exam_1_20150304202940 Flashcards
Etiology
Cause
Pathogenesis
sequence of cellular or tissue events in response to the etiologic agent, from initial stimulus to the ultimate expression of the disease
morphologic changes
structural alterations in cells and organs of the body that characterize the disease or are diagnostic of the etiologic process
clinical significance
functional consequences of the morphologic changes
Cell Adaptations
hypertrophy: increase in size (Myocardial fibers)atrophy: shrink or decrease in sizehyperplasia: increase in number of cells/increased rate of cellular divisionMetaplasia: reversible change in which one adult cell type is replaced by another adult cell type (can result in neoplasia)
Cell Injury cause and types
Causes: hypoxia, physical or chemical agents and drugs, infectious agents, immunological reactions, genetic defects, nutritional imbalance, agingTypes: metaplasia (reversible)(irreversible): disturbance in cell membrane and cell wall, mitochondrial dysfunction
What happens to the cell when it is injured and dies?
-ATP depletion-decreased ATP synthesis anaerobic metabolism and acidosis -number of Na/K pumps decrease more Na in cell pulls more water-dilation of ER causes decreased protein synthesis -accumulation of free radicals with not enough antioxidants-Ca influxes which causes more damage and can cause cell death/catabalize cell membrane-Mitochondrial damage and loss of membrane integrity results in cell death -apoptosis (cell eats self)
What are the two types of cell death?
Necrosis:-abnormal and not regulated-loss of membrane integrity-stimulates inflammation (increase leukocytes triggers lysosomes to release enzymes for digestion of cell substances)Apoptosis:-normal and regulated (can become abnormal in disease)-physiological (cell no longer needed) or pathological (cell is threat)-contents of cell shrink, membrane remains intact and does not stimulate inflammation
What are free radicals?
chemicals that have a single unpaired electron in outer orbit (unstable!)produced during mitochondrial respirationcause cell damage by reacting with nucleic acids, and other cellular proteins and lipids
What are the two types of oxygen derived free radicals?
- Reactive Oxygen Intermediates (ROS)types: O2 superoxide H2O2 hydrogen peroxideOH hydroxyl radical produced in phagocytic leukocytes and mainly macrophages and neutrophils 2. Nitric oxide Intermediates (NOS)produced by leukocytes and other cellstypes: physiological {endothelial (eNOS), neuronal (nNOS),}non-physiological {inducible (iNOS)}
What free radical causes the most damage?
OH hydroxyl radical
What regulates free radicals?
Antioxidants (physiological substances that protect the body against damage from chemical reactions caused by free radicals)Function: bind to and break down free radicals by enzymesblock formationbind to ions to take free radicals away and out of cellrepair damage they cause in cell
Types of Antioxidants
catalase (enzyme from perioxisomes organelle)superoxide dismutase (SOD)gluthione peroxidase (GSH)CoQ10Vitamin E, A, C, and Beta-CaroteneSynthetic Ones (dopamine and other meds)
What is oxidative stress?
When the balance between free radicals and antioxidants is off and there is more free radicals than antioxidants.
Which NOS is the problem/causes damage?
iNOS is induced by inflammatory cytokines and responsible for production of NO in inflammatory reactions; also critical for wound healing
What is the role of the three NOS?
vascular smooth muscle relaxation, vasodilationantagonizes platelet activationdecreases leukocyte recruitmentmicrobicidal agent
Where do all blood cells reside?
stem cell pool, bone marrow pool, and peripheral blood pool
What does thrombopoieten do?
peptide produced by liver, kidneys, skeletal muscle, and marrow stoma responsible for clotting factors and platelet production
The myeloid stem cells differentiate into…
interluekins, erythrocytes, thrombocytes, monocytes, myelocyte (granulocyte: neutrophils, eosinophils, basophils)
What cells differentiate from lymphoid stem cells?
plasma cell, NK cells, T cells, B cells
What are the types of leukocytes?
- monocytes (immature) produced in bone marrowmature to macrophages in tissuethey are the FRONT LINE because they are already there and they are more efficient than neutrophils (they can phagocytize up to a 100 before they die)replicate in tissuesecrete inflammatory metabolites and cytokinesare antigen presenting cells to activate T and B cells2. Neutrophilsmature in bone marrow (mature-segs/immature-band cells)LARGEST IN CIRCULATIONdigest 3-20 before dying release cytokines and facilitate inflammation3. eosinophils (destroy parasites, involved in allergic responses)4. basophils (release histamine, leukotrienes, prostaglandins and platelet activating factor in inflammation; have IgE receptors and bind to IgE antibody; ALLERGY)
What are the types of lymphocytes?
- T cells (most abundant)originate in bone marrow&mature within the thymusreside in the T cell zones of lymphoid tissue and spleenTypes: T helper, T cytotoxic, T suppresser, MEMORY cells2. B cellsmature in bone marrow and reside in lymph nodes of cortex and medulla and spleen B zonesantigen receptors on surface: IgM and IgD Types: plasma cell and MEMORY 3. NK cellstarget virus, malignant, and other mutant cellssecrete cytokines to activate macrophages and T cellsNO MEMORY
How many antigens can a T cell react with?
one
What is a plasma cell?
a B cell that has been activated to secrete antibodies (immunoglobulins IgG, A, E)
How do NK cells work?
release enzymes: perforin and granzyme onto surface of cellperforin disrupts membrane and granzyme enters cell and causes lysisor it will attach it’s Fas receptor to a Fas ligand on the target cell and this causes: Fas-Fas ligand Mediated Apoptosis
What is margination and rolling referring to? And why is “adhesion” necessary?
Leukocytes travel the vascular system rapidly so in inflammation they have to be slowed down and brought to source of trauma or infection.-Margination: during inflammation slowing of the circulation causes leukocyte accumulation at the periphery of the vessel -Rolling: leukocytes tumble along the endothelial surface to escape vascular system.endothelial selectins E and P and leukocytes selectin L adhere to slow them down and attach to the endothelium to keep them at the site of trauma/inflammation
What are chemical mediators of inflammation?
HISTAMINE: released by mast cells, basophils and plateletsaction: vasodilation and increase permeabilitySEROTONIN: produced by rap he nuclei or dorsal horns of spinal cord and released by plateletsaction: causes vasoconstriction and increased vascular permeabilityARACHIDONIC ACID (AA): when cells are injured the phospholipid bilayer of membrane is released and converted to AAPLATELET ACTIVATING FACTOR: released from platelets, basophils, mast cell, and leukocytes and endothelial cells to produce platelet aggregation, vasodilation, bronchoconstriction, and increased leukocyte adhesion to endothelium, chemotaxis and degranulationCYTOKINES: proteins that transmit messages between cellsthey are produced by many cell types (interleukins, TNFs, interferons, colony stimulating factors)*stimulate growth, differentiation, and function of leukocytes and immune cells; involved in systemic inflammatory response and *Stimulates HEMAtopoeisis ROS and NITRIC OXIDE (NO): macrophages, neutrophils release it and use it as cytotoxic agent for killing microbes and tumor cells; relaxes vessels(vasodilation); NEUROPEPTIDES: example Substance P neurotransmitter: pain impulse regulates vessel tone and moderate permeability
What are the two pathways of metabolism of AA?
- Cyclooxygenase pathwayCOX1 and COX2 enzymes act on AA to produce prostaglandins(vasodilation, involved in pain, fever and hyperalgesia) and prostacyclin (vasodilation, inhibits platelet aggregation) and thromboxane (vasoconstriction and promotes platelet aggregation)2. Lipoxygenase pathwayenzymes act on AA to produce leukotrienes (increase vascular permeability, promote neutrophil recruitment and adhesion, vasoconstrictor, bronchospasm) and lipoxins (vasodilation, inhibit neutrophil recruitment)
What drugs inhibit the two pathways of metabolism of AA?
ASA, NSAIDS, COX2 inhibitors and steroids inhibit cyclooxygenase pathway.steroids also inhibit lipoxygenase pathway
What does the plasma-derived interrelated systems of inflammation mean?
*already circulating plasma proteins are involved and when each system is activated then they all are activated
What are the plasma-derived interrelated systems of inflammation?
- Complement Systemroutes of activation: -classic pathway: C1 (activated by antigen-antibody complexes)-lectin pathway: C1 (activated by plasma lectin that binds to carbs on surface of microbes) -alternative pathway: C3 (activated by microbial products, plasmin, and lysosomes released by neutrophils)2. Kinin System-triggered when XII is activated =XIIa-results in release of bradykinin (vasodilation, increase permeability, extravascular smooth muscle contraction, acts with prostaglandins to INDUCE pain)-reactivates XII to allow for amplification of initial stimulus-activates the fibrinolytic cascade which produces plasmin (**PLASMIN activates complement system)3. Clotting Systemintrinsic pathway (XII activated when it touches exposed collagen)extrinsic pathway
Which is the most critical component of the Complement system that needs to be activated?
**C3 is the MOST critical: cleavage occurs by three pathways (classic, alternative, and lectin pathway)stimulates neutrophils and macrophages to phagocytizeC3a, 4a and 5a activate mast cells, basophils to stimulate histamine and serotonin releaseC5 activates AA metabolism lipoxygenase, and C5a is a chemotactic agent for leukocytesC6-9 form membrane attack complex (MAC)
What is the MAC?
creates pores in the membrane and influx of water and ions destroy cell
What factor is needed to activate C3 of complement system?
XII activates when it touches exposed collagen; it then activates the fibrinolytic system to produce plasmin and plasmin activates C3
What are the 2 primary types of T helper cells?
TH1 and TH2
What protein markers are on T helper cells?
CD3 and CD4
What is major histocompatability complex?
MHC is a cluster of genes located on chromosome 6; expressed on surface of cells; MHC1 antigens: found on surface of all nucleated cellsMHC2 antigens: found mostly on B cells, macrophages, dendrite cells**the point is to tell self cells from foreign invaders by the sequence of peptides
Which class of MHC does the cytotoxic T cells kill?
MHC1 only
What is the point of the suppressor T cell?
limits binding of antigen to lymphocyte and helps prevent excessive response
How many signals do T cells and B cells need to activate?
2
How many classes of immunoglobins of B lymphocytes are there?
5 clases (IgM, IgG, IgA, IgE, IgD)
What is an antibody?
it is secreted into body fluids to bind to antigens to create a ANTIGEN-ANTIBODY COMPLEX; inactivates or neutralizes bacterial toxins, virus act as opsinin by marking it for attack
What activates the complement system?
plasmin, IgG antigen complex
How does the B cell become a plasma cell that secretes IgG, IgA, or IgE antibodies specific to the organism?
after the helper T cell has been activated and differentiates, Th2 secretes IL 4 and IL 5IL 4 and 5 modify B cell to become plasma cell
What is the platelet membrane consist of and how is it important in coagulation?
it contains phospholipids and when released forms AA that metabolized to Thromboxane A2 (platelet aggregation) they also express receptors P selectin that is necessary for endothelial adhesion
How are platelets activated?
by exposure to collagen, platelet activating factor (PAF), thrombin, vWF and others
What are the granules secreted by platelets?
Factor V, XIII, heparin neutralizer (platelet factor 4 PF4), growth factors for growing more platelets and inflammatory cells, serotonin and histamine, calcium needed for coagulation cascade, ADP needed for platelet aggregation
What facilitates the aggregation and stabilization of platelets?
thromboxane A2, ADP, Fibrinogen and ADP causes changes in Gp IIb-IIIa and fibrinogen to form a bridge between platelets
What does the endothelium have to assist in clotting?
secretes endothelin that causes vasoconstrictionsynthesizes Factor III thromboplastin (activates extrinsic)produces vWF that binds platelets to collagen when exposed to endothelial cells
Coagulation Cascade
**most clotting factors are synthesized in liver and they circulate in the blood in an inactive form; **activation of many clotting factors need Ca ant platelet phospholipids **intrinsic cascade is activated by factor XII by exposure to collagen **extrinsic pathway activated by factor III by tissue injury
What stimulates plasmin?
Factor XIIa and endothelial t-PA
What does Protein C inactivate and what disease is caused with protein C resistance?
inactivates Va and VIIIa; mutation to the factor V gene; will cause hyper coagulability states
Protein C and S do not allow deactivation of what factors?
Va and VIIIa
problems with platelets
thrombocytosis: too manycaused by recovery from iron deficiency anemia, secondary to inflammation response and myeloproliferative disordersthrombocytopenia: too fewliver problems (thrombopoietin)bone marrow problemsor problems involving destruction of platelets
Heparin Induced Thrombocytopenia
heparin binds to platelet protein PF4 hapten and IgG antibodies bind to the heparin PF4 complex that causes platelet to aggregate, and destroys platelets; this binding also causes endothelial damage
What gene is effected in hemophilias?
X-linked recessive gene
What factor is affected with Hemophilia A and B?
A-factor VIIIB-factor IX
What clotting factor is effected in von Willebrand Disease? What is the result?
VIII is carried on vW so when vW is decreased the factor VIII is no longer circulating as long and decrease in VIII being circulated
When is DIC most likely to occur?
after sepsis, obstetric complications, malignancy and trauma
Erythrocyte Function/structure
-About 4-6 million with 120 day lifespan-Bi-concave form increases O2 access (main fund to transport O2)-Mature RBC - no nucleus or mitochondria-Hgb molecules fill RBC cytoplasm
Hgb Molecule
Made of alpha & beta chainsContain 4 heme/globin groupsEach heme carries one O2 molecule via Fe binding site
Erythropoiesis
-Stimulated by Renal erythropoeitin in bone marrow-After age 20, RBC produced in vertebrae, sternum, ribs, and pelvis marrow.-Expand to more bones in case of anemia.-Most rbc mature in marrow -Nucleated RBC in blood indicate disease (infection)>2% retic count means rapid formation of RBC=infection-Old RBC lose reversible deformability and removed from circulation.
Reversible Deformability (RD)
-Cells must change shape as they pass capillaries/microcirculation.-Ability to change back to biconcave shape-Spleen is testing ground for RBC RD
Erythrocyte Destruction
-Hgb phagocytized by macrophages et broken down to heme, iron, and glob in.-Heme - degraded to bilirubin. Unconj in blood, conj in liver.-Iron - in blood as transferrin, TIBC, stored in liver or sk. muscle. Overload in liver/spleen called hemosiderin.
Body Responses to Anemia - true for all anemias
-Increased erythropoeitin & hematopoeitin-Extramedullary hematopoeisis-Blood shift to brain/heart-Tachycardia (increased heart workload)-Fatigue, weakness, dyspnea-Tissue hypoxia
Morphological Classification of Anemia - know
-Normocytic, normochromic- decreased cell #-Microcytic, hypochromic - abnormal hgb production, missing components-Macrocytic, normochromic- large cells (juvenile,nucleated)
Definitions - know
Poikilocytosis - alteration in cell shapeAnisocytosis- “ “ sizeHemoglobinemia - hgb in plasmaHemoglobinurea - urine exertion of hgbHemosideriuria - iron excretion via urine (brown)Hemosiderosis - increased iron storage in kidneys, spleen, liver.
Normocytic Anemia - etiology
- Loss of RBCs - hemorrhage- Increased destruction of RBCs (intra or extravascular hemolysis - premature lysis of erythrocytes in circulation) called hemolytic anemia- Decreased production of RBCs (aplastic or chronic disease anemia)
Normocytic -Intravascular hemolysis
Intravascular hemolysis- breakdown in circulating blood (mechanical injury, transfusion reaction, exogenous factors)
Normocytic -Intravascular hemolysis- clinical manifestation
marked erythropoeisishemoglobinemiahemoglobinuriahemisiderinuriahemisiderosishyperbilirubinemia
Normocytic -Extravascular hemolysis
Defective rbcs trapped in spleen. Anemias associated Hereditary spherecytosis, G6DP, sickle cell.
Normocytic - Extravas hemolysis -Hereditary Spherocytosis
-Etiology -autosomal genetic disorder-Patho - gene mutation causing deficiency in Spectrin (alpha or beta) which is protein on cell surface.-RBC membrane instability through tight spaces is compromised and becomes spherical. Unable to fit through spleen circulation therefore; destroyed.
Normocytic - Extravas hemolysis - Hereditary Spherocytosis- clinical manifestation
-Aplastic crisis-Splenomegaly and jaundice-Blood smear - anisocytosis, spherocytes, Howell-Jolly bodies-Increased hematopoiesis-Increased reticulocytesTreatment - splenectomy
Normocytic - Extravas Hemolyisi - Glucose-6-Phosphate Dehydrogenase Deficiency G6DP
-Common in African Americans/Mediterranean/Males-Etiology- mutation to G6DP gene-Patho - G6DP deficiency - enzyme required for glutathione production (antioxidant)-Lack of glutathione (deal with free radicals) results in oxidative stress damage to RBCs.–Older cells vulnerable, infections and drugs increase oxidative stress.
Normocytic, Extravas Hemolysis - G6DP clinical manifestation
-Hemolytic anemia - more severe in mediterraneon form-Hemoglobinemia-Hemoglobinuria-Blood smear - spherical cells (poikilo and anisocytosis) and Heinz and bite cells.
Normocytic - Extravascular Hemolysis -Sickle Cell
-Epi - 1 in 500 Afr. Americans with 8% carrying the cell trait. Also occurs in Mid. Eastern and S. Asian countries.-Etiology - mutation in beta globulin gene of hgb molecule
Normocytic - Ex. Hemolysis - Sickle cell path
- transforms hgbA (HbA) into hgb S.(HbS) Sickle cell disease = all hgbS (HbS)-Decreased PaO2, pH, volume, dehydration and cold cause Hbs to sickle.-Sickling - beta chaings in Hbs turn into viscous gel stretching into sickle shape.-Initially reversible but eventually irreversible.
Normocytic - Ex. Hemolysis - sickle cell clinical manifestation
-Vaso-occlusive cirisis causing tissue hypoxia and pain (bones, liver, lung, brain, spleen, rhabdomyolysis).-Sequestration crisis (RBCs pool in spleen, chronic hemolysis, decreased blood volume)-Aplastic crisis - very few RBCs in circulation - erythrocyte survival rate to 10-20 days, infection prone)-Blood smear - elevated retic count due to increase RBC production)-Bone marrow hyperplasia and extramedulary hematopoiesis.
