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89 Cards in this Set
- Front
- Back
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Define hematopoiesis
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production of the formed elements of the peripheral blood -- erythrocytes, leukocytes, and blood platelets
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Functions of RBCs?
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oxygen delivery
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Fxns of WBCs?
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Neutrophils -- phagocytosis, bacterial defense
Eosinophils -- mediators of allergic rxns; combat parasitic infections Basophils -- mast cell precursors; vasoactive amines, neurotransmitters monocytes -- precursors of tissue macrophages; involved in phagocytosis, immune regulation lymphocytes -- cell and humoral immunity, plasma cell precursors, Ig production, viral immunity, immune surveillance megakaryocytes -- precursors of blood platelets, hemostasis, vascular integrity |
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What four elements are required in the process of hematopoiesis?
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1. stem cell pool
2. hematopoietic cytokines 3. supportive microenvironment (stroma) 4. essential nutrients |
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Describe pluripotent hematopoietic stem cells (PHSCs)
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-- primitive mesenchymal cells which can produce mature cells of erythroid, myeloid, lymphoid, and megakaryocyted lineages
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What type of cell surface markers do PHSCs possess?
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-- express CD34 cell surface antigen which is lost as cells differentiate
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Where are PHSCs found?
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In the adult, most of these cells are found in the bone marrow, but they are capable of freely circulating in peripheral blood
-- only account from 0.05 - 0.1% of total bone marrow cells and an even smaller percentage found in peripheral blood |
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What are the two important properties of PHSCs?
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1. self renewal
2. differentiation |
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Describe the actions of PHSCs in the marrow of a normal healthy person.
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1. Most are neither dividing nor differentiating.
-- Cells are considered to be in a prolonged intermitotic interval -- Comprise the reserve stem cell pool 2. Smaller fraction of total PHSCs are dividing but not differentiating -- Mech of self-renewal 3. Tiny portion of PHSCs are beginning to differentiate along one of several pathways of development |
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Where do PHSCs originate?
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Mesenchymal tissue
-- blood islands are the earliest sites of PHSC prolif and differentiation -- can migrate from yolk sac to liver and spleen where hematopoiesis takes place through 15th week of life -- at week 15, PHSCs take up residence in bone marrow which becomes primary site |
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What can happen during times of hematopoietic stress?
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Liver and spleen may revert to their fetal role and produce blood cells in the adult
EX: marrow is replaced by metastatic cancer or fibrosis EX: chronic myelogenous leukemia or agnogenic myeloid metaplasia -- liver and spleen may become massively enlarged b/c of reversion to blood-forming organs |
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Define extramedullary hematopoiesis.
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Hematopoiesis outside the bone marrow
-- can occur b/c PHSCs can migrate freely through the blood UNUSUAL: EH can occur in other organs such as lung, peritoneal cavity, or even brain |
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What drives hematopoietic differentiation?
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CYTOKINES -- hormones that regulate blood cell production by acting on specific cell receptors capable of binding the particular cytokine
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Describe the fxn of erythropoietin (EPO).
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EPO stimulates RBC growth and development
-- produced by JG cells in the kidney in response to hypoxia -- EPO level inversely correlated w/ Hct -- binds to specific receptors on erythroid precursor cells (CFU-e) in the BM and stims their growth and development |
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How is EPO used therapeutically?
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1. pts w/ renal failure
2. following chemo 3. to anyone w/ anemia due to inappropriately low EPO level Has been abused by athletes in order to increase hemoglobin |
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Describe the function of Granulocyte colony stimulating factor (G-CSF).
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Stimulates granulocyte growth and development
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Therapeutic use of G-CSF?
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1. following chemotherapy
2. following BM transplantation |
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Describe the fxn of Granulocyte-macrophage colony stimulating factor (MG-CSF).
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Stimulates early precursors as well as more mature granulocytic cells
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Therapeutic use of GM-CSF?
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Similar to G-CSF
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Describe the fxn of interleukin-11 (IL-11).
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IL-11 stimulates megakaryocytes (platelet precursor cells)
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Therapeutic use of IL-11?
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Used following chemotherapy to increase platelet count
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List some other important cytokines and their fxns that are NOT commonly used as drugs.
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IL-2 -- lymphocyte development and activation
IL-3 -- general growth factor for all hematopoietic cells IL-6 -- inflammatory mediator thrombopoietin -- growth and differentiation factor for megakaryocytes stem cell factor -- survival factor for very immature hematopoietic cells |
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Which cytokines can INHIBIT bone marrow hematopoiesis?
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a-interferon and TNF
a-interferon is used clinically to treat chronic myelogenous leukemia (CML) |
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Describe the hematopoietic receptor superfamily.
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-- small, span the plasma mbrn once, and generally DO NOT have intrinsic kinase activity.
-- once bound by approp cytokine, form dimeric mbrn cmplx w/ either a second identical receptor (homodimer), or w/ another receptor unit (heterodimer) -- dimeric cmplx activates tyrosine kinases that set into motion a signal transduction cascade for division or differentiation |
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Describe cell types that comprise the stroma.
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1. endothelial cells
2. fibroblasts 3. fat cells 4. macrophages 5. extracellular matrix composed of collagen, fibronectin, and proteoglycans -- contains binding sites for developing hematopoietic precursor cells |
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Stroma fxn?
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1. rich source of hematopoietic cytokines
-- close juxtaposition of stromal cells w/ developing BM permits high local conc of cytokines, facilitating differentiation -- in this setting, cytokines fxn as paracrine hormones 2. regulation of egress from the bone marrow |
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Describe how hematopoietic cells egression from BM is regulated.
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1. adhesion molecules on surfaces of maturing blood cells bind to stromal cells and CT to retain cells in BM until maturation is complete
2. cells must penetrate pores in the endothelium that are much smaller than an RBC -- cells w/o nuclei (RBCs) -- cells w/ very distensible nuclei (PMNs, monocytes, lymphocytes, stem cells) Abnormalities involving either of the above regulatory steps can occur in pathologic conditions such as leukemias, causing release of immature cells into peripheral blood. |
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What are the essential nutrients needed for hematopoiesis?
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insulin
GH TH insulin-like growth factor Other impt nutrients include: Fe (Hb synth) B12 folic acid |
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Relationship of hematocrit vs. hemoglobin?
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Hct is usually about 3x the Hb
EX: Hct of 45% would occur w/ Hb of 15gm/dL |
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Which is the most important RBC index?
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Mean corpuscular volume (MCV)
-- avg size of a red cell among the pt's population of RBCs. -- used to classify anemia as normo, micro, or macrocytic |
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Describe the function of Granulocyte colony stimulating factor (G-CSF).
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Stimulates granulocyte growth and development
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Therapeutic use of G-CSF?
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1. following chemotherapy
2. following BM transplantation |
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Describe the fxn of Granulocyte-macrophage colony stimulating factor (MG-CSF).
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Stimulates early precursors as well as more mature granulocytic cells
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Therapeutic use of GM-CSF?
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Similar to G-CSF
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Describe the fxn of interleukin-11 (IL-11).
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IL-11 stimulates megakaryocytes (platelet precursor cells)
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Therapeutic use of IL-11?
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Used following chemotherapy to increase platelet count
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List some other important cytokines and their fxns that are NOT commonly used as drugs.
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IL-2 -- lymphocyte development and activation
IL-3 -- general growth factor for all hematopoietic cells IL-6 -- inflammatory mediator thrombopoietin -- growth and differentiation factor for megakaryocytes stem cell factor -- survival factor for very immature hematopoietic cells |
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Describe the function of Granulocyte colony stimulating factor (G-CSF).
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Stimulates granulocyte growth and development
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Which cytokines can INHIBIT bone marrow hematopoiesis?
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a-interferon and TNF
a-interferon is used clinically to treat chronic myelogenous leukemia (CML) |
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Therapeutic use of G-CSF?
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1. following chemotherapy
2. following BM transplantation |
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Describe the hematopoietic receptor superfamily.
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-- small, span the plasma mbrn once, and generally DO NOT have intrinsic kinase activity.
-- once bound by approp cytokine, form dimeric mbrn cmplx w/ either a second identical receptor (homodimer), or w/ another receptor unit (heterodimer) -- dimeric cmplx activates tyrosine kinases that set into motion a signal transduction cascade for division or differentiation |
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Describe the fxn of Granulocyte-macrophage colony stimulating factor (MG-CSF).
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Stimulates early precursors as well as more mature granulocytic cells
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Describe cell types that comprise the stroma.
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1. endothelial cells
2. fibroblasts 3. fat cells 4. macrophages 5. extracellular matrix composed of collagen, fibronectin, and proteoglycans -- contains binding sites for developing hematopoietic precursor cells |
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Therapeutic use of GM-CSF?
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Similar to G-CSF
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Describe the fxn of interleukin-11 (IL-11).
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IL-11 stimulates megakaryocytes (platelet precursor cells)
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Stroma fxn?
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1. rich source of hematopoietic cytokines
-- close juxtaposition of stromal cells w/ developing BM permits high local conc of cytokines, facilitating differentiation -- in this setting, cytokines fxn as paracrine hormones 2. regulation of egress from the bone marrow |
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Therapeutic use of IL-11?
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Used following chemotherapy to increase platelet count
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List some other important cytokines and their fxns that are NOT commonly used as drugs.
|
IL-2 -- lymphocyte development and activation
IL-3 -- general growth factor for all hematopoietic cells IL-6 -- inflammatory mediator thrombopoietin -- growth and differentiation factor for megakaryocytes stem cell factor -- survival factor for very immature hematopoietic cells |
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Which cytokines can INHIBIT bone marrow hematopoiesis?
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a-interferon and TNF
a-interferon is used clinically to treat chronic myelogenous leukemia (CML) |
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Describe the hematopoietic receptor superfamily
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-- small, span the plasma mbrn once, and generally DO NOT have intrinsic kinase activity.
-- once bound by approp cytokine, form dimeric mbrn cmplx w/ either a second identical receptor (homodimer), or w/ another receptor unit (heterodimer) -- dimeric cmplx activates tyrosine kinases that set into motion a signal transduction cascade for division or differentiation |
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Describe cell types that comprise the stroma.
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1. endothelial cells
2. fibroblasts 3. fat cells 4. macrophages 5. extracellular matrix composed of collagen, fibronectin, and proteoglycans -- contains binding sites for developing hematopoietic precursor cells |
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Stroma fxn?
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1. rich source of hematopoietic cytokines
-- close juxtaposition of stromal cells w/ developing BM permits high local conc of cytokines, facilitating differentiation -- in this setting, cytokines fxn as paracrine hormones 2. Regulation of egress cells from the bone marrow |
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1. rich source of hematopoietic cytokines
-- close juxtaposition of stromal cells w/ developing BM permits high local conc of cytokines, facilitating differentiation -- in this setting, cytokines fxn as paracrine hormones |
1. adhesion molecules on surfaces of maturing blood cells bind to stromal cells and CT to retain cells in BM until maturation is complete
2. cells must penetrate pores in the endothelium that are much smaller than an RBC -- cells w/o nuclei (RBCs) -- cells w/ very distensible nuclei (PMNs, monocytes, lymphocytes, stem cells) Abnormalities involving either of the above regulatory steps can occur in pathologic conditions such as leukemias, causing release of immature cells into peripheral blood. |
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What are the essential nutrients needed for hematopoiesis?
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insulin
GH TH insulin-like growth factor Other impt nutrients include: Fe (Hb synth) B12 folic acid |
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Relationship of hematocrit vs. hemoglobin?
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Hct is usually about 3x the Hb
EX: Hct of 45% would occur w/ Hb of 15gm/dL |
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Which is the most important RBC index?
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Mean corpuscular volume (MCV)
-- avg size of a red cell among the pt's population of RBCs. -- used to classify anemia as normo, micro, or macrocytic |
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What is a differential count?
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It reports the distribution of the various WBC types in the total WBC count
-- reported as both a percent and an absolute number |
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What does a decrease in more than one cell line suggest?
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It suggests a general decrease in BM fxn -- especially if there is a decrease in all three cell lines (pancytopenia)
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What does a decrease in only one cell line suggest?
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Usually due to processes that occur to the blood cells after they leave the marrow:
destruction loss sequestration Ex: anemia due to bleeding, or thrombocytopenia due to sequestration of platelets in the spleen |
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Tear drop cells suggest?
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1. Replacement of bone marrow w/ fibrosis
2. Metastatic tumor |
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Large atypical lymphocytes suggest?
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viral illness as the cause of low cell counts
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Hypogranular platelets suggest?
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Myelodysplastic syndrome as a cause of marrow failure
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Very immature myeloid cells (myeloblasts) in a peripheral smear suggest?
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myeloid leukemia in the bone marrow
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What is the gold standard for determination of BM fxn?
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Bone marrow biopsy and aspiration
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What % cellularity should we see in a core biopsy?
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Should be roughly 100% minus the patient's age.
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What does DECREASED cellularity in a BM biopsy suggest?
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hematopoietic suppression by:
-- drugs -- chemotherapy -- certain viral infections -- an autoimmune process such as aplastic anemia |
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What does INCREASED cellularity in a BM biopsy suggest?
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-- hematologic malignancies
-- myelodysplastic syndromes -- HIV disease |
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The core biopsy is also examined for infiltrative diseases such as...?
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metastatic solid tumors
hematologic malignancies infections fibrosis |
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A BM Aspirate can be used to examine...
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individual cells -- the presence and normal maturation of all three primary cell types
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Megaloblastic changes in a BM aspirate suggest?
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1. B12/folate deficiency
2. drugs that disturb DNA metabolism -- chemotherapy -- sulfa drugs -- antivirals |
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Megaloblastoid changes in a BM aspirate suggest?
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myelodysplastic syndromes
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The BM aspirate can be sent for cytogenetic analysis to look for which malignancies?
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1. CHRONIC MYELOID LEUKEMIA - translocation involving chrom 9 and 22 [t(9,22)]; also known as Philadelphia chromosome
2. FOLLICULAR CENTER CELL LYMPHOMA - t(14,18) |
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What, in general, can cause BM failure?
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Any process that disrupts the stroma, the stem cells, the committed precursors, or that occupies marrow space
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What is the first evidence of BM failure?
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pancytopenia
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Which primary hematologic malignancies can cause BM failure?
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1. Acute and chronic leukemias
2. Hodgkin's and non-Hodgkin's lymphoma 3. Multiple Myeloma 4. Myelodysplastic syndrome |
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What is myelodysplastic syndrome?
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a "pre-malignant" condition which causes hypercellular marrow that paradoxically results in peripheral cytopenia -- usually as result of ineffective hematopoiesis (premature cell death) if precursors in the marrow.
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What infiltrative processes can cause BM failure?
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1. Metastatic tumors -- breast, colon, prostate, lung can occupy marrow space and crowd out normal hematopoiesis
2. Fibrosis from myeloprolif diseases or as result of previous marrow injury (radiation, drugs) 3. Granulomas in disseminated TB or sarcoidosis |
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What is an important clue in the peripheral blood smear for the presence of an infiltrative process in the marrow?
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tear-drop RBCs
leukoerythroblastic reaction -- presence of immature WBCs and nucleated RBCs |
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How do we diagnose BM failure due to infiltration?
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bone marrow biopsy and aspiration
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What processes can suppress the BM?
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1. DRUGS & TOXINS -- sulfa drugs, chemotherapy, anti-epileptics, antibiotics, benzene, pesticides
2. ETOH -- common cause of mild to moderate pancytopenia 3. GVHD -- following allogeneic BM transplant, or rarely, following blood transfusion in the elderly or immunosuppressed pt 4. WHOLE BODY IRRADIATION |
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How do we Dx BM failure due to suppression?
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BM biopsy and aspiration in conjxn w/ clinical data
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What infectious processes can suppress the BM?
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1. VIRAL - EBV, CMV, end stage HIV, viral Hep (usually non-A,B,C)
2. FUNGAL - histoplasmosis, aspergillis 3. MYCOBACTERIAL INFECTION |
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How do we Dx BM failure due to an infectious process?
Tx? |
BM biopsy and aspiration in conjxn w/ serologies, culture, etc.
Tx is to treat underlying condition; BM failure due to viral Hep is usually autoimmune in nature |
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What is Idiopathic Aplastic Anemia?
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Complex disease that may have either an autoimmune or a clonal (premalig) stem cell origin (or both).
1. AUTOIMMUNE -- T cell inhib of BM precursor cells that display novel autoAg. Inhib cytokines are elaborated by the activated T cells potently inhib hematopoiesis. 2. CLONAL -- likely b/c IAA is assoc w/ stem cell disorder paroxysmal nocturnal hemoglobinuria (PNH); can progress to acute leukemia |
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How do we Dx aplastic anemia?
Tx? |
BM biopsy demonstrating aplasia -- the decrease or absence of hematopoietic cells
Tx: allogeneic stem cell or BM transplantation (patients under 40) OR immunosuppression w/ anti-thymocyte globulin (ATG), cyclosporine, and prednisone |
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What is Fanconi's anemia?
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An inherited cause of BM failure
-- autosomal recessive -- pancytopenia -- defects of skin, musculoskeletal, and urogenital tissues -- caused by defects in DNA repair -- hematopoietic stem cells accumulate DNA damage leading to apoptosis |
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How do we Dx Fanconi's anemia?
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Chemically induce DNA damage in cultured lymphocytes.
-- Normal lymphocytes -- can repair most of the damage -- FA -- dramatic increase in DNA strand breaks, translocations, etc. |
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Tx of Fanconi's anemia?
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-- corticosteroids and androgens are often successful in partially correcting pancytopenia
-- more recently, stem cell/BM transplant has been successful |
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Major concern about pt's with treated Fanconi's anemia?
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Underlying defect in DNA repair causes susceptibility to other cancers that may ultimately limit the ability of any of these modalities to effect long term survival.
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