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156 Cards in this Set
- Front
- Back
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Four things that thrombin does?
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Cleaves fibrinogen to fibrin
Activates more platelets Signals for production of more TF by endothelial cells Congerts V to Va and VIII to VIIIa |
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What is purpose of VIIIa?
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Cofactor for IXa
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What is purpose of Va?
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Cofactor for Xa
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What does PT test for?
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II, V, VII, X, fibrinogen
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What does aPTT test for?
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II, V, VIII, IX, X, XI, XII, contact factors, fibrinogen
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Vitamin K dependent factors?
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II, VII, IX, X, proteins C and S
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What is role of Tissue Factor Protease Inhibitor in clotting cascade?
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Binds circulating Xa and VIIa; inactivates Xa
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What is responsible for inhibiting VII pathway?
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TFPI
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What is role of Protein C?
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Activated Protein C (APC) inactivates V and VIII; activated by thrombin bound to thrombomodulin
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Role of AT-III?
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Suicide substrate; looks like substrate to thrombin, Xa, IXa, others; complex is cleared in liver
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Three endogenous fibrinolytic agents?
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TAFI, PAI, alpha-2 anti plasmin
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What inhibits platelet activation in normal (uninjured) vasculature?
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NO, PGI2, CD39
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What do activated platelets secrete to help recruit additional platelets?
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ADP, TxA2, thrombin
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Treatment for von Willebrand's disease?
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DDAVP causes release of vWF from endothelial storage sites; can also use plasma derived VIII concentrates that retain vWF activity
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What type of bleeding is seen in hemophila?
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Delayed; joint bleeding
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What does unfractionated heparin do?
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Activates AT-III which causes irreversible inactivation of serine proteases in clotting cascade (IIa, IXa, Xa, XIa, XIIa)
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What does low molecular weight heparin do differently than unfractionated?
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Inhibits Xa but not IIa
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What causes HIT or HATT?
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Antibodies to heparin-PF4 complex that develop in up to 10% of patients on heparin
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Two IV direct inhibitors of thrombin and Xa?
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Lepirudin and Argatroban
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Three oral direct inhibitors of factor Xa?
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Ximelegatran, rivaroxiban, apixaban
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What protein levels fall first on warfarin?
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VII and protein C
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Important drug interactions with warfarin?
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Drugs that displace warfarin from albumin increase amount of active (free) warfarin
Drugs that increase P450 expression decrease effects of warfarin |
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Four plasminogen activators developed for clinical use?
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Streptokinase, Urokinase, Rt-PA, APSAC
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Three main classes of anti-platelet drugs?
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1. Block agonist receptor on surface
2. Inhibit signal transduction inside platelets 3. Prevent activated platelets from binding fibrinogen |
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Two drugs that block ADP receptors on platelets?
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Ticlopidine and Clopidogrel
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Two drugs that inhibit signal transduction inside platelets?
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Aspirin and Dipyridamole
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Three drugs that inhibit platelet-fibrin binding?
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Abiciximab, Epifibatide, Aggrastat (all antibodies against alpha Iib-beta-3)
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Virchow's Triad?
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(factors important in thrombus formation)
1. Endothelial Injury 2. Abnormal blood flow 3. Hypercoagulability |
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What is EPO and where is it produced?
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Erythropoietin; produced in kidney; stimulates proliferation of erythroid cells in bone marrow
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Causes of microcytic anemia?
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Iron deficiency, thalassemia, anemia of chronic inflammation, sideroblastic anemia, severe lead poisoning
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Causes of normocytic anemia?
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Sickle cell, most hemolytic anemias, anemia due to blood loss, chronic disease, mild iron deficiency
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Causes of macrocytic anemia?
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B12 deficiency, folate deficiency, myelodysplastic syndrome
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Where is iron absorbed? Why?
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Predominantly in duodenum; requires low pH
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Two major categories of causes of microcytic anemia?
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Decreased heme synthesis and decreased globin synthesis
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Most common cause of nutritional anemia throughout world?
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Iron deficiency
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What is pagophagi, pica, and spoon nails a sign of?
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Iron deficiency
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What is hepcidin?
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Peptide hormone produced by liver that inhibits iron absorption
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What causes megaloblastic anemia? Most common cause?
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Reduction in DNA synthesis out of proportion to RNA synthesis; Usually responds to B12 or folate supplementation
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What causes pernicious anemia?
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Lack of intrinsic factor (IF)
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Hypersegmentation of neutrophil nuclei is hallmark of what?
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Megaloblastic anemia (B12 deficiency, etc)
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What causes "acute megaloblastic anemia"?
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Nitrous Oxide exposure
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In what conditions are target cells seen?
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Decreased hemoglobin synthesis: iron deficiency, thalassemias, etc.
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Three proteins that bind free Hg in plasma:
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Haptoglobin, Hemoplexin, Albumin
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What does direct Coombs' test test for?
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IgG antibodies bound directly to a red cell surface
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Sex linked hereditary hemolytic anemia?
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G6PD deficiency
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In what condition are Heinz bodies seen?
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G6PD deficiency
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What is hyperplasia? Hypertrophy?
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Hyperplasia: increase in number of cells
Hypertrophy: increase in size of cells |
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Main morphologic changes in acute inflammation?
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fluid exudation and neutrophil emigration
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Main morphologic changes in chronic inflammation?
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lymphocyte and macrophage infiltrate
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What is the "acute phase reaction"?
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Systemic effect of inflammatory state; caused by systemic responses to cytokines; fever, elevation in wbc, malaise, anorexia, increased fibrin, etc
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What happens to ESR in inflammatory state?
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It rises; increased fibrinogen causes red cells to clump and settle faster
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What is required for the identification of granulomatous inflammation?
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Epitheliod histiocytes
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What cells are first to appear at site of infection?
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Neutrophils (the foot-soldiers)
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What cells appear later in an inflammatory respons eand can differentiate into longer lived tissue-based cells?
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Monocytes (the calvary)
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What cells accumulate at sites of parasitic infection?
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Eosinophils (the camel guard)
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What cells are more indicative of chronic inflammation or intracellular microbes?
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Lymphocytes (special forces)
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Important Ig superfamily molecules in leukocyte-endothelial adhesion?
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ICAM-1, JAM-A, VCAM-1
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Family of molecules that mediates initial adhesive interactions of leukocytes to endothelium cells?
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Selectins
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What type of molecules principally mediate leukocyte "rolling"?
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Selectins
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What molecules principally mediate leukocyte activation?
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Integrins
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What molecules mediate firm adhesion of leukocytes to endothelial cells?
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Integrins and Ig superfamily members
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Neoplasia of epithelial tissue is called:
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Carcinoma
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Neoplasia of connective tissue is called:
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Sarcoma
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Neoplasia of hematopoietic tissue is called:
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Leukemia or Lymphoma
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What is role of RB1 protein in cell cycle? (protein that is defective in retinoblastoma)
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Regulates transit from G1 to S phase
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Three main pro-angiogenic factors:
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VEGF, FGF1, FGF2
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Endogenous inhibitors of angiogenesis (3):
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TSP1, PF4, IFNalpha
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Two proteins that are involved in increasing VEGF production:
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Ras, EGFR
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Protein that causes decreased production of TSP-1
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Myc
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|
Name of anti-VEGF antibody drug approved for cancer treatment
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Bevacizumab (avastin)
|
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Four major drug classes used in chemotherapy:
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1. Direct DNA damage
2. Inhibitors of chromatin remodeling 3. Inhibitors of DNA synthesis 4. Tubulin interactive drugs |
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What chemo drug causes direct DNA damage?
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Cisplatin
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What chemo drug is an inhibtor of chromatin remodeling?
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Doxorubicin
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What chemo drug is an inhibitor of DNA synthesis?
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Methotrexate
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What chemo drug affects tubulin?
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Paclitaxel
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Lymphoma with bonodal age curve?
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Hodgkin's Lymphoma
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EBV and hodgkin's lymphoma?
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EBV found in just under 1/2 of all cases; may be epiphenomenon
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HIV and hodgkin's lymphoma?
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HL increased in HIV positive individuals but not considered AIDS defining illness
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Is staging or classifying more important in Hodgkin's Lymphoma?
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Staging
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Small B cell NHL that is BCL2+?
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Follicular Lymphoma
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Monoclonal antibody to CD20; What is name and what is it used to treat?
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Rituximab; used to treat Follicular Lymphoma and RA
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What percentage of FL cases transform into DLBCL?
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30-50%
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How do you define an aggressive case of FL?
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More than 15 centroblasts per field
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Lymphoma with trabecular bone marrow growth?
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Follicular Lymphoma
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What causes expression of BCL2 in Follicular Lymphoma?
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translocation (14;18)
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What is abnormal behaviour that causes pathogenesis in FL?
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Cells in germinal center refuse to die
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What is Richter's transformation?
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Transformation of CLL/SLL to DLBCL
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Smudge cells are seen in what disease?
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CLL/SLL
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Zap 70 is important in what disease and how?
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CLL/SLL; two forms of disease; the more aggressive form is derived from a naïve B cell that has not traversed the germinal center; has an unmutated IgV segment and is Zap 70+
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MALT lymphoma is subtype of what?
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Marginal Zone Lymphoma;
the three types are: Nodal, Splenic, Extranodal (MALT is subset of extranodal) |
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What is lymphoma associated with chronic infection of H. pylori, Campylobacter, etc.?
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MALT lymphoma (subset of Marginal Zone Lymphoma)
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What lymphoma often presents in GI tract with sudden growth in size and pain?
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Diffuse Large B Cell Lymphoma
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What is best predictor of outcome in DLBCL?
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NOT morphology; starting to do gene expression profiling which is leading to subdivisions based on RNA patterns
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Three forms of Burkitt Lymphoma:
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Endemic (African), Sporadic (Wester), Immunocompromised
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In what form of lymphoma does the Ki67 staining reach 100%?
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Burkitt Lymphoma
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What causes stimulus for proliferation in Burkitt Lymphoma?
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overexpression of cMYC oncogene due to t(8;14) translocation
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Neoplasm of plasma cells is called what?
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Multiple Myeloma
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Pathogenic expression of what marker allowes cells in multiple myeloma to home in on bone marrow?
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CD56
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What lymphoma/leukemia is characterized by lytic bone lesions and pathologic fractures?
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Multiple Myeloma
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What are Bence Jones proteins and in what condition are they found?
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Excess light chains produced in multiple myeloma that cross the glomerular filter into the urine
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What cytogenetic change is associated with a more aggressive form of multiple myeloma?
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Deletion of 13q
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What mutations are associated with the myeloproliferative diseases?
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BCR-ABL fusion protein and JAK2 mutation
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What disease is the Philadelphia chromosome associated with? What causes it?
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Chronic Myelogenous Leukemia; translocation (9;22)
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what does t(9;22) cause?
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Production of Hybrid BCR-ABL protein that causes inhibition of apoptosis
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Differential of chronically elevated Hg?
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Polycythemia vera; Secondary polycythemia (increased EPO production); Relative polycythemia
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What is APL?
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Acute promyelocytic leukemia; subtype of AML with t(15;17); more favorable outcome but can cause fatal bleeding and DIC; responds to retinoic acid treetment
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In what condition are Auer rods seen?
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AML
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What is bioavailability of IV drugs?
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100%
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What are the three compartments of drug distribution in the body?
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Plasma, Interstitial Fluid, Intracellular Fluid
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In first order kinetics, a constant _________ of a drug is metabolized per unit time.
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Fraction
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In zero order kinetics, a constant _________ of a drug is metabolized per unit time.
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amount
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What drugs follow zero order kinetics?
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Aspirin, alcohol, phenytoid
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What is Phase I metabolism?
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Conversion of drug to more polar metabolite; oxidation via cytochrome P-450 system
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What is Phase II metabolism?
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Coupling endogenous substrate to drug to increase excretion
|
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What member of CYP450 family is responsible for metabolism of many drugs?
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CYP3A4
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Two compounds that increase activity of CYP3A4?
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Rifampin, St. Johns Wort
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What do Gs proteins activate downstream?
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Adenylyl cyclase; involves cAMP
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What effect do Gi proteins have downstream?
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Inhibit Adenylyl cyclase
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What do Gq proteins activate downstream?
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PLC-beta; involves Ca++
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What do G12 proteins activate downstream?
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Rho
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What are eicosanoids?
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Any product of arachidonic acid pathway; includes prostaglandins, thromboxane, leukotrienes, HETEs and EETs
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What are the isoeicosanoids?
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Free radical catalized isomers of eiconsanoids
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What are the prostanoids?
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Prostaglandins and thromboxane; defined as products of COX enzymes
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In platelets, COX___ produces ________.
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COX1; Thromboxane A2
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In endothelial cells, COX____ produces ___________.
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COX2; Prostacyclin I2
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What are the effects of Prostaglandin E1 and E2?
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Inhibit gastric acid secretion, regulate renal blood flow, regulate salt and H20 homeostasis, induce uterine contractions, general pro-inflammatory effects
|
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What are the effects of Prostaglandin F2alpha?
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Induces valcular smooth muscle and uterine contraction; vasoconstrictor; pro-inflammatory effects
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What is an Addisonian crisis?
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Caused by sudden withdrawal of glucocorticoids without adequte weaning time for hypothalamic pituitary axis to restart endogenous production; can be fatal
|
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Four main classes of immunosuppressive drugs:
|
1. Glucocorticoid steroids
2. Cytotoxic drugs -- alkylating (Cyclophosphamide) and antimetabolites (MAMS) 3. Calcineurin inhibitors -- Cyclosporine and Tacrolimus 4. Antibody reagents |
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What are the four antimetabolite cytotoxic drugs used in immunosuppressive therapy?
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Methotrexate, Azathioprine, Mycophenolate, Sirolimus
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What is the mechanism of cyclophosphamide?
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Alkylates DNA; interferes with T and B cell proliferation
|
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What is the mechanism of methotrexate?
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Inhibits folate dependent enzymes involved in purine synthesis
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What is the mechanism of Azathioprine?
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Prevents proliferation of CD4+ and CD8+; pro-drug; purine derivative; note that has major drug interactions with allopurinol and bactrim!
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What is mechanism of Cyclosporine?
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Complexes with cytoplasmic receptor protein and binds to calcineurin; prevents translocation and nuclear import of subuint of NF-AT (T cell transcription factor)
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Special notes about cyclosporine use?
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No marrow suppression! Drug interactions with rifampin, calcium channel blockers, and others
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What is prototype of monoclonal Abs used as immunosuppressive therapy?
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Anti-CD3; causes depletion of peripheral lymphocytes and reduction of IL2 formation
|
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What HLA type is associated with ankylosing spondylitis?
|
HLA-B27
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What HLA type is associated with rheumatoid arthritis?
|
HLA-DR4 (HLA-DRB1*04) -- shared epitope
|
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Best understood co-stimulatory pathway used in T cell activation?
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CD80/86:CD28
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TNFalpha inhibitors used in treating RA?
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Etanercept, Adalimumab, Infliximab
|
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What part of cell cycle is abnormal in SLE?
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B cell check points
|
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What causes neonatal lupus?
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Anti Ro/La antibodies
|
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What part of apoptosis is abnormal in SLE?
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Phagocytosis and clearing of immune complexes and apoptotic cells
|
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What disease has an increased incidence in Choctaw Native Americans?
|
Scleroderma
|
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What rheumatologic disease has about 25% chance of acute renal crisis?
|
Scleroderma
|
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What is leading cause of death in scleroderma patients?
|
Lung disease
|
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What is unusual about HLA-B27?
|
Forms dimers; may react with CD4+ T cells instead of CD8+
|
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What defines reactive arthritis?
|
Seronegative asymmetric arthritis following rethitis, cervicitis, or infectious diarrhea
|
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What rheumatologic disease has about a 1:1 male:female ratio, with males predominating in diagnoses made under 45 yo and females over 65?
|
Osteoarthritis
|
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Four important enzymes in purine metabolism?
|
PRPP synthetase
Amidophosphoribosyltransferase HGPRT Xanthine oxidase (inhibited by allopurinol) |
|
In what disease are "inflammasomes" important?
|
Gout
|
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What form of vasculitis typically spares the lungs and glomeruli?
|
PAN (medium vessel vasculitis; polyarticular nodosa)
|
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Is PAN associated with ANCA?
|
No
|
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Two forms of ANCA associated vasculitis?
|
Microscopic polyangitis (MPA) and Wegner's granulomatosis
|
|
What form of JRA is indicated by quotidian fever?
|
Systemic JRA
|
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What are the two main DMARDS for RA?
|
Methotrexate (folate inhibitor) and Leflunomide (pyrimidine antagonist)
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