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171 Cards in this Set
- Front
- Back
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Name four cells that develop from a common lymphoid progenitor.
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lymphocytes (B and T cells)
NK cells dendritic cells |
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Name six cells that develop from a common myeloid progenitor.
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Granulocytes (neutrophils, eosinophils, basophils)
Monocytes (from marcophages) dendritic cells mast cells erythrocytes platelets |
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NK Cell, formed where?
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bone marrow
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T Cell, formed where?
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thymus
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B Cell, formed where?
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bone marrow
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Dendritic cells, formed where?
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bone marrow
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Macrophages, formed where?
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blood
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Osteoclasts, formed where?
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blood
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Neutrophil, formed where?
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bone marrow
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Eosinophil, formed where?
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bone marrow
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Basophil, formed where?
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bone marrow
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Mast cell, formed where?
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bone marrow
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Platelets, formed where?
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bone marrow
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Erythrocytes, formed where?
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bone marrow
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Dendritic cells, function?
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present antigens to T cells
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Mast cells, function?
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contain histamine and inflammatory mediators
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Erythrocytes, function?
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(RBC)
transport O2 and CO2 |
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Neutrophils, function?
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phagocytose and destroy invading bacteria
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Eosinophils, function?
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destroy larger parasites and modulate allergic inflammatory responses
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Basophils, function?
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release histamine (and in some species serotonin) in certain immune reactions
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Monocytes, function?
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become tissue macrophages, which phagocytose and digest invading microorganisms and foreign bodes as well as damaged senescent cells
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B cells, function?
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make antibodies
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T cells, function?
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kill virus-infected cells and regulate activities of other leucocytes (WBCs)
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NK cells, function?
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kill virus-infected cells and some tumor cells
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Platelets, function?
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initiate blood clotting
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Which type of granulocytes are the most common?
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neutrophils
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List two key features of the bone marrow:
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highly vascularized
easy movement of cells and signaling pathways |
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List cells present in the bone marrow
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stromal cells
fibroblasts adipocytes osteoblasts multipotent stem cells progenitor cells |
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List the two types of cell communication involved in differentiation of parent cells
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Cell-cell interactions (stromal cells and stem cells)
Receptor stimulation by cytokines |
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IL-1, cell lines stimulated and cytokine source?
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erythrocyte
granulocyte megakaryocyte monocyte macrophages fibroblasts endothelial cells |
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IL-2, cell lines stimulated and cytokine source?
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T and B lymphocytes
NK cells TH1 lymphocytes |
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IL-11, cell lines stimulated and cytokine source?
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Erythrocyte
Granulocyte Megakaryocyte Fibroblasts Osteoblasts BM stromal cells |
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Erythropoietin, cell lines stimulated and cytokine source?
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Erythrocyte
Kidney Kupffer cells |
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G-CSF, cell lines stimulated and cytokine source?
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Granulocyte
Endothelial Cells Fibroblasts Monocytes |
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GM-CSF, cell lines stimulated and cytokine source?
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Erythrocyte
Granulocyte Megakaryocyte Endothelial cells Fibroblasts Monocytes T lymphocytes |
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Thrombopoietin, cell lines stimulated and cytokine source?
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Megakaryocyte
Liver Kidney BM Stromal Cells |
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What is the most common signaling system? Which cytokines do not use this pathway?
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Jak-Stat
IL-1, M-CSF, SCF, and FL (tyrosine kinases) |
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Identify each cell type on the Hematopoietic Cell Types chart.
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See chart on Maija's sketch paper.
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Explain what happens when a cytokine binds to a receptor and starts a Jak-Stat pathway.
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1. Binding of cytokine cross-links adjacent receptors and JAKs cross-phosphorylate each other on tyrosines.
2. Activated JAKs phosphorylate receptors on tyrosines. 3. After STATs dock on specific phosphotyrosines on the receptor, the JAKs phosphorylate them. 4. STATs dissociate from receptor and dimerize via their SH2 domain. 5. STATs translocate to nucleus, bind to DNA and other gene regulatory proteins and activate gene transcription. |
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Explain multilineage.
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growth factors that mainly affect progenitors/BFUs/CFUs
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Explain specific lineages.
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Growth factors that mainly affect maturation.
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Where is EPO synthesized?
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mainly in the peritubular cells in the kidney cortex and the upper medulla
minor quantities are made in the adult liver |
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What effect does chronic kidney disease have on iron levels?
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EPO is not synthesized and anemia results
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When is EPO synthesized?
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when renal cells sense low oxygen, which reflects low erythrocyte number
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Where does EPO act?
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EPO acts primarily on BFU-E and CFU-E and increases hemoglobin synthesis in developing cells.
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Which erythroid forming cell is more sensitive to EPO? IL-3?
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EPO = CFU-E
IL-3 = BFU-E |
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What signaling pathway does EPO activate?
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Jak-Stat, duh.
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What are the two forms of recombinant EPO?
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Epoietin alfa
Darbopoetin alfa |
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Which drug has a longer half-life, Epoetin alfa or Darbepoetin alfa?
What is the dosing schedule of each? |
Darbepoetin alfa
Epo alfa is typically TIW Darbo alfa is typically qW |
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What are the four approved indications for Epo alfa?
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Anemia in CKD Patients
Anemia in Chemotherapy Patients Anemia in AIDS patients on zidovudine Transfusion reduction in patients scheduled to undergo surgery |
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What are the two approved indications for Darbo alfa?
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Anemia in CKD Patients
Anemia in Chemotherapy Patients |
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What is the main untoward effect of EPO therapy?
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hematocrit and hemoglobin can increase too rapidly, resulting in HTN and clotting due to increased blood viscosity
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What does GM-CSF stimulate?
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progenitor CFUs
neutrophil, monocyte, and eosinophil cell lineages |
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What is the MOA of GM-CSF?
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acts on membrane receptors through a Jak-Stat signal
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What therapeutic forms of GM-CSF are available?
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Sargramostim
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What are the main uses of Sargramostim?
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simtulate myelopoiesis in bone marrow transplants and other neutropenias
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What are the main untoward effects of Sargramostim?
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mild bone pain
flu-like symptoms joint pains (arthralgia) edema pleural and pericardial effusion |
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What does G-CSF stimulate?
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CFU-G
(enhances neutrophil activity) (reduces inflammation) |
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What is the MOA of G-CSF?
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acts on membrane receptors through a Jak-Stat signal
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What therapeutic forms of G-CSF are available?
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Filgrastim
Pegfilgrastim |
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What are the main uses of G-CSF?
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stimulate myelopoiesis in bone marrow transplants and other neutropenias
decreases number of PBSC collections needed |
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What are the main untoward effects of Peg- and Filgramatim?
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very few
better tolerated than Sargramostim (which is also well tolerated) injection site rash, mild bone pain |
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Which -stim has the longest half-life? Effect?
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Pegfilgrastim
allows one dose per cycle instead of daily dosing |
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How are each of the -stim's produced?
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Sargramostim--recombinant DNA system in yeast expression system
Filgramastim--recom. DNA using E. coli Pegfilgramastim--recom. DNA using E. coli and bound to glycol |
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Which of the following stimulates neutrophil production: GM-CSF, G-CSF?
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both!!!!!! yea!!!!
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What does Thrombopoietin stimulate?
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CFU-Meg (Megakaryocytes) and Megakaryocytes (platelets)
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Where is TPO produced? How is it regulated?
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Predominately by the liver and to a lesser extent the kidney and bone marrow stromal cells.
Platelet level in the bone marrow determines production levels. Also, inflammation increases liver TPO production. |
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How are platelets produced?
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Megakaryocytes (located in the bone marrow) bud off in the local blood sinuses and form platelets
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What is the MOA of TPO?
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acts on membrane receptors primarily through a Jak-Stat signaling mechanism
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What are the therapeutic uses of TPO?
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used to prevent thrombocytopenia produced previously by chemotherapy
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What are the therapeutic forms of TPO?
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Oprelvekin
(non-glycosylated, made in E. coli) |
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What are the main untoward effects of TPO?
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fluid retention (resulting in tachycardia, palpitations, edema)
blurred vision, injection site rash, paresthesia |
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What effect do platelets have on TPO level?
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Platelets bind and remove TPO from the bloodstream. If platelet count is low, more TPO reaches the bone marrow and more platelets are produced.
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Define anemia
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reduced concentration of erythrocytes or hemoglobin
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What three deficiencies can cause anemia? What type?
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Inadequate iron - microcytic anemia
Vitamin B12 and folic acid deficiency - macrocytic anemia |
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What are the common causes of macrocytic anemia?
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folic acid deficiency
vitamin b12 deficiency liver disease alcohol hypothyroidism drugs (sulfonamides, zidovudine, antineoplastic agents) myelodysplastic syndromes |
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What are the common causes of microcytic anemia?
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Iron deficiency
Thalassemias |
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What are the main sources of iron?
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Food
iron fortified flour/cereals certain vegetables red meats |
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Where is iron located in the body? (rank from highest concentration to lowest concentration)
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hemoglobin > storage > myoglobin > enzymes = transport
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Describe the structure of hemoglobin
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Two pairs of globulin chains (alpha and beta) with a heme moiety in each chain. Each heme moiety contains an iron molecule
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How is hemoglobin synthesis controlled?
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Low iron = low heme = HRI inhibits elF2 (elongation factor) and hemoglobin synthesis
Iron levels control hemoglobin synthesis |
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Where is iron stored?
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liver
bone marrow spleen (and RES which removes aged blood cells) |
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Explain iron metabolism
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Iron is absorbed from the intestine into the plasma
80% of plasma iron goes to the erythroid marrow to make erythrocytes large fraction goes to spleen for storage some plasma iron moves to the interstitial fluid erythroid marrow iron is combined into new erythrocytes circulating erythrocytes are destroyed in RES after 120 days RES iron is returned to the plasma and stored |
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How much iron is excreted by males each day?
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1 mg
(mostly through gut, some through skin and urine) |
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What stressors increase iron loss?
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severe blood loss
menstruation blood from GI tract pregnancy lactation |
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How is elemental iron absorbed?
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absorbed primarily in the ferrous state (Fe2+) in the duodenum (iron reductase converts (Fe3+ to Fe2+)
DCT1 cotransporter moves Fe2+ and H+ |
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How is heme iron absorbed?
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heme transporter in the duodenum
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What happens to ferrous iron once it is absorbed?
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Most is converted to Fe3+ (ferric form) by ferroxidase
Fe3+ is bound to apoferritin to form ferritin Ferroportin transports Fe2+ to the plasma Hephaestin converts Fe2+ to Fe3+ so it can bind to transferring in the plasma |
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What happens when plasma iron levels are low?
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Little iron-transferrin is taken up into intestinal cells
Fe3+ dissociates from aconitase Iron-free aconitase post-translationally modifies mRNA |
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What four things does aconitase control?
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Iron-free aconitase:
increases DCT1 synthesis increases transferrin receptor synthesis increases ferroportin synthesis decreases ferritin synthesis |
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What happens when plasma iron levels are high?
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Iron-Tf complex is taken up into cell
iron associates with iconitase opposite of iron-free aconitase effects |
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Which agents increase iron absorption? Decrease?
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Ascorbic acid and succinate increase
PPIs, H2 antagonists, Al-, Ca2+, and Mg2+ antacids, cholestyramine, tetracycline, doxycycline, phytates, phosphates, and MEALS decrease |
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Describe plasma iron transport
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1. Transferrin binds 2 Fe3+ molecules from absorption or RES degradation
2. Transferrin delivers Fe to transferrin receptors which is then internalized by endocytosis into the cell and then into an endosome 3. Low pH causes iron to be released from transferrin 4. The receptor-endosome is returned to the cell membrane where neutral pH causes receptor to release transferrin |
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How are plasma iron levels regulated?
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Hepcidin is release from the liver in response to elevated iron levels. Hepcidin binds to ferroportin causing internalization of the transporter. There is less ferroportin present and less iron is released into the bloodstream.
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What factors trigger hepcidin release?
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high plasma iron levels
inflammation (IL-6) (EPO suppresses hepcidin release) |
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How much iron do children, adolescents, and adults need daily on a per weight basis?
Do people receive enough iron in their diets? |
children, adolescents, and adult females need about 20 ug/kg daily
adult males need about 13 ug/kg daily Males receive enough iron even in poor diets while females may not |
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Describe the sequence of development of anemia?
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Store depletion->ID erythropoiesis->ID anemia
(recovery occurs in the opposite direction and treatment may continue after person is no longer anemic in order to fill storage) |
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What is the general treatment for ID anemia?
dosing? |
oral iron preparations
200 mg of ferrous iron/day divided into 2 or 3 equal doses for 3 to 6 months after the anemia resolves |
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How does iron absorption relate to dose and size of iron stores?
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Iron absorption is:
-inversely related to the level or iron in the dose -inversely related to the size of the iron stores |
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What component of iron preparations is important in dosing?
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elemental iron
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List six forms or oral iron preparations
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Ferrous sulfate
Ferrous sulfate (exsiccated) Ferrous gluconate Ferrous fumarate Polysaccharide iron complex Carbonyl iron |
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What are the benefits of sustained release iron preparations?
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nothing, they suck
side effects may be less but there is less iron absorption too |
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Name three parenteral iron preparations
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Sodium Ferric Gluconate
Iron Dextran Iron Sucrose |
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When are each of the three parenteral iron preparations indicated for use?
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SFG: treatment of IDA in patients receiving hemodialysis and EPO
ID: treatment of IDA in patients who do not respond to oral therapy IS: treatment of IDA in patients receiving hemodialysis and Epo alfa |
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What warnings are associated with each of the three parenteral iron preparations?
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SFG: no black box warning
ID: black box for anaphylactic reaction IS: black box for anaphylactic reaction |
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What routes can each of the three parenteral iron preparations be given through?
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SFG: IV
ID: IV or IM IS: IV |
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What are the common adverse effects of Sodium Ferric Gluconate?
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cramps, nausea and vomiting, flushing, hypotension, rash, pruritus
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What are the common adverse effects of Iron Dextran?
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pain and brown staining at injection site, flushing, hypotension, fever, chills, myalgia, anaphylaxis
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What are the common adverse effects of Iron Sucrose?
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leg cramps, hypotension
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Which parenteral iron formulation is the safest?
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Sodium Ferric Gluconate
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What are the main side effects of oral iron therapy?
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GI irritation, nausea, diarrhea, and constipation
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What are the main side effects of IM iron therapy?
IV therapy? |
IM: skin discoloration, local inflammation, some pain
IV: dizziness, syncope, fever, chills, rash constricting chest pain, cardiac arrest (very rare) |
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What is deferoxamine used for?
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used during iron poisoning and to decrease iron levels in patients receiving frequent hemodialysis
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What is deferasirox used for?
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decrease iron levels in patients receiving frequent hemodialysis
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What are the signs of iron poisoning?
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abdominal pain, diarrhea, vomiting
pallor or cyanosis, drowsiness, hyperventilation, CV collapse |
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What is the treatment of iron poisoning?
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induce vomiting
gastric lavage deferoxamine (parenteral) |
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What are the benefits of using deferasirox over deferoxamine?
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fewer side effects
oral dosing |
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Describe causes and effects of megaloblastic anemia
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Vitamin B12 and folic acid deficiencies can lead to the production of unusually large, immature RBCs
B12 and FA are involved in the production of DNA, purines, and AAs in all dividing cells |
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How are B12 and FA related?
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low B12 levels result in folate trapping and DNA synthesis slows down (results in slow division of cells and consequently big cells)
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What role does FA play in cell production?
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tetrahydrofolate transfers one carbon fragments in DNA production, purine synthesis, and AA formation
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What does a high methylmalonyl-CoA level in the urine indicate?
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megaloblastic anemia (B12 is required to convert MM-CoA to Succinyl-CoA)
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What are the signs and symptoms of megaloblastic anemia?
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FA and B12 deficiency: tiredness, weakness, dyspnea
B12 deficiency only: paresthesia, ataxia, moodiness, mental slowness, poor memory, depression |
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What role does B12 play in cell production?
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involved in folate synthesis
involved in conversion of MM-CoA to Succinyl acid (myelin synthesis) |
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What is the daily requirement for B12 for adults? Peds?
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2.4 mcg
less for peds |
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What are good sources of B12?
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fortified cereals, meat, fish, and dairy products
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List and explain the seven causes of B12 deficiency
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1. Dietary deficiency (rare)
2. Inadequate intrinsic factor (required for B12 absorption) 3. Defective ileal absorption (defective transport protein) 4. Congenital absence of transcobalamin II (affects absorption) 5. Interference with reabsorption of B12 secreted in the bile (liver secretes basal level of B12 daily) 6. Abnormal amounts of transobalamins I and III in plasma (only TCII can transport) 7. Defective tissue B12 uptake or folate supply |
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Name two types of B12 preparation
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Cyanocobalamin
Hydroxocobalamin |
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What dosage forms are available for B12 replacement?
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Cyanocolbalamin (oral, parenteral IM or deep SC)
Hydroxocobalamin (IM or deep SC) (preferred b/c of longer duration of action) |
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What are the main sources of FA?
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chicken liver, cereal, vegetables
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What is the daily FA requirement for adults? Adolescents? Pregnant women?
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Adults (400 mcg)
Adolescents (300 mcg) Pregnant Women (600 mcg) |
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List and explain causes of FA deficiency:
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1. Inadequate diet (alcoholism can decrease FA levels)
2. Intestinal diseases (folates are absorbed in the jejunum) 3. Decreased plasma protein binding (uremia, cancer, alcoholism all decrease) 4. Defect in bile reabsorption and transport to tissues (uremia, cancer, and alcoholism decrease) 5. Inadequate B12 (results in trapping) 6. Antifolate drugs can block metabolism (methotrexate, anticonvulsants, OCs) |
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Name two preparations of folic acid (include forms)
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Folic acid (oral, IM) (preferred)
Folinic acid (oral or parenteral) |
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What three blood entities are at highest concentration in the blood?
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erythrocytes
platelets neutrophils |
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What are the general similarities of the cytokines that stimulate blood cell production?
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glycoproteins
activate high affinity, low capacity receptors |
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What is the advantage of carbonyl iron?
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lower risk of cardiac death in overdose
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Why might patients require parenteral iron administration?
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malabsorption of iron
intolerance to oral iron patients receiving EPO as routine supplement (already IV) severe iron deficiency |
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1
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multipotent hemopoietic stem cell
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2
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multipotent hemopoietic progenitor
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3
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common lymphoid progenitor
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4
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common myeloid progenitor (CFU-GEMM)
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5
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NK precursor
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6
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Pre T Cell
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7
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Pre B Cell
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9
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CFU-GM
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10
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CFU-En
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8
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no name
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11
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CFU-Baso
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12
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CFU-Mast
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13
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BFU-Meg
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14
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BFU-E
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15
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CFU-Meg
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16
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CFU-E
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17
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NK Cell
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18
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T Cell
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19
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B Cell
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20
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Dendritic Cell
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21
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Dendritic Cell
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22
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Monocyte
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23
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Neutrophil
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24
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Eosinophil
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25
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Basophil
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26
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Mast Cell
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27
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Megakaryocyte
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28
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Erythrocyte
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29
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Macrophage
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30
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osteoclast
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31
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platelets
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A
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SCF/FL
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B
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IL-1,2,3,4,6
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C
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GM-CSF
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D
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IL-6, IL-11, TPO
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