1. PATHOLOGY OF BONE MARROW
Doç. Dr. Işın Doğan Ekici

2. The blood is a mixture of cellular elements, fluid, proteins and metabolites.

4. Functions of blood: Respiration, Nutrition, Waste elimination,
Thermoregulation,
Immune defense,
Acid-base balance,
Water balance,
Internal communication. 3

5. Blood has four major elements:
Red blood cells
White blood cells
Platelets
Plasma- proteinaceaus solution in which cells circulate and carries nutrients, metabolites, antibodies, hormones, proteins of blood clotting system and other molecules.

6. HEMOPOIESIS The site of blood formation
(hemopoiesis) changes several times during fetal development;
the earliest sites being the yolk sac and then the liver and spleen
at 5 months the fetal bone marrow begins to produce white cells and platelets
at 7 months red cell production starts in the marrow

7. In postnatal life, under normal circumstances, the formation of cellular elements of the blood (hemopoiesis) occurs in the bone marrow.

8. Bone marrow contains a stromal matrix which provides the correct microenvironment for stem cell growth. Embryo : Yolc Sac Fetus: Spleen/ Liver

10. Proliferation of the stem and progenitor cells is under control of the hormone-like inducers of growth and differantiation, produced by stromal cells of the microenvironment
STROMAL CELLS
Macrophages
Fibroblasts
Reticulum cells
Fat cells
Endothelial cells
EXTRACELLULAR MATRIX
Fibronectin
Hemonectin
Laminin
Collagen
Proteoglycan (acid mucopolysacharides e.g. chondroitin, heparan)

11. Blood islands in Yolk sac Liver* Spleen* & lymph nodes
SITES OF HEMATOPOIESIS embryonic
Blood islands in Yolk sac
Liver*
Spleen* & lymph nodes
Developing bones-Red marrow
* * In adult marrow disease*, these organs may again be sites of hematopoietic tissue - ectopic myeloid tissue
* e.g., myelofibrosis

12. HEMOPOIETIC PROGENITOR CELLS
All cellular elements of the blood originate from a common pluripotential progenitor stem cell (hemopoietic stem cell-hsc)
The main types of multipotential progenitor cell derive from the pluripotential hemopoietic stem cell
-lymphoid progenitor cells, which give rise to the different types of lymphocyte (B and Tcells types- -granulocyte/erythroid/monocyte/megakaryocyte (CFU-GEMM or CFU-MIX) which give rise to main
types of blood cell

13. The types of committed progenitor cell derived from the multipotential
CFU-GEMM (CFU-MIX) cells are:
erythroid (CFU-E), which give rise to red cell precursor cells
granulocyte/monocyte progenitor cells (CFU-GM), which give rise to granulocytes and monocytes by forming further subsets of specific progenitor cells (CFC-G and CFC-M)
eosinophil (CFU-Eo), which give rise to eosinophils
Basophil (CFU-Bas),which give rise to basophils
megakaryocytic (CFC-Meg), which give rise to megakaryocytes (and so platelets)

15. HEMATOPOIESIS Lineages
Lymphopoiesis
HEMATOPOIESIS Lineages
Monocytopoiesis
Granulopoiesis
stem
cell
Pluripotent stem cell
Erythropoiesis
Thrombopoiesis
Pro-erythroblast
Lymphoblast
Monoblast
Myeloblast
Megakaryoblast
Basophilic erythroblast
Pro-Myelocyte
Polychromatic erythroblast
Myelocyte
Orthocromatic erythroblast
Metamylelocyte
Reticulocyte
Megakaryocyte
Band granulocyte
Lymphocyte
RBC
Platelets
Granulocyte
Monocyte

16. { HEMATOPOIESIS Subdivisions Lymphopoiesis stem Granulopoiesis cell
PMN
Bas
Lym
Mon
Eos
Pla
RBC {
Lymphopoiesis
stem
cell
Granulopoiesis
Monocytopoiesis
Myelopoiesis
Erythropoiesis
Megakaryopoiesis Thrombopoiesis

17. HEMOPOIESIS
The pluripotential stem cells are found in very small numbers in blood cell formation sites and even smaller numbers in the peripheral blood.
The pluripotential stem cells divide and give rise to cells with a more retricted line of growth.

18. Blood cells have limited lifespans, and need to be replaced
with precisely matching numbers -
Hematocytopoiesis
Young replacing cells come, by many divisions and steps of differentiation, from stem cells
stem
cell
HEMATOPOIESIS

19. STEM CELLS KEEP REPLACEMENT GOING
STEM CELLS HAVE TO REPLACE THEMSELVES BY DIVISION, AS WELL AS TO PROVIDE CELLS TO DIFFERENTIATE
Symmetric division
The two ways this can happen are shown
stem
cell
Asymmetric division

20. Pluripotential stem cells are capable of forming any type of blood cell,
Multipotential progenitor cells are capable of forming a spesific but a wide range of blood cells,
Committed progenitor cells are capable of forming only one or two types of blood cell,
Maturing cells are undergoing structural differentiation to form one cell type and are incapable of division

23. THE BONE MARROW
The bone marrow is the main site of hemopoiesis-also contains macrophages which remove aged and defective red cells from the circulation by phagocytosis
Bone marrow has a highly developed set of vascular sinusoids
Bone marrow support cells have important roles in hemopoiesis-fibroblast-like support cells (reticular cells) that synthesize collagenous reticulin fibers, extracellular matrix materials, and certain growth factors.

24. NORMAL BONE MARROW

25. GRANULOPOIESIS
The formation of granulated white cells is termed granulopoiesis
This takes place under the influence of cytokines
The first recognizable precursor of neutrophil formation is myeloblast
Maturation from myeloblast to neutrophil takes 7-8 days and 5 cell divisions between myeloblast and metamyelocyte stages

26. After metamyelocyte stage no further multiplication division takes place
Mature neutrophils remain in the marrow for 5 days and then released into the blood
After circulating for about 6 hrs, they migrate into the peripheral tissues

27. Granulopoiesis

29. Neutrophils Production and differantiation: 6-10 days
Reserve pool (BM): times the circulation
Migrate into tissues and perform phagocytic function
Survival: 2-4 days

30. NORMAL LYMPHOCYTE AND NEUTROPHIL

32. Increase in the number of circulating neutrophils may occur by two mechanisms:
A large number of neutrophils , are loosely adharent to the sinusoidal endothelium in the bone marrow, in bacterial infection they are poured into the circulation
To maintain a high blood neutrophil count , there is increased proliferation increased proliferation of granulocyte precursors- this is regulated by secretion of cytokines-IL-1, GM-CSF and G-CSF

33. Neutrophilic Granules
Primary granules
Acid phosphatase
Myeloperoxydase
Esterase
Secondary granules
Aminopeptidase
Lysozyme
Collagenase

34. EOSINOPHILS

36. EOSINOPHIL

38. BASOPHILS

40. BASOPHIL

42. MONOCYTES

43. MONOCYTE

44. Monoctes are derived from CFC-M cells under the influence of cytokines
They have no reserve pool, they leave the marrow soon after their formation

45. Lymphocytes

46. Lymphocytes Assist the phagocytes in the defence
Produced in bone marrow from pluripotent cells
Two main groups: T-, B- lymphocytes
Natural Killer

47. T-Cell
T-cell: 65-80% of circulating lymphoctes

48. B-Cell 5-15 % of circulating lymphocytes
B-cells which have matured and secrete immunoglobulin are termed plasma cells

49. Natural Killer Non-T, non-B cells.
The majority Large granular lymphocytes (LGL) (can kill targets without MHC restriction).
Antibody dependent cellular cytotoxic (ADCC) are able to kill tumour and virus-infected cells. (they are also involved in graft rejection)

52. ERYTHROPOIESIS
Erythropoiesis is associated with the formation of distinct precursor cells termed erythroblasts.
Red cells are the terminal differentiated progeny of one cell line of pluripotent bone marrow stem cells which is committed to erythropoiesis only

53. Differentiation of these cells into
mature red cells is associated with:
decrease in cell size
Hb production
gradual decrease and eventual loss of all cell organelles
changing cytoplasmic staining from basophilia to eosinophilia due to Hb
condensation and eventual loss of the nucleus

54. ERYTHROPOIESIS
Red cell formation occurs in small erythroblastic islands consisting of one or two specialized macrophages surrounded by red cell progenitor cells in the marrow
When mature, the red cell contacts nearby sinusoidal endothelium and passes out to enter circulation

56. Control of Erythropoiesis15

57. Stimuli for RBC production
The kidney, hepatocytes and the interstitial cells of veins produce the hormone erythropoietin.
Extrarenal sites of conversion may include some tumors and cysts:
leiomyomas,
cerebral hemangioblastomas,
some renal cysts.

58. Erythrocytes 18

60. The bone marrow has three mechanisms at its disposal to respond to an acute decrease in circulating erythrocytes:
The marrow can increase the number of cells in the erythroid pool by increasing the number of stem cells that will differentiate into erythrocytes;
The marrow can decrease the time it takes for each erythroid cell to reach maturation; or
The marrow can release reticulocytes into the bloodstream earlier.

61. Peripheral blood Leukoerythroblastic smear Causes
young red cells and young granulocytes in the bloodstream.
Causes
agnogenic myeloid metaplasia
metastatic carcinoma
lymphoma
leukemia
bone marrow hyperplasia / extramedullary hematopoiesis
severe hemolysis.

62. RBC morphology Hereditary elliptocytosis ("hereditary ovalocytosis")
Lack the central pallor of biconcave RBC's
Autosomal dominant hemolytic syndrome

63. SPHEROCYTES

64. Thalassemia cells tend to be smaller with a higher hemoglobin concentration,

65. Nucleated RBCs in severe beta-thalassemia

66. Ring cells
Iron stays in normoblast mitochondria
Etiology:
Alcoholism
Drugs (isoniazid, etc)
Lead poisoning
Pyridoxine responsive anemia
Preleukemia ("myelodysplasia").

67. Fragmented RBC's known as "schistocytes"

68. Target cells - iron deficiency

69. Target cells and schistocytes - Hb C disease

70. RETICULOCYTES

71. ERYTHROID HYPERPLASIA

72. NORMAL BONE MARROW

73. Megakaryocytic hyperplasia

74. APLASTIC ANEMIA

76. MEGAKARYOCYTES
Megakaryocytes are the largest cells seen in bone marrow aspirates
Cytoplasmic maturation involves the elaboration of granules

78. MEGAKARYOCYTES