Hematopoiesis 06 07

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Hematopoiesis 06 07

  1. 1. Hematopoiesis www.freelivedoctor.com
  2. 2. Hematopoiesis general <ul><li>myeloid tissue </li></ul><ul><li>lymphoid tissue </li></ul>www.freelivedoctor.com
  3. 3. Hematopoiesis general <ul><li>myeloid tissue </li></ul><ul><li>bone marrow </li></ul><ul><li>lymphoid tissue </li></ul>www.freelivedoctor.com
  4. 4. Hematopoiesis general <ul><li>myeloid tissue </li></ul><ul><li>bone marrow </li></ul><ul><li>erythrocytes </li></ul><ul><li>platelets </li></ul><ul><li>granulocytes </li></ul><ul><li>monocytes </li></ul><ul><li>lymphoid tissue </li></ul>www.freelivedoctor.com
  5. 5. Hematopoiesis general <ul><li>myeloid tissue </li></ul><ul><li>bone marrow </li></ul><ul><li>erythrocytes </li></ul><ul><li>platelets </li></ul><ul><li>granulocytes </li></ul><ul><li>monocytes </li></ul><ul><li>lymphoid tissue </li></ul><ul><li>thymus </li></ul><ul><li>lymph nodes </li></ul><ul><li>spleen </li></ul>www.freelivedoctor.com
  6. 6. Development of Blood Cells <ul><li>3 wk : formation of blood islands from yolk sac </li></ul><ul><li>6 wk : liver becomes hematopoietic organ </li></ul><ul><li>6-8 wk : spleen (until 8th month) </li></ul><ul><li>12-14wk : bone marrow (life-long) </li></ul>www.freelivedoctor.com
  7. 7. Development of Blood Cells <ul><li>3 wk : formation of blood islands from yolk sac </li></ul><ul><li>6 wk : liver becomes hematopoietic organ </li></ul><ul><li>6-8 wk :spleen (until 8th month) </li></ul><ul><li>12-14wk : bone marrow (life-long) </li></ul><ul><li>Bone Marrow </li></ul><ul><ul><li>red marrow </li></ul></ul><ul><ul><li>yellow marrow </li></ul></ul>www.freelivedoctor.com
  8. 8. pluripotent stem cell committed stem cells Hematopoiesis www.freelivedoctor.com lymphoid stem cell trilineage myeloid stem cell
  9. 9. Hematopoiesis www.freelivedoctor.com Proliferative potential differentiation
  10. 10. Normal Marrow Composition granulocytes & precursors erythroid precursors Lymphocytes, monocytes unidentified or disintegrated cells www.freelivedoctor.com 60% 20% 10% 10%
  11. 11. Normal Marrow <ul><li>myeloid to erythroid ratio = 3 : 1 </li></ul><ul><li>dominant myeloid cells </li></ul><ul><li>myelocytes </li></ul><ul><li>metamyelocytes </li></ul><ul><li>granulocytes </li></ul><ul><li>dominant erythroid cells </li></ul><ul><li>polychromatophilic normoblasts </li></ul><ul><li>orthochromic normoblasts </li></ul>www.freelivedoctor.com
  12. 12. Myeloblast <ul><li>cell division: + </li></ul><ul><li>~2% of nucleated cells in BM </li></ul><ul><li>size: 8-13  m diameter </li></ul><ul><li>cytoplasm: basophilic (many free ribosomes) no granules </li></ul><ul><li>nucleus: undifferentiated round to ovoid coarse nucleoli --> sieve-like appearance </li></ul>www.freelivedoctor.com
  13. 13. Promyelocyte <ul><li>cell division: + </li></ul><ul><li>~5% of nucleated cells in BM </li></ul><ul><li>size: 20  m diameter </li></ul><ul><li>cytoplasm: deep blue azurophilic granules abundant rER, free ribosome numerous mitochondria well developed Golgi </li></ul><ul><li>nucleus: round to ovoid occasionally indented prominent nucleoli </li></ul>www.freelivedoctor.com
  14. 14. Myelocyte <ul><li>cell division: + </li></ul><ul><li>5-20% of nucleated cells in BM </li></ul><ul><li>cytoplasm: specific granules decreased in basophilia </li></ul><ul><li>nucleus: ovoid irregular shape disappearing of nucleoli dense and compact chromatin </li></ul>www.freelivedoctor.com
  15. 15. Metamyelocyte <ul><li>no more cell division </li></ul><ul><li>~22% of nucleated cells in BM </li></ul><ul><li>size: 10-18  m diameter (slightly larger than mature PMN) </li></ul><ul><li>cytoplasm: prominent secondary granules </li></ul><ul><li>nucleus: slightly indented, kidney-shaped dense chromatin no nucleolus </li></ul>www.freelivedoctor.com
  16. 16. Granulocyte maturation <ul><li>stem cell: <0.1% </li></ul><ul><li>myeloblasts: ~2% promyelocytes: ~5% </li></ul><ul><li>myelocytes: 5-20% </li></ul><ul><li>metamyelocytes: ~22% </li></ul><ul><li>granular leukocytes </li></ul>www.freelivedoctor.com
  17. 17. Lifespan of blood cells <ul><li>RBC 120 days </li></ul><ul><li>platelet 10 days </li></ul><ul><li>granulocytes circ : 9 hours </li></ul><ul><li>tissue : days </li></ul><ul><li>lymphocyte circ : variable (hours to years) </li></ul><ul><li>tissue : weeks to years </li></ul>www.freelivedoctor.com
  18. 18. Hematopoietic Microenvironment <ul><li>stem cell(s) </li></ul><ul><li>stromal cells </li></ul><ul><li>growth factors </li></ul><ul><li>stimulation </li></ul>www.freelivedoctor.com
  19. 19. Hematopoietic Response hypoxia infection antigen hemorrhage www.freelivedoctor.com RBC granulocyte/monocyte lymphocyte platelet
  20. 20. Hematopoietic Microenvironment Stromal cells : fibroblasts endothelial cells adipocytes www.freelivedoctor.com Growth Factors
  21. 21. Hematopoietic Growth Factors ( SCF, IL-6, GM-CSF , etc.) <ul><li>glycoprotein hormones </li></ul><ul><li>secreted by </li></ul><ul><ul><li>bone marrow stromal cells </li></ul></ul><ul><ul><li>T-cells </li></ul></ul><ul><ul><li>monocytes </li></ul></ul><ul><li>regulate division and differentiation of hematopoietic cells </li></ul><ul><li>responsible for basal hematopoiesis and maintaining blood counts in normal ranges </li></ul><ul><li>greatly increased secretion in response to infection </li></ul>www.freelivedoctor.com
  22. 22. 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
  23. 23. 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
  24. 24. Hematopoietic Growth Factors (IL-6, GM-CSF, SCF, etc.) <ul><li>Bacterial & viral products </li></ul><ul><li>monocyte </li></ul>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
  25. 25. 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
  26. 26. Erythropoiesis <ul><li>erythropoietin-independent stage: </li></ul><ul><ul><li>GM-CSF </li></ul></ul><ul><ul><li>SCF </li></ul></ul><ul><li>erythropoietin-dependent stage: </li></ul><ul><ul><li>erythropoietin </li></ul></ul>marrow stromal cells IL-3 (activated T-cells) hypoxia(liver, kidney) www.freelivedoctor.com
  27. 27. <ul><li>early phase: </li></ul><ul><li>Neutropoiesis: </li></ul><ul><li>Monopoiesis: </li></ul><ul><li>Eosinopoiesis: </li></ul><ul><li>Basopoiesis,Mastpoiesis: </li></ul>Granulopoiesis G-CSF M-CSF www.freelivedoctor.com GM-CSF SCF IL-3 IL-5 IL-3 GM-CSF SCF IL-3
  28. 28. Megakaryopoiesis <ul><li>may also play a role </li></ul>GM-CSF IL-3 SCF IL-6 www.freelivedoctor.com
  29. 29. Lymphopoiesis <ul><li>B-cells: </li></ul><ul><ul><li>initial stage: </li></ul></ul><ul><ul><li>later stage: </li></ul></ul><ul><ul><li>final proliferation and Ab secretion: </li></ul></ul><ul><li>T-cells: </li></ul><ul><li>CD8 cells: </li></ul><ul><li>CD4 cells: </li></ul>www.freelivedoctor.com IL-7 SCF Fcg rec IL-4 IL-6 GM-CSF IL-6 IL-2 Ag TCR/CD3 CD28
  30. 30. B-cell maturation www.freelivedoctor.com
  31. 31. B-cell transformation www.freelivedoctor.com
  32. 32. Lymph node www.freelivedoctor.com
  33. 33. Spleen www.freelivedoctor.com
  34. 34. T-cell transformation www.freelivedoctor.com
  35. 35. Markers <ul><li>Stem cell: CD34, c-kit rhodamine, Hoechst dyes (pale) </li></ul><ul><li>B-cell: CD19, CD20, (CD22), CD79a </li></ul><ul><li>T-cell: CD3, CD2, CD5, CD4/CD8 </li></ul><ul><li>NK-cell: CD16, CD57, CD56 </li></ul>www.freelivedoctor.com
  36. 36. RBC variation and irregularity www.freelivedoctor.com
  37. 37. anisocytosis poikilocytosis <ul><li>anisocytosis (aniso = unequal) </li></ul><ul><li>various sizes </li></ul><ul><li>poikilocytosis (poikilo = various) </li></ul><ul><li>various shapes </li></ul>www.freelivedoctor.com
  38. 38. elliptocytes <ul><li>- heredirary elliptocytosis </li></ul><ul><li>- iron def. anemia </li></ul><ul><li>myelofibrosis with myeloid metaplasia </li></ul><ul><li>- megaloblastic anemia </li></ul><ul><li>- sickle cell anemia </li></ul><ul><li>- normal (<10% of cells) </li></ul>www.freelivedoctor.com
  39. 39. spherocytes <ul><li>- hereditary spherocytosis </li></ul><ul><li>- acquired hemolytic anemia (e.g. AIHA) </li></ul><ul><li>- physical or chemical injury </li></ul><ul><ul><li>- heat </li></ul></ul>www.freelivedoctor.com
  40. 40. leptocytes (target cells) <ul><li>- liver disease </li></ul><ul><li>(obstructive jaundice) </li></ul><ul><li>- post splenectomy </li></ul><ul><li>- hemoglobinopathies </li></ul><ul><li>(hypochromic anemias) </li></ul><ul><ul><li>thalassemia </li></ul></ul><ul><ul><li>Hgb C disease </li></ul></ul><ul><ul><li>Hgb H disease </li></ul></ul>beta thalassemia relative increase of cell membrane --> “target” formation www.freelivedoctor.com
  41. 41. schistocytes (cell fragments) <ul><li>indication of hemolysis </li></ul><ul><li>- megaloblastic anemia </li></ul><ul><li>- severe burns </li></ul><ul><li>- traumatic hemolysis </li></ul><ul><li>- microangiopathic hemolytic anemia (helmet cells, triangular cells) </li></ul>“ helmet cell” www.freelivedoctor.com
  42. 42. acanthocytes (irregular surface spicules) <ul><li>irregularly spiculated cells </li></ul><ul><li>with bulbous/rounded ends of spicules </li></ul><ul><li>- abetalipoproteinemia </li></ul><ul><li>- liver disease </li></ul>www.freelivedoctor.com
  43. 43. echinocytes (crenated cells, burr cells) <ul><li>regularly contracted cells with smooth surface undulation </li></ul><ul><li>- uremia </li></ul><ul><li>- artifact </li></ul><ul><li>- hyperosmolarity </li></ul><ul><li>- discocyte-echinocyte transformation (may be associated with reduced ATP of RBCs) </li></ul>www.freelivedoctor.com
  44. 44. bite cells <ul><li>Removal (“bites”) of membrane by splenic macrophages </li></ul><ul><li>- G6PD deficiency </li></ul>www.freelivedoctor.com
  45. 45. dacrocytes (teardrop cells) <ul><li>- thalassemia </li></ul><ul><li>- myelofibrosis </li></ul>www.freelivedoctor.com
  46. 46. drepanocytes (sickle cells) <ul><li>- sickle cell anemia </li></ul>www.freelivedoctor.com
  47. 47. rouleaux <ul><li>lined up RBCs in a row </li></ul><ul><li>- multiple myeloma </li></ul>www.freelivedoctor.com
  48. 48. basophilic stippling <ul><li>irregular basophilic granules </li></ul><ul><li>(remnants of RNA) </li></ul><ul><li>fine stippling : </li></ul><ul><li>increased production of RBCs (reticulocytosis) </li></ul><ul><li>coarse stippling : </li></ul><ul><li>lead poisoning </li></ul><ul><li>impaired Hgb syntheisis </li></ul><ul><li>megaloblastic anemia </li></ul><ul><li>other sever anemias </li></ul>www.freelivedoctor.com
  49. 49. sideroblast/siderocyte <ul><li>inorganic iron-containing granules (Pappenheimer bodies) </li></ul><ul><li>- sideroblastic anemia </li></ul><ul><li>abnormally trapped iron in mitochondria forming a ring around nucleus </li></ul><ul><li>- post splenectomy </li></ul>www.freelivedoctor.com ring sideroblasts intermediate sideroblast siderocyte
  50. 50. Howell-Jolly body <ul><li>remnant of nuclear chromatin </li></ul><ul><li>single: </li></ul><ul><ul><li>megaloblastic anemia </li></ul></ul><ul><ul><li>hemolytic anemia </li></ul></ul><ul><ul><li>post splenectomy </li></ul></ul><ul><li>multiple: </li></ul><ul><ul><li>megaloblastic anemia </li></ul></ul><ul><ul><li>other abnormal erythropoiesis </li></ul></ul>www.freelivedoctor.com
  51. 51. Heinz bodies <ul><li>denatured hemoglobin </li></ul><ul><li>- G6PD deficiency </li></ul>www.freelivedoctor.com
  52. 52. leukemoid reaction <ul><li>an excessive leukocytic response </li></ul><ul><li>leukocytosis of 50 x10 9 /L or higher with shift to the left </li></ul><ul><li>or </li></ul><ul><li>lower counts with considerable numbers of immature granulocytes </li></ul><ul><li>quantitative or qualitative changes in lymphocytes or monocytes </li></ul>www.freelivedoctor.com
  53. 53. leukemoid reaction hemolysis hemorrhage malignancy Hodgkin disease myelofibrosis TB burns eclampsia parasite infectious lymphocytosis pertussis TB www.freelivedoctor.com neutrophilic eosinophilic lymphocytic
  54. 54. leukoerythroblastic reaction solid tumors lymphomas myeloprolif dis acute leukemias benign hematologic conditions hemolysis misc. www.freelivedoctor.com
  55. 55. reactive WBC proliferations <ul><li>leukocytosis </li></ul><ul><ul><li>(1) increased PMN </li></ul></ul><ul><ul><ul><li>i. increased production </li></ul></ul></ul><ul><ul><ul><ul><li>a. acute inflammation </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- pyogenic bacterial infection </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- tissue necrosis </li></ul></ul></ul></ul></ul><ul><ul><ul><li>ii. increased release of stored RBCs from BM </li></ul></ul></ul><ul><ul><ul><ul><li>a. corticosteroids </li></ul></ul></ul></ul><ul><ul><ul><ul><li>b. stress </li></ul></ul></ul></ul><ul><ul><ul><ul><li>c. endotoxin </li></ul></ul></ul></ul>www.freelivedoctor.com
  56. 56. increased PMN <ul><li>(1) increased bands (“left shift”) </li></ul><ul><li>(2) reactive morphologic changes </li></ul><ul><ul><li>a. Döhle bodies (aggregates of rough ER) </li></ul></ul><ul><ul><li>b. toxic granulations (prominent granules) </li></ul></ul><ul><ul><li>c. cytoplasmic vacuoles </li></ul></ul><ul><li>(3) increased leukocyte alkaline phosphatase (LAP) </li></ul> neoplasm (CML) : decreased LAP www.freelivedoctor.com
  57. 57. reactive WBC proliferations <ul><li>leukocytosis </li></ul><ul><ul><li>(2) increased eosinophils </li></ul></ul><ul><ul><ul><li>i. allergies & asthma (type I hypersensitivity reaction) </li></ul></ul></ul><ul><ul><ul><li>ii. parasites </li></ul></ul></ul><ul><ul><ul><li>iii. drugs </li></ul></ul></ul><ul><ul><ul><li>iv. certain skin diseases </li></ul></ul></ul><ul><ul><ul><li>v. cancer (adenocarcinoma) </li></ul></ul></ul>www.freelivedoctor.com
  58. 58. reactive WBC proliferations <ul><li>leukocytosis </li></ul><ul><ul><li>(3) increased monocytes (monocytosis) </li></ul></ul><ul><ul><ul><li>i. chronic disorders </li></ul></ul></ul><ul><ul><ul><ul><li>a. collagen vascular diseases </li></ul></ul></ul></ul><ul><ul><ul><ul><li>b. inflammatory bowel disease (IBD) </li></ul></ul></ul></ul><ul><ul><ul><li>ii. infection </li></ul></ul></ul><ul><ul><ul><ul><li>a. TB </li></ul></ul></ul></ul>www.freelivedoctor.com
  59. 59. reactive WBC proliferations <ul><li>leukocytosis </li></ul><ul><ul><li>(4) increased lymphocytes (lymphocytosis) </li></ul></ul><ul><ul><ul><li>i. viral diseases </li></ul></ul></ul><ul><ul><ul><ul><li>a. infectious mononucleosis </li></ul></ul></ul></ul><ul><ul><ul><li>ii. chronic inflammatory process </li></ul></ul></ul>www.freelivedoctor.com
  60. 60. infectious mononucleosis <ul><li>- one of causes of lymphocytosis </li></ul><ul><li>- a virus-induced disease </li></ul><ul><ul><li>Epstein-Barr virus (EBV) </li></ul></ul><ul><ul><li>CMV </li></ul></ul>www.freelivedoctor.com
  61. 61. <ul><li>(1) EBV invades B-cell via CD21 (CR2) </li></ul><ul><li>(2) cytotoxic (CD8) T-cells respond against invaded B-cells </li></ul>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
  62. 62. <ul><li>(3) heterophil antibody production </li></ul><ul><ul><li>(heterophil antibody : antibody against other species) </li></ul></ul><ul><ul><li>monospot test (Paul-Bunnell reaction) </li></ul></ul><ul><ul><ul><li>checking for heterophil antibody </li></ul></ul></ul><ul><ul><li>CMV-infectious mono: usually heterophil Ab neg </li></ul></ul>infectious mononucleosis www.freelivedoctor.com
  63. 63. <ul><li>patient population: </li></ul><ul><ul><li>adolescents and young adults </li></ul></ul><ul><ul><li>(“kissing disease”) </li></ul></ul><ul><li>Sx: “triad” plus one </li></ul><ul><ul><li>Fever </li></ul></ul><ul><ul><li>Sore throat (gray-white memb. on tonsils) </li></ul></ul><ul><ul><li>Lymphadenitis (post auricular nodes) </li></ul></ul><ul><ul><li>Hepatosplenomegaly </li></ul></ul><ul><ul><li>self-limited clinical course (resolving in 4-6 wks) </li></ul></ul>infectious mononucleosis www.freelivedoctor.com
  64. 64. <ul><li>complications: </li></ul><ul><ul><li>hepatic dysfunction (“hepatitis”) </li></ul></ul><ul><ul><li>splenic rupture </li></ul></ul><ul><ul><li>rash (if treated with ampicillin) </li></ul></ul>infectious mononucleosis www.freelivedoctor.com
  65. 65. lymphadenopathy <ul><li>acute non-specific lymphadenopathy </li></ul><ul><ul><ul><li>tender enlargement of lymph nodes </li></ul></ul></ul><ul><ul><li>bacterial lymphadenitis </li></ul></ul><ul><ul><ul><li>usually focal involvemnt </li></ul></ul></ul><ul><ul><ul><li>may see PMNs within lymph nodes </li></ul></ul></ul><ul><ul><ul><li>stellate microabscesses = Cat-scratch Dz </li></ul></ul></ul><ul><ul><li>viral infection </li></ul></ul><ul><ul><ul><li>usually generalized involvement </li></ul></ul></ul><ul><ul><ul><li>reactive T-cell immunoblasts (LN & peripheral blood) </li></ul></ul></ul>www.freelivedoctor.com
  66. 66. lymphadenopathy <ul><li>chronic non-specific lymphadenopathy </li></ul><ul><ul><ul><li>non-tender enlargement of lymph nodes </li></ul></ul></ul><ul><ul><li>follicular hyperplasia (B-cells) </li></ul></ul><ul><ul><ul><ul><li>rheumatoid arthritis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>toxoplasmosis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>early HIV infection </li></ul></ul></ul></ul><ul><ul><li>paracortical lymphoid hyperplasia (T-cells) </li></ul></ul><ul><ul><ul><ul><li>viral infection </li></ul></ul></ul></ul><ul><ul><ul><ul><li>drugs (Dilantin) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>systemic lupus erythematosus (SLE) </li></ul></ul></ul></ul><ul><ul><li>sinus histiocytosis (macrophages) </li></ul></ul>www.freelivedoctor.com
  67. 67. www.freelivedoctor.com

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