Hematology/Oncology/ID PDF

Hematology/Oncology/ID BMS 0.4 The student will identify the following basic structures and characterize the relationship of the body systems to one another: integumentary system, fascia & potential spaces, mucous and serous membranes, skeletal system (cartilage, bones, joints), muscular system (mu...

Hematology/Oncology/ID BMS 0.4 The student will identify the following basic structures and characterize the relationship of the body systems to one another: integumentary system, fascia & potential spaces, mucous and serous membranes, skeletal system (cartilage, bones, joints), muscular system (muscle tissue), cardiovascular system (heart, blood & vessels), lymphoid system & nervous system. - Heart circulation: Arteries, arteriole, capillaries, Venules, vein, right atria, right ventricle, lungs, left atria, left ventricle (start at arteries) - Veins bring deoxygenated blood from body back to the heart (towards) - Arteries take oxygenated blood from heart to body (away) - Capillaries surrounded with body cells to facilitate exchange of nutrients, gases, and waste between blood and tissues - Endothelial cell structure: o Tunica adventitia: outermost layer of connective tissue, “anchor” vessel in place o Tunica Media: elastic + smooth muscle, middle layer ▪ Arteries have thicker tunica media than veins due to being under more pressure o Tunica Intima: endothelium is part of this layer, simple squamous endothelium (slide 7) - Veins hold more blood than arteries and they are under lower pressure - Veins have valves to prevent back flow due to gravity or internal pressure - Muscle contraction forces vein valves to open moving blood towards the heart while also closing valves preventing back flow (slide 11) - Systemic circulation: circulation of blood from heart to body and back to heart o Left ventricle, aorta, systemic arteries, arterioles, capillaries, systemic venules, veins, superior or inferior vena cava, right atria - Pulmonary circulation: right ventricle, pulmonary trunk, right and left pulmonary arteries, lungs, right and left pulmonary veins, left atria - BLOOD VESSEL NAMES** - Blood return from body to lungs: o Right/Left brachiocephalic veins, superior and inferior vena cava, pulmonary trunk, right/left pulmonary arteries - Blood return from lungs to body: o Right/left pulmonary veins, ascending aorta, descending aorta, right brachiocephalic artery, left common carotid artery, left subclavian artery - Lymphatic system functions to: o return overflow interstitial fluid to the circulation system (blood) o Protect the immune system o Transport dietary fat - Primary lymphatic organs: o Thymus (t + B cells) o Red bone marrow - Secondary lymphatic organs: o Tonsils o Lymph nodes (cervical, axillary, inguinal) o Spleen o MALT in small intestine - Lymphatic system is an open system that starts at capillaries, slower system - Lymph is essentially plasma without the plasma proteins - Interstitial fluid travels into open lymphatic capillaries - Order of Lymph flow: (lymph travels towards the heart) o Interstitial fluid —> lymphatic capillaries —> lymphatic vessels—> afferent vessel —> Lymph node —> efferent blood vessel —> lymphatic trunks —> Right and Left lymphatic ducts—> drain into subclavian veins o Lymph nodes act as immune surveillance for what is passing through - Lymphatic trunks: o Paired: jugular, subclavian, bronchomediastinal, lumbar  o Unpaired: Intestinal ▪ Flows into cisterns chyli (lumbar also drain here) - Skeletal system: o Protection: collagen +calcium phosphate salts (strength and resistant to bend) o Support^ o Lever for movement o Storage for minerals o Hematopoiesis - Bone marrow stored inside the bone o Red Bone marrow – produces formed elements o Yellow bone marrow – inactive red marrow but can activate when needed - Bone marrow stored: in spongy bone on epipshyeal ends, medullary cavity long bones, spongy bone of flat bone BMS 1.1 The student will identify the basic structures, functions and characterize their relationship to one another for the bone marrow derivatives of the skeletal system (erythrocytes, leukocytes & thrombocytes). - Fetal growth: o Initially RBC growth is stimulated in the yolk sac o Then stimulated by liver, spleen, and bone marrow o ALL bones produce red blood cells until 5 - Long bones produce RBC until 20 - Adults: o Spongy bone in vertebrae, sternum, ribs, iliac bone - Blood – specialized fluid of connective tissue, suspended within plasma - Five functions of Blood: o Transport ▪ Nutrients, vitamins, o2, hormones towards interstitial fluid ▪ Waste material, co2, hormones from the interstitial fluid o Regulate ph and ions o Restrict fluid loss at injury site o Defend toxins + pathogens o Stabilize temperature - Blood is 100.4 F to create homeostasis between our external environment and inside - Blood makes up 7% of our body: o Males: 5-6 L o Females: 4-5 L - Blood ~45% solids - Blood is slightly alkaline 7.35-7.45 or 7.4 (weak base) - Blood contains: (slide 40) o Plasma (water, plasma proteins, solutes) o Formed elements (RBC, WBC, platelets) - Centrifuging blood causes fractionation- separation of whole blood into plasma and formed elements - Plasma 55% TOTAL BLOOD* o 92% water * o 7% proteins (Albumin ~60%, Globulin ~35%, Fibrinogen 4%, Regulatory pp proerythroblast -> erythroblasts (go through several steps to expel nucleus ->Hb)-> reticulocyte —> Erythrocyte (MATURE) - Balance between production and destruction !!! ~1% produced to ~1% destroyed - Leukocytes develop fully in red BM - Monocytes do not develop fully in bone marrow o Develop into macrophages in peripheral tissue - Lymphocytes — > after dev. Migrate to peripheral tissues (spleen, lymph node, tonsils)  o B cells develop in BM o T cells in thymus - 5 types of leukocytes: (never let monkeys eat bananas) - Granulocytes: o Neutrophil o Eosinophil o Basophil - Agranulocytosis: o Monocyte o Lymphocyte - All are bigger than RBC, lymphocyte only slightly larger - Neutrophils: o Polymorphonuclear leukocytes o 3-5 lobed o Pale granules in cytoplasm o Active – first at site of injury/infxn o Form PUS (semi digested material from phagosomes) ▪ Not just neutrophil form ▪ Necrotic tissue, dead neutrophils, dead macrophages, tissue fluid o Phagocytic (microbes) >> internalize to phagosomes >> digest o Pale granules —> lysosomal enzymes (pathogen membrane) + bactericides (H202/superoxide) o “Left shift” —> large # of immature neutrophils on PBS >> bacterial infxn - Eosinophils: o Acidophils (red/pink granule) o Bilobed w/ red granules o Chemotaxis o Weak phagocytic activity o Active against parasites (Worms) ▪ Immunomodulatory – attach to juvenile forms of parasite Granules (lysosomes) Reactive form of O2 Larvacidal protein o Decrease inflammation from basophils and mast cells in allergic rxn o Worms >> schistosomiasis, ascariasis, trichnosis o D/o that increase eosinophils = Asthma/allergies, atopic dermatitis, AML - Basophils: o Bilobed (irregular lobes) & purple granules o Fn similar to mast cells (release histamine + heparin) o Also release bradykinin, slow reaction substance in anaphylaxis (SRSA), lysosomal enzymes o Release of chemicals occur when >> IgE ab attached to cell or antigen bind to ab cause cell to rupture o Rupturing mast/basophils >> histamine, heparin, SRSA, increased blood flow, platelet activating factors, etc o Immediate hypersensitivity (Type 1) ▪ Mast cell degranulation through allergen-specific IgE ▪ Heparin, histamine release >> IgE attached or binding antigen-ab cause cell rupture ▪ Sneezing itching runny nose itchy throat ▪ Anaphylaxis/shock = life threatening o Enter peripheral tissue and become MAST CELLS - Monocytes- o Large spherical cells with indented c shaped nuclei, pale-light blue AGRANULAR cytoplasm o Role in immune defenses and tissue repair o Enter peripheral tissues and become MACROPHAGES o Phagocytosis and antigen presenting functions ▪ Engulf, digest microbes  ▪ Secrete substances that attract immune system cells and fibroblast to injury site - Phagocytosis: cell eating o Microbes, malignant cells, adoptive cells o Contain lysosomes with digestive enzymes - Eosinophils and basophils are weak phagocytic cells - Lymphocytes: o 20-30% of circulating WBC o Migrate in and out of blood o Located in lymphatic tissues or organs o Types: T, B, and NK - T-cells: o Cell-mediated immunity o Attack foreign cells directly - B-cells: o Antibody mediated or humoral immunity o Differentiate into plasma cells (activated b cells) → secrete antibodies - Natural Killer cells: o Most are innate, not specific immunity o Secrete cytotoxic cytokines to destroy abnormal tissue o BMS 1.2 The student will describe the cell nomenclature resulting in production of erythrocytes. - Hematopoiesis: process of producing formed elements by myeloid and lymphoid stem cells - Erythropoiesis: building RBC in myeloid tissue, requires—> ▪ Amino acids ▪ Iron ▪ B12 (cobalmin) ▪ B6 (pyridoxine) ▪ B9 (folic acid) o Foods rich in folic acid – avocado, bell peppers, beets, oranges, nuts, seeds, leafy greens - Erythropoietin: o stimulate stem cells to form proerythroblasts o Promote release of reticulocytes from bone marrow o Released from the kidneys in response to LOW renal oxygenation from—> ▪ Dysfunctional RBC ▪ Low blood volume ▪ Poor oxygenation ▪ Poor blood flow o Low renal oxygenation —> hypoxia -Inducible factor 1 (HIF-1) —> hypoxia response element on DNA —> EPO transcription - Regulation of RBC production o When RBC DROP in blood: ▪ Low o2 detected in kidneys ▪ Increased secretion of EPO by kidneys ▪ EPO enter blood bind to receptor in red BM ▪ Increased stimulation of Red BM produce RBC ▪ Increased RBC production (increased O2 carrying capacity o When RBC INCREASE in the blood: ▪ Increased o2 detected at kidneys ▪ Decreased secretion of EPO ▪ Decreased stimulation of red BM ▪ Lower RBC (lower O2 carrying capacity) o Factors such as CO2 (hypoxia) can affect this - Hematopoietic origin & differentiation o Stem cells in BM divide to produce: ▪ Myeloid stem cells: become erythrocytes, thrombocytes, and most leukocytes (neutrophil, basophil, eosinophil, monocyte) ▪ Lymphoid stem cells: eventually become lymphocytes (T-cell, B-cell, natural Killer cell - Progenitor cells: o Often called CFU o Only give rise to one cell type o 4 major types: ▪ Erythroid —> erythrocytes ▪ Thrombocytic—> platelets ▪ Granulocyte-Monocyte —> all granulocytes and monocytes ▪ Lymphoid —> B lymphocytes, T lymphocytes, Natural killer cells - Precursor Cells: o -blasts o Mature into functional final cell o Both progenitor and precursor divide more rapidly than stem cells —> require Colony stimulating factors or hemopoeitic growth factors - Erythrocyte formation only takes place in Red bone marrow - EPO from kidneys stimulate this - Myeloid cells become mature RBC - All formed elements originate from hemocytoblasts —> myeloid and lymphoid Stem cells - Lymphopoiesis= lymphoid stem cells differentiate into lymphocytes BMS 1.3 The student will characterize hematopoiesis (erythrocytes, leukocytes & thrombocytes) in terms of histologic environment, role of regulatory cytokines, nutritional requirements, stem cell differentiation/proliferation, and maturation sequence of morphologic changes. BMS 1.4 The student will state the usual lifespan of erythrocytes and describe the process of cell removal, hemoglobin production and break-down, and bilirubin metabolism. - HEME (iron ions) o Associated with oxygen (oxyhemoglobin) = bright red o Not combined with oxygen (deoxyhemoglobin) = purple-blue - Site on globulin (protein/amino acids) — co2 bind to carbaminohemoglobin o Co2 released from body attaches to amino groups on the hemoglobin proteins o This creates carbaminohemoglobin o Helps transfer co2 to the lungs where it can be expelled o Binds to a different portion on hemoglobin that o2 - Over time, red blood cells decrease in enzyme activity and ATP levels o Circulate for 120 days o Decrease in resilience —> burst when passing into spleen o Hb phagocytized by : macrophages in spleen and Kupffer cells (liver) and macrophages in BM o Iron transported by transferrin to the red BM to be reused o Iron may also be stored as ferritin in the liver and tissues o Porphyrin (heme ring) secreted into bile —> bilirubin - Macrophages in spleen (1) and liver (2) engulf RBC membrane rupture - Bilirubin formation and excretion: o Phagocytes break Hb into -> globulin, heme (biliverdin), iron recycling (transferrin, ferritin) o Biliverdin (GREEN) converted to bilirubin (YELLOW) in liver o Bilirubin -> excreted as bile by liver, jaundice (buildup), converted by intestinal bacteria (urobilin + stercobilin) = stool color BMS 1.5 The student will define mean corpuscular volume (MCV) and differentiate microcytosis, normocytosis, and macrocytosis. - MEASURING RBC: o RBC count: reports number of RBC in 1 microliter of blood o Hemoglobin (g/L): measure Hb in blood o Hematocrit (Ht or HCT): % of RBC centrifuged in whole blood, volume of red cell mass to plasma (also known as packed cell volume) – 3x Hb o Mean Corpuscular Volume (MCV): mean cell volume, average RBC volume - Normochromic, normocyte = normal in size and color - Hypochromic, microcyte = loss of color and smaller - Hyperchromic, macrocyte = full of color and bigger - Megaloblastic = large nucleated RBC precursors w no condensed chromatin o Impaired DNA synthesis - Non-megaloblastic: no impairment of DNA synthesis - Microcytic anemia have decreased MCV o Examples are: IDA, Thalassemias, Abnormal heme synthesis, other (Cu def, zinc poison) - Hallmark of Thalassemias: o Decreased hb o Decreased MCV o Increased reticulocytes - Normocytic anemias o Hemolytic anemias o Anemia of chronic disease/inflammation o BM disorder o Nutritional (Fe, b12, b9) o Renal insufficiency - Macrocytic anemia: increased MCV o B12 def o Folate deficiency o Inborn errors of metabolism o Ethanol abuse/LD o Reticulocytosis o Abnormal DNA synthesis - B12 deficiency o Decreased intake, absorption o Pernicious anemia – lack of intrinsic factor made by parietal cells in stomach ▪ Caused by failure of gastric parietal cells to produce intrinsic factor permitting absorption of b12 - B12 rich foods: fish, meat, poultry, eggs, milk products, nutrional yeast, legumes - Folate def: DNA synthesis defects o Ability to repair DNA is decreased o B12 is a cofactor for activation of folic acid o Foods -> legumes, leafy greens BMS 1.6 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms of disease to hematopoietic and lymph tissue changes and classify the following types of hematopoietic disorders: Cytopenias, Anemias (Blood loss, Hemolytic, Hypoproliferative) and Proliferative disorders (Secondary erythrocytosis) - Autosomal dominant disorders: 50% of offspring get disease o Von willebrand Disease o Factor V Leiden o Protein S + C Deficiency o Antithrombin II deficiency - X Linked recessive: 50% of male offspring obtain, daughters are carriers unless both X obtain recessive gene  o Hemophilia A (VIII) — spontaneous mutation o Hemophilia B (IX) — Spontaneous mutation o G6PD deficiency —protect RBC from oxidative stress - Autosomal Recessive: 25% offspring obtain disease o Sickle Cell anemia o Alpha thalassemias o Hemophilia C (XI) - Spontaneous mutation is not Mendelian genetics — cannot be predicted - Anemia: deficit in RBC - Polycythemia: overproduction of RBC (PV) - Pathogenesis of anemia —> decreased RBC production OR increased RBC destruction and blood loss - Polycythemia Vera: o BM stem cells are normal o Also presence of abnormal clonal stem cells o ETIOLOGY —> unregulated one plastic proliferation - Anemia: o HCT or Hb lower than normal o Caused by several conditions o Hypo-proliferative RBC or amnt of Hb ▪ Iron, b12, folate def ▪ Dec EPO production ▪ Cancer ▪ Inflammation (cytokines decrease availability of iron) o Bleeding ▪ GI, GU, trauma o Hemolytic ▪ Sickle Cell ▪ Thalassemia ▪ Hb variants ▪ Drug induced ▪ Autoimmune o Reticulocytes are slightly immature RBCs – slightly larger and still have some cellular RNA ▪ In a PBS, reticulocytes may be seen after an increased production of RBCs - If RBC lifespan shortened significantly ( to hypoxia tissue d/o, inappropriate increase in EPO, increased EPO sensitivity BMS 1.7 The student will explain maturation sequence and function of: neutrophilic granulocytes, eosinophilic granulocytes, basophilic granulocytes, and tissue mast cells. BMS 1.8 The student will explain the effects of over-production and under-production of leukocytes. BMS 1.9 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms of disease to hematopoietic and lymph tissue changes and classify the following types of hematopoietic disorders: Cytopenias —> Leukopenias (Neutropenia, Lymphocytopenia) and Proliferative disorders —-> Reactive leukocytosis (Neutrophilia, Lymphocytosis, Monocytosis, Eosinophilia) - Neutropenia – low number of neutrophils >> risk of infxn o Decreased production o Destruction o Peripheral pooling - ANC = WBC count and %WBC that are neutrophils x2 - INNATE IMMUNITY = N, M, E, B - Neutrophilia: increased neutrophils o “left shift” o Total WBC generally increased not always o Caused >> mobilization of immature neutrophils from BM to blood to move out of sit of infxn - Reactive Leukocytosis: elevated number of absolute lymphocytes in circ. o 2ndary response to another disease process or clonal d/o of BM ▪ Basophlia – chickenpox, colitis, anemia ▪ Eosinophilia – allergic dx, infxn (worms), autoimmune ▪ Monocytosis – infxns, drugs, poison, colitis ▪ Infections causing- viral, TB, parasitic, hypersensitivity rxn, stress drugs o Lymphocytopenia- less than 18% of differential count ▪ Most have reduction specifically in CD4 helper T cells (MC) ▪ Due to accelerated t cell destructions or enzyme deficiencies that aid in construction of purines ▪ BMS 1.10 The student will explain activation sequence and function of thrombocytes - Thrombocytopoiesis: platelet production in the bone marrow, controlled by hormones thrombopoietin, interleukin-6, Multi- CSF o Megakaryocytes: giant, remain in bone marrow, manufacture platelets from their cytoplasm, release into circulation BMS 1.11 The student will describe the molecular basis for activation, progression and control, and the observed physiologic effects associated with each of the following hemostasis processes: vascular constriction, platelet adhesion & aggression, coagulation (intrinsic & extrinsic pathways), fibrinolysis, von Willebrand factor. - Hemostasis: the cessation of bleeding o Vascular phase — a cut triggers vascular spasm (shrinking, contraction), short term ▪ Endothelial cells contract, expose basal lamina ▪ Endothelial cells release (adp, TF, prostacyclin, endothelins) – stimulate smooth muscle contraction and cell division ▪ Endothelial membranes become sticky to seal off blood flow o Platelet phase (15 secs after injury) ▪ Adhesion- stick to endothelial surface, basal laminate, and exposed collagen fibers ▪ Form platelet plug- closes small breaks (Vitamin k, ADP, TXA2, clotting factors, CA2+, vWF, Gllb/Gllla, Platelet derived growth factor) o Coagulation phase (+feedback) ▪ Fibrin network covers platelet plug, traps and seals area ▪ Clotting factors – required or clotting, produced by liver (III, IV, VIII) and platelets (fibrinogen, fibronectin, V, VIII) ▪ Blood clotting – convert circulating fibrinogen into fibrin (water soluble) - Bleeding normally stops after 1-4 minutes - Platelet Plug size restriction: o Prostacyclin- inhibit platelet aggregation, released by endothelial cells o Inhibitory compounds – released by WBC - Naturally Circulating elements:  o Thrombogenic- platelets, platelet activator factor, clotting factor, fibrinogen, vWF o Antithrombogenic – antithrombin, Protein c + s, plasminogen - If you lose something in the common pathway there is no way to clot ***** - The coagulation cascade is a chain reaction of enzymes and pro enzymes - Extrinsic pathway: o Activated by TF (or thromboplastin) – damaged cells release o TF + Ca2+ + VIIa activate X (common pathway activated) o TF+ Ca2+ + Xa + Va —> prothrombin activator / prothrombinase complex o This splits prothrombin into thrombin ▪ Self accelerating bc thrombin activates V increasing reactivity of complex o Run PT (prothrombin time) to measure clinically - Intrinsic Pathway: not essential, backup system o Activation by exposure/trauma to collagen o Collagen activates XII and platelets release platelet factor 3** o XIIa + enzymes activate XI o Ca2+ + XIa activate IX o Ca2+ + IXa + VIIIa activates X o Ca2+ + Xa + Va —> prothrombin activator/prothrombinase complex o This splits prothrombin into thrombin o Run aPTT (activated partial thromboplastin time) to clinically measure - Common pathway (Coagulation phase) – begins 30 seconds or more after injury o Forms enzyme prothrombinase o Convert prothrombin into thrombin o Thrombin activates fibrinogen to fibrin - Non-enzymatic factors o V, VIII, TF o V and VIII bind to surface of activated platelets – act as receptors - THROMBIN o Help convert fibrinogen into fibrin and cross link fibrin XIIIa o Form + feedback loop triggering generation of V, VIII, XI = accelerate clotting o Bind to thrombomodulin (receptor) on endothelial cells — activate Protein C which inhibit factor V (cannot clot) - Hypo-coagulable states: not able to coagulate (less clotting) o Excess bleeding can result from: ▪ Thrombocytopenia (deficiency in platelet #) ▪ Von willebrands disease (deficiency in platelet function) ▪ Deficiency of pro-coagulation proteins (Liver failure) ▪ Over production of of anti coagulation proteins (thrombomodulin, protein c+s, antithrombin III) ▪ Vitamin K deficiency (II, VII, IX, X) - Control of Clotting o Clot retraction/lysis ▪ Platelets contract and pull torn area together ▪ 30-60 min o Fibrinolysis ▪ Slowwwww process of dissolving a clot ▪ Thrombin and tissue plasminogen activator (tPA) activate plasminogen ▪ Plasminogen produces plasminogen —> digest fibrin strands o Autolysis of clot — fibrinolytic system ▪ Plasminogen form plasmin (tPA activates) ▪ Injured tissue + endothelium naturally release tPA after repair is complete and clot is no longer needed ▪ Plasminogen trapped in clot so that the clot can be dissolved slowly and not release pieces into circulation ▪ Plasmin digests: fibrin, fibrinogen, prothrombin (II), V, VIII, XII - Clotting area restriction: prevent venous thrombosis or hypercoagulable state o Anticoagulants (plasma proteins) ▪ Antithrombin III** o Heparin o Thrombomodulin — stimulate protein C o Protein C: stimulate plasmin formation — breakdown fibrin strands** o Protein S: a vitamin k dependent anticoagulant works with protein C to stop factor V and VIII ** o Prostacyclin— inhibit platelet aggregation o Slide 83 - Prevention of blood Clotting o Endothelial factors ▪ Cells smooth surface prevent activation ▪ Endothelial cells Repels platelets and clotting factors ▪ Thrombomodulin in endothelial tissue bind to thrombin (inactivate) ▪ Protein C inactivate Va VIIIa o Removal of thrombin ▪ 85-90% of formed thrombin trapped in clot — prevents excessive spread of clotting ▪ Antithrombin III — inhibit X and II — remove thrombin rapidly o Heparin (slide 87) ▪ Combine with ATIII — increase effectiveness ▪ Remove XIIa, XIa, IXa, Xa, IIa (thrombin) ▪ Released by mast cells and basophils — allergic rxn BMS 1.12 The student will define the role of vitamin K and calcium in coagulation. - Calcium ions + Vitamin K essential to clotting process - Calcium combines with: o factor VII to create a complex to activate X (extrinsic) o Factor VIII to create complex to activate X (intrinsic) - Vitamin K is necessary in aiding II, VII, IX, and X in clotting – without lead to excess bleeding - Protein S is a vitamin k dependent anticoagulant works with protein C to stop factor V and VIII - Protein C is vitamin K dependent - Vitamin K helps clotting factors bind to calcium and calcium helps clotting factors activate enabling platelet aggregation BMS 1.14 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms involved to the development of the following bleeding diathesis categories: Vessel wall abnormalities, Platelet related disorders (Reactive thrombocytosis, Thrombocytopenia, Thrombotic microangiopathies, Defective platelet function), Coagulopathies, Disseminated intravascular coagulation (DIC). - Vessel wall Abnormalities: o Endothelial cells line vessel wall that control permeability, flow, interxns, angiogenesis, and inflammatory response o Normal endothelium is antithrombotic o When stimulated – becomes prothrombotic – activate coagulation cascade, inhibit fibrinolysis, and active platelets o Endothelium derived vasoconstrictors are platelets activators and promote thrombosis - Thrombocytopenia: inadequate # of platelets o Causes: ▪ autoimmune disease (lupus, RA) — immune attacks platelets ▪ Drugs (alcohol, thiazide, diuretics) ▪ Bone marrow failure (viral infections, leukemia, nutritional deficiencies, chemo/radiation) ▪ Hyperspleism — increase size destroys more platelets - Thrombocythemia (Thrombocytosis): over responsive, too many platelets ▪ Due to overproduction of pro-inflammatory cytokines ▪ Platelets are acute phase reactants —> numbers increase responding to stimuli  ▪ JAK2 mutation in 50% of cases ▪ Clonal disorder of multipotent hematopoietic progenitor cells ▪ Large platelets seen on smear - Reactive thrombocytosis: elevated platelet count in response to trigger o Not due to bone marrow overproduction or clonal expression of progenitor cells o Causes: ▪ Acute blood loss ▪ Allergic reactions ▪ Cancer ▪ Chronic kidney disease ▪ IDA ▪ Hemolytic anemia - Thrombocytopathy: adequate # but abnormal function of platelets o Congenital or acquired o Causes: ▪ Drug induced (ASA, NSAIDS) ▪ Bone marrow failure (viral) ▪ Hypersplenism - Genetic hypocoagulopathies: o MC*** Von willebrand disease ▪ Mutated vWF ▪ Autosomal Dominant ▪ Binds platelets to damaged blood vessel wall normally Attach to collagen at site if injury, then bind platelets to that site Stabilizes VIII so clot formation occurs correctly o 2nd common Hemophilia A ▪ X linked recessive ▪ MC hemophilia ▪ Mutated factor VIII o 3rd common Hemophilia B ▪ X linked recessive ▪ Mutated factor IX o Defect in Hemophilia C XI ▪ Rare ▪ Autosomal recessive BMS 1.15 The student will differentiate the epidemiology, pathogenesis, pathophysiology and genetic/molecular basis for each of the following categories of hypercoagulable states: Primary (genetic) thrombophilia (Factor V Leiden, Increased levels of factors I, VIII, IX, and XI, Protein deficiencies: AT-III, Protein C, Protein S) and Secondary (acquired) thrombophilia (Multifactorial, Heparin-induced thrombocytopenia (HIT) syndrome, Antiphospholipid antibody syndrome) - Hyper coagulability states: prone to clotting o Conditions of increased platelet function o Conditions of increased clotting activity ▪ Both predisposed to thrombosis - Increased platelet function o Problem — sticky platelets —> platelet clots—> blood flow disrupted o Causes: disturbed blood flow, endothelial damage, increase platelet activation o Conditions: atherosclerosis, diabetes mellitus, smoking, elevated blood lipids, thrombosis (post splenectomy, chronic inflammatory states) - Primary Thrombophilia: prone to clotting o Factor V Leiden o Protein C & S Deficiency o Increased levels of factor I, VII, IX, X - Factor V Leiden o Autosomal Dominant o Gene mutation of factor Va on chromosome 1 lead to mutation of factor V protein o Reduced anticoagulant function, increased procoagulant role o Slide 93 - Inherited thrombophilias: protein C + S deficiency o Protein S Deficiency (Slide 94) ▪ Vit K dependent glycoprotein ▪ Cofactor for protein c ▪ Made in liver, endothelial cells, and megakaryocytes ▪ Levels increase with age, lower in females ▪ Autosomal dominant (homozygous form= incompatible to life) o Protein C deficiency (slide 97) ▪ Autosomal dominant (rare to see homozygous form) ▪ May be acquired (infection, septic shock) ▪ Vitamin k dependent protein — in liver ▪ Activated by thrombomodulin and protein s ▪ Active protein c inactivates coagulation factor Va and VIIIa o Antithrombin Deficiency (slide 98) ▪ Potent inhibitor of the coagulation cascade ▪ Non-vitamin k dependent protease ▪ Inhibit coagulation by lysine thrombin and Xa ▪ Accentuated power with heparin o BODYs NATURAL COAGULANTS — Protein c + s and ATIII - Increased levels of I, VIII, IX, and X o Uncommon cause of venous thrombosis o Not yet proven genetic, but suspected o Patients usually identified after thrombotic event - Secondary (Acquired) Thrombophlia o Heparin induced thrombocytopenia (HIT) ▪ Result from antibody formation to platelet factor IV and heparin complex Platelet aggregates immunologically removed Platelet aggregate antibodies bind to vessel wall causing thrombosis (PE, MI, stroke) o Disseminated intravascular coagulation (DIC) (slide 105) ▪ Spread of clots within the vessels ▪ Hypercoagulable state lead to impaired blood flow ▪ Can lead to both thrombosis and bleeding extra clots consume platelets & fibrinolysis are abnormally active or break down clots leading to high amounts of fibrin degradation products ▪ Caused by many conditions (usually underlying condition) Severe sepsis, OB complications, snake bites, leukemia, drugs) ▪ Initiated by massive uncontrolled activation of coagulation Platelets, coagulation factors, and anticoagulants are all consumed Severe hemorrhage, multiple organ failure, micro-clots Uncontrolled production of fibrin due t exposure of blood with high TF, suppression of anticoagulant mechanisms, and abnormal fibrinolysis BMS 1.16 The student will describe the pathophysiology and infer the clinical consequences of the following types of thrombotic and embolic disorders: Deep venous thrombosis (DVT), Arterial (and cardiac) thrombosis, Pulmonary embolism. - Thrombus – abnormal clot - Embolus – when abnormal clot floats - Thromboembolic conditions caused by: endothelial roughening (atherosclerosis, infection, trauma, heart valves, bypass surgery) or slow flow (prolonged air travel, vegetative state) - Pulmonary embolism o Part of the process called venous thromboembolic disease o Formation in the extremity of deep vein thrombosis and embolic disease to lungs o Inheritable causes: ▪ mutated natural anticoagulants — AT III (no inactivate thrombin) and Protein C + S (no inactivate V & VIII) ▪ mutated factor V Leiden (not inactivated by protein C) - Acquired & inherited factors of DVT o Venous stasis o Hypercoagulaopathy o Vascular endothelium dysfunction/injury BMS 1.17 The student will characterize the difference between innate and acquired immunity. - Innate defenses (NON-SPECIFIC) o Natural killer Reponses o Skin, gastric acid o Neutrophils and macrophages o Lysozymes and complement o Fever, phagocytosis, inflammation - Acquired (ADAPTIVE) Defenses (SPECIFIC IMMUNITY) o B cells: ab mediated (activated b cells) o T cells: cell mediated → activated t cells o ONLY THESE TWO ARE SPECIFIC NOTHING ELSE - B cells: become plasma cells o Made in liver in (fetal) → RBM produces after birth o Activated b lymphocytes = Plasma cells ▪ Produce antibodies (immunoglobins) ▪ The best at fighting BACTERIA or toxins they produce ▪ Help identify viral antigens o Hand back and let ab to the work - MATURE B cell (Plasma cells) o Marker CD19 and CD20 o Secrete ab that combine with foreign microbes and kill it ▪ Ab is first a b cell receptor on bcell (BCR) ▪ BCR cleaves → antibody ▪ Active plasma cells produce more ▪ BCR interact with microbe directly or with help from CD4 (helper t cells) o Activated b lymphocytes enlarge → ▪ Plasmablasts Form plasma cells Produces lots of gamma globulin ▪ Lymphoblasts Form new lymphocytes Memory cells --. Reactivate when needed & high potency response - T cells : attack foreign bodies directly o Start in RBM → REQ → thymus (matured here) o CD4 or CD8 → before leaving thymus o Divide rapidly, diverse, and each lymphocyte only react to ONE antigen o CD8 = best at fighting INTRAcellular microbes (aka viral) o Surface receptors on T-cells → react with specific antigens → activation o Activation → replication → some remain in tissue others create MEMORY CELLS o T CELLS HAVE TO INTERACT WITH ANOTHER CELL IN BODY o Activated t cells → produces cytotoxic cytokines or USE cytokines as chemotaxis - Natural Killer o 1st to respond → alarm normal normal cells o Secrete cytotoxic cytokines to destroy abnormal tissues - OVERVIEW AB PRODUCTION o Antigen presents to T cell → present to b cell → b cell produce specific ab → ab attach to specific antigen - Immunoglobin = Ab o Contain heavy and light chain o Heavy chain = constant region (Fc) → determine biological properties of Ig o light chain = variable region (Fab) → antigen binding site - Action of Ab → how they eliminate foreign antibody o Neutralization – cover toxic antigen site o Agglutination – antigen bound in clump o Precipitation – soluble antigen and ab form insoluble complex o Complement – ab bind to membrane of invading agent → cell rupture o Opsonization – phagocytosis (flag invader) - Complement system o Activated by microbes and enhance immune system o Proteins produced in liver and present in plasma o 3 fns: ▪ Lyse antibody coated cells ▪ Mediate opsonization ▪ Inflammatory response o Help activate mast cells, basophils and other WBC o Membrane lesions = MAC COMPLEX → lyse cells o Complement proteins must organize on surface of pathogen to initiate MAC ▪ Ex ) C3b, C5b → activate - Antibodies o IgM: not an effective killer, but 1st used ▪ Primary immune response – b cell produces when first activated ▪ Binds complement o IgG: good killer, crosses placenta ▪ 75% of ab produced ▪ Respond to bacteria, viruses, and RBC ▪ Crosses placenta – aid in baby’s early life ▪ Bind complement ▪ Secondary immune response – four subclasses (1,2,3,4) o IgA ▪ In exocrine fluids ▪ Protect urinary tract, respiratory and bowel infxn ▪ NOT bind complement o IgE: allergies ▪ Less than 1 % - unless invading parasite ▪ NOT bind complement ▪ Histamine relase – Fc bind strong to basophils & mast cells o IgD: not common, make B cells stay on track ▪ Less than 1% ▪ NOT bind complement ▪ Cell bound on surface of B cells ▪ May help CD4 - IgM first in immune response but not very efficient – after secondary antigen injection IgG able to react much quicker to aid immune system (slide23) - MHC on surface of all cells o Major histocompatibility complex – tissue antigen o Found on surface of cells – variation is genetic  o Function: ▪ bind pathogen and display on surface ▪ t cells receptors and MHC must interact for T cell to activate ▪ recognition of self to T cells o Human leukocyte antigen is MHC in humans o MHC 1 → present on all nucleated cells o MHC 2 → present foreign peptides on antigen presenting cells (macrophages, dendritic cells, b cells) - T cells and MHC o MHC 1 → foreign peptides to cytotoxic t cell (nucleated cells) o MHC 2 → foreign peptides to HELPER t cells (select # of cells) o CD8 (cytotoxic t cell) → kills infected cells by secreting toxic cytokines o CD4 (helper t cells) → secrete cytokines activating macrophages, CD8, & B cells o Suppressor T cells → regulate activity (CD8) - MHC 1 + CD8 → present endogenous antigens like viral peptide and kill - MHC 2 + CD4 → present exogenous antigens like bacteria & coordinate immune response - T lymphocyte activation o Antigen presenting cells (macrophages) ingest antigen and present to helper t cell → secrete IL-1 + cytokines that promote lymphocyte growth/diff o Helper t cells → cytokines → stimulate b an t cell proliferation/diff o B AND T CELLS REQ antigenic stimulation to REPRODUCE - CD4 helper t cells o ~70% of t cells o Aids virus destroys these o Lymphokines – IL2,3, 4,5, 6 o Interferon-y → alert cells about foreign body - CD8 Cytotoxic t cells o Directly attach to microorganisms ▪ Secrete perforins → fluid into cell→ cytotoxin into cell → killer pulls away from victim o Kill tissue invaded by VIRUS o Kill CANCER cells o Heart transplants cell - CD25 Suppressor t cells o Regulate overreactions of system o Protect against autoimmune responses o Inhibit b-lymphocyte production, mediate ig tolerance, suppress tcell - Monocyte-macrophage cell system o Monocyte → in blood o Macrophage → in tissue o Macrophage particulate in phagocytosis, inflammation and cellular immunity ▪ Mainly involved in NONSPECIFIC immunity and include phagocytic cells: Neutrophils, eosinophils, basophils, mast cells, mononuclear phagocytes o Derived from stem cell in BM o Monocytes → circulate to inflammation or migrate to multiple tissues o Macrophages have cell surface receptors → one for Fc portion in Ig ▪ also have receptor for complement component (opsonization) o cells of immune system found in blood, body tissues, thymus, liver, spleen, lymph nodes and external areas → compromise RES ▪ help clean up the body and remove pathogens + coordinate immune response ▪ monocytes, mobile or fixed tissue macrophages, specialized endothelial cells - inflammation o increases blood flow and nutrients to an area o acute, granulomas, or chronic (worst) o NONSPECIFIC response to crossing first line of defense o Typically localized  o Initiate complement system, histamine + bradykinin, proinflammatory cytokines (ILs and TNF) o Blood flow from the capillaries - Inflammation Steps: o Vasodilation o Increased capillary permeability o Clotting interstitial fluid o Monocyte and granulocyte migration into tissue o Swelling of tissue cells (histamine, complement, coagulation factors) o Wall off effect (fibrinogen clot – block lymphatic system) - Platelets release clotting factors → mast cells (vasodilators) → neutrophils (kill+phagocytosis) → macrophages (cytokines) → inflammatory response continue - Macrophages: o Mobile during inflammatory. Already in tissue - Neutrophils: o Margination → through capillaries → chemotaxis (within in an hour) o Neutrophilia in BM - Monocyte → macrophages → develop lysosomes - BM produces granulocytes and monocytes within 3 or 4 days Immediate Hypersensitivity 1: ALLERGIC o Mast cell degranulation through igE o Reaction in minutes o Anaphylaxis - Type 2: Cytotoxic o IgG or IgM complement & lysis o Minutes to hours, within a day o Thrombocytopenia, autoimmune hemolytic anemia, ITP transfusion mismatch rxn - Type 3: Immune complex o Antigen-antibody complex o Complement o 3-6 hours re-exposure o 4-10 days to create antibodies - Type 4: Delayed o T cell orchestrated o A week, more than 12 hours after - Immunization o Active immunity through many different kinds o Dead organisms, toxoids, mRNA, live attenuated - BMS 1.23 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms of disease to hematopoietic and lymph tissue changes and classify the following types of hematopoietic disorders: Neoplastic disorders (Acute and chronic lymphocytic leukemia, Acute and chronic myelogenous leukemia, Lymphoma: Hodgkin’s and Non-Hodgkin’s, Polycythemia rubra vera, Essential thrombocythemia) - Leukemia: o Involve blood and BM o High wbc - Lymphoma: o cells arising from lymphoid tissue (spleen tonsils etc) o solid tumors in lymphatic and RE system - Acute MYELOID leukemia o Myeloblasts in bone marrow o Age 60 and up o From hemopoietic stems cells in marrow → interfere with maturation of myeloid WBC → death o Rare but lethal o Risks:  ▪ Genetic → promyelocytic gene on chromosome 15 or translocation of RARA on chromosome 17 ▪ Preexisting blood d/o → myelodysplastic syndrome or myeloproliferative neoplasms ▪ Environmental o Auer rods in myeloblasts - Chronic myelogenous leukemia o Abnormal granulocytes → MOST neutrophils & some basophils and eosinophils o Translocations between 9 and 22 → small 22 → Philadelphia chromosome o Uncontrollable cell division - Acute Lymphoblastic lymphoma/leukemia o Malignancy in Hemopoietic progenitor cell → too many lymphoblasts in BM o Replace BM o Almost ~80% caused by b cell abnormalities → hypermethylation high rates - B cells live in Bone marrow → lymphoid leukemias and lymphomas are from this origin (~75-90%) - T cells live in Thymus - Chronic lymphocytic leukemia o Overproduction of abnormally functioning B-lymphocytes (mature) o Decreases Ig and decrease antibody response o ~80 % are B cell (CD19) ▪ CD19 b cell receptor o PBS → observe mature lymphocytes at high # o Involves the blood in malignancy - Lymphoma o CLL/small lymphocytic lymphoma (NH lymphoma) o Form solid organ tumors in lymph tissue → bone marrow → spleen/liver o ~90% bcell origin - Hodgkin Lymphoma o Mature b-cells with IG V gene mutations or antigen selected germinal center b cells o Bone marrow Bx → Reed Sternberg cells o Transcription disrupted → cell surface marker and RNA process deregulated ▪ Loss of apoptosis ▪ Increase cytokine ▪ Inflammatory - Non-Hodgkins o Lymphoid solid tumors o B cell origin (diffuse large b cell ) o Can be derived from: B cell pro, t cell pro, mature b cells, mature t cells, NK cells o Aggressive → p53 (diffuse bcell) = MC or Burkitt lymphoma (c-myc) o Indolent → CLL/Small lymphocytic lymphoma (bcl-6) or follicular (bcl-2) - All the (3 letters) are disruptions in cellular activity that cause uncontrolled cell divisions^ BMS 1.24 The student will define and differentiate the following bacterial based on normal physiology, etiology, and pathophysiology (changes to normal pathology). Gram positive bacteria, Gram negative bacteria, Spirochetes, and Atypical bacteria - Infection: lodgement + replication of organism in tissue of host o Characteristics: ▪ Pathogen able to enter, multiply, damage tissue, and resist host defense o Pathogenicity: ability of pathogen to produce disease o Virulence: how severe is pathogen to host - Virulence factors o Adhesion, invasiveness, toxigenicity, communicability, prevent phagocytosis (fibrin barrier), and break through tissue barriers (fibrinolysis) o Anything that makes pathogen more effective in host - Bacterial: o Resident flora – on or in cell without causing infection o Pathogens – produce disease, bind to receptor on human host cells o Single celled o Structure ▪ Nucleoid, cytosol, cell envelope, cell wall, protein/DNA synthesis, cell division ▪ Cocci, bacilli, spirochete ▪ Counter effect of osmostic pressure ▪ Attachment for bacteriophages ▪ Flagella, fimbriae, pili  ▪ Antigenic determinant ▪ Resistance to abx o Aerobic = oxygen o Obligates = REQ o2 ▪ Acid fast: mycobacterium tuberculosis o Facultative: prefer aerobic but live in anaerobic too ▪ Gram - = E. coli ▪ Gram + = staphyliococci o Anaerobic = grow w/ no o2 ▪ GI tract, infections abdominally, aspiration pneumonia ▪ Gram + = Clostridia o Gram + ▪ Thick PG → homogenous sheath ▪ teichoic acid + lipoteichoic acid → immune reposne ▪ Retain crystal violet and stain PURPLE ▪ More permeable ▪ Ex) clostridium, staphylococcus, streptococcus (b, a, gamma hemolytic) ▪ - Genus Clostridium, family clostridiaceae o Botulism ▪ Clostridium botulinum ▪ Obligate anaerobe, bacilli, g+ ▪ Neurotoxic protein ▪ Block neurotransmitter → no Ach → skeletal muscle can’t contract ▪ Req zn o Tetanus ▪ Clostridium tetani ▪ Obligate anaerobe, g+ ▪ Enter through → circulation ▪ Rigid paralysis (lock jaw) ▪ Req zn ▪ Neurotoxin → CNS → inhibit normal functions → muscle spasms - Catalase - enzyme on all living organisms exposed to o2 o + = req o2 – enzyme protects from toxic byproducts o – = ferment - Facultative anaerobes or anaerobes - Staphylococcus o G+ , catalase + o Clustered cocci o Highly infectious at low amnt o Virulence factors→ ▪ Evade phago by capsule production ▪ Enzymes – promote growth of host tissue ▪ Endotoxins o S. aureus ▪ more virulent ▪ carriers in nose or skin o S. epidermidis ▪ Normal skin microbiota ▪ Less virulent ▪ Opportunistic infxn - Streptococci o G+ , catalase - o Paired or chained cocci o Non motile o Facultative anaerobe o Virulence factors→ ▪ Lipoteichoic acid – attachment ▪ Hyaluronic acid capsule → inhibit phago o Alpha hemolytic – partial hemolysis → E.coli o Beta hemolytic – complete lysis (clearing) → S. pyogenes o Gamma hemolytic – no hemolysis → S. epidermidis o Lancefield Classification: A-T  ▪ A, B, D (frequent) → slide 76 for examples ▪ C, G, F (less frequent) - Gram – o LPS outer membrane o Thin PG → less permeable o Periplasmic space o Lose crystal violet + stain PINK from safranin o Porins – cells leaving or entering cell o Endotoxin from Lipid A in LPS → interact w many other cells → sepsis o ABX resistance → b lactamase o Other examples – B. pertussis, H. influenzae, N. meningitides, N. gonorrhoeae, Klebsiella, E. coli, H. pylori - Rickettsia rickettisii o RSMF o Weak G- (special stain) o Transmitted via wood tick bite o Obligate intracellular pathogen o Must have cell to survive o Rickettsia typhi – endemic typhus o Pathogen into dermis → through lymph and blood → edema/inflammation → thrombocytopenia - Spirochetes: o Treponema, borrelia, leptospira o Spiral shaped, motile o Not g+ or – o Borellia burgdoferi – weak gram - stain (lyme disease)* ▪ MC in US ▪ Tick saliva ▪ Control protein expression minimize antigenic targets → dec immune recog ▪ Don’t produce toxins ▪ Spread through blood or lymph o Treponema pallidum – syphilis → d/o of blood vessels → diffuse multiple organs → chronic inflammation o Leptospira → leptospirosis (weils disease) BMS 1.25 The student will define and differentiate the following mycobacterial based on normal physiology, etiology, and pathophysiology (changes to normal pathology). Tuberculosis and Atypical mycobacterial disease - Nontypical bacteria walls o “Fungus-like bacteria” o Mycobacterium and nocardia – lack typical cell wall o G+ cell wall with mycolic acid o Acid fast stain o Difficult to treat o High degree of resistance to certain chemicals - Mycobacterium o Aerobic o Acid fast o Rod shaped o Slow growing o Outer membrane NOT cell wall o G+ rods o Difficult to treat o Ex) tuberculosis and leprosy o Mycobacterium tuberculosis ▪ Aerosol drops ▪ Disseminate ability → MC lungs ▪ Primary TB Lodge in lung or alveoli → phago by alveolar macrophages Macrophage → lymph → generate t cell immune response ▪ Atypical Mycobacterium Macrophages → IL-12 → IFN → activate neutrophils and macrophages → destroy pathogen ▪ Mycobacterium leprae Skin sores, nerve damage Via droplet from nose/mouth BMS 1.26 The student will describe the taxonomy of pathogenic human viruses based on viral structure: Identify and characterize the stages of viral infection, viral gene expression, viral replication, and cytopathic effect at the cellular level and describe the biology of the human immunodeficiency [retro] virus (HIV) molecular structure and replicative cycle and the epidemiology, pathogenesis, and transmission - Virus → smallest infectious particle o Infect healthy cells – destroy or alter function o Virions – released particles outside the cell → viral spread o Difficult to treat – immune response aid o Latency or minimal immune response ▪ Virus integrate with host cell genetic material o ABX don’t work o Obligate intracellular parasite o Nucleic acid surrounded by proteins o May have outer membrane envelope o Nonliving o Encode proteins for replication – do not replicate on its own - Shapes: o Spherical/icosahedral MC*** o Helical o Polyhedral o Complex - Structure: (slide 96) 1. Nucleic acids: o SS or DS DNA o SS sense RNA (+) o SS or segmented antisense RNA (-) o DS segmented RNA 2. Capsid 3. Structural proteins (form capsid or attachment) 4. Non-structural proteins (replication, assembly, progession) 5. Envelope (lipid bilayer) - Life cycle: o Attachment → entry → replication + gene expression → assembly → release o Receptors→ endocytosis or fuse with PM → transcription/lation in cytoplasm of host cell→ viral proteins made by host cell and mature → spread to new cells - Naked (non-enveloped) Virus o MORE STABLE o More VIRULENT o Not damaged by hostile env (dry, acidic, heat etc) o Spread easily by touch - Course of infection o Primary rep→ where virus replicates after entry, determine local or systemic o Systemic spread→ cell-cell → blood stream → CNS o Secondary rep → susceptible organs or tissue following systemic - Routes of entry o Skin, **conjunctiva, mucous mem**, resp. tract, GI, GU - Herpesvirdae family o DsDNA, enveloped o 8 infect humans o Latent infections in specifc tissues o Icosahedral o HHV-1 ▪ Enveloped, DsDNA ▪ Icosahedral ▪ Herpes labialis (cold sores) → Epitehlia cells (P Infxn) ▪ Recurrent → latent in ganglion neurons → acute diseade o HHV-2 ▪ Enveloped, DsDNA ▪ Icosahedral ▪ Genital herpes → epithelial cells, no abx (p infxn) ▪ Reccurent → reactivation of genital HSV w/ abx corresponding infxn o HHV-3  ▪ Varicella Zoster virus ▪ Enveloped, DsDNA ▪ icosahedral ▪ Varicella → p ifxn → nasopharynx → latent in dorsal root ganglia ▪ Zoster → 2ndary infxn → shingles → reactivation in sensory ganglia o HHV-4 ▪ EBV → infectious mono ▪ Enveloped, DsDNA ▪ icosahedral ▪ replicate in epithelial cells of oropharynx and b lymphocytes ▪ salivia ▪ Asymptomatic shedder → for life → replicates continuously at low levels o HHV-5 ▪ Enveloped, DsDNA ▪ icosahedral ▪ salivary glands and kidney ▪ slow replication ▪ continuously replicates at low levels for life - Papillomaviridae family o HPV ▪ Non-enveloped ▪ DsDNA ▪ Icosahedral ▪ Cervical cancer to skin warts ▪ HPV6 and 11 →genital warts, benign cervical cancer ▪ HPV-16 and 18→ cervical cancer (high risk) - Factors that influence mutation rate: o genome size, ss or ds, polymerase activity, proof reading, post replicative repair o RNA and NAKED RNA are highest in mutations - RNA Viruses o Many combos of genome and capsid structure o ss EXCEPT for Reoviridae o ALL non-enveloped viruses have icosahedral 1. Filoviridae family o Ebola ▪ Enveloped ▪ SSRNA ▪ Helical ▪ Ebola virus disease or ebola hemorrhagic fever ▪ Very virulent → hemorhagic disease ▪ Rapid mutations and adaptable ▪ Fruit bat → contact with fluid, tissue, or ingestion of feces ▪ Human – human ▪ Infect monocytes, macrophages, and dendritic cells by receptor → lymph nodes → blood → spleen and liver → systemic inflammation and fever ▪ Worst → infected cells cause failure of APC to react immune system 2. Rhabdoviridae family o Rabies (lyssavirus) ▪ Enveloped ▪ SSRNA ▪ Bullet shaped helical ▪ Saliva ▪ Inflammatory to CNS ▪ Paralytic → muscle weakness ▪ Virus replaice for months in muscle cells → nerves→ CNS → skin , eyes, salivary glands 3. Orthomyxoviridae family o Influenza ▪ A & b respiratory ▪ SSRNA (negative-stranded RNA) ▪ Enveloped ▪ Glycoprotein spikes : hemagglutin (HA) & neuraminidase (NA) → antigenic (receptor binding) ▪ Self-limiting  ▪ Respiratory transmission ▪ 4 types → A, B, C, D ▪ A and B → seasonal epidemics ▪ Influenza A → pandemic ▪ Hemagglutin → H1, H2, H3 ▪ Neurominidase → N1, N2 4. Coronaviridae family o SARS-CoV-2 or COVID-19 ▪ Enveloped ▪ SSRNA (+) ▪ bind to ACE-2 and many different cell types ▪ mostly respiratory epithelial ▪ SARS – severe acute respiratory syndrome ▪ MERS – middle east respiratory syndrome ▪ Mild to severe resp illness ▪ E2 spike surface protein → antigenic → bind to host 5. Flaviviridae family o Zika Virus ▪ Enveloped ▪ SSRNA ▪ Icosahedral ▪ Related to dengue, yellow fever and west nile virus ▪ Aedes mosquito bite – female ▪ Link to Guillian barre syndrome – muscle weakness + numbness of limbs → damage nerve ▪ Amino acid composition → mimic nerve myelin protein → immune react destroy myelin 6. Retroviridae family o Reverse transcriptase → make complement DNA of viral RNA o HIV ▪ Enveloped retrovirus SSRNA genome → technically not RNA virus b/c it uses DNA to replicate ▪ Appears spherical ▪ Targets CD4 cells and macrophages and dendritic cells*** ▪ Enter by CD4 receptor AND CCR5 or CXCR4 (chemokine co-receptor) ▪ Sexual, blood, semen, bodily fluids ▪ Deplete CD4 → AIDS ▪ Exposure → HIV increase in blood → incubate (massive turnover of CD4 cells) → AIDS (when too many CD4 to be replaced ▪ LIFE CYCLE: Bind and fuse Entry viral attachment protein – gp120 to CD4 cell and CCR5 or CXCR4 co-receptors Reverse transcription Integration Viral RNA + protein expression Assembly + budding Maturation ▪ Gp41 mediate fusion of viral and cell membranes ▪ Gp120 pretty consistent (we target in drugs) ▪ Slide 127 for more BMS 1.27 The student will define and differentiate the following fungi based on normal physiology, etiology, and pathophysiology (changes to normal pathology). Superficial mycoses, Subcutaneous mycosis, and Systemic mycosis - Fungal o Domain: Eukarya ▪ Molds (hyphae) ▪ Yeasts (buds) -- ▪ Mushrooms o Mycosis (s): fungal infection of animals o Mycoses (pl): relatively large organism with nuclear membrane, cytoplasm, and organelles ▪ resident microbes that are kept at bay by competing resident bacteria ▪ antibiotics → alter resident flora → flourish of competitor bacteria ▪ Yeast → UNICELLULAR Connected by pseudo hyphae Very common  Aerobic or anaerobic Budding yeasts reproduce asexually → budding off daughter cells Ex) candida albicans ▪ Mold → MULTICELLULAR Most are multicellular filaments → hyphae Network of branching hyphae = mycelium Spores → airborne → long incubation in the body o Use sexual or asexual reproduction Use enzymes to degrade material + use as energy Penicillin was a mold Opportunistic molds cause disease by →allergic sensitivity, growth of mold in body, or ingested/inhaled mycotoxins ▪ OPPORTUNISTIC pathogens → immunocompromised host o Dimorphic fungi → appear as both yeast and mold in a life cycle ▪ Change in response to the environment (diverse adaptability) ▪ Ex) Histoplasma capsulatum → lung infection o Mycoses can be classified by their site of infection: ▪ Superficial ▪ Cutaneous ▪ Subcutaneous ▪ Systemic (deep) o Route of acquisition → airborne, cutaneous, percutaneous o Virulence differs between fungi - Superficial & cutaneous mycoses o Outer layers of skin → hair, nails o DO NOT invade living tissue o Dermatophytes - Subcutaneous mycoses o Found in soil or organic matter o Introduced through a wound site → trauma to deeper skin o Localized at site of injury → slowly spread to surrounding tissue o Asymptomatic or minimal o Experience redness or itching o Found in temperate regions (sporotrichosis → soil) o Immunocompromised more at risk - Systemic Mycoses (deep) o Pathogenic + opportunistic fungi o Slowly spread to surrounding tissue → immunocompromised pt o Asymptomatic or minimal o Almost always infect lungs (histoplasmosis, cryptococcus, pneumocystis, aspergillosis, candidiasis) o Other examples are → coccidioidomycosis and blastomycosis o most times inhaled - Candidiasis o 20 species o Candida albicans MC o Dimorphic o Aerobe → favor moist surfaces o Superficial or deep (kidneys, liver, spleen, brain, heart) o Catheters common entry for deep o Evade host barrier by adhesins o Risk: Immunocompromised host, broad spectrum abx, chemotherapy, corticosteroids o Virulence factors: ▪ Secretory IgA destruction ▪ Surface hydrophobicity & adherins ▪ Phenotype switching & binding to complement ▪ Hydrolytic enzyme production - Cryptococcus o 17 species o YEAST state o Inhalation of microscopic fungi o C. neoformans (immunocompromised) & C. gattii (rare, sub tropical) o Invasive opportunistic infection → lungs  o Lead to pneumonia or meningitis - Pneumocystis o Pneumocystis jirovecii o Airborne → lung infection o YEAST-LIKE o Pathogenic (immunocompromised) o Defining for HIV / AIDS - Histoplasmosis o Histoplasma capsulatum → lung infection o Dimorphic o Grows inside macrophages o Inhalation of spores o Similar to TB o Immunocompromised pt, severe respiratory issues, chronic immunosuppressive therapy, neutropenic BMS 1.28 The student will define and differentiate the following parasite (and disease state) based on normal physiology, etiology, and pathophysiology (changes to normal pathology). Protozoa and Helminthic - Parasite – living organism that acquires nutritional requirements through another living organism - Parasitic o Protozoa → complex unicellular ▪ No cell wall → motile ▪ Parasitic or live independently ▪ Transmission → sexual contact, contaminated water/food, vector ▪ Amoebiasis (amebiasis) Amoebic dysentery Entaomoeba histolyca, E. dispar, E. moshovskii One-celled parasites Fecal-oral Surface lectin → adhere epithelial of colon ▪ Giardia Giardia intestinalis, G. lamblia, G. duodenalis tough outer shell fecal-oral ▪ Malaria Plasmodium falciparum Vector-borne → mosquitos Liver and RBC affected o Helminth → multicellular - Phylum Nemathelminthes (round worms) → Nematodes o GI sx!!!!! → N/V/D o Travelling to countries with poor sanitation Ascariasis o Ascaris lumbricoides Parasite o Ingest eggs in contaminated soil → exposure to pigs o Larvae released in duodenum of host o Travel to liver and lungs o Mature in lungs → cough → swallowed → reenter GI tract Trichinosis o Trichinella spiralis o Foodborne → usually undercooked or raw pork o Ingested as larvae → invade small intes. o Migrate → lymph → blood o Prefer oxygen rich tissue (lung, heart muscle, brain) Hookworm o Ancylostoma duodenale or Necator americanus parasites o Immature hookworms → skin in mostly feet o Move throughout day to different attachment → upper mucosa o Ingest blood o Secrete anticoagulant → cause old site to bleed Pinworm o Enterobius vermicularis o Eggs deposited by pregnant females  o Contact with contaminated item o Ileum and cecum only o Asymptomatic - Phylum Platyhelminthes (flatworms) o Class Cestoidean (tapeworms) → Cestodes ▪ Beef tape worm ▪ Pork tapeworm ▪ Fish tapeworm o Class Trematoda (flukes) → Trematodes ▪ Liver fluke Ingest undercooked, smoked, or salted fish (freshwater) ▪ Lung fluke (paragonimiasis) Ingest undercooked or pickled crab or crayfish Live in lungs, deposit eggs in bronchi ▪ Intestinal fluke Ingesting undercooked or salted fish ▪ Blood fluke (shistosomiasis) Penetrate skin by direct contact Acute → chronic Chronic→inflammation → ulceration → hemorrhage of small intes. Pictures to remember: