryocyte progenitor cells – produced in the bone marrow – stored in the spleen where they are slowly released o Incapable of mitotic division – no nucleus or DNA o Contain granules that are proinflammatory – biochemical mediators that are released when activated o Life expectancy: 8-10 days o Eliminated: tissue macrophage system within the spleen Basics of clotting cascade; don’t need to memorize all the steps, just understand the basics of what does what  Components: o Vasculature, platelets, blood proteins (clotting factors)  Sequence of hemostasis: o Local constriction  Intravascular smooth muscle contracts reducing blood flow  Platelets are responsible for much of the vasoconstriction via thromboxane A2  Constriction can last minutes to hours allowing for platelet plug and then blood clot o Formation of the platelet plug (primary hemostasis)  Adhesion: mediated by the binding of platelet surface receptor glycoprotein Ib to vWF “anchor”  Activation: smooth platelet spheres change to spiny projections and degranulation (platelet- release reaction) results in the release of various potent biochemicals – see below  Aggregation: facilitated by fibrinogen bridges between receptors on the platelets  Clot retraction: fibrin strands shorten and become denser and stronger to approximate the edges  Positive feedback loop o Formation of blood clot (secondary hemostasis)  Release of prothrombin activator changes prothrombin to thrombin  Thrombin changes fibrinogen to fibrin  Fibrin meshes with blood cells, platelets, and plasma to form clot o Clot retraction and clot dissolution (fibrinolysis)  Clot retraction assisted by platelets, expresses serum  Control of hemostatic mechanisms – excessive clotting prevention o Endothelium regulatory factors on the cell surface prevents the formation of spontaneous clots in normal vessels by several anticoagulant mechanisms:  Production of nitric oxide (NO) and prostacyclin I2 (PGI2)  Thrombin inhibitors (antithrombin III)  Tissue factor inhibitors (tissue factor pathway inhibitors)  Degrading activated clotting factors (thrombomodulin – protein C) o Fibrin: in clot absorbs excess thrombin o Antithrombin III inactivates excess thrombin o Heparin: produced by mast cells and basophils – enhances activity of antithrombin III o Coumadin: acts by competing with vitamin K and inhibits the production in the liver of prothrombin and other clotting factors o Plasminogen: activated and becomes plasmin  Breaks apart fibrin to dissolve clot  Plasminogen activator is released by damaged tissues  Clinical connection: TPA – used to dissolve clots Chemical mediators associated with clotting  Antigenic binding site (paratope) - matching portion on lymphocyte receptor  Antibodies/immunoglobulins  Produced by plasma cells – classes of antibody: IgG, IgA, IgM, IgE, IgD  Function: host protections Understand the basics of the physiology of inflammation including the cell types and which ones activate and come later  Inflammation – limit and control the inflammatory process, prevent and limit infection and further damage, initiate adaptive immune response, prepare the area of injury for healing o Mast cell degranulation  Histamine: vasoactive; causes temporary rapid constriction of large blood vessels and dilation of the post capillary venules; retraction of endothelial cells lining the capillaries – edema  H1 receptor (proinflammatory): on smooth muscle cells – bronchi (bronchoconstriction)  H2 receptor anti-inflammatory): parietal cells of stomach - induces gastric acid secretion  Granulocytes/Phagocytes  Neutrophils: predominate in early inflammatory response o Attracted by neutrophil chemotactic factor released in mast cell degranulation o Ingest dead cells, bacteria, cellular debris – short lived and become a component of the purulent exudate o Primary role: burns, bacteria in nonsterile lesions  Agranulocytes/Phagocytes  Monocytes and macrophages: predominate in late inflammatory response o Highly phagocytic, responsive to cytokines, promote wound healing o Involved in activation of adaptive immunity  Plasma protein systems: provide a biochemical barrier against invading pathogens o Complement system, coagulation system, kinin system o Interactions among the three plasma protein systems prevent injury to the host tissue and guarantee activation when needed o Complement system: destroy pathogens directly; functions in anaphylaxis, mast cell degranulation, leukocyte chemotaxis, cell lysis o Coagulation system: forms clot, prevents spread of infection, stops bleeding, provides framework for repair and healing – fibrin o Kinin system: bradykinin – causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, leukocyte chemotaxis  Cellular mediators o Mast cells – activator of inflammation; contained in tissue close to vessles o Dendritic cells – connect the innate an adaptive immune response o Inflammatory response is initiated when tissue injury occurs or when pathogen associated molecular patterns (PAMPs) are recognized by pattern recognition receptors (PRRs) on cells of the innate immune system o Chemokines or cytokines: regulate innate or adaptive resistance by affecting other neighboring cells – either proinflammatory or anti-inflammatory  Cytokines – interleukins (enhance acquired immune response); interferon (viral infection protection; prevents viruses from infecting healthy cells); TNF (promotes inflammation); chemokines (attract leukocytes to site of inflammation)  Systemic manifestations o Fever (endogenous pyrogens; act directly on hypothalamus), leukocytosis, increased levels in circulating plasma proteins  Local manifestations - “cardinal signs”: redness, heat, swelling, pain, loss of function Granulocytes vs agranulocytes  Granulocytes: BEN o Basophils, eosinophils, neutrophils + mast cells (granulocyte-like – not blood cells) o Characteristics:  Membrane bound granules in cytoplasm – enzymes capable of destroying microorganisms, catabolize debris is ingested during phagocytosis  Involved in inflammatory and immune functions  Amoeboid movement – diapedesis – migrate through vessel walls and sites where needed  Produced in bone marrow – granulopoiesis o Basophils (<1%)  Contain histamine  Increase in: sites of allergic inflammatory reactions, parasitic infection - exoparasites (ticks)  Secrete inflammatory mediators; contribute to local inflammatory response o Eosinophils (1-4%)  Ingest antigen-antibody complexes and viruses  Release cytokines and leukotrienes that augment the inflammatory response  Increase in: type I hypersensitivity allergic reactions, asthma, parasitic infections o Neutrophils (55%)  Defend against infection; polymorphonuclear neutrophils (PMN’s)  Serve as phagocytes in early inflammation  Ingest and destroy microorganisms and debris and then die in 1-2 days o Mast cells – tissue cell, not blood cell  Highly similar to basophils  Central cells in inflammation; activation and degranulation cause increased permeability of blood vessels and smooth muscle contraction  Contain IgE receptors; histamine and heparin – released by degranulation and synthesis of lipid- derived chemical mediators such as leukotrienes (similar to histamine), prostaglandins (induce pain), and platelet activating factor (causes endothelial cell retraction to increase vascular permeability, leukocyte adhesion to endothelial cells, and platelet activation)  Increased in: allergy and anaphylaxis  Agranulocytes: o Lymphocytes, NK cells, monocytes, and macrophages o Lymphocytes (36%)  Major cells of the immune system  Mature T cells, B cells, plasma cells  Lifespan: days, months, years depending on type o NK cells are “lymphocyte like” (5-10%)  Found in peripheral blood and spleen  Kill tumor cells and virally infected cells  Recognize MHC I surface receptors  Do not have to be induced by antigens – don't have high specificity o Monocytes  Found in tissue and lymphoid organs; monocytes are precursor to macrophages  Provide the main line of defense against bacteria in the bloodstream  Cleanse the blood o Macrophages  Remove old and damaged cells, large molecules  Major antigen-processing and antigen-presenting cells that initiate immune responses  Initiate wound healing and tissue remodeling o Dendritic cells – similar to macrophages  Antigen-processing and antigen-presenting cells that initiate immune responses Primary vs. Secondary responses  Primary response o Initial exposure leads to lag or latent phase o B cell differentiation o Clonal selection – antigen processing and presentation – when T and B cells interact with antigen o IgM produced first followed by IgG against specific antigen – igM detected in 5-7 days o Primer of the individual’s immune system  Secondary response o Second exposure; more rapid o Rapidity is caused by the presence of memory cells that do not have to differentiate o Larger amounts of antibody are produced  IgM in similar quantities to primary response; igG in much greater numbers Know the basics of pathophysiology of infection; bacterial and viral  Process of infection o Transmitted by: direct contact, indirect contact (vectors – ticks), droplet vs airborne, vertical vs horizontal o Invasion  Invade surrounding tissues by evading the host’s defense mechanisms o Multiplication  Warm and nutrient-filled environment - microorganisms to multiply rapidly o Spread  Local or systemic; compromised immune system – spreads quicker  Clinical infectious disease o Incubation: period from initial exposure to the onset of first symptoms o Prodromal: occurrence of initial mild symptoms of discomfort and fatigue o Invasion: invades further and affects other body tissues o Convalescence: recovery occurs and symptoms decline; disease is fatal or latent  Clinical manifestations: o Fatigue, malaise, weakness, loss of concentration, generalized aching, loss of appetite o Fever – hallmark of infection; adaptive host-defense response  Factors affecting disease development o Communicability, immunogenicity, entry portal, mechanism of action, infectivity, pathogenicity, virulence, toxigenicity  Classification o Endemic: high but constant rates of infection in a particular population o Epidemic: more new cases than normal; exceeds the number usually observed o Pandemic: epidemic spreading over large area such as continent or worldwide  Bacterial o Gram-negative vs gram-positive o Attach through pili – various transmission routes – result In direct confrontation with individual’s defense mechanisms – colonization o Invasion – exotoxins and endotoxins  Produce toxins and extracellular enzymes to destroy phagocytic cells  Coat antibody – preventing complement activation or phagocytosis  Degrade immune cells  Bind and neutralize antibodies  Evade complement  Cause immune suppression  Resistance develops with alteration of surface molecules that express antigens o Endotoxic shock – septic shock: increased vascular permeability – loss of large volumes of plasma – hypotension, CV shock – bacteria in blood – cytokines released causing vasodilation, hypotension, decreased oxygen delivery, CV shock – can lead to DIC  Viral o Most common affliction of humans; intracellular parasites o Examples: MS, TB skin test, contact allergic reactions, type I DM, Hashimoto disease, Chron’s disease o Antigenic targets: Allergy to plant resins, metals, acetylates, chemicals in rubber, cosmetics, detergents, topical antibiotics  Haptens that react with normal self-proteins in the skin – result in contact dermatitis  Ex: detergents, poison ivy Allergy response – see type I hypersensitivity reaction above  Anaphylaxis - Acute type I hypersensitivity reaction  Causes sudden, rapidly progressive urticaria and respiratory distress – can lead to vascular collapse, systemic shock, and even death  Systemic or localized  Anaphylactic reaction o Initial exposure to antigen - immune system produces IgE antibodies in lymph nodes o Antibodies bind to membrane receptors on mast cells in connective tissues and on basophils o Re-exposure – antigen will bind to adjacent igE antibodies  Response to antigen – igM and igG recognize and bind to antigen o Release of chemical mediators  IgE, histamine, serotonin, leukotrienes o Intensified response – mast cells release more histamine o Vasodilation o Respiratory distress – histamine in lungs causes endothelial cell destruction and fluid leak into alveoli o Deterioration – mediators increase vascular permeability causing fluid to leak into vessels o Failure of compensatory mechanisms – endothelial cell damage causes basophils and mast cells to release heparin and mediator-neutralizing substances – irreversible Endotoxins and exotoxins and their roles  Invasion of bacterial infections  Endotoxins: contained in the cell walls of gram-negative bacteria and released during lysis of bacteria o Pyrogenic bacteria: activate inflammation and produce fever  Exotoxins: enzymes released during growth o Damages cell membranes, activates second messengers, inhibits protein synthesis Understand immunoglobulins and their role  Produced by plasma cells – classes of antibody: IgG, IgA, IgM, IgE, IgD  IgA: body secretions o Type I found in the blood; type II found in secretions o Defends against pathogens on body surfaces  IgD: director – regulating cell activity o Low concentration; easily broken down o Located on surface of developing B lymphocytes and function as antigen receptor  IgE: emergency – involved with immediate response, initiates inflammatory reaction o Mediator in allergic responses o Bound to mast cells – stimulates release of mast cells causing degranulation o Defender against parasites  IgG: gestation – passive immunity given to newborns; primary antibody in immune resonse o Most abundant class (80%) o Most of the protective activity against infections; found in all body fluids; four classes  IgM: major – largest in size; first produced during primary response o Only found in vascular system – too large Autoimmunity vs. alloimmunity and pathophysiology of diseases discussed  Autoimmunity: misdirected response against the host’s own cells - breakdown of tolerance during which the body’s immune system begins to recognize self-antigens as foreign o Ex: sequestered antigens, infectious disease with molecular mimicry, neoantigens, survival of a forbidden clone, or defective peripheral tolerance o Genetic factor – familial association o Systemic lupus erythematosus (SLE)  Type III hypersensitivity – chronic multisystem inflammatory disease  Autoantibodies against nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets, etc.  Deposition of circulating immune complexes containing antibody against the host’s DNA  More common in females; 20-40 years old; blacks>whites; genetic predisposition  Clinical manifestations:  Arthralgias or arthritis, vasculitis and rash, renal disease, hematologic changes – anemia, cardiovascular disease  Transient lupus like syndrome – develops from prolonged use of medications (procainamide, hydralazine) - can be triggered by UV radiation and infectious agents  4/11 findings: facial (malar) rash, discoid rash, photosensitivity, oral or nasopharyngeal ulcers, nonerosive arthritis, serositis, renal disorders, neurologic disorders, hematologic disorders, immunologic disorders, and presence of antinuclear antibodies (ANA’s)  No cure; UV exposure worsens symptoms  Alloimmunity: directed against beneficial foreign tissues (transfusions, transplants, fetus o Individual's immune system reacting against antigens on the tissues of other members of the same species o Transient neonatal alloimmunity, transplant reaction, transfusion reactions o Transfusion reaction  Type II hypersensitivity reaction  ABO system  Antibodies are of the IgM class  O: universal donor  AB: universal recipient  rH system  Primary expressed on erythrocytes  rH positive: expresses the D antigen on the RhD protein; vice versa rH negative  RH negative can make anti-D if exposure to rHD positive – can cause hemolytic disease to newborn if newborn disease if infant is rH positive o Graft reaction  Matching HLA antigen is most critical for graft acceptance  Classified according to:  Hyperacute: immediate and rare; preexisting antibody to graft antigens  Acute: cell-mediated response against unmatched HLA antigens  Chronic: months or years; due to a weak cell-mediated reaction against minor HLA  Deficiencies in immunity o Impaired function of T cells, B cells, phagocytes, and/or complement  Primary (congenital): genetic  Secondary (acquired): caused by other illnesses – more common  Normal physiologic conditions and psychologic stress; dietary insufficiencies; malignancies and metabolic disease; environmental and physical trauma; medical treatments; infections and AIDS, stressors  Hallmark signs: recurrent, severe infections – often with opportunistic organisms Physiology of the stress response; including the substances involved and their effect on the body  General Adaptation Syndrome o Nonspecific response to noxious stimuli o Three stages  Alarm: arousal of body defenses – fight or flight  Stressor triggers the hypothalamic-pituitary-adrenal (HPA) axis  Activates sympathetic nervous system  Resistance (adaptation): mobilization that contributes to fight or flight  Begins with the actions of adrenal hormones – cortisol, epinephrine, and norepinephrine  Exhaustion: progressive breakdown of compensatory mechanisms; may lead to the onset of disease  Only occurs if stress continues and adaptation is not successful  Stress response o Initiated by the central nervous system and the endocrine system  Corticotropin-releasing hormone (CRH) is released from hypothalamus – peripherally released at inflammatory sites o SNS aroused during stress response  Causes adrenal gland medulla to release catecholamines – stimulate fight or flight  Large amts of epinephrine: effects CV – increasing CO, blood flow to brain, heart, lungs, skeletal muscles; dilate airways  Small amts of norepinephrine – effects complement epinephrine o Constricts blood vessels of viscera and skin shifting blood to vital organs; increases mental awareness  Hypothalamic CRH stimulates the pituitary gland to release a variety of hormones o Anterior pituitary gland: prolactin, endorphins, growth hormone and ACTH  Systemic disorders o Chronic fatigue  Microorganism responsible: nonspecific indicator  CM: lack of energy, listlessness, fatigue that interferes with participation in family/work/leisure activities, fatigue >6 months, impaired memory, post exertional malaise, unrefreshing sleep, muscle pain, joint pain, headaches, sore throat, tender cervical or axillary nodes o Fever of unknow origin  Microorganism responsible: 5 causes – infection, neoplasms, autoimmune disease, misc, undiagnosed – usually viral  CM: fever at least 3 weeks on several occasions; undiagnosed after 1 week of workup in hospital or 3 weeks as outpatient  Bioweapons o Anthrax  Microorganism responsible: gram + spore-forming aerobic rod Bacillus anthracis  CM: cutaneous or pulmonary infection – prodromal symptoms then brief period of improvement followed by rapid onset of high fever, severe respiratory distress, shock and death within 24-36 hours o Botulism  Microorganism responsible: Clostridium botulinum; neurotoxin – spore forming anaerobe found in soil  CM: symmetric cranial neuropathies, blurred vision or diplopia, symmetric descending weakness in a proximal to distal patter, respiratory dysfunction *neuro symptoms o Plague  Microorganism responsible: Yersinia pestis; nonmotile bacillus  CM:  Bubonic (fleas): enlarged painful regional lymph nodes (bubones); fever, chills, prostration, gangrene in distal regions  Pneumonic (droplet inhalation): fever, weakness, rapidly developing pneumonia with SOB, chest pain, cough, blood or watery sputum  Must isolate o Smallpox  Microorganism responsible: orthopoxvirus; DNA virus  CM: high fever, malaise, severe aching pains, prostration – later with papular rash on face and spreads to UE and LE – rash progresses to vesicular and then later pustular – most dense on face  Must isolate  Plasma cell disorders o Multiple myeloma  Neoplastic proliferation of single plasma cell line  Monoclonal immunoglobulin – leads to many copies of one specific immunoglobulin – normally IgG or IgA  Bone marrow elements replaced by malignant plasma cells – anemia; leukopenia; thrombocytopenia  CM: bone pain, pathological fractures, loss of height; normocytic normochromic anemia; renal failure; recurrent infections (most common cause of death); cord compression o Hodgkin's lymphoma  Cancer of lymphatic system  Ann Arbor staging  CM: *lymphadenopathy; normal symptoms – prodromal symptoms o Non-Hodgkin's lymphoma  Diverse group of solid tumor that occur with malignant transformation and growth of B or T lymphocytes or their precursors in the lymphatic system  B cell lymphomas (85% of all cases) - usually starts in lymph nodes and spreads to blood and bone marrow  Twice as common as Hodgkin’s  CM: more advanced disease at presentation; *lymphadenopathy, prodromal symptoms less common than in HL; hepatosplenomegaly, abdominal pain, recurrent infections o Leukemias  Neoplastic proliferation of abnormal WBCs – accumulation of abnormal WBCs interfere with production of normal WBCs, RBCs and platelets  Myelogenous leukemia = granulocytes or monocytes  Lymphocytic leukemia = lymphocytes  Acute vs. chronic  AML  Mostly in adults  Response to therapy not favorable  ALL  Lymphoblasts on histology  Most common in children under age 15  Very responsive to therapy  CNS involvement associated with B cell phenotype; increased LDH; rapid leukemic cell proliferation  AML AND ALL CM: pancytopenia, recurrent infections, splenomegaly, hepatomegaly, lymphadenopathy, bone and joint pain, CNS involvement, testicular involvement (ALL), anterior mediastinal mass (T cell ALL), skin nodule (AML)  CML  Normally >40 y/o  Can transform to acute leukemia o Blast crisis – accelerated phase of blast and promyelocyte production o Associated with translocation of t(9,22) - Philadelphia chromosome  Shorter survival and decreased response to treatment (90%)  CM: may be asymptomatic, prodromal symptoms, recurrent infections, easy bruising/bleeding, anemia, splenomegaly, hepatomegaly, lymphadenopathy  CLL  Most >60 y/o; most common leukemia in western world; least aggressive  CM: normally asymptomatic, discovered on routine CVC (lymphocytosis), generalized painless lymphadenopathy, splenomegaly, frequent URI’s o Advanced disease: fatigue, weight loss, pallor, skin rashes, easy bruising, bone tenderness, pain