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Hematopoiesis 06 07
 

Hematopoiesis 06 07

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    Hematopoiesis 06 07 Hematopoiesis 06 07 Presentation Transcript

    • Hematopoiesis www.freelivedoctor.com
    • Hematopoiesis general
      • myeloid tissue
      • lymphoid tissue
      www.freelivedoctor.com
    • Hematopoiesis general
      • myeloid tissue
      • bone marrow
      • lymphoid tissue
      www.freelivedoctor.com
    • Hematopoiesis general
      • myeloid tissue
      • bone marrow
      • erythrocytes
      • platelets
      • granulocytes
      • monocytes
      • lymphoid tissue
      www.freelivedoctor.com
    • Hematopoiesis general
      • myeloid tissue
      • bone marrow
      • erythrocytes
      • platelets
      • granulocytes
      • monocytes
      • lymphoid tissue
      • thymus
      • lymph nodes
      • spleen
      www.freelivedoctor.com
    • Development of Blood Cells
      • 3 wk : formation of blood islands from yolk sac
      • 6 wk : liver becomes hematopoietic organ
      • 6-8 wk : spleen (until 8th month)
      • 12-14wk : bone marrow (life-long)
      www.freelivedoctor.com
    • Development of Blood Cells
      • 3 wk : formation of blood islands from yolk sac
      • 6 wk : liver becomes hematopoietic organ
      • 6-8 wk :spleen (until 8th month)
      • 12-14wk : bone marrow (life-long)
      • Bone Marrow
        • red marrow
        • yellow marrow
      www.freelivedoctor.com
    • pluripotent stem cell committed stem cells Hematopoiesis www.freelivedoctor.com lymphoid stem cell trilineage myeloid stem cell
    • Hematopoiesis www.freelivedoctor.com Proliferative potential differentiation
    • Normal Marrow Composition granulocytes & precursors erythroid precursors Lymphocytes, monocytes unidentified or disintegrated cells www.freelivedoctor.com 60% 20% 10% 10%
    • Normal Marrow
      • myeloid to erythroid ratio = 3 : 1
      • dominant myeloid cells
      • myelocytes
      • metamyelocytes
      • granulocytes
      • dominant erythroid cells
      • polychromatophilic normoblasts
      • orthochromic normoblasts
      www.freelivedoctor.com
    • Myeloblast
      • cell division: +
      • ~2% of nucleated cells in BM
      • size: 8-13  m diameter
      • cytoplasm: basophilic (many free ribosomes) no granules
      • nucleus: undifferentiated round to ovoid coarse nucleoli --> sieve-like appearance
      www.freelivedoctor.com
    • Promyelocyte
      • cell division: +
      • ~5% of nucleated cells in BM
      • size: 20  m diameter
      • cytoplasm: deep blue azurophilic granules abundant rER, free ribosome numerous mitochondria well developed Golgi
      • nucleus: round to ovoid occasionally indented prominent nucleoli
      www.freelivedoctor.com
    • Myelocyte
      • cell division: +
      • 5-20% of nucleated cells in BM
      • cytoplasm: specific granules decreased in basophilia
      • nucleus: ovoid irregular shape disappearing of nucleoli dense and compact chromatin
      www.freelivedoctor.com
    • Metamyelocyte
      • no more cell division
      • ~22% of nucleated cells in BM
      • size: 10-18  m diameter (slightly larger than mature PMN)
      • cytoplasm: prominent secondary granules
      • nucleus: slightly indented, kidney-shaped dense chromatin no nucleolus
      www.freelivedoctor.com
    • Granulocyte maturation
      • stem cell: <0.1%
      • myeloblasts: ~2% promyelocytes: ~5%
      • myelocytes: 5-20%
      • metamyelocytes: ~22%
      • granular leukocytes
      www.freelivedoctor.com
    • Lifespan of blood cells
      • RBC 120 days
      • platelet 10 days
      • granulocytes circ : 9 hours
      • tissue : days
      • lymphocyte circ : variable (hours to years)
      • tissue : weeks to years
      www.freelivedoctor.com
    • Hematopoietic Microenvironment
      • stem cell(s)
      • stromal cells
      • growth factors
      • stimulation
      www.freelivedoctor.com
    • Hematopoietic Response hypoxia infection antigen hemorrhage www.freelivedoctor.com RBC granulocyte/monocyte lymphocyte platelet
    • Hematopoietic Microenvironment Stromal cells : fibroblasts endothelial cells adipocytes www.freelivedoctor.com Growth Factors
    • Hematopoietic Growth Factors ( SCF, IL-6, GM-CSF , etc.)
      • glycoprotein hormones
      • secreted by
        • bone marrow stromal cells
        • T-cells
        • monocytes
      • regulate division and differentiation of hematopoietic cells
      • responsible for basal hematopoiesis and maintaining blood counts in normal ranges
      • greatly increased secretion in response to infection
      www.freelivedoctor.com
    • Basal Hematopoiesis G-CSF SCF: stem cell factor GM-CSF: granulocyte-macrophage colony-stimulating factor G-CSF: granulocyte colony-stimulating factor www.freelivedoctor.com SCF IL-6 GM-CSF
    • Antigen-amplified hematopoiesis www.freelivedoctor.com TNF  IL-3 GM-CSF IL-4 IL-1 TNF  IL-1 SCF IL-6 GM-CSF G-CSF Ag Ag
    • Hematopoietic Growth Factors (IL-6, GM-CSF, SCF, etc.)
      • Bacterial & viral products
      • monocyte
      IL-1 TNF  G-CSF M-CSF T-cell GM-CSF IL-3 Fibroblast Endothelial cell IL-6 GM-CSF G-CSF www.freelivedoctor.com
    • Hematopoiesis GROWTH FACTORS ERYTHROPOIESIS GRANULOPOIESIS MEGAKARYOPOIESIS LYMPHOPOIESIS generation of each specific lineage of mature blood cells is regulated by a specific set of hematopoietic growth factors. www.freelivedoctor.com
    • Erythropoiesis
      • erythropoietin-independent stage:
        • GM-CSF
        • SCF
      • erythropoietin-dependent stage:
        • erythropoietin
      marrow stromal cells IL-3 (activated T-cells) hypoxia(liver, kidney) www.freelivedoctor.com
      • early phase:
      • Neutropoiesis:
      • Monopoiesis:
      • Eosinopoiesis:
      • Basopoiesis,Mastpoiesis:
      Granulopoiesis G-CSF M-CSF www.freelivedoctor.com GM-CSF SCF IL-3 IL-5 IL-3 GM-CSF SCF IL-3
    • Megakaryopoiesis
      • may also play a role
      GM-CSF IL-3 SCF IL-6 www.freelivedoctor.com
    • Lymphopoiesis
      • B-cells:
        • initial stage:
        • later stage:
        • final proliferation and Ab secretion:
      • T-cells:
      • CD8 cells:
      • CD4 cells:
      www.freelivedoctor.com IL-7 SCF Fcg rec IL-4 IL-6 GM-CSF IL-6 IL-2 Ag TCR/CD3 CD28
    • B-cell maturation www.freelivedoctor.com
    • B-cell transformation www.freelivedoctor.com
    • Lymph node www.freelivedoctor.com
    • Spleen www.freelivedoctor.com
    • T-cell transformation www.freelivedoctor.com
    • Markers
      • Stem cell: CD34, c-kit rhodamine, Hoechst dyes (pale)
      • B-cell: CD19, CD20, (CD22), CD79a
      • T-cell: CD3, CD2, CD5, CD4/CD8
      • NK-cell: CD16, CD57, CD56
      www.freelivedoctor.com
    • RBC variation and irregularity www.freelivedoctor.com
    • anisocytosis poikilocytosis
      • anisocytosis (aniso = unequal)
      • various sizes
      • poikilocytosis (poikilo = various)
      • various shapes
      www.freelivedoctor.com
    • elliptocytes
      • - heredirary elliptocytosis
      • - iron def. anemia
      • myelofibrosis with myeloid metaplasia
      • - megaloblastic anemia
      • - sickle cell anemia
      • - normal (<10% of cells)
      www.freelivedoctor.com
    • spherocytes
      • - hereditary spherocytosis
      • - acquired hemolytic anemia (e.g. AIHA)
      • - physical or chemical injury
        • - heat
      www.freelivedoctor.com
    • leptocytes (target cells)
      • - liver disease
      • (obstructive jaundice)
      • - post splenectomy
      • - hemoglobinopathies
      • (hypochromic anemias)
        • thalassemia
        • Hgb C disease
        • Hgb H disease
      beta thalassemia relative increase of cell membrane --> “target” formation www.freelivedoctor.com
    • schistocytes (cell fragments)
      • indication of hemolysis
      • - megaloblastic anemia
      • - severe burns
      • - traumatic hemolysis
      • - microangiopathic hemolytic anemia (helmet cells, triangular cells)
      “ helmet cell” www.freelivedoctor.com
    • acanthocytes (irregular surface spicules)
      • irregularly spiculated cells
      • with bulbous/rounded ends of spicules
      • - abetalipoproteinemia
      • - liver disease
      www.freelivedoctor.com
    • echinocytes (crenated cells, burr cells)
      • regularly contracted cells with smooth surface undulation
      • - uremia
      • - artifact
      • - hyperosmolarity
      • - discocyte-echinocyte transformation (may be associated with reduced ATP of RBCs)
      www.freelivedoctor.com
    • bite cells
      • Removal (“bites”) of membrane by splenic macrophages
      • - G6PD deficiency
      www.freelivedoctor.com
    • dacrocytes (teardrop cells)
      • - thalassemia
      • - myelofibrosis
      www.freelivedoctor.com
    • drepanocytes (sickle cells)
      • - sickle cell anemia
      www.freelivedoctor.com
    • rouleaux
      • lined up RBCs in a row
      • - multiple myeloma
      www.freelivedoctor.com
    • basophilic stippling
      • irregular basophilic granules
      • (remnants of RNA)
      • fine stippling :
      • increased production of RBCs (reticulocytosis)
      • coarse stippling :
      • lead poisoning
      • impaired Hgb syntheisis
      • megaloblastic anemia
      • other sever anemias
      www.freelivedoctor.com
    • sideroblast/siderocyte
      • inorganic iron-containing granules (Pappenheimer bodies)
      • - sideroblastic anemia
      • abnormally trapped iron in mitochondria forming a ring around nucleus
      • - post splenectomy
      www.freelivedoctor.com ring sideroblasts intermediate sideroblast siderocyte
    • Howell-Jolly body
      • remnant of nuclear chromatin
      • single:
        • megaloblastic anemia
        • hemolytic anemia
        • post splenectomy
      • multiple:
        • megaloblastic anemia
        • other abnormal erythropoiesis
      www.freelivedoctor.com
    • Heinz bodies
      • denatured hemoglobin
      • - G6PD deficiency
      www.freelivedoctor.com
    • leukemoid reaction
      • an excessive leukocytic response
      • leukocytosis of 50 x10 9 /L or higher with shift to the left
      • or
      • lower counts with considerable numbers of immature granulocytes
      • quantitative or qualitative changes in lymphocytes or monocytes
      www.freelivedoctor.com
    • leukemoid reaction hemolysis hemorrhage malignancy Hodgkin disease myelofibrosis TB burns eclampsia parasite infectious lymphocytosis pertussis TB www.freelivedoctor.com neutrophilic eosinophilic lymphocytic
    • leukoerythroblastic reaction solid tumors lymphomas myeloprolif dis acute leukemias benign hematologic conditions hemolysis misc. www.freelivedoctor.com
    • reactive WBC proliferations
      • leukocytosis
        • (1) increased PMN
          • i. increased production
            • a. acute inflammation
              • - pyogenic bacterial infection
              • - tissue necrosis
          • ii. increased release of stored RBCs from BM
            • a. corticosteroids
            • b. stress
            • c. endotoxin
      www.freelivedoctor.com
    • increased PMN
      • (1) increased bands (“left shift”)
      • (2) reactive morphologic changes
        • a. Döhle bodies (aggregates of rough ER)
        • b. toxic granulations (prominent granules)
        • c. cytoplasmic vacuoles
      • (3) increased leukocyte alkaline phosphatase (LAP)
       neoplasm (CML) : decreased LAP www.freelivedoctor.com
    • reactive WBC proliferations
      • leukocytosis
        • (2) increased eosinophils
          • i. allergies & asthma (type I hypersensitivity reaction)
          • ii. parasites
          • iii. drugs
          • iv. certain skin diseases
          • v. cancer (adenocarcinoma)
      www.freelivedoctor.com
    • reactive WBC proliferations
      • leukocytosis
        • (3) increased monocytes (monocytosis)
          • i. chronic disorders
            • a. collagen vascular diseases
            • b. inflammatory bowel disease (IBD)
          • ii. infection
            • a. TB
      www.freelivedoctor.com
    • reactive WBC proliferations
      • leukocytosis
        • (4) increased lymphocytes (lymphocytosis)
          • i. viral diseases
            • a. infectious mononucleosis
          • ii. chronic inflammatory process
      www.freelivedoctor.com
    • infectious mononucleosis
      • - one of causes of lymphocytosis
      • - a virus-induced disease
        • Epstein-Barr virus (EBV)
        • CMV
      www.freelivedoctor.com
      • (1) EBV invades B-cell via CD21 (CR2)
      • (2) cytotoxic (CD8) T-cells respond against invaded B-cells
      infectious mononucleosis pathophysiology CD8 T-cells Atypical lymphocytes (Downey cells) Monocyte-like appearance (“mononucleosis”) Peripheral condensation of cytoplasm (“ballerina skirt” appearance) [enlargement] www.freelivedoctor.com
      • (3) heterophil antibody production
        • (heterophil antibody : antibody against other species)
        • monospot test (Paul-Bunnell reaction)
          • checking for heterophil antibody
        • CMV-infectious mono: usually heterophil Ab neg
      infectious mononucleosis www.freelivedoctor.com
      • patient population:
        • adolescents and young adults
        • (“kissing disease”)
      • Sx: “triad” plus one
        • Fever
        • Sore throat (gray-white memb. on tonsils)
        • Lymphadenitis (post auricular nodes)
        • Hepatosplenomegaly
        • self-limited clinical course (resolving in 4-6 wks)
      infectious mononucleosis www.freelivedoctor.com
      • complications:
        • hepatic dysfunction (“hepatitis”)
        • splenic rupture
        • rash (if treated with ampicillin)
      infectious mononucleosis www.freelivedoctor.com
    • lymphadenopathy
      • acute non-specific lymphadenopathy
          • tender enlargement of lymph nodes
        • bacterial lymphadenitis
          • usually focal involvemnt
          • may see PMNs within lymph nodes
          • stellate microabscesses = Cat-scratch Dz
        • viral infection
          • usually generalized involvement
          • reactive T-cell immunoblasts (LN & peripheral blood)
      www.freelivedoctor.com
    • lymphadenopathy
      • chronic non-specific lymphadenopathy
          • non-tender enlargement of lymph nodes
        • follicular hyperplasia (B-cells)
            • rheumatoid arthritis
            • toxoplasmosis
            • early HIV infection
        • paracortical lymphoid hyperplasia (T-cells)
            • viral infection
            • drugs (Dilantin)
            • systemic lupus erythematosus (SLE)
        • sinus histiocytosis (macrophages)
      www.freelivedoctor.com
    • www.freelivedoctor.com