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PHCOL 401 > Quiz #7 (12/2-12/7) > Flashcards

Quiz #7 (12/2-12/7) Flashcards

1
Q

Functions of blood

A

Functions to transport substances to tissues including oxygen, nutrients, hormones, leukocytes, red cells and platelets. Also functions to remove waste from the body including carbon dioxide and nitrogenous waste products

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2
Q

RBCs

A

for oxygen delivery. There are between 2-3 X10^13 RBC in the body and about 2X10^11 new RBC are made each day

Hemoglobin are > 90% of RBC weight

Hemoglobin binds heme (porphyrin) groups that are complexed with iron (oxygen binding)

Hemoglobin A (adult) is a tetramer of 2 alpha, and 2 beta subunits

Hemoglobin F (fetal) is a tetramer of 2 alpha and 2 gamma subunits. Fetal hemoglobin has a higher binding affinity for oxygen because fetus needs oxygen from mother

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3
Q

RBC:WBC: platelets

A

should be close to 600:1:15

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4
Q

Anemia

A

deficiency of red blood cells or hemoglobin in blood. Never is normal and is generally a major sign of disease. Most common cause is an insufficient supply of iron, vitamin B12/cobalamin or folate

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5
Q

Kinetic approach to anemia

A
  1. Decreased RBC production: lack of nutrients, bone marrow disorders or suppressions (drugs, chemotherapy, etc), or low levels of trophic hormones (EPO)
  2. Increased RBC destruction: Anemia occurs when the bone marrow is unable to keep up with the need to replace more than about 5% of the RBC mass per day
  3. Blood loss: surgery, ulcer, cancer, internal bleeding and excessive blood draws
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6
Q

Morphologic approach to anemia

A

Based on cell size

  1. Macrocytic (large RBC) anemia: Can be caused by folate and/or vitamin B12 deficiency, lack of intrinsic factor or by drugs that interfere with DNA synthesis
  2. Microcytic (small RBC) anemia: Is a decreased hemoglobin content within the RBC. Can be caused by iron deficiency (most common), disorders of heme biosynthesis or reduced hemoglobin production (thalassemias)
  3. Normocytic (normal RBC) anemia: Can be caused by renal disease or cancer
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7
Q

Iron

A

absorbed in the duodenum

Once in blood stream is carried by transferrin to erythroid precursors for synthesis of hemoglobin

Iron storage is in the liver

Iron can also be reclaimed from RBC

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8
Q

Folic acid

A

: absorbed in jejunum. Involved in DNA synthesis

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9
Q

B/12 and intrinsic factor

A

: absorbed in ileum. Important in SAM formation which donates methyl groups and causes DNA methylation which controls gene expression.

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10
Q

Hereditary hemolytic anemia causes

A

has a genetic link

  1. Abnormal shape: hereditary spherocytosis
  2. Abnormal hemoglobin: hemoglobin S replaces hemoglobin A (sickle hemoglobin in sickle-cell anemia)

3 .Defective hemoglobin synthesis: thalassemia minor and major; globin chains are normal but synthesis is defective

4 .Enzyme defects: glucose-6-phosphate dehydrogenase (G6PD) deficiency predisposes to episodes of acute hemolysis, allergy to sulfa drugs, fava beans. Variable in society

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11
Q

Sites of hematopoiesis

A

Prenatal: yolk sac, liver and bone marrow (later right before birth)

Postnatal: skeleton. vertebral and pelvis are the major then sternum and ribs

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12
Q

Blood development lineages

A

Lymphoid lineages: Plasma cells, CTL and helper T cells. IL-7 is a common cytokine

Myeloid lineages: Erythrocytes (EPO), Platelets (IL-11 and Tpo), basophils, eosinophils (GM-CSF), neutrophils (G-CSF and GM-CSF) and macrophages (GM-CSF)

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13
Q

Erythropoietin (Epo)

A

Stimulates erythroid proliferation and differentiation in red cell progenitors in bone marrow.

Feedback control of RBC production is through Epo. This is necessary to prevent death and promote proliferation of committed precursors. Feedback shifts non-committed progenitor cells into the erythroid lineage. Feedback targets CFU-Es by upregulating their production as well as stabilizing these cells.

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14
Q

HIF-1

A

is a heterodimeric transcription factor that binds hypoxia-response elements that are associated with a broad range of transcriptional targets, particularly Epo.

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15
Q

HIF-1 control of EPO

A

Normal oxygen levels (normoxia): HIF-1 isn’t needed. hydroxylation causes HIF-1alpha to be either degraded by the proteasome or can be blocked from recruiting a transcriptional coactivator, p300.

Hypoxia (lack of oxygen): HIF-1alpha is stabilized and can activate Epo production. Epo increases production of RBC

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16
Q

MOA EPO

A
  1. hemaopoietic factors interact with membrane receptors of the cytokine receptor super family
  2. Binding of cytokines (like EPO) to their receptors (like EPOR) phosphorylates and activates JAK
  3. Activated JAKs phosphorylates STAT proteins, which dimerize and translocate to the nucleus.
  4. In the nucleus, STATS act as transcription factors to bind to regulatory elements in the genome to activate gene transcription.
  5. Regulation: SOCS (suppressor of cytokine signaling) proteins, protein phosphatases, ubiquitination and degradation of JAK, and PIAS (protein inhibitor of activated STAT)
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17
Q

Therapeutic Uses of Epo

A
  1. Anemia caused by chronic kidney disease: Target hematocrit range is 30-36%
  2. Anemia caused by cancer treatment: Used previously but recent studies have shown an increased risk of death and tumor growth in chemo patients taking anti-anemia drugs
  3. Anemia in critically ill patients: Not used anymore because recent studies have found no benefit and high risk of thrombosis associated with use.
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18
Q

Blood doping

A

history of abuse in endurance sports including cycling, rowing, distance running, and cross country skiing. Some studies show there is lack of evidence for efficacy because your oxygen transport is already optimized. Epo has not been shown to boost RBC in these people.

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19
Q

Adverse effects of EPO

A

Associated with an increased risk of hypertension in patients with kidney disease

Caution in cancer patients receiving chemotherapy because the risk of stroke and increased death related to malignancy may outweigh any potential benefit of erythropoietin in the absence of severe anemia.

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20
Q

GM-CSF

A

stimulates the proliferation and differentiation of myeloid cell lineages including monocytes, macrophages, neutrophils and eosinophils. It is secreted by macrophages, T cells, mast cells, endothelial cells and fibroblasts

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21
Q

Sargramostim

A

recombinant GM-CSF

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22
Q

G-CSF

A

enhances phagocytic and cytotoxic activities of neutrophils, with little effect on monocytes, macrophages and eosinophils. More selectivity, better tolerated. Produced by endothelial cells, macrophages, and a number of other immune cells.

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23
Q

Filgrastim

A

recombinant C-CSF

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24
Q

Therapeutic uses of G-CSF and GM-CSF

A
  1. Treat neutropenia, which is an abnormally low number of neutrophils.
  2. Neutropenia is common in cancer patients after chemotherapy, AIDS patient and bone marrow transplantation patients.
  3. Also used in autologous stem cell transplantation with patients that undergoing high-dose chemotherapy with extreme myelosuppression. Before chemotherapy, hematopoietic stem cells are mobilized from bone marrow into peripheral blood by treatment with G-CSF, GM-CSF and collected with apheresis. Myelosuppression is counteracted by re-infusion of patient’s own HSC after chemotherapy
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25
Q

Side effects of G-CSF and GM-CSF

A

GM-CSF: fevers, malaise, arthralgias (joint pain), myalgias, and capillary leak syndrome characterized by peripheral edema and pleural or pericardial effusions. Allergic reactions can also occur

G-CSF: bone pain which clears upon discontinuation. Much better tolerated

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26
Q

IL-11

A

stimulates the proliferation and differentiation of megakaryocytes and platelets.

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27
Q

Oprelvekin

A

Recombinant IL-11

28
Q

Thrombopoetin (Tpo)

A

stimulates the proliferation and differentiation of megakaryocytes and regulates downstream production of platelets.

29
Q

Romiplostim

A

IgG fusion with tpo fragment. Recombinant Tpo is not approved for therapeutic use.

30
Q

Therapeutic Uses of IL-11

A

Used to treat thrombocytopenia, which is an abnormally low number of platelets.

Thrombocytopenia commonly seen in vitamin B12 or folic acid deficiency, leukemia or myelodysplastic syndrome and myelosuppression associated with chemotherapy

31
Q

Side effects with IL-11

A

excessive fluid retention with edema and cardiac decompensation, renal impairment, allergic and severe reactions.

32
Q

Organs of the immune system

A

Bone marrow: source of blood cells

Thymus: maturation of T cells

Spleen: hematopoietic organ, site of macrophage antigen presentation and antibody response

Lymph nodes and vessels: source of lymphocytes

33
Q

Cells of the immune system

A

lymphocytes: B-cells (antibody production), T-cells and large granular lymphocytes (both of these produce cytokines).
phagocytes: mononuclear phagocyte (cytokine and complement production), neutrophils and eosinophils

Auxiliary cells: basophils, mast cells and platelets all produce inflammatory mediators

34
Q

Innate immunity

A

Rapid response. General molecular patterns. Limited diversity of immune system, with no memory and is nonreactive to self. Barriers include skin, mucosal epithelia and blood proteins include complement. Cells include phagocytes, NKC, innate lymphoid cells

35
Q

PPRs in innate

A

Pattern recognition receptors include Toll-like receptors (TLR), C-type lectin receptors (CLRs) and nucleotide-binding oligomerization domain-like receptors (NLR)s. Expressed by tissue macrophages and dendritic cells. Used to detect PAMP (pathogen associated molecular patterns) like LPS.

36
Q

Complement in innate

A

Primary functions are chemotaxis through C3a and C5a, opsonization through C3b and cell lysis through the MAC complex

37
Q

Adaptive immunity

A

longer response. Specific for microbial and nonmicrobial antigens, can be very specific. Very large diversity of response, with memory and is nonreactive to self. Barriers contain lymphocytes and antibodies. Blood proteins are antibodies and cells are lymphocytes.

38
Q

Cell mediated adaptive immunity

A

Cell-mediated: phagocytosed microbes are displayed on macrophages. Helper T cells bind to it, recognize it and activate it to allow other T cells to come bind the same antigen

39
Q

Humoral adaptive immunity

A

Humoral: B lymphocyte responds to extracellular microbe. Antibody is excreted to block infection and eliminate extracellular microbes.

40
Q

Antibodies

A

V(D)J recombination is the mechanism for diverse binding selectivity in the B-cell receptor (antibodies) and T-cell receptors.

Immunoglobulin isotypes: IgG and IgM are most important in plasma. IgG is dominant in extracellular fluid around the body. IgE is dominant in mast cells. Fetus gets mostly IgG. Brain usually has no immunoglobulins.

Functions: neutralization, opsonization, sensitization for killing by NK cells, sensitization of mast cells and activation of complement

41
Q

MHC Class

A

Major histocompatibility complex. Large gene family involved in immune function. HLA complex is the human version of the MHC genes. HLA genes are involved in the process of identifying self and non-self and are responsible for tissue rejection in organ transplants

Class I: present on most cells, bind endogenous antigens synthesized in a cell. Present antigen to CD8 cytotoxic T cell lymphocytes. And presence of foreign or over-abundant antigens targets cell for destruction

Class II: Present only on antigen-presenting cells and binds exogenous antigens. Present antigen to CD4 helper T cell lymphocytes

42
Q

T-cell activation

A

is a 2 step process

Signal 1: MHC + TCR. dendritic cell presents antigen on a MHC molecule and the T-cell receptor engages MHC + antigen complex

Signal 2: co-stimulatory molecules and receptors act on T-cell to activate or negatively regulate. Examples are CD80/86 (APC) CD28 (T-cell) to activate the T-cell.

43
Q

Immunopathology

A

Hypersensitivity: allergic reactions to harmless antigens

Immunodeficiency: unable to stop an infection

Autoimmune disorder: immune system targets self-antigens

Examples: Type 1 diabetes, RA, MS
Stems from an abnormal immune response to the tissues or substances in your own body.

44
Q

Immunosuppression

A

intentionally reducing activation or decreasing efficiency of the immune system.

45
Q

Immunosuppressive drugs

A

are used to prevent rejection of organ transplants, treat autoimmune disease, asthma, allergic rhinitis, psoriasis, eczema, or to treat graft-versus-host disease (GVHD) after allogeneic HCT. Activated T cells are the main mediators of immunologic rejection, attacking donor organ

46
Q

MOA immunosuppressives

A

Many mechanisms that act to suppress the cell cycle

pathways of immunoregulation: T-cell activation; steroids and NF-kappaB; calcium levels, calcineurin, NFAT, IL-2 synthesis; autocrine stimulation by IL-2 to mTOR and cell cycle; DNA synthesis and proliferation

47
Q

Azathioprine

A

purine analog that inhibits DNA synthesis and proliferation of cells, especially fast-growing cells without a method of nucleotide savage, such as lymphocytes. T cells and B cells are particularly affected by the inhibition of purine synthesis.

48
Q

Mycophenolate

A

IMP dehydrogenase inhibitor. Metabolized in the liver to the active form mycophenolic acid (MPA) which inhibits IMPD. IMPD controls the rate of de novo guanine (purine) synthesis in the proliferation of B and T cells

49
Q

Corticosteroids

A

The endogenous steroid hormone is cortisol

Examples: prednisone, hydrocortisone, fluticasone

MOA: two possible processes. 1) bind to GR (nuclear) then to GRE to alter expression of target genes, increasing anti-inflammatory genes 2) To block T cell activation and reduce inflammation genes

50
Q

Calcineurin inhibitors

A

cyclosporine and tacrolimus. Both are natural products from fungus and bacteria respectively. Contain macrolide rings. They bind to and inhibit calcineurin which inhibits translocation of transcription factors NF-AT into the nucleus. This results in reduced transcriptional activation of early cytokine genes for IL-2, TNF-alpha, GM-CSF, interferons and other IL. Proliferation of lymphocytes is reduced.

51
Q

mTOR inhibitors

A

Sirolimus (Rapamycin) and Everolimus. Inhibit IL-2 mediated signaling and results in cell cycle arrest at G1-S and thereby blocks activation of T and B cells by cytokins. Macrolides.

52
Q

Anti-lymphocyte antibodies

A

ADCC: antibody-dependent cell-mediated cytotoxicity. NK cells actively lyse target cells whose membrane-surface antigens have been bound by specific antibodies

Examples: Alemtuzumab (Campath) mAB to CD52 on mature lymphocytes; Muromonab-CD3 (OKT3) mAB to CD3 on T cells, Rituximab (Rituxan) mAB to CD20 on B cells

53
Q

Anti-IL2R Antibodies

A

daclizumab and basiliximab. Used in kidney transplants and have higher specificity than anti-lymphocyte antibody drugs.

54
Q

Targeting CD80/86

A

Belatacept (Nulojix) and Abatacept
Effectively blocks second signal to prevent T cell from activating. : binds to CD80 and CD86 on antigen presenting cells.

55
Q

Rho(D) Immune Globulin (RhoGAM)

A

prevents Rh hemolytic disease of the newborn. Rhesus (Rh) factor is a protein on the surface of RBC. Rh + is more common. Prevents B-cell and antibody development

56
Q

Phospholipase A2 mechanism

A
  1. Activated through calcium signaling or ligand-receptor signaling (ligands include serotonin, glutamate, FGF, IFN-alpha, IFN-gamma). phosphorylation of cytoplasmic PLA2 (cPLA2)
  2. Calcium binding to the C2 domain of phospho-CPLA2 triggers binding to plasma membrane
  3. cPLA2 hydrolyses phospholipids to release arachidonic acid AA and lysophospholipids
  4. AA is converted to prostaglandins by COX enzymes which can be inhibited by NSAIDS
  5. Arachidonate 5-lipoxygenase, 5-LOX converts AA to to leukotrienes
57
Q

COX enzymes

A

COX-1: housekeeping enzyme expressed in almost all tissues and is cyto-protective. Constitutively expressed

COX-2: immediate-early response gene that is induced at sites of inflammation and during tumor progression by cytokines and mitogens

58
Q

Adverse effects of NSAIDs

A

Cardiovascular: fluid retention, hypertension, edema and rarely myocardial infarction and CHF

GI: abdominal pain, dysplasia, nausea, vomiting and rarely ulcers or bleeding
“Dual insult”: Primary insult is direct acid damage and secondary insult is prostaglandin inhibition (COX-1 and COX-2)
Treatment is discontinuation or COX-2 inhibitors

Renal: acute kidney injury, renal insufficiency, renal failure, hyperkalemia and proteinuria

Other less important: CNS, hematologic, hepatic, pulmonary and skin adverse events

59
Q

Aspirin effects

A

Low doses: sufficient to irreversibly acetylate COX-1 resulting in an anti-thrombotic, cardio-protective effect. Usually have to take life-long due to rebound effect with withdrawal that may cause increased risk of heart attack, deep vein thrombosis etc…

Intermediate doses: analgesic and antipyretic effects. Inhibition of COX-1 and COX-2

High doses: anti-inflammatory. Rarely used at this dose though due to adverse GI effects and other NSAIDs work better

60
Q

RA

A

Autoimmune disease affecting about 1% of the population. Involves thickening and inflammation of synovial membrane and immune response begin attacking the natural synovial cells. IL-1 activates osteoclasts and MMP to degrade the matrix of the bone. TNF-alpha also activates.

70% of joint erosions detectable by radiograph of hands and feet occur in the first two years of disease

Increases risk of infections, cardiovascular disease, lymphoma, and shortened life expectancy

Cause is unknown but risk factors include females, age older than 60, smoking, and certain HLA class II genotypes and mutations

61
Q

Methotrexate

A

DMARD for RA. Anti-neoplastic and anti-rheumatic drug (acts through different mechanisms). In RA inhibits AICAR transformylase leading to an accumulation of AMP. AMP is exported and extracellulary is converted to adenosine which is a potent inhibitor of inflammation.

62
Q

TNF-alpha blocking agents

A

DMARD for RA. antibodies against TNF-alpha which contributes to osteoclast activation and differentiation (remodeling of bone)
Examples: Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumab
Side effects: acute infusion reaction, delayed infusion reactions, neutropenia, and infection including TB manifestation

63
Q

Glucocorticoids

A

DMARD for RA. prednisone. Bind to glucocorticoid receptors to repress gene expression of many pro-inflammation genes.

64
Q

Gout

A

Caused by build-up of urate crystals in joints, bones and soft tissues. Urate is a poorly soluble end product of purine metabolism.

65
Q

Gout risk factors

A

risk factors include males, old age, ethnicity, obesity, diets rich in meat and seafood, and alcohol. Hyperuricemia (urate concentration > solubility of urate in extracellular fluid) is necessary to develop gout but the majority of hyperuricemia patients do not develop gout

66
Q

Gout pathogenesis

A

Uric acid crystals in the joint are taken up by macrophages as part of the innate immune response

Macrophages produce IL-1-beta via intracellular inflammasomes

IL-1-beta helps recruit neutrophils from the blood stream to the affected joint

Activation and degranulation of neutrophils contribute to pain associated with an acute gout flare

67
Q

Gout treatment

A

NSAIDs: first line treatment

Colchicine: microtubule inhibitor to block phagocytosis. Side effects are extensive and include diarrhea, nausea, vomiting.

Uricosuric agents: probenecid and sulfinpyrazone increase uric acid excretion by blocking reabsorption of uric acid by kidney. Lowers levels of uric acid in joints

Allopurinol: inhibits xanthine oxidase which produces uric acid. Xanthine and hypoxanthine are more soluble than uric acid and eventually are converted to uric acid. Cleared better from body

PHCOL 401 (9 decks)

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