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hematopoiesis_06-07.ppt hematopoiesis_06-07.ppt Presentation Transcript

  • Hematopoiesis Masatoshi Kida, MD Dept. of Pathology University of Vermont
  • Hematopoiesis general
    • myeloid tissue
    • lymphoid tissue
  • Hematopoiesis general
    • myeloid tissue
    • bone marrow
    • lymphoid tissue
    View slide
  • Hematopoiesis general
    • myeloid tissue
    • bone marrow
    • erythrocytes
    • platelets
    • granulocytes
    • monocytes
    • lymphoid tissue
    View slide
  • Hematopoiesis general
    • myeloid tissue
    • bone marrow
    • erythrocytes
    • platelets
    • granulocytes
    • monocytes
    • lymphoid tissue
    • thymus
    • lymph nodes
    • spleen
  • 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)
  • 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
  • pluripotent stem cell committed stem cells Hematopoiesis lymphoid stem cell trilineage myeloid stem cell
  • Hematopoiesis Proliferative potential differentiation
  • Normal Marrow Composition granulocytes & precursors erythroid precursors Lymphocytes, monocytes unidentified or disintegrated cells 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
  • 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
  • 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
  • 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
  • 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
  • Granulocyte maturation
    • stem cell: <0.1%
    • myeloblasts: ~2% promyelocytes: ~5%
    • myelocytes: 5-20%
    • metamyelocytes: ~22%
    • granular leukocytes
  • 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
  • Hematopoietic Microenvironment
    • stem cell(s)
    • stromal cells
    • growth factors
    • stimulation
  • Hematopoietic Response hypoxia infection antigen hemorrhage RBC granulocyte/monocyte lymphocyte platelet
  • Hematopoietic Microenvironment Stromal cells : fibroblasts endothelial cells adipocytes 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
  • Basal Hematopoiesis G-CSF SCF: stem cell factor GM-CSF: granulocyte-macrophage colony-stimulating factor G-CSF: granulocyte colony-stimulating factor SCF IL-6 GM-CSF
  • Antigen-amplified hematopoiesis 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
  • 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.
  • Erythropoiesis
    • erythropoietin-independent stage:
      • GM-CSF
      • SCF
    • erythropoietin-dependent stage:
      • erythropoietin
    marrow stromal cells IL-3 (activated T-cells) hypoxia(liver, kidney)
    • early phase:
    • Neutropoiesis:
    • Monopoiesis:
    • Eosinopoiesis:
    • Basopoiesis,Mastpoiesis:
    Granulopoiesis G-CSF M-CSF 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
  • Lymphopoiesis
    • B-cells:
      • initial stage:
      • later stage:
      • final proliferation and Ab secretion:
    • T-cells:
    • CD8 cells:
    • CD4 cells:
    IL-7 SCF Fcg rec IL-4 IL-6 GM-CSF IL-6 IL-2 Ag TCR/CD3 CD28
  • B-cell maturation
  • B-cell transformation
  • Lymph node
  • Spleen
  • T-cell transformation
  • 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
  • RBC variation and irregularity
  • anisocytosis poikilocytosis
    • anisocytosis (aniso = unequal)
    • various sizes
    • poikilocytosis (poikilo = various)
    • various shapes
  • elliptocytes
    • - heredirary elliptocytosis
    • - iron def. anemia
    • myelofibrosis with myeloid metaplasia
    • - megaloblastic anemia
    • - sickle cell anemia
    • - normal (<10% of cells)
  • spherocytes
    • - hereditary spherocytosis
    • - acquired hemolytic anemia (e.g. AIHA)
    • - physical or chemical injury
      • - heat
  • 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
  • schistocytes (cell fragments)
    • indication of hemolysis
    • - megaloblastic anemia
    • - severe burns
    • - traumatic hemolysis
    • - microangiopathic hemolytic anemia (helmet cells, triangular cells)
    “ helmet cell”
  • acanthocytes (irregular surface spicules)
    • irregularly spiculated cells
    • with bulbous/rounded ends of spicules
    • - abetalipoproteinemia
    • - liver disease
  • 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)
  • bite cells
    • Removal (“bites”) of membrane by splenic macrophages
    • - G6PD deficiency
  • dacrocytes (teardrop cells)
    • - thalassemia
    • - myelofibrosis
  • drepanocytes (sickle cells)
    • - sickle cell anemia
  • rouleaux
    • lined up RBCs in a row
    • - multiple myeloma
  • 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
  • sideroblast/siderocyte
    • inorganic iron-containing granules (Pappenheimer bodies)
    • - sideroblastic anemia
    • abnormally trapped iron in mitochondria forming a ring around nucleus
    • - post splenectomy
    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
  • Heinz bodies
    • denatured hemoglobin
    • - G6PD deficiency
  • 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
  • leukemoid reaction hemolysis hemorrhage malignancy Hodgkin disease myelofibrosis TB burns eclampsia parasite infectious lymphocytosis pertussis TB neutrophilic eosinophilic lymphocytic
  • leukoerythroblastic reaction solid tumors lymphomas myeloprolif dis acute leukemias benign hematologic conditions hemolysis misc.
  • 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
  • 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
  • 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)
  • reactive WBC proliferations
    • leukocytosis
      • (3) increased monocytes (monocytosis)
        • i. chronic disorders
          • a. collagen vascular diseases
          • b. inflammatory bowel disease (IBD)
        • ii. infection
          • a. TB
  • reactive WBC proliferations
    • leukocytosis
      • (4) increased lymphocytes (lymphocytosis)
        • i. viral diseases
          • a. infectious mononucleosis
        • ii. chronic inflammatory process
  • infectious mononucleosis
    • - one of causes of lymphocytosis
    • - a virus-induced disease
      • Epstein-Barr virus (EBV)
      • CMV
    • (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]
    • (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
    • 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
    • complications:
      • hepatic dysfunction (“hepatitis”)
      • splenic rupture
      • rash (if treated with ampicillin)
    infectious mononucleosis
  • 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)
  • 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)
  •