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156 Cards in this Set

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