Immunology / hemolymphatics Flashcards

Question

Inflammatory response - vascular events - step 11 - fever

Answer 1

- IL-1 and TNF-𝜶 cause the fever - They will act on brain, liver and bone marrow Brain: act on hypothalamus - IL-1 and TNF-𝛼 stimulates the secretion of PGE2 -> PGE2 resets the body temperature (raise the setpoint) and initiates fever. Fever significance o Denatures some of the proteins, DNA of the bacteria - makes it harder to survive. o Speeds up the metabolism → initiate quicker healing process. Liver: in response to IL-1 and TNF-𝛼, it will produce acute phase reactant proteins o C-reactive peptide (CRP) o Ceruloplasmin o Haptoglobin o Fibrinogen o Ferritin Good for determining active inflammation → C-reactive peptide (CRP) IL-6 also can act on liver and cause the release of acute phase reactant proteins (produced by macrophages and lymphocytes). Bone marrow: TNF-𝛼, IL-1, IL-3, IL-5 act on the stem cells → Stimulate the bone marrow to produce more white blood cells - causes leukocytosis.

Answer 2

1) Pseudopods Macrophages and neutrophils will make pseudopods o Cytoskeleton → actin filaments and myosin filaments ▪ Able to change shape toward to literally come around the bacteria ▪ Latch onto it and pull it inside the cytosol inside specific endosome/vesicle (phagosome) 2) Phagosomes + lysosome → phagolysosome Inside the macrophage and neutrophil, there are vesicles with the G- bacteria (phagosome) - the bacteria still have their antigens (proteins, sugar molecules or glycoproteins) on their cell walls. Inside of the cell, macrophage and neutrophil have another specific vesicles → lysosome (has hydrolytic enzymes that helps to break down bacteria - cell walls, peptidoglycan, internal structures). These two vesicles will fuse together → phagolysosome. After the fusion, hydrolytic enzymes are released -> starts breaking down the cell wall and internal structures. 3) Overall result - destruction of the bacterial cell wall, fungi cell wall, viral, fungal, parasitic. Only leave antigens at the end and all the bacterial and viral substances are gone.

Answer 3

Neutrophil is not antigen-presenting cell The phagolysosome fuses with cell membrane → exocytosis -> spits out the antigens into the interstitial space and they go to LN - adaptive immunity. Sometimes -> bacteria that are hard to break down with necessary lysosomes -> it requires the sacrifice of the neutrophil itself. Oxidative / respiratory burst - Neutrophils have capability of taking O2 and convert it into free radicals: O2 →O2- →H2O2 →OH- or HOCl o O2- (superoxide anion) o H2O2 (hydrogen peroxide) o OH- (hydroxide free radicals) o HOCl (hypochlorite acid) ▪These free radicals come in and destroy the bacteria’s protein, cell wall, DNA. ▪ Free radicals aren’t specific -> it can also destroy the neutrophil’s protein, membrane. If this neutrophil is about to die because of the free radical reactions -> whenever it undergoes of fragmentation, it can start releasing its own DNA/chromatin (chromatin is made of DNA + histone proteins) -> Neutrophil Extracellular Traps (NETs). NETs -> the chromatin histone proteins can bind on the foreign bacteria antigens -> now it is possible to produce antibodies against this complex. It also can activate another enzyme → cathepsin G. Now the pathogen can be destroyed by cathepsin G or opsonization by white blood cells.

Answer 4

Macrophage is an antigen-presenting cell (they can present antigens on their cell membrane) They have specific gene sequence on chromosome 6 responsible for producing specific proteins -> there’s recombination where the DNA within that area can actually shuffle around and produce different types of mRNA → different types of proteins. Example: There are 3 types of antigen (circle, square, triangle) within the phagolysosoma of the macrophage. Macrophages be able to produce different proteins specific to fit that antigen, called MHC, Major histocompatibility complex, specifically type II. MHC II will bind to different types of antigens, and then those molecules will be exposed on the cell membrane bound with antigens. Additional information - there are MHC I - found in ALL nucleated cells in the body. Therefore, antigen-presenting cells also have MHC I molecules because they’re nucleated.

Answer 5

Complement is a part of the innate immune system (nonspecific). - Proteins made by liver in inactive form. - Normally complement proteins are circulating in the plasma. - Inflammatory response causes ↑ vascular permeability -> complement proteins are activated and leave blood and enter tissue to attack the pathogens (together with phagocytosis cascade). - This complement system includes 3 pathways.

Answer 6

Starts at C1 and is antibody mediated: - There are antibodies constantly circulating plasma and lymphatic fluid. - In inflammatory reactions, specific memory antibodies can leak out into tissues (increased vascular permeability). - These are antibodies that maybe have previously been exposed to the bacteria before (e.g. IgM, IgG, and antibodies) and can bind to the bacterial antigens via the Fc portion -> the Fc portion is very attractive to the complement proteins. - As soon as the antibody binds to the antigen, this attracts the first complement protein called C1 to attach to the Fc portion. - Then another protein called C4 binds to the C1, and the chain is as follows: C1 → C4 → C2 → C3 - There is an enzyme called C3 convertase cleaves the C3 protein into C3a and C3b. - C3a moves away and C3b remains in the pathway and continue the chain as follows: C1→C4→C2→C3b→C5b→C6→C7→C8→C9 - The C5 protein undergoes the same cleaving process as the C3, this means an enzyme called C5 convertase cleaves C5 into C5a and C5b - C5a moves away and C5b remains in the pathway. - Mast cells released various molecules like histamines, leukotrienes, prostaglandins... (at the beginning of the process, vascular events). - During this process, mast cells release proteases that act on C3a and C5a (that where cleaved off C3 and C5) to activate them. - Active C3a and C5a become great chemotactic agents and ENHANCE the inflammatory response.

Answer 7

- C5b→C6→C7→C8→C9 can break off from the main pathway and form a pentameric protein channel - Membrane Attack Complex, MAC. - This Membrane Attack Complex (MAC) forms a membrane pore that can bind into the bacterial cell membrane. The purpose of MAC: there is an open movement between the inside and outside the pathogenic cells -> water, Na+, can move in and cause CELL LYSIS.

Answer 8

Once the pentameric protein channel is formed (MAC), what is left of the complement still attached to the bacteria is: C1→ C4→ C2→ C3b - C3b is now exposed -> C3 it is an opsonin, making the pathogen more susceptible (more yummy!) to phagocytosis. - C3b binds to a receptor called C3b receptor on macrophages / neutrophils and triggers phagocytosis and engulfs all the complement proteins and the pathogenic cells. - When it breaks the pathogen cells down, antigen then gets exposed with the MHC II molecule (in macrophages) -> recall: neutrophil undergoes the same process but releases the product via exocytosis and into the LN in the end. Overall result of Complement Classical pathway: 1. MAC formation - PRODUCES CELL LYSIS 2. Opsonization - ENHANCES PHAGOCYTOSIS 3. Release of C3a and C5a -> ENHANCES CHEMOTAXIS

Answer 9

The difference in this pathway is that there is NO antibody mediated effect (no antibody attached to the surface of the pathogen): - In some cases, C3b protein can bind directly to the bacterial antigen, and the main chain is as follows: C3b → C5b → C6 → C7 → C8 → C9 Note: In between C3b and C5b, there is a molecule called Factor B C3b → Factor B →C5b → C6 → C7 → C8→ C9 C3a and C5a are released and interact with the proteases released by the histamines - this enhances the inflammatory response (via chemotaxis) (same as in Classical pathway). The same process of the Classical Pathway occurs: - C5b→C6→C7→C8→C9 break off and form the MAC -> this gets pushed into the bacterial cell membrane -> MAC initiates lysis of the pathogenic cell. - Again, when these molecules break off, C3b is exposed again. - The macrophages/neutrophils/dendritic cells bind via the C3b receptor and opsonization occurs (enhancement of phagocytosis process).

Answer 10

- Remember antigens on pathogenic cell can be sugar molecules, proteins or glycoproteins... - Some pathogen cells have specific type of antigen called Mannose. - Mannose binding lectin circulating the blood stream can bind to the mannose antigen on the pathogen cell. - This forms a mannose binding lectin complex. - C4 binds to this complex and the chain is as follows: C4→C2→C3b→C5b→C6→C7→C8→C9 - And the same process occurs again: C5b→C6→C7→C8→C9 break off and form the MAC -> triggers lysis of the cell. - C3a and C5a are released and interact with the proteases released by the histamines which enhances the inflammatory response. - What remains is: C4→C2→C3b - And again, the exposed C3b binds to macrophages/neutrophils/dendritic cells and opsonization and phagocytosis occurs.

Answer 11

1) Toll-like receptors • Proteins that are present in the cell membrane or the vesicles inside of the cell that respond to pathogens and elicit via specific responses. • Part of the pattern recognition receptors (PRRs) that bind PAMPs and DAMPs • Expressed on dendritic cells, macrophages, B cells, cytotoxic T cells as well as endothelial and epithelial cells • Activation leads to up regulation of inflammatory pathways NFkB and mitogen activated protein kinase (MAPK) -> acute phase proteins, coagulation factors, TNF-alpha, IL-1, IL-6, IL-8, IL-12, interferon 2) Interferons • Signal nearby host cells to let them know the presence of pathogens so that they can start making anti-viral peptides. • Signal macrophages and natural killer cells to proliferate

Answer 12

IRF – Interferon Regulatory Factors - When a virus infects a generalized tissue cell or a macrophage, usually, it results to death of the cell (lytic cycle). - Whenever a cell is damaged by virus, IRF TRANSCRIPTION FACTOR will activate IRF gene -> will produce an mRNA that will be translated to proteins forming interferons – alpha, beta, gamma. - Those interferons will be secreted out of the cell.

Answer 13

1) Alpha and Beta Both can be secreted by generalized tissue cells Beta-interferons can also be secreted by platelets Effects Activate Protein Kinase R cascade of a nearby unaffected cell - Protein kinase R (antiviral peptide) -> if the virus tries to penetrate the cell with Protein kinase R, it will be destroyed. Activate nearby natural killer cells -> some infected cells might down regulate the expression of MHC I molecules -> NK cells will notice cells that do not have MHC class I and induce apoptosis. 2) Gamma Secreted by immune system cells like lymphocytes Effects Binds to macrophage receptors activating macrophage proliferation. It will also make the macrophage bigger, hungrier, and increase its expression of MHC I and MHC II receptors.

Answer 14

- When generalized tissue cells are infected, virus can activate the cell’s IRF signaling mechanisms. - Interferons alpha and beta are secreted and in turn activate a healthy cell. - Healthy cell produces protein kinase R and other antiviral peptides - Protein Kinase R act like scissors, chopping the virus into pieces once it enters the healthy cell -> inhibiting the virus from infecting the healthy cell. - NK cells are also activated causing apoptosis of MHC-I deficient cells.

Answer 15

- When a macrophage gets infected, virus can also activate its IRF signaling mechanisms. - Interferons alpha and beta are secreted and in turn activate a healthy cell. - Healthy cell produces protein kinase R and other antiviral peptides. - Protein Kinase R acts like scissors, destroying the virus once it enters the healthy cell -> inhibiting the virus from infecting the healthy cell. - NK cells are also activated causing apoptosis of MHC -I deficient cell. - Interferon gamma is also secreted causing macrophage proliferation and activation, resulting to a stronger immune response.

Answer 16

TLRs are expressed in innate immune cells such as dendritic cells (DCs) and macrophages as well as non-immune cells such as fibroblast cells and epithelial cells. Subtypes: Technically, there are 11 subtypes. However, TLR-10, its function is unknown. TLRs dimerize when activated - combine with another TL receptor nearby to form a complex TLR1, TLR-2, TLR-3,...., TLR-9, TLR-11 There can be TLR in the membrane, or in the inside of the cell on membrane of vesicles (endosomes).

Answer 17

Cascade of events: TLR in the cell membrane, when activated, stimulate the vesicular TLRs. Membrane dimers: - TLR 1 + TLR 2 -> respond to GPI - anchoring proteins - parasites - TLR 2 + TLR 6 -> respond to zymogens (fungi) and LTA (gram +) - TLR 4 + TLR 4 -> respond to LPS (gram -) - TLR 5 + TLR 5 -> respond to flagellin (E. coli) - TLR 11 + TLR 11 -> respond to bacteria that damage the urogenital system Vesicular TLRs, in turn, will activate certain transcription factors - TLR 3 + TLR 3 -> responds to double stranded RNA virus - TLR 9 + TLR 9 -> responds to CpG DNA within bacteria - TLR 7 + TLR 7 -> responds to single stranded RNA - TLR 8 + TLR 8 -> responds to double stranded RNA Transcription factors cause activation of GENES that will produce mRNAs encoding proteins - AP1, IRF, NFKB

Answer 18

- AP1 Transcription Factor - activates protein signaling molecules - Interferon Regulating Factors - stimulate the production of interferons - Nuclear Factor Kappa Beta - stimulate the production of cytokines such as o Tumor Necrosis Factor Alpha (TNF-α) o Interleukin 1-Beta (IL-1β) o Interleukin 18 (IL-18) -can also activate NK cells IL-β and IL-18 still need to be acted upon by CASPASES for them to be activated.

Answer 19

To enhance the inflammatory response via different mechanisms - Chemotaxis - via secretion of protein signaling molecules - Protect healthy cells from the viruses - via secretion of interferons - Initiate leukocytosis, activation of pyrogenic effect, activation of bone marrow, activation of liver to produce acute phase reactive proteins - via secretion of TNF-α, IL-1β, and IL-18

Answer 20

Before entering the lymph nodes, there are cellular events happening in order to bring the antigens inside the lymph node: 1) Macrophages - the antigens that were pulled away from bacterial microbe may be expressed on MHC II molecules on cell surface. - These macrophages are referred as Antigen Presenting Cells (APCs) - The APCs interact then with T-helper cells Antigen Presenting cells (APCs) - Macrophages - Dendritic Cells - B-cells 2) Neutrophils - the antigens are exocytosed into interstitial fluid and then carried to nearby lymph nodes - this is the free antigen.

Answer 21

- Lymph nodes contain germinal centers which contains large amount of B-cells (AKA B-lymphocytes) - B-lymphocytes contains specific types of receptor on their membrane which is called the B-cell receptors - they are formed through recombination -> each of these B-cell receptors have different binding domains -> hence, each receptor can bind different types of antigen. - B-cell receptors - they are IgD antibodies.

Answer 22

Before the binding, the B-lymphocyte is naïve since it hasn’t gone any immunogenicity response. -> Activation happens when the free antigen circulating inside the LN, by random chance binds onto the B-cell receptor that was designed to fit that antigen. -> Activates B-cells through signaling mechanisms to the nucleus. -> the B-lymphocytes, now more mature, undergo receptor mediated endocytosis of antigen-antibody complex into B cell. -> Chromosome number 6 of the B cell produce MCH II molecules which fit perfectly to the antigen that has been phagocytosed. -> MCH II with antigen fuses on to the cell membrane - activated B-lymphocyte (Antigen Presenting Cell). - > Activated B-lymphocyte -> have B-cell receptors, including the MHC II molecules with the foreign antigen on its membrane → important to make more specific types of antibodies specific to the antigens. It still cannot undergo proliferation.

Answer 23

Before interacting with the antigens, the T helper cell is a naïve T-helper cell → have receptors which can respond to the molecule but still not activated and unspecific Remember -on the membrane of the macrophages, there are: o MHC I molecules with some type of self-antigen - all nucleated cells must have it. o MHC II molecules which expresses the antigen.

Answer 24

T naïve cells can become either T helper 1 or T helper 2, depending on the factors that activate them. IL2 and IL4 will produce T helper 2 cells. Primary signal MHC II molecules on cell membrane of macrophages -> will interact with CD4 (CD = cluster of differentiation) molecule on T helper cells Antigen which is expressed on the MHC II molecule -> will interact with T-cell receptor (TCR) specific to that antigen on T-helper cells (like the B-cell, due to recombination, every T-cell have different types of receptors specific to the type of antigens). This interaction sends primary signals to the nucleus through CD3 molecules. Secondary signal B7 molecules on macrophage surface -> will interact with CD28 on naïve T helper cells → send secondary signal / co-stimulation to the nucleus together with CD3. Third signal The macrophages secrete IL1 molecule → this sends the third signal to the nucleus. Activation of the T-cell leads to the production and secretion of IL-2: - IL2 can bind on the T-cell (autocrine - binding to the same cell that produces it) - IL2 and IL4 will stimulate proliferation of the now called T helper 2 cells. - T helper 2 cells will produce IL4, IL5 and IL6

Answer 25

Now with the production of IL4 and IL5 by T helper 2 cells, B-lymphocytes can proliferate. The B-cell and T-helper cell interaction as was listed, triggers T-helper cells to release cytokines: IL-4 and IL-5 → converts naïve T cell into TH2 cells IL-4 - Activates B-cells to start proliferating (clonal expansion) → become immunocompetent. - This B-cell have specific B-cell receptor to the specific foreign antigen and MHC II molecules with the foreign antigen, expresses on its membrane -> can recognize any types of antigens due to the specific B-cell receptor. IL-5 - Promotes differentiation of proliferated B cells into memory B cells and plasma cells IL-5/IL-6 - Stimulate plasma cells to produce antibodies against specific antigens on pathogens: o Neutralization - the antibodies bind to all the surface antigens on the pathogen -> block the antigen from attaching to healthy host cells which can cause damage. o Precipitation reaction - Antibody bind to the freely circulating antigen (causes precipitation and enhances opsonization) - Free antigen-antibody complexes may deposit into tissues causing type 3 hypersensitivity o Lysis - Antibodies binds to the same antigens on the pathogen - stimulates the complement system -> produces membrane attack complex - cell lysis. o Agglutination - When there’s a mismatch/incompatible blood - will have antigens on the RBCs surface -> antibodies bind to the antigen on the RBCs - agglutination. o Opsonization - When the pathogen is marked for destruction by the antibody → the pathogen will be destroyed by the macrophages either through the complement cascade as already mentioned (lysis) or directly via antibody- dependent cellular phagocytosis. Humoral immunity: activation of B lymphocytes, activation of T helper cells into T 2 helper and leading to B cell proliferation, maturation into plasma cells and leads to the production of antibodies.

Answer 26

- Hormone like molecules called interleukins that act to regulate immune responses - Over 100 identified -> IL1, IL2, IL4, IL5, IL6, IL8, IL10, IL11, IL12, TNF alpha, TNF beta, TGF beta, INF alpha, INF beta, INF gamma IL1 – activates T cells and macrophages, induces synthesis of adhesion molecules on endothelium, up regulates iNOS and COX2, increases corticosteroid release, causes fever IL2 – activates macrophages, NK cells, and lymphocytes IL4 – activates lymphocytes and monocytes, stimulates IgE production IL5 – causes differentiation of eosinophils IL6 – activates lymphocytes and causes differentiation of B cells, stimulates production of acute phase proteins, causes fever IL8 – causes chemotaxis of neutrophils, basophils and T cells IL10 – anti-inflammatory IL11 – stimulates production of acute phase proteins IL12 – stimulates INFgamma production from TH1 cells and NK cells, induces TH1 cells TNF alpha and beta – general pro-inflammation TGF beta – causes immunosuppresion INF alpha and beta – induces cells to resist viral infection INF gamma – activates macrophages and inhibits TH2 cells

Answer 27

Triggered by endogenous antigen - the antigen is INSIDE the cell causing damage to the cell Mediated through the cytotoxic T-cells - recognize MHC - I in infected / damaged cells by CD8. T cytotoxic cells have TCR receptors - normally, they do not recognize the self antigen attached to the MCH - I (would lead to autoimmune disease), but when the cell is infected, the self antigen is modified and recognized by the TCR on the T cytotoxic cell.

Answer 28

Kills virus infected cells and neoplastic (cancerous) cells When cells are infected by virus or are cancerous this happens: - The virus can get integrated into the DNA → creates viral proteins that can get integrated into the self-peptide → leads to expression of viral antigen or cancer antigens on MHC-I complex - MHC-1 complex of infected or cancerous cells interact with CD8 molecule on cytotoxic T cell - The cancerous or viral antigen on infected or cancerous cells (on MHC - I) interact with TCR on cytotoxic T-cell - gets activated -> they release perforins and granzymes Perforins -> creates pores in infected or cancerous cells Granzymes - moves through the pores and activates pro-apoptotic genes, leading to cell apoptosis.

Answer 29

- They are NOT a part of the adaptive/acquired immunity, but the mechanism of action is very similar to cytotoxic T- cells - NK cells are large agranular lymphocytes - The activated natural killer cells release perforins and granzymes which trigger apoptosis of viral infected cells They can kill by 3 ways: - Absent MHC-I expressed on surface - Different MHC-I expressed on surface (MICA) - Through IgG mechanism

Answer 30

1) Absent MHC I molecule expressed on the surface - All nucleated cells must have MHC I molecule expressed on the surface - If a viral pathogen infects tissue cells -> virus induces abnormal MHC I complex or inhibits MHC I formation. - This foreign MHC I or Absent MHC I due to viral infection → activates natural killer cells 2) Different type of MHC I expressed on the surface (MICA) - MICA doesn’t contain beta 2 molecule (normal structure of MHC I molecule contains the alpha 1, alpha 2, alpha 3 and beta 2 subunits). - This foreign MHC I like molecule activates natural killer cells 3) Through IgG mechanism - If IgG antibodies made by plasma cells bind viral antigens expressed on MHC-I complex this allows natural killer cells to bind to Fc portion of IgG antibody via their CD-16 protein this activates the natural killer cells -> then they release perforins and granzymes and trigger apoptosis.

Answer 31

Mediated by immunoglobulins binding to antigens and then effector cells binding to that immune complex. - Type I -> Immediate reaction within 15-30 minutes usually, but can be up to 12 hours post-exposure to antigen. IgE mediated - Type II -> Reaction within minutes to hours. IgG or IgM mediated - Type III -> Reaction up to 10 hours post-exposure. IgG or IgM mediated with complement involved - Type IV -> Delayed reaction typically 2-3 days post-exposure, but can be longer. T cell mediated

Answer 32

Loss of immune tolerance resulting in destruction of body’s own tissues - Alloimmune reactions -> antibody from member of same species reacts with antigens on affected individual’s cells: transfusion reaction, transplant reaction - Primary reaction: antibody directed against a self antigen - Secondary reaction: antibody directed against absorbed antigen on cell surface

Answer 33

- Glucocorticoids -> decrease circulating T lymphocytes, inhibit neutrophil and monocyte chemotaxis and phagocytosis, inhibit cytokines, decrease mast cell numbers and histamine synthesis - Cyclosporine -> inhibits T lymphocyte growth (primarily T helper cells), inhibits cytokines (IL2) - Azothiaprine -> antagonizes purine metabolism inhibiting RNA and DNA synthesis and mitosis, inhibits coenzyme formation - Cyclophosphamide -> alkylating agent inhibits RNA and DNA synthesis, phosphorylating activity causes cytotoxicity, exact immunosuppressive mechanism of action not known - Mycophenolate -> non-competitive reversible inhibition of inosine monophosphate dehydrogenase (required for purine synthesis in T and B cells)

Answer 34

1) Microparticles - Membrane derived exocytic vesicles formed when there is disruption of phospholipid asymmetry * Phosphatidylserine (PS) and phosphatidylethanolamine (PE) * Phosphatidylcholine and sphingomyelin - Produced by -> platelets, endothelial cells, erythrocytes, neutrophils, monocytes and lymphocytes - Contain membrane, cytosolic and nuclear components of their cell of origin - Associated with pro-inflammatory and procoagulant effects -> targeting these effects can be a novel therapeutic option for many disease states - Serve as biomarkers of vascular injury and inflammation 2) Targeted immunosuppressives -> research into medications that suppress specific cytokines and proteins within the inflammatory cascade are ongoing 3) Inflammation in Sepsis -> research is more fully elucidating the complex pathways and roles of inflammatory mediators in sepsis - Regulatory T cells have recently been found to play a larger role in the immune dysfunction seen with sepsis - Loss of balance between the inflammatory response in sepsis and the compensatory anti-inflammatory response is being investigated

Answer 35

- Increased production (appropriate) - Increased production (inappropriate) - Demargination - Decrease egress from circulation

Answer 36

Bone marrow and marginated neutrophils along endothelial walls - both serve as buffer for fluctuations in peripheral demand.

Answer 37

TRUE - dogs have up to a 5 days supply of neutrophils in the bone marrow storage pool (based on normal rates of utilization). If the inflammatory nidus is acute and fulminant with rapid depletion of bone marrow neutrophil stores prior to any regeneration, neutropenia may ensue.

Answer 38

De novo generation of neutrophils is required - occurs via myeloid progenitor cell proliferation in the bone marrow - complex response known as emergency granulopoiesis.

Answer 39

G-CSF (granulocyte - colony stimulating factor) GM-CSF (granulocyte monocyte - colony stimulating factor) IL3 IL6 FLT3 ligand

Answer 40

To produce new neutrophils takes time To tide over the lag period between the need of neutrophils and releasing new ones -> previously produced band neutrophils or even earlier granulocytic precursors are released into circulation -> left shift.

Answer 41

With serial monitoring every 24-48h due to their short half-life (6-8h) and the dynamic interplay between production and consumption.

Answer 42

When granulocytic precursors outnumber mature neutrophils in circulation. It has been found to increase the risk of death or euthanasia in hospitalized dogs and cats. In cats, not only the presence but the severity of the DLS (ratio of mature to immature neutrophils, N/I index), predicts a higher risk of mortality.

Answer 43

Marked leukocytosis due to a strong inflammatory stimulus that can mimic a neoplastic response. Dogs and cats with extreme neutrophilia secondary to neoplasia were more likely to die than other etiologies.

Answer 44

- Signs of dysplasia, associated with increased granulopoiesis and inflammation - Changes are mostly in cytoplasm -> presence of Dohle bodies, increased cytoplasmic basophilia, vacuolation of the cytoplasm and rarely, the presence of primary granules. - Giantism of neutrophils and neutrophilic precursors is also a sign of toxicity. - Can be helpful in differentiating cases of inflammation (toxic changes often present) from steroids/stress and epinephrine response (toxic changes not present). - Presence of toxic changes is associated with increased hospitalization time in both dogs and cats, and degree of toxicity is associated with risk of mortality in dogs.

Answer 45

- Rarely seen in dogs and cats - Due to neoplasia: * Primary in the bone marrow (granulocytic leukemia - very rare) * Paraneoplastic response secondary to release of growth factors from a wide array of different neoplasms: HSA, mast cell tumors, thymoma, ovarian carcinoma, pulmonary adenocarcinoma.

Answer 46

- In cats, approx. 70% of total blood neutrophils are in the marginated pool vs 50% in dogs. - As they are marginated, not circulating, normally not part of the measured neutrophil concentration - demmargination can dramatically increase the neutrophil concentration -> this is seen in response to corticosteroids and epinephrine.

Answer 47

- Stress leukogram - Both endogenous and exogenous steroids can cause demargination of neutrophils and decreased transit into tissues. - Magnitude of neutrophilia - 15K - 25K cells / uL in dogs and cats. - Maximal response within 8h - Count goes back to normal in 24h if no more steroids are administered - Steroids - hallmark is lymphopenia - peripheral lymphocyte count is low due to redistribution. - Lymphopenia faster than neutrophilia - seen within in 4h, and takes longer to resolve.

Answer 48

- Release of epinephrine with excitement causes marginated neutrophils to be released into circulation. - Effect is seen immediately and resolves within 30min. - Epinephrine normally results in a lymphocytosis, secondary to mobilization from the thoracic duct and blockage of entry into lymphoid organs.

Answer 49

- Most important cause is corticosteroids - Irish setters - genetic disorder, leukocyte adhesion deficiency (LAD) - neutrophils lack surface receptors (CD18) to be able to bind to endothelial cells therefore they cannot enter the tissues and they accumulate in blood. - Extremely high neutrophil concentrations occur (50,000 - 100,000+ cells /uL) and many hypersegmented neutrophils may be seen. - Animals are susceptible to infections and die young.

Answer 50

- Circulating neoplastic cells can occasionally cause leukocytosis. - Middle-aged to older dogs (less common in cats) - Marked leukocytosis - 15K to 1600K cells / uL - Neoplastic cells: small, mature lymphocytes - Indolent and slowly progressive

Answer 51

- Associated with large, immature circulating cells. - Aggressive, high-grade malignancies. - Grave prognosis. - Associated with concurrent cytopenias. - Machines do not identify reliably neoplastic cells - blood smear

Answer 52

Can frequently give clues to underlying disease processes.

Answer 53

- Address underlying condition. - Magnitude of neutrophilia often correlates with the severity of the disease process. - Monoclonal therapy against neutrophils - tested in lab animals * Induces a leukocyte adhesion deficiency syndrome that may impose a risk for exacerbating sepsis. * Argument against this therapies - alterations in neutrophil morphology, mechanics and motility - worse outcomes noted in septic patients with larger and less granular neutrophils.

Answer 54

- Decreased production by bone marrow - Increased utilization - Increased destruction

Answer 55

- Non-bacterial infectious diseases the most common etiology in dogs and cats - These agents most likely target bone marrow precursors - Dogs -> parvovirus accounted for 53% cases of neutropenia - increasing severity of leukopenia associated with increased mortality vs a WBC > 4.5x10^3/uL at 24h post admission - positive predictive value for survival of 100%. - Cats -> FIV / FeLV accounted for 10% and 24% of neutropenic patients. Feline panleukopenia - also a potent cause of neutropenia, similar to parvo, increased severity of neutropenia associated with increased risk of mortality. - Other diseases: neoplasia, necrosis, myelofibrosis, RT and drug toxicity. - When is due to drugs / toxins - many are accompanied by anemia, thrombocytopenia or both.

Answer 56

Neutropenia secondary to increased demand from marked inflammation, bacterial sepsis or endotoxemia accounted for 17% of feline cases and 10% of canine cases. Early stages of sepsis can be associated with neutropenia: * Experimental model of endotoxin mediated sepsis in dogs - severe leukopenia observed 3h after induction of sepsis. * Leukopenia is due to neutropenia - lymphocytes and monocytes stay constant * By 24h - rebound leukocytosis secondary to neutrophilia seen. * Neutropenia suspected due to transient margination of neutrophils secondary to endotoxin-mediated up regulation of adhesion molecules on neutrophils.

Answer 57

Immune-mediated destruction of neutrophils is rarely seen in dogs, even more rare in cats. Dogs with corticosteroid-responsive idiopathic neutropenia - young (<4y) and lower neutrophils compared to patients with known causes of neutropenia.

Answer 58

- Can be severe enough to cause mild leukopenia - Most cases is due to endogenous or exogenous steroids - hallmark of stress leukogram - Other causes -> lymph losing diseases, viral dz (including parvo) and other infectious dz.

Answer 59

- Treat underlying condition - Most vets - do not initiate treatment until neutrophils are < 2500 cells / uL - Human guidelines - propensity to develop an infection is significant when neutrophils < 1000 cells / uL. - Goal of management - prevent infection. - Febrile neutropenia secondary to chemotherapy -> patients expected to have a short nadir in neutrophil concentration may be easily managed as outpatients. - Therapy with atb: based on degree of fever, magnitude of leukopenia / neutropenia and patient characteristics. Important information: * Has the patient been previously on antibiotics? * Results of a culture? * What pathogen is most likely? * What are the regional susceptibility patterns? - Broad spectrum atb should be initiated in all febrile neutropenic patients - potentiated penicillin or fluoroquinolone. - If patient has signs of SIRS or sepsis -> combination of amino glycoside with a B-lactam antimicrobial is preferred - change based on culture and susceptibility when available. - Hospitalization vs outpatient - weight risks. - G-CSF has been recommended to aid in the earlier increase of neutrophils from bone marrow - potential to produce more leukocytes - study in parvo ineffective in increasing neutrophils and improving survival. - Canine recombinant G-CSF - shown to improve neutrophil concentrations in neutropenic patients - option when available?

Answer 60

- Regenerative - blood loss or hemolysis. Acute development of anemia will appear non-regenerative due to insufficient time elapsed to see a regenerative response. - non-regenerative - ineffective erythropoiesis (primary bone marrow pathology or systemic disease causing bone marrow suppression).

Answer 61

- Pluripotent hematopoietic step cells in the bone marrow give rise to all adult stages of erythrocytes, leukocytes and platelets. - Red cell line undergoes several mitoses -> each successive cell division is smaller than the previous one, with increasing hemoglobin content. - Once achieving a critical hemoglobin concentration, reticulocytes are released into the peripheral circulation via diapedesis. - Within 48h any residual basophilic material in the reticulocyte is lost, forming mature erythrocytes.

Answer 62

- Glycoprotein produced by kidneys in response to hypoxia. - Primary regulator of erythropoiesis. - Other substances like thyroxine or cortisol can augment erythropoiesis. - Sufficient iron stores are essential for Hb function. - Life-spam: erythrocytes persist for approximately 104 days in the periphery of the dog and 73 in the cat. - Aged erythrocytes - cleared by erythrophagocytic system.

Answer 63

- Symptoms are non-specific and milder than with regenerative anemia. - Chronic anemia has some degree of physiological compensation. * Increased CO via NO mediated vasodilation * Rheological changes promoting lower systemic vascular resistance. * Down side of this relative hypovolemia - increased sympathetic discharge and RAAS activity, risking hypervolemia and cardiac remodeling over time. * Volume overload is considered a risk in chronic anemia, especially in cats. * Compensatory increases in synthesis of 2,3-DPG with a right shift of the oxygen dissociation curve can also occur in dogs.

Answer 64

All mature and immature erythrocyte stages. PCV with estimation of TS is extremely valuable. Hematocrit can be calculated from the RBC count and mean cell volume (MCV) from automated machines - higher error than with manual PCV.

Answer 65

Due to superior leukocyte staining.

Answer 66

Depends on institution, but normally dogs are considered anemic when PCV <35% and cats, <30%.

Answer 67

- Polychromasia - Anysocytosis - Nucleated red cells - Polychromatophil -> recitulocytes that are basophilic due to the staining of their nuclear material.

Answer 68

Methylene blue.

Answer 69

Two: aggregate and punctate. Aggregate - used to assess regeneration - shorter lived than punctate.

Answer 70

Presence of parasites Schisctocytosis Spherocytosis Erythrophagocytosis

Answer 71

MCV - average erythrocyte size MCHC - hemoglobin content.

Answer 72

- Non-regenerative: normocytic normochromic (normal MCV and MCHC) - Regenerative - classically considered macrocytic (high MCV) and hypochromic (low MCHC). - Iron deficiency - microcytic (low MCV) and hypochromic (low MCHC). - most common reason for iron deficiency is chronic blood loss, typically from GI, that becomes non-regenerative over time. - Diagnostic accuracy of MCV and MCHC to identify regeneration - 70% and 66% respectively. - Other diseases can result in macrocytosis (FeLV) and microcytosis (PSS), which limits the sensitivity of MCV as the sole indicator of regeneration.

Answer 73

- Indicates variation in erythrocyte size -> regenerative anemia associated with high RDW, non regenerative with a low RDW. - Helps identify regeneration in dogs - reported diagnostic accuracy of 69%. - Combination of RDW and polychromatic improved diagnostic performance to 79%.

Answer 74

- Other cell lines should also be assessed. - Pancytopenia - suggests primary BM pathology. - Preservation of other cells can be bone marrow or extramarrow disease.

Answer 75

- To characterize the pathology as accurate as possible. - Cytology could say low-cellularity -> could be a non-diagnostic sample or a truly hypoplastic process. - CBC should also be submitted along with the bone marrow sample to guide interpretation.

Answer 76

- Animals should be deeply sedated or anesthetized, with analgesia. - Anatomical locations - proximal humerus, iliac crest and trochanteric fossa of the femur are some possible locations. - Sternal marrow aspiration using hypodermic needles has been described in beagles -> provided good-quality diagnostic samples and associated with lower pain scores. - bone marrow needle depends on patient size -> generally Illinois sternal needles are preferred for smaller patients, and Jamshidi for larger.

Answer 77

- Small, <0.5mL - Larger samples -> risk of hemodilution - Transfer it promptly to glass slides -> should contain visible spicules of bone marrow. - Same procedure repeated to take a core biopsy but removing the stylet.

Answer 78

FALSE - produces a MORE severe anemia.

Answer 79

- Of aplastic anemia, where hematopoietic marrow space is replaced with adipose tissue. - Neutrophils have the shortest half-life, neutropenia might be evident within 5 days, followed by thrombocytopenia after 8-10 days, and then anemia weeks later.

Answer 80

- Idiopathic - Infections (E. canis, parvovirus) - Toxins / drugs (azathioprine, procarbazine, estrogens, phenylbutazone) - Immune-mediated diseases. Cats: - Idiopathic - FeLV - Renal disease - Drug reactions Guarded prognosis.

Answer 81

Not routinely. It could offer a cure.

Answer 82

Pure red cell aplasia (PRCA) and Non regenerative IMHA (NRIMHA) - WBCs and PLT are unaffected. - Absence of all red cell precursors on bone marrow = PRCA - NRIMHA = destruction of later stages of erythrocyte development. - NRIMHA vs peripheral IMHA -> spherocytosis is uncommon, icterus not observed and Cooms positivity is rare with NRIMHA. - Both managed with long-term immunosuppressive agents. - Response to therapy between 61% to 77% in PRCA, 88% of cats alive 60 days after dx. - Time to recovery is slow in both dogs and cats - Potential for need of >1 blood transfusion. - In contrast to IMHA - thrombosis is rare and thromboprophylaxis not routinely used. - Secondary PRCA and NRIMHA - described and associated with FeLV in cats, parvovirus in dogs, adverse effects of human recombinant erythropoietin therapy and estrogen toxicity.

Answer 83

- Should always be considered. - Leukemia involves the neoplastic proliferation of one hematopoietic cell line in the marrow, with secondary suppression of the other cell lines - anemia develops later than neutropenia and thrombocytopenia. - Disseminated lymphoma, malignant histiocytoma (MH) - both can cause nr anemia. - MH can cause regenerative anemia too due to erythrophagocytosis by malignant histiocytes. - Myelodysplasic syndromes - dysplasic rather than neoplastic hematopoietic precursor development.

Answer 84

- Anemia or renal disease is common - likely multifactorial. * EPO deficiency considered the major cause. * Increased concentrations of cytokines in uremia may also inhibit erythropoiesis. * Functional iron deficiency has been reported in cats with renal disease. * Uremic gastropathy causing ulceration - uncommon cause of anemia in dogs and cats. - Thyroxine augments the effects of EPO - mild NR anemia may be seen in hypothyroid dogs. - Some dogs with Addison's - anemia -> supports role of cortisol in erythropoiesis - inconsistent finding. Concurrent GI bleed could contribute to the anemia. - Anemia of inflammatory disease (AKA anemia of chronic disease) - usually mild, normocytic and normochromic. * IL1, IL6 and TNF alpha - may result in up regulation of acute phase protein hepcidin -> promotes a state of relative iron deficiency, blunting erythropoiesis and promoting a low-grade anemia.

Answer 85

- Blood products and hemoglobin oxygen-carrying solutions may be required in animals with hemodynamic compromise due to their anemia. - Disease-specific considerations -> immunosuppression, exogenous EPO... - Anabolic steroids (nandrolone) may be considered in chronic NR anemia, especially of renal disease - proven efficacy lacking in small animals. - Lithium - psychiatric medication -> could have applications for aplastic pancytopenia - no data available in vetmed.

Answer 86

- Anemia that results from increased erythrocyte destruction and shortened red blood cell lifespan. - Usually extravascular, with macrophages erythrocyte destruction in spleen, liver and bone marrow. Splenomegaly frequently present. - Intravascular less common, leads to hemoglobinemia and hemoglobinuria. - With either, the rate of erythrocyte destruction can exceed hepatic clearance, resulting in hyperbilirrubinemia and icterus.

Answer 87

- Lethargy, weakens, exercise intolerance and inappetence. Some might have pigmenturia. - Hx: details on medications, diet, travel and past illnesses. Dietary indiscretion (onions, zinc) may result in hemolysis. Travels to certain locations - possibility of tick-borne disease or erythroparasites. - PE - tachycardia, tachypnea, cardiac murmur, gallop sounds, snappy pulses, pallor, jaundice, splenomegaly and pigmentaruria.

Answer 88

- Anemia - confirmed via decreased PCV / Ht / Hb. - Reticulocyte count is essential - hemolytic anemia are almost always regenerative - absolute reticulocyte count >60K/uL in the dog, or aggregate reticulocyte count > 50k/uL in the cat. - Can be NR anemia if: early in the disease process prior to BM response or if it targets the RBCs precursors. - Always evaluate a blood smear and SAT - we can detect spherocytes, Heinz bodies, eccentrocytes, erythroparasites and schistocytes that might help our ddx.

Answer 89

- Immune-mediated hemolytic anemia (IMHA) - Alloimmune hemolytic anemia - Oxidative hemolyisis - Zinc & Copper toxicity - Erythroparasites - Inherited erythrocyte defects - Microangiopathic hemolysis - Hypophosphatemia

Answer 90

- Most common cause of hemolysis in dogs. - Immune targeting of and damage to the erythrocyte membrane. - Hemolysis is most commonly extravascular, but can be intravascular. - Can be secondary to an inciting cause, or part of a systemic immune disease. - If cause not discovered -> autoimmune hemolytic anemia (AIHA).

Answer 91

- American Cocker Spaniel - Miniature Schnauzers - English springer spaniels - Old English sheepdogs - Poodles - Spayed females. Less common in cats.

Answer 92

- Demonstration of immune-mediated RBC destruction by one or more of the following: * Presence of spherocytes on a blood smear

Answer 93

- Demonstration of immune-mediated RBC destruction by one or more of the following: * Presence of spherocytes on a blood smear * Positive SAT * Positive direct Coombs test

Answer 94

- Result from phagocytosis of a portion of the RBC membrane. - Microcytic, spherical erythrocytes w/o central pallor - Hard to distinguish from normal erythrocytes in cats - not reliable for IMHA in this species.

Answer 95

- Assesses autoagglutination - Drop of blood mixed with an equal or greater volume of 0.9% NaCl on a slide - Macroagglutination can be grossly visualized - Microagglutination should be assessed by the presence of rouleaux. - True autoagglutination will persist after saline addition.

Answer 96

- Detects antibodies or complement on the RBCs surface. - Sensitivity of 60% to 70 %.

Answer 97

- Depends on clinical findings and geographical location. - CXRAY, AUS, UA, UC, serology / PCR for tick-borne pathogens.

Answer 98

- IMHA is thombophilic - incidence of thromboembolism is significant and a frequent cause of mortality. - Assessment of hypercoagulability should be done via TEG. - D-dimers - occur in dogs w/ IMHA, uncertain if reliable as indicator of hypercoagulability.

Answer 99

- Immunosuppression to decrease the rate of erythrocyte destruction. - Treat underlying disease if any. - Prophylactic antithrombotics. - pRBCs transfusion if necessary.

Answer 100

- Corticosteroids the mainstay of immunosuppressive therapy. - Prednisone or prednisolone at 1-2mg/kg q12h. Large dogs do not exceed 40-60mg/day. - Cats: prednisolone preferred - results in higher plasma concentrations. - If oral therapy cannot be tolerated - dexamethasone at 0.15 - 0.3 mg/kg IV / Sq q12h. - Response seen within 2-10 days (stabilization or increase in RBCs. In NRIMHA it might take weeks to months. - Continued at initial dose for 3-4 weeks - then slowly taper based on response to treatment. Faster tapering is possible if underlying condition is removed. - Adjunctive immunosuppressive therapy might be necessary - azathioprine, mycophenolate, cyclosporin, human IVIg, cyclophosphamide, danazol and leflunomide. Cyclophosphamide no longer recommended - no benefit or increased mortality in different studies.

Answer 101

- Optimal therapy not established yet. - A study in dogs with IMHA suggested improved survival when ultra-low-dose aspirin (0.5-1mg/kg q24h) was included. - One study showed improved survival with individually adjusted dose of UF heparin based on anti-FXa activity vs fixed low-dose UF heparin administration.

Answer 102

- Splenectomy has been described as treatment option for patients that are non-responsive to drug therapy. - Plasmapheresis has been described in one patient, but has to be further evaluated.

Answer 103

- Reported mortality - 40% to 70% - Numerous negative prognostic indicators have been proposed - thrombocytopenia, tbil > 5mg/dL, increased BUN, presence of band neutrophils, prolonged PT/PTT, evidence of hypocoagulable state via TEG, hypoalbuminemia, increased ALT, increased ALP. Little agreement between studies.

Answer 104

Occur with hemolytic transfusion reactions and neonatal isoerythrolysis

Answer 105

- Acute hemolysis that occurs in a neonate due to incompatibility between maternal and neonatal blood types. - Usually seen in cats when a type A or type AB kitten is born to a type B queen. - Does not occur in utero because cats have endotheliochorial placentation. - Queens type B secrete anti-type A antibodies in their colostrum and milk - can be absorbed by neonatal kittens for the first 16 hours of life. - Kittens are born healthy but develop hemolysis at a few days of age, and rarely live more than 1 week. - Can be avoided by typing queens and toms to ensure compatible coupling. - if incompatible coupling - kittens born of a type B queen and type A tom, can be placed with a type A queen for the first 24h, or fed commercial milk for 24h and 1-3mL of serum from a type A cat can be administered PO/SQ to transfer passive immunity.

Answer 106

- Denaturation of hemoglobin resulting in Heinz body formation - RBC membrane damage - Oxidation of ferrous iron to the ferric form, resulting in methemoglobinemia.

Answer 107

Feline erythrocytes due to a greater number of reactive sulfhydryl groups an reduced ability to metabolize oxidative agents.

Answer 108

They cause erythrocyte rigidity and resultant shortened lifespan. Causes of HB formation: - Allium species (onion, garlic) - Methylene blue - DL-methionine - Phenacetin - Compounds which also cause methemoglobinemia (acetaminophen, benzocaine and phenazopyridine) - DKA, hyperthyroidism and lymphoma in cats can lead to HB formation. - Commercial foods and drug preparations with propylene glycol are associated with HB formation, but do not generally result in anemia.

Answer 109

Best identified in a blood smear with new methylene blue staining

Answer 110

Dx of HB anemia requires a history of exposure and visualization of HBs in many erythrocytes, together with evidence of hemolysis.

Answer 111

- Removal of oxidant agent - Antioxidant therapy (NAC or SAMe) - Supportive care

Answer 112

- From ingestion of zinc-containing objects: US pennies minted after 1982, bolts screws or topical skin protectants. - Severe intravascular hemolysis, GI signs and occasionally, pancreatitis. - Should be suspected in any patient with acute hemolytic anemia in the absence of autoagglutiation - AXRAY!

Answer 113

- RX evidence of metallic foreign objects and/or possible exposure - Can be confirmed with elevated zinc blood levels - treatment should not be delayed waiting for results.

Answer 114

- Ingestion of copper containing foreign bodies - Severe hepatocellular necrosis in dogs with copper storage disease. - Mechanism by which copper induces hemolysis is incompletely understood - lipid peroxidation suspected to play a role.

Answer 115

- Prompt removal of foreign objects (endoscopy / surgery) - Appropriated fluid therapy essential due to potential for renal injury caused by hemoglo binemia. - Blood transfusion administered PRN. - Antacids recommended to reduce gastric acidity and leaching of metal from the source. - Chelation therapy rarely necessary if the source is removed. - If chelation is necessary -> calcium disodium EDTA is typically recommended (25mg/kg IV q6h). - Prognosis is excellent with timely and aggressive intervention.

Answer 116

- Mycoplasma haemofelis (cats) - Cytauxzoon relis (cats) - Babesia spp. (dogs)

Answer 117

- Mycoplasma haemofelis causes acute hemolytic anemia in cats - A causative role of other Mycoplasma species is less clear. - Dx: visualization of the organism via blood smear, or confirmation of the presence of parasite DNA via PCR. - Cats w/ mycoplasmosis should be tested for immunosuppressive diseases. - Treatment - doxycycline (5mg/kg PO q12h) or tetracycline (20mg/kg PO q8h) for 3 weeks

Answer 118

- Cytauxzoon relis causes severe, fulminant hemolysis, DIC and organ dysfunction in cats. - Associated with a very high mortality rate. - Dx achieved by visualization of protozoa in erythrocytes or by PCR testing (PCR might be easier). - Tx: supportive care, azithromycin and atavaquone or diminazene (not available in the US). - Guarded prognosis.

Answer 119

- Babesia spp causes hemolytic anemia in dogs. - B. canis affects all breeds, with greyhounds most commonly reported. - B. gibbon is associated with recent dog bites - most common in American pit bull terriers. - From acute disease w/ severe intravascular hemolysis to subacute / chronic disease with mild/moderate anemia. - IMHA appears to occur frequently and depending on location, concurrent infection with E. canis is not uncommon. - Severe cases -> DIC, SIRS. - Dx: identification of intraerythrocytic pyriform bodies on blood smear (best from an ear prick), serology or PCR. - Work up should include evaluation for IMHA and E. canis. - Tx: diminuzione or imidocarb diproprionate, as well as short, tapering course of steroids. - Effective treatment of B. gibbon -> combination of metronidazole, enrofloxacin and doxycycline, or a combination of clindamycin, diminazine and imidocarb diproprionate.

Answer 120

- Erythroenzymopathies - Erythrocyte membrane defects

Answer 121

- Piruvate kinase (PK) -> helps cells turn glucose into energy (ATP) during glycolysis. Red cells rely on this process for energy, and so, PK deficiency leads to a deficiency in energy and to premature red cell destruction (hemolysis). - Reported in several dog breeds (basenjis, beagles, dachshunds, toy Eskimos, WHWT and cairn terriers) and in cats. - Chronic course, mild signs. - Dogs (not cats) typically develop myelofibrosis and osteosclerosis, and will usually die from hemosiderosis-induced hepatic failure or bone marrow failure. - Genetic tests available. - No specific treatment -> pRBCs PRN but caution - contain iron, can facilitate hemosiderosis. - Prednisone and splenectomy potential therapy in cats, not in dogs.

Answer 122

- Cocker Spaniels and English Springer spaniels. - Chronic, well compensated hemolysis with acute bouts of hemolytic anemia associated with exertion. - Hyperventilation and alkalemia that accompany exertion or stress result in accelerated hemolysis of the alkaline-fragile erythrocytes. - Suspected based on breed and clinical course, and confirmed via genetic testing. - Excellent prognosis with environmental changes. - Acute hemolytic episodes can be managed supportively. pRBCs rarely needed.

Answer 123

- Described in both dogs and cats. - Hemolysis of variable severity - associated with RBC osmotic fragility, no immune-mediated RBC targeting. - Stomatocytes - over hydrated, "bowl" shaped RBCs - Hereditary stomatocytosis described in standard and miniature schnauzers, Alaskan Malamutes. - No specific treatment - management is palliative for anemia. - Severe osmotic fragility with resultant hemolytic anemia and splenomegaly - described in Somali, Abyssinian and Siamese cats. - Dx confirmed via osmotic fragility testing. - Steroids and splenectomy reported beneficial.

Answer 124

- Results from mechanical fragmentation of erythrocytes traversing vessels that are narrowed by fibrin deposition. - Presence of schistocytes (sheared erythrocytes) on blood smear. - Causes: DIC, hemolytic uremic syndrome, dirofilariasis and splenic torsion. - Anemia normally subclinical, but overt anemia can develop in severe cases.

Answer 125

- Severe hypophosphatemia - <1.5-2.0mg/dL - Causes hemolysis via depletion of erythrocytic ATP and GDP. - Commonly associated with referring syndrome, insulin therapy in DKA patients and excessive administration of phosphate binding drugs. - Tx: supplementation of Kph (0.03-0.06mmol/kg/h CRI over 4-6h) until serum phosphorus level are in the low-mid normal range.

Answer 126

TRUE - they have a large storage pool of mature neutrophils in their bone marrow, as well as mar- ginated neutrophils along endothelial walls, which both serve as a buffer for fluctuations in peripheral demand

Answer 127

Granulocyte-colony stimulating factor (G-CSF), GM-CSF, IL-3, IL-6, and FLT3 ligand.

Answer 128

When granulocytic precursors outnumber mature neutrophils in circulation The presence of a DLS, irrespective of the total leukocyte concentration, has been found to increase the risk of death or euthanasia in hospitalized dogs and cats

Answer 129

Describes a marked leukocytosis due to a strong inflammatory stimulus that can mimic a neoplastic response. Dogs and cats with marked neutro- philic leukocytosis (mean absolute neutrophil concen- trations of 53 798 cells/μL, and 59 046 cells/μL respec- tively) had high mortality rates

Answer 130

presence of Dohle bodies increased cytoplasmic basophilia vacuolation of the cytoplasm rarely the presence of primary granules Giantism of neutrophils and neutro- philic precursors They can be helpful in dif- ferentiating cases of inflammation (toxic changes often present) from corticosteroid/stress and epinephrine responses (toxic changes not present). The presence of toxic changes is associated with increased hospitaliza- tion time in both dogs and cats, and degree of toxicity is associated with risk of mortality in dogs

Answer 131

primary neoplasia of the bone marrow (i.e. granulocytic leukemia – very rare) or may represent a paraneoplastic response secondary to release of growth factors (e.g. GM-CSF) from a wide array of different neo- plasms: hemangiosarcoma, mast cell tumors, thymoma, ovarian carcinoma, pulmonary adenocarcinoma

Answer 132

Body response to corticosteroids (stress leukogram) * The magnitude of the neutrophilia is variable, but is frequently 15 000– 25 000 cells/μL in dogs and cats * Maximal response occurs within 8 hours, and if no further steroids are administered/ released, the count will return to normal within 24 hours * hallmark is lymphopenia Response to epinephrine * The effect is seen immediately, and resolves within 30 minutes. Conversely to corticos- teroids, epinephrine normally results in a lymphocytosis

Answer 133

Corticosteroids

Answer 134

Parvovirus Panleukopenia

Answer 135

Erythropoietin Kidney

Answer 136

Thyroxine cortisol

Answer 137

Neoplasia Anemia of inflammatory disease

Answer 138

* Bone marrow disorders (~53% of the cases) * Infectious diseases and neoplasia were most common (22% and 20%, respectively)

Answer 139

TRUE - Due to the different forms of reticulocytes in cats, the absence of identifiable reticulocytes does not exclude regeneration. Conversely, evidence of any degree of reticulocytosis on smear examination in a cat indicates an acute and pro- found regenerative response.

Answer 140

Iron deficiency or myelophthisis (Myelophthisic anemia is anemia characterized by the presence of immature erythrocytes in the peripheral blood due to infiltration of the bone marrow by abnormal tissue) If hemolysis is suspected, evaluate for evidence of oxidative damage (Heinz bodies, eccentrocytes), immune-mediated destruction (spherocytes), physical damage (schistocytes) or parasitemia.

Answer 141

Aggregate reticulocytes, in which the organelles are coalesced into aggregates, and punctate reticulocytes, in which the organelles are present as small particles. Aggregate forms are released from the marrow and, after approximately 12 hours, develop into punctate forms that persist in the circulation for 9–20 days. Aggregate forms therefore indicate active regeneration, whereas punctate forms indicate recent, cumulative regeneration

Answer 142

Acute hemorrhage or hemolysis of less than 2–4 days duration concomitant disease that precludes an appropriate bone marrow response (e.g. renal failure) immune-mediated hemolytic anemia (IMHA) in which the immune response targets red cell precursors.

Answer 143

104 days 73 days

Answer 144

Elevated sympathetic tone causes increased heart rate and myocardial contractility * decreased blood viscosity results in increased venous return and decreased left ventricular afterload, thereby increasing stroke volume --> rheological changes promoting lower systemic vascular resistance * Increased CO via NO-mediated vasodilation * redistribution of blood flow also occurs, with reduced flow to splanchnic vascular beds and associated sparing of circulation to the coronary and cerebral vasculature Non-hemodynamic compensatory mechanisms occur with chronicity: * increased 2,3-DPG concentrations (increasing DO2)

Answer 145

After the NO-mediated vasodilation, the body senses a "relative hypovolemia" which will activate the sympathetic system and RAAS

Answer 146

Polychromasia, anisocytosis, and nucleated red cells

Answer 147

flow cytometry new methylene blue

Answer 148

blood loss, typically GI

Answer 149

The red cell distribution width (RDW) indicates variation in erythrocyte size, with regenerative anemia being associated with a high RDW and non-regenerative with a low RDW.

Answer 150

Proximal humerus trochanteric fosa of the femur Iliac crest Sternal marrow aspiration using hypodermic needles

Answer 151

When performing a bone marrow aspirate, only small volumes of marrow (e.g. < 0.5 mL) are required, with larger samples risking inadvertent hemodilu- tion of the sample.

Answer 152

Aplastic anemia

Answer 153

Neutrophils

Answer 154

Idiopathic, infections (e.g. Ehrlichia canis, parvovirus, FIV, FeLV), toxins/drugs (azathioprine, procarbazine, estrogens, phenylbutazone) or immune-mediated diseases, renal disease, neoplasia

Answer 155

Characterized by immune-mediated erythrocyte precursor destruction with white cell and platelet counts being unaffected. NRIMHA classically involves destruction of later stages of erythrocyte development with a dis- tinct maturation block In contrast to peripheral IMHA, spherocytososis is uncommon, icterus is not observed, and Coombs positivity is rare. In compar- ison to peripheral IMHA, thromboembolic sequelae appear rare and thromboprophylaxis is not routinely employed

Answer 156

Leukemia Disseminated Lymphoma Malignant histiocytosis

Answer 157

Malignant histiocytosis

Answer 158

Represent a group of disorders characterized by dysplastic rather than neoplastic hematopoietic precursor development in the marrow. --> although secondary myelodysplasia associated with lymphoma, IMHA, and drug reactions has been reported.

Answer 159

Replacement of hematopoietic tissue with fibroblasts can be a primary or secondary disease entity.

Answer 160

Anemia of renal disease Anemia of inflammatory disease Hypothyroidism (mild) Hypoadrenocorticism

Answer 161

*Erythropoietin deficiency * Increased concentrations of cytokines in uremia can inhibit erythropoiesis and shorten erhytrocyte lifespan *functional iron deficiency has been reported in cats with renal disease *Uremic gastropathy causing ulceration (uncommon cause of anemia in dogs)

Answer 162

Hepcidin (the iron regulatory hormone produced by hepatocytes) inhibits the iron-exporting activity of ferroportin (which is both the hepcidin receptor and the sole cellular iron exporter through which iron is transferred to blood plasma) Inflammatory cytokines including inter- leukin-6, interleukin-1, and tumor necrosis factor-alpha may result in upregulation of the acute phase protein, hepcidin. Hepcidin promotes a state of relative iron deficiency, blunting erythropoiesis

Answer 163

Characterized by low serum iron levels (hypoferremia), but it differs from iron-deficiency anemia in that iron stores are preserved in marrow macrophages, as well as in splenic and hepatic macrophages that recycle senescent erythrocytes

Answer 164

They shorten erythrocyte lifespan

Answer 165

The long lifespan of erythrocytes buffers the consequences of decreased erythropoiesis during most acute infections. In chronic infections or inflammatory disorders, erythrocyte counts are often reduced to an anemic steady state in which the destruction of erythrocytes matches their decreased production.

Answer 166

Hepatocytes Macrophages

Answer 167

"TNF-α and interferon-γ PU.1 BFU-E *PU.1, favors myeloid differentiation •GATA1 favors erythroid differentiation •BFU-E (burst-forming unit, erythroid) --> first precursor fully committed to erythroid differentiation"

Answer 168

spherocytes on a blood smear positive saline agglutination test positive direct Coombs test

Answer 169

Spherocytes result from phagocytosis of a portion of the RBC membrane. They are recognized as microcytic, spherical erythrocytes without central pallor.

Answer 170

FALSE - Because they are hard to distin- guish from normal erythrocytes in cats, spherocytosis is not a reliable test for IMHA in this species

Answer 171

The direct Coombs test detects antibodies or complement on the erythrocyte surface.

Answer 172

thrombocytopenia serum bilirubin concentration >5 mg/dL increased BUN presence of band neutrophils prolongation of PT or PTT evidence of a hypocoagulable state via TEG hypoalbuminemia increased ALT and ALP

Answer 173

Caused by alloantibodies directed against non-self erythrocyte antigens. Alloantibodies can occur naturally, or following sensitization hemolytic transfusion reactions neonatal isoerythrolysis

Answer 174

Usually seen in cats when a type A or type AB kitten is born to a type B queen. NI does not occur in utero because cats have endotheliochorial placentation. However, type B queens secrete anti-type A antibodies in their colostrum and milk, which can be absorbed by neonatal kittens for the first 16 hours of life. Kittens are born healthy but develop hemolysis at a few days of age, and rarely live more than 1 week.

Answer 175

Leads to denaturation of hemoglobin, resulting in Heinz body formation * Heinz bodies (HB) result in erythrocyte rigidity and resultant shortened lifespan RBC membrane damage oxidation of ferrous iron to the ferric form, resulting in methemoglobinemia

Answer 176

Zinc toxicity

Answer 177

Calcium disodium EDTA

Answer 178

Mycoplasmosis *Mycoplasma haemofelis Cytauxzoon felis Babesiosis Erlichia

Answer 179

Pyruvate kinase (PK) deficiency PK --> typically has a chronic course, with mild clinical signs. Dogs, but not cats, with PK deficiency frequently develop myelofibrosis and osteosclerosis, and will usually die from hemosiderosis-induced hepatic failure or bone marrow failure Breeds: basenjis, beagles, dachshunds, toy Eskimos, West Highland white terriers, and cairn terriers and in cats Phosphofructokinase (PFK) deficiency --> characterized by chronic, well-compensated hemolysis with acute bouts of hemolytic anemia associ- ated with exertion. The hyperventilation and alkalemia that accompany exertion or stress result in accelerated hemolysis of the alkaline-fragile erythrocytes. Breeds: cocker spaniels and English springer spaniels

Answer 180

Stomatocytes are overhydrated, “bowl”-shaped RBCs. Hereditary stomatocytosis --> erythrocyte membrane defect

Answer 181

Microangiopathic hemolysis schistocytes (sheared erythrocytes) on blood smear DIC, hemolytic uremic syndrome, dirofilariasis, and splenic torsion

Answer 182

Severe hypophosphatemia (<1.5–2.0 mg/dL) causes hemolysis via depletion of erythrocytic ATP and DPG. It is most commonly associated with refeeding syndrome, insulin therapy in patients with DKA, and excessive administration of phosphate-binding drugs

Answer 183

Methemoglobinemia (>20%)

Answer 184

1. Prominent spherocytosis (only dogs --> feline erythrocites do not consistently display central pallor) ** A threshold of ≥5 spherocytes/×100 oil immersion field therefore could be considered supportive of a diagnosis of IMHA, but 3-4 spherocytes/×100 oil immersion field also may be consistent with IMHA provided no other cause of spherocytosis is identified 2. Positive SAT without washing * Saline agglutination testing performed by mixing 4 drops of saline with 1 drop of blood has a reported specificity of 100% (95% CI, 95%-100%)c for IMHA in dogs * To decrease false positives, confirming that agglutination persists after washing erythrocytes 3 times in a 1:4 ratio with saline is recommended for animals with equivocal results 3. Demonstration of anti-erythrocyte antibodies: Positive DAT (Direct antiglobulin test) or FC (Flow cytometry) * Collect sample before start treatment At least 2 of these have to be present…..OR: 1. Positive SAT after washing

Answer 185

Oxidative damage envenomation Piruvate k deficitency fragmentation diserythropoiesis hypersplenism

Answer 186

1. Spherocytosis 2. Hyperbilirrubinemia: * At least 1 of the following is considered sufficient evidence for hyperbilirubinemia: icterus, total serum or plasma bilirubin concentration above reference interval, bilirubinuria in cats, or ≥2+ bilirubin on a urine reagent strip in dogs 3. Hemoglobinemia/hemoglobinuria * by visual examination of plasma or measurement of cell-free hemoglobin 4. Erhythrocyte ghosts

Answer 187

Piroplasms (Babesia gibsoni) (high evidence) Anaplasma phagocytophilum and A. platys (low evidence)

Answer 188

Hemotropic Mycoplasma haemofelis (high evidence) Babesia felis (intermediate level of evidence) Feline leukemia (low evidence)

Answer 189

FALSE - Routine testing for pancreatitis in dogs and cats with IMHA is not recommended, unless clinical presentation suggests that it is a credible differential diagnosis

Answer 190

- We propose a unified model for the pathogenesis of IMHA and a new system of nomenclature, in which the disease is categorized as “non-associative” and “associative” rather than “primary” and “secondary,”. - This clarification is needed because the word “primary” implies that all triggers have been definitively ruled out, whereas “secondary” implies causation. - We propose that the term “associative” be used when a comorbidity is identified. In some cases, the comorbidity might have caused the IMHA (secondary IMHA), whereas in others it might be coincidental (primary IMHA). - “Non-associative” IMHA cases are those in which comorbidities are not identified in the diagnostic evaluation, and include primary (“idiopathic”) and cryptogenic cases. - The latter implies that an underlying cause was not identified, perhaps because the underlying pathomechanisms are not currently understood, or the comorbidity could not be detected using available testing.

Answer 191

Dogs with IMHA typically are euvolemic, making pRBC preferable to whole blood because the plasma provides no added benefit, increases the risk of volume overload, and may increase the risk of transfusion reaction. Fresh pRBC, ideally no older than 7-10 days, are recommended for use in dogs with IMHA. If these are not available, older units may be used but may be associated with a greater risk of complications and increased mortality

Answer 192

BHS scavenge nitric oxide, potentially activating platelets and causing vasoconstriction, which increases risk of hypertension. BHS exert a greater colloid osmotic (oncotic) pressure than do RBCs, increasing the risk of intravascular volume expansion and hypertension. Transfused RBCs also are likely to have a longer circulating half-life than BHS, although the half-life of transfused RBCs is difficult to estimate in dogs with active hemolysis BHS could be administered if pRBC or whole blood are not available. However, BHS currently is unavailable in many countries, including the United States

Answer 193

In particular, we suggest treating with 2 immunosuppressive drugs in the following situations: * The dog has clinical features at presentation consistent with severe or immediately life-threatening disease. * The PCV/Hct does not remain stable, with an absolute decrease of ≥5% within 24 hours, during the first 7 days of treatment with a glucocorticoid * The dog has continued to be dependent on blood transfusions after 7 days of treatment * The dog develops or, based on previous treatment, is expected to develop severe adverse effects related to the use of glucocorticoids at any time during its treatment. This is of particular relevance for dogs >25 kg in body weight.

Answer 194

serum bilirubin urea concentrations

Answer 195

Azathioprine: 2 mg/kg q24h. After 2-3 weeks, the dosing interval may be increased to every other day until treatment is discontinued. Cyclosporine: 5 mg/kg PO q12h. Mycophenolate mofetil: 8-12 mg/kg PO q12h Leflunomide: 2mg/kg PO q24h

Answer 196

Cyclophosphamide

Answer 197

Administration of IV immunoglobulin (IVIG) at a dosage of 0.5-1 g/kg as a single infusion may be considered as a salvage measure in dogs not responding to treatment with 2 immunosuppressive drugs, but we do not recommend it for routine treatment

Answer 198

3-6 months 4-8 months

Answer 199

Azathioprine * Severe Hepatotoxicity (idiosyncratic) --> reversible increase in ALT activity in the absence of clinical signs --> occurs in approximately 15% of German Shepherd dogs and may be more common in German Shepherds.--> usually develops in the first few weeks of treatment; if the drug is well tolerated for the first 2 to 4 weeks, it tends to be well tolerated in the long-term. * Severe Myelosuppresion (idiosyncratic) --> causes mild to moderate poorly regenerative anemia --> can be delayed and occur months into treatment * GI signs --> usually self limited Cyclosporine * Gingival overgrowth * Hypertricosis * Hepatotoxicity (idiosyncratic - rare) * GI signs Mychophenolate mofetil * ulcerative colitis * Reported prevalence of diarrhea can be ≥20%, and may be delayed for 1-2 weeks after starting treatment. * myelosuppresion Leflunomide *cutaneous drug reactions, hepatotoxicity, and pulmonary lesions (as found in human patients) may be recognized in dogs in the future. * The most common adverse effects reported with leflunomide administration in dogs are occasional inappetence, lethargy, vomiting, and diarrhea

Answer 200

1000 and 3000 cells/μL <1000 cells/μL

Answer 201

Recombinant granulocyte colony stimulating factor

Answer 202

1. Evaluate for trigger factors 2. Perform Therapeutic drug monitoring (TDM) 3. IVIG Always consider: *Diagnostic confidence * Drug dose * Client compliance *Poor GI absorption *Administration with food

Answer 203

Recommend that immunosuppressive and antithrombotic medications be stopped or their dosage decreased to a minimum before surgery is undertaken

Answer 204

We recommend that thromboprophylaxis be provided for all dogs with IMHA, except those with severe thrombocytopenia (platelet count <30 000/μL)

Answer 205

Based on the pathophysiology of venous thromboembolism commonly encountered in dogs with IMHA, we suggest that a regimen incorporating anticoagulants may be preferred for thromboprophylaxis, particularly during the first 2 weeks after diagnosis. The available anticoagulants may be used alone or combined with antiplatelet drugs. If treatment with an anticoagulant, and its associated monitoring, is not available or feasible, we suggest administration of antiplatelet drugs in preference to no antithrombotic drug. Weak recommendations: * We suggest the administration of unfractionated heparin (UFH) with individual dose adjustment (using an anti-Xa assay) in preference to other drugs. This drug should not be used without individual dose adjustment. If this is not available or feasible, we suggest administering injectable low-molecular-weight heparins or direct PO Xa inhibitors. When using injectable low-molecular- weight heparins, we suggest individual dose adjustment (using an anti-Xa assay) may be useful to achieve a therapeutic dose * If antiplatelet drugs are administered, we suggest that clopidogrel be used in preference to aspirin

Answer 206

The acetylcholine receptor (AChR) muscle specific kinase (MUSK)

Answer 207

1. Focal * defined as weakness in ≥1 focal skeletal muscle group that does not involve the appendicular skeletal muscles. These focal skeletal muscle groups are the facial, esophageal, pharyngeal, and laryngeal skeletal muscles 2. generalized * appendicular skeletal muscle weakness, which can range from mild to severe, with or without facial, esophageal, pharyngeal, or laryngeal skeletal muscle involvement 3. Acute Fulminant * acute, rapidly progressive and very severe form of generalized MG frequently but not necessarily causing respiratory failure and death

Answer 208

MG--> characterized by autoantibodies against the NMJ, with a reported onset from 6 months of age onwards CMS --> no autoimmunity against the NMJ is present (antibodies for AChRs is negative), with reported onset in the first weeks to months of life, and a genetic basis is generally identified or suspected

Answer 209

Paraneoplastic syndrome AChR striational autoantibodies against titin and the ryanodine receptor

Answer 210

Methimazole is a thioureylene antithyroid agent that inhibits formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin. This process take place by interfering with oxidation of iodide ion and iodotyrosyl groups through inhibition of the peroxidase enzyme. However, it does not affect the thyroid gland’s ability to trap inorganic iodide or release preformed hormones (T3 and T4).

Answer 211

Criteria: * general and neurological examination, pharmacologic, and electrophysiologic findings consistent with MG * normalization of clinical signs after acetylcholinesterase inhibitor (AChE-I) treatment * serum AChR autoantibody testing by radioimmunoassay being negative at least twice **Acetylcholine receptor autoantibody testing by radioimmunoassay is negative in approximately 2% of dogs with generalized MG and they are referred to as seronegative.

Answer 212

Positive NMJ autoantibody testing by measurement of AChR autoantibody concentration using radioimmunoassay * An AChR antibody titer >0.6 nmol/L is diagnostic for MG in dogs

Answer 213

* skeletal muscle weakness and fatigability * pharmacological testing and electrophysiology * presence or absence of a cranial mediastinal mass * thiourylene medication administration in cats

Answer 214

3.4% and 52%, respectively.

Answer 215

"1. acetylcholinesterase inhibitors (AChE-Is) 2. Immunosuppression 3. Supportive care * Tx for aspiration pneumonia * Plasmapheresis * IVIG * Assisted ventilation * plasmapheresis and IV immunoglobulins are used for the management of myasthenic crises for all subgroups Order would vary if it's a dog or a cat: DOGS start symptomatic treatment, usually with pyridostigmine and then add immunosuppression, usually with prednisolone if clinical remission is not achieved with symptom- atic treatment alone is a suggested approach (obtained from human medicine) --> given the high incidence of megaesophagus and therefore risk of aspiration pneumonia ** corticoids also can transiently worsen muscle weakness in MG by causing corticosteroid myopathy ** For mild disease, anticholinesterase agents and altered feeding procedures may be suffi- cient. For more severe disease, early use of immune suppressants or immunomodulators (a substance that has some effect on the immune system) may be required CATS cats are suggested to be more prone to the adverse effects of AChE-Is. Furthermore, immunosuppression with corticosteroids is thought to be more beneficial, and cats appear more tolerant to the adverse effects of corticosteroids, unlike dogs, which often experience exacerbation of their skeletal muscle weakness

Answer 216

Clinical remission is defined by the resolution of clinical signs of MG, whereas immune remission is defined by the resolution of clinical signs in conjunction with discontinuation of treatment and normalization of serum AChR autoantibody concentration

Answer 217

Immune remission is frequent and hence treatment often can be discontinued Long-term outcome is usually excellent if the dog does not succumb to aspiration pneumonia or respiratory failure before achieving immune remission

Answer 218

Yes * In focal and generalized thymoma-associated MG in dogs, anecdotal evidence suggests that a complete thymectomy is necessary for these patients to achieve immune remission * thymomas can occupy a large amount of space in the thorax, invade local tissues, metastasize to other organs, or induce hemothorax which might result in death No * A major caveat to thymectomy however is the requirement for general anesthesia which is a substantial risk for dogs and cats with MG, and the surgery itself can cause a clinically relevant postoperative exacerbation of skeletal muscle weakness and fatigability, which is thought to be the result of surgical stress

Answer 219

40% to 60% 15%

Answer 220

Pre-synaptic, synaptic, postsynaptic and concurrent pre and postsynaptic the suggested classification (based on the human medicine classification) is --> 1. according to the affected NMJ component 2. the mechanism of the defect of neuromuscular transmission 3. the affected protein 4. ultimately the mutated gene

Answer 221

T- lymphocyte CD41 T (helper) lymphocytes

Answer 222

30% to 50%

Answer 223

In contrast to people and cats, dogs are prone to megaesophagus because the canine esophagus contains more skeletal muscle than smooth muscle.

Answer 224

Severe hypoglycemia diabetic neuropathy electrolyte abnormalities such as hypokalemia and hyperkalemia Other myopathies or neuropathies (polyradiculoneuritis or polymyositis) endocrine disorders (hypoadrenocorticism, hypothyroidism) tick paralysis botulism organophosphate toxicity

Answer 225

Type II (cytotoxic - mediated by autoantibodies)

Answer 226

Ultra-short acting anticholinesterase agent, edrophonium chloride. A positive response is defined as a temporary increase in muscle strength 0.1–0.2 mg/kg IV in dogs No improvement in muscle strength does not exclude a diagnosis of MG Dogs with generalized MG often have a positive response to the edrophonium response test while fulminant MG dogs typically do not. Fulminant dogs may not have enough AChRs available to elicit a noticeable response

Answer 227

Enzyme located near the AChR. MuSK induces acetylcholine clustering at the postsy- naptic membrane Some antibody-negative MG in people is associated with autoantibodies against the enzyme, MuSK One seronegative myasthenic dog has been documented with autoantibodies against MuSK.

Answer 228

Weakness, abdominal pain, hypersalivation, and diarrhea, Bradycardia can be seen due to excessive vagal activity

Answer 229

Pyridostigmine bromide --> preferred in most clinical situations because of its longer duration of action and fewer GI side effects. neostigmine bromide

Answer 230

Immunosuppressant drugs used for treatment of MG essentially belong to 3 general groups based on varying mechanisms of actions: inhibitors of the cell cycle, immunosuppressors of T cells, and B-cell depleters. Drugs that interfere with the cell cycle block both T and B cell proliferation and exhibit their effects on the resting (G1) and DNA synthesis (S) phases of the cell cycle. Those that suppress T cells, such as cyclosporine, act specifically in the T cells on specific sites and receptors The drugs that inhibit the cell cycle include leflunomide, azathioprine, cyclophosphamide, and mycophenolate mofetil (MMF). Glucocorticoids, cyclosporine, and tacrolimus are immunsuppressors of T cells Rituximab depletes B cells.

Answer 231

ABCB1-1Δ (MDR-1)

Answer 232

lower body weight Diagnosis of lymphoma administration of doxorubicin or vincristine

Answer 233

Lymphoma is the most common cause of HM in dogs and generally is associated with the cranial mediastinal form or other intermediate to high-grade T-cell variants.

Answer 234

Anal sac apocrine gland adenocarcinoma multiple myeloma Thymoma thyrod carcinoma SCC Mamary gland carcinoma/adenocarcinoma melanoma primary lung tumors bone tumors chronic lymphocytic leukemia histiocytic sarcoma Parathyroid gland tumors

Answer 235

Other mechanisms include the production of prostaglandins, osteoclast activating factor (OAF), and receptor activator of nuclear factor kappa-B ligand (RANKL), which is a type II membrane protein which plays a role in the control of control bone regeneration and remodeling, activation of vitamin D, and direct tumor osteolysis.

Answer 236

Nephrogenic diabetes insipidus -hypercalcemia can cause renal tubular insensitivity to antidiuretic hormone (ADH).

Answer 237

Sodium and calcium utilize a similar renal reabsorptive mechanism, so providing additional sodium to renal tubules will diminish calcium reabsorption and increase calciuresis.

Answer 238

Glucocorticoids are effective at controlling hypercalcemia via inhibition of osteoclast activating factor, prostaglandins, and vitamin D, promoting calciuresis.

Answer 239

Higher stage lymphomas (stage IV hepatic and splenic involvement and stage V bone marrow involvement)

Answer 240

The syndrome is a result of massive cancer cell death releasing cellular components, leading to hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia. The ensuing hyperkalemia may lead to cardiac or muscular abnormalities and can be life-threatening. This syndrome generally manifests within the 48 hours following therapy. Malignant lymphocytes have four times as much phosphorus as normal lymphocytes and the ensuing hyperphosphatemia results in hypocalcemia due to precipitation of calcium phosphate in the renal tubules and other tissues. Hypocalcemia can cause tetany, muscle cramps, and seizures. A calcium supplement may be required. Large volumes of purines (adenine and guanine) are then released and converted to uric acid via the purine degradation pathway and excreted in the urine. With the high concentrations of uric acid generated by tumor lysis, uric acid may precipitate as monosodium urate crystals and can result in an acute uric acid nephropathy and subsequent acute kidney failure.

Answer 241

Tissue factor (TF) and cancer procoagulant (CP)

Answer 242

Pericardectomy is also possible via either thoracoscopy or thoracotomy and may relieve signs of tamponade, but has not been shown to prolong survival.

Answer 243

1. Hypercalcemia of malignancy 2. hypoglycemia 3. Polycytemia 4. anemia 5. thrombocytopenia 6. coagulopathy/DIC 7. Hypertrophic osteopathy 8. Fever

Answer 244

hepatocellular carcinomas lymphoma/leukemia gastrointestinal leiomyoma/leiomyosarcoma plasmacytoid tumors oral melanoma mammary carcinoma hemangiosarcoma renal adenocarcinoma **due to production of other factors such as insulin-like growth factors (IGFs), accelerated glucose utilization by the tumor or failure of hepatic gluconeogenesis and/or glycogenolysis.

Answer 245

Abdominal ultrasound detects about 40% while CT detects closer to 75% of the tumors

Answer 246

Absolute, secondary and inappropiate * Polycythemia (>55% for a dog and >50% in a cat) may be relative (dehydration) or absolute. Absolute polycythemia can be either primary or secondary. Primary polycythemia is polycythemia vera, a myeloproliferative disease. Secondary polycythemia may be appropriate, in cases of hypoxia, or inappropriate, which is consistent with a PNS.

Answer 247

Excessive erythropoietin (EPO) production by the tumor, kidney hypoxia with subsequent EPO release, production of an EPO-related hormone, or changes in EPO metabolism

Answer 248

Renal carcinoma, renal lymphoma, nasal fibrosarcoma, and renal fibrosarcoma

Answer 249

The preoptic area of the anterior hypothalamus (AH).

Answer 250

Changes in ambient and core body temperatures are sensed by the peripheral and central thermoreceptors, and information is conveyed to the AH via the nervous system. The thermoreceptors sense that the body is below or above its normal temperature (set point) and subsequently cause the AH to stimulate the body to increase heat production and reduce heat loss through conservation if the body is too cold or to dissipate heat if the body is too warm.

Answer 251

Hyperthermia

Answer 252

True fever is a normal response of the body to invasion or injury and is part of the acute-phase response. The term fever is reserved for those hyperthermic animals in whom the set point in the AH has been reset to a higher temperature. In hyperthermic states other than fever, temperature elevation is not a result of the body attempting to raise its temperature but is due to the physiologic, pathologic, or pharmacologic changes that cause heat gain to exceed heat loss.

Answer 253

increased neutrophil numbers increased phagocytic ability enhanced T and B lymphocyte activity increased acute-phase protein production by the liver increased fibroblast activity increased sleep.

Answer 254

interleukin 1, interleukin 6, and tumor necrosis factor α are considered the most important fever- producing cytokines.

Answer 255

Exogenous pyrogens stimulate production of endogenous pyrogens (Macrophages are the primary immune cells involved, although T and B lymphocytes and other leukocytes may play sig- nificant roles.) --> endogenous pyrogens travel to AH where they bind to the vascular endothelial cells within the AH and stimulate the release of prostaglandins (PGs), primarily PGE2 and possibly PGF2α . The set point is raised and the core body temperature rises through increased heat production and conservation.

Answer 256

Hyperpyrexic syndrome is associated with moderate to severe exercise in hot and humid climates. This syndrome may be more common in hunting dogs or dogs that “jog” with their owners. In humid environments, evaporative cooling via panting is minimal. In addition, heavy exercise may lead to vasodilation and increased blood flow to skeletal muscles but vasoconstriction of cutaneous vessels, thus compromising peripheral heat loss.

Answer 257

Disturbed calcium metabolism pharmacologic agents such as inhalation anesthetics (especially halothane) and muscle relaxants such as succinylcholine.

Answer 258

Dantrolene sodium MOA = muscle relaxant --> acts by binding to the ryanodine receptor to depress excitation-contraction coupling in skeletal muscle.

Answer 259

Hyperthyroidism and pheochromocytoma can lead to an increased metabolic rate or vasoconstriction, resulting in excess heat production, decreased ability to dissipate heat, or both. These conditions rarely lead to severe hyperthermia that requires total body cooling.

Answer 260

Benefits * hyperthermia may inhibit viral replication, increase leukocyte function, and decrease the uptake of iron by microbes (which is often necessary for their growth and replication). Detriments * increases tissue metabolism and oxygen consumption, thus raising both caloric and water requirements * hyperthermia leads to suppression of the appetite center in the hypothalamus but usually not the thirst center * Animals that have sustained head trauma or a cerebrovascular accident may suffer more severe brain damage if coexisting hyperthermia is present * Body temperatures above 107° F (41.6° C) often lead to increases in cellular oxygen consumption that exceed oxygen delivery, resulting in deterioration of cellular function and integrity

Answer 261

Body temperatures above 107° F (41.6° C) often lead to increases in cellular oxygen consumption that exceed oxygen delivery, resulting in deterioration of cellular function and integrity *DIC * cerebral edema * arrhythmias * liver (hypoglycemia, hyperbilirubinemia) * gastrointestinal tract (epithelial desquamation, endotoxin absorption, bleeding) * kidneys (acute kidney injury)* hypoxemia, hyperkalemia, skeletal muscle cytolysis, tachypnea, metabolic acidosis, tachycardia, tachypnea, and hyperventilation Exertional heat stroke and malignant hyperthermia may lead to severe rhabdomyolysis, hyperkalemia, hypocalcemia, myoglobinemia, and myoglobinuria and elevated levels of creatine phosphokinase

Answer 262

TRUE - This may result in a further increase in metabolic rate, oxygen consumption, and subsequent water and caloric requirements. Unless a fever is life threatening, this type of nonspecific therapy is counterproductive.

Answer 263

FXII Kallikrein Kallikrein Bradykinins

Answer 264

classic pathway Molecules --> immunoglobulin E receptors, mast cells, basophils, histamine, prostaglandins, leukotrienes, serotonin, and platelet-activating factor. alternative pathway IgG, Fcγ, macrophages, and platelet-activating factor Pathophysiology

Answer 265

PAF, rather than histamine, is primarily responsible for the development of shock in the alternative pathway

Answer 266

With previous sensitization, IgE is produced and bound to the cell surface of mast cells and basophils by high-affinity receptors for the Fc portion of the immunoglobulin (FcεRIs). With repeated exposure, the antigen causes crosslinkage of two IgE molecules, and the cell is activated to release the anaphylaxis mediators: histamine, heparin, tryptase, kallikreins, proteases, proteoglycans, eosinophilic chemotactic factor of anaphylaxis, and neutrophil chemotactic factor of anaphylaxis

Answer 267

Immunoglobulin E [IgE] IgG, IgM immune complex mediated (IgG, IgM complex) T lymphocyte

Answer 268

(1) immune-mediated inactivation/activation reactions involving biologically active molecules (2) antibody-mediated cytotoxic or cytolytic reactions (3)immune complex reactions (4) allergic reactions (5) T lymphocyte– mediated cytotoxicity (6) delayed hypersensitivity reactions (7) granulomatous reactions

Answer 269

TRUE -situation in which antigen-specific IgE and IgG are both present and there is more IgG than IgE. In this situation, antigen is likely to bind to IgG in blood or lymph before it can bind to mast cell–associated IgE.

Answer 270

H1 * Skin (angioedema, pruritus), smooth muscle bronchoconstriction * activation results in rhinitis, pruritus, and bronchoconstriction, and convertion of L-arginine into NO by endothelial cells * mediates coronary artery vasoconstriction and cardiac depression --> inotrophy and chronothropy inhibition H2 * mediates gastric acid production * inhibits duodenum bicarb release (creates a very acid enviroment) * when stimulated, produce coronary and systemic vasodilation and increases in HR and ventricular contractility H3 * They inhibit endogenous norepinephrine release from sympathetic nerves * Activation accentuates the degree of shock (compensatory neural adrenergic stimulation is blocked) H4 * plays a rol in chemotaxys and inflammatory cytokines production

Answer 271

Phospholipase A2

Answer 272

seconds to minutes minutes hours

Answer 273

A relative hypovolemia occurs as up to 50% of the circulating volume is lost into the tissues by the sudden increase in vascular permeability.

Answer 274

Stimulation of β-adrenergic receptors enhances the production of adenyl cyclase and subsequent conversion of adenosine triphosphate to cyclic adenosine monophosphate. The cAMP system inhibits the antigen-induced release of histamine and other anaphylactic mediators.

Answer 275

PROS * Alpha-1 adrenergic stimulation is responsible for potent vasoconstriction of the small arterioles, which can have life-saving cardiovascular effects. Furthermore, the vasoconstriction decreases mucosal edema and helps relieve upper airway obstruction. * Beta-2 effects further alleviate respiratory signs by increased bronchodilation and decreased histamine release, while beta-1 adrenergic effects increase cardiac contractility * * The cAMP system inhibits the antigen-induced release of histamine and other anaphylactic mediators. * In a canine ragweed anaphylactic shock model, epinephrine was effective in attenuating the circulatory collapse only when given by continuous IV infusion. * Although ineffective for treatment of cardiovascular collapse, single IV or IM boluses may be beneficial for bronchoconstriction and laryngeal edema * Epinephrine acts in part by phosphorylation and inactivation of the PAFr --> so if you can give epi early on (before all the mediators get produced) --> reduced morbidity/mortality (in humans) *Epi can help with capillary leak syndrome by mediating formation of cAMP (reversing the effects of the Ca/calmodulin/myosin kinase pathway) CONS * In contrast to these findings in human medicine, distributive shock in canine anaphylaxis may be due to pooling of venous blood in the hepatic circulation and the use of epinephrine as a first-line treatment is controversial * Results of the canine ragweed model suggest that in the treatment of anaphylaxis, once the mediators have been released, epinephrine acts primarily as a vasopressor in augmenting hemodynamic recovery and has no special pharmacologic properties that improve immunologic recovery * progressively less effective with time

Answer 276

TRUE - Subcutaneous administration is not recommended due to potent vasoconstriction and unpredictable absorption in states of anaphylactic shock.

Answer 277

1. Glucagon --> has inotropic, chronotropic, and vasoactive effects that are independent of β-receptors and causes endogenous catecholamine release (airway protection must be ensured because glucagon frequently causes emesis) Human patients taking β-blockers have an increased incidence and severity of anaphylaxis and can develop a paradoxic reaction to epinephrine.

Answer 278

Although they are not useful during the acute phases of anaphylaxis, H1 and H2 antihistamines are frequently administered after epinephrine to reduce pruritus and gastric acid secretion

Answer 279

Glucocorticoids block the arachidonic acid cascade and may reduce the severity of the late-phase reaction. *beneficial effects are not seen for at least 4 to 6 hours * glucocorticoids themselves may cause allergic reactions and even anaphylaxis

Answer 280

IL4 participates in the activation of the transcription factor STAT6, which increases responsiveness to several mast cell– and macrophage- generated mediators, including histamine, PAF, serotonin, and leukotriene C4

Answer 281

Inhibits the vasodilation that occurs via NO, usually used in refractory cases not responding to epinephrine.

Answer 282

Vaccine-proteins Venoms (insect and reptile) and antivenoms HW disease (report of a case during surgery of lung lobectomy and accidental disecction of an adult worm) Blood products Radiographic contrast agents Medications *NSAIDS *Corticosteroids (report after low dose dex-suppresion test) * antibiotics (cephalosporines...) * Vit K IV * opioids * Triple ab ophtalmic ointment (cats) Heat/cold Food

Immunology / hemolymphatics Flashcards

Physiology (1 -> 60) - from Ninjanerd videos / notes and VECCademy power point - try to study in order