Hematopoiesis.pdf........................
- 2. Hematopoiesis • The continuous, regulated process of formation or Production of blood cells is called as haematopoiesis. • Also called as Hemopoiesis
- 4. Bone Marrow There are two types of bone marrow: • Red marrow composed of hematopoietic tissue (active marrow) • Yellow marrow composed of fat cells (inactive marrow). • Active sites of haematopoiesis are: pelvis, vertebra, skull, ribs, sternum, and proximal ends of long bones
- 6. Hematopoietic (hemopoietic) System • It consists of all organs and tissues involved in hematopoiesis, and these are divided into myeloid tissue and lymphoid tissue. • The pluripotent hematopoietic stem cell (HSC) is the progenitor of all the cells in blood and gives rise to cells of both myeloid and lymphoid system. 1. The myeloid tissue consists of bone marrow (medullary cavity) and the cells derived from it, which include • Red blood cells (RBCs/ erythrocytes) • White blood cells (WBCs/leukocytes, except lymphocytes) • Platelets (thrombocytes)
- 7. Hematopoietic (hemopoietic) System 2. The lymphoid tissue consists of thymus, lymph nodes and spleen. • The common lymphoid progenitor cell gives rise to B cell, T cell and natural killer (NK) cell precursors. • They mature to form respective lymphoid cells.
- 8. Functions of Blood Cells
- 9. Stem cells • All blood cells are derived from hematopoietic stem cells, which are present in small numbers in the bone marrow • The haematopoietic stem cell is the most primitive cell in the bone marrow. • ability of proliferation, self-renewal, and differentiation along several lineages. • Red cells, granulocytes, monocytes, and platelets are derived from myeloid stem cell while B and T lymphocytes are formed from lymphoid stem cell through intermediate stages.
- 10. Stem cells • The hematopoietic system is a hierarchy of cells in which pluripotent hematopoietic stem cells proliferate and differentiate. • After several steps, HSCs finally give rise to mature blood cells. • This hierarchy consists of: 1. Hematopoietic stem cells 2. Progenitor cells a. Multipotent progenitor cells b. Committed (unipotent) progenitor cells 3. Precursor cells 4. Maturing and mature cells.
- 14. Compensatory hyperplasia: • In adults during pathological states, whenever there is an increased demand for blood cells, the bone marrow undergoes compensatory hyperplasia. • This results in replacement of the fatty marrow by hematopoietic tissue. Extramedullary hematopoiesis: • The myeloid lineage blood cells arising outside the marrow elsewhere in the body are designated as extramedullary hematopoiesis. • In certain conditions like myelofibrosis, haematopoiesis can become re- established in liver, spleen, and lymph nodes resulting in splenomegaly and hepatomegaly.
- 15. Regulation of Hematopoiesis The growth of different hematopoietic cells is regulated by a number of hematopoietic growth factors, which in general are called cytokines. Most important growth factors acting on various cells are : • Stem cells: Stem cell factor (also called c-KIT ligand), IL-6 and FLT3-ligand. • CMP Progenitor cells: Multipotent committed progenitors – Granulocyte-macrophage colony-stimulating factor (GM-CSF) – Thrombopoietin – IL-3, IL-5, IL-6 and IL-11 Committed progenitors – Erythropoietin – Granulocyte colony-stimulating factor (G-CSF) – Thrombopoietin • Lymphopoiesis is regulated by several interleukins (most important being IL-1,2,4,5,6,7,9).
- 16. Erythropoiesis
- 17. Erythropoiesis • Erythropoiesis is the process by which marrow hematopoietic stem cells pass through several stages, proliferate, differentiate and mature to form red blood cells. • Progenitors and red cells are together known as erythron.
- 18. Erythroid series There is progressive condensation of the nuclear chromatin which is eventually extruded from the cell at the late erythroblast stage. The cytoplasm contains progressively less RNA and more hemoglobin.
- 19. • Earliest erythrocyte precursor • Also called as Proerythoblast • Each produces 8-32 mature RBC • 15-20 µm , high N/C ratio, large bluish-purple nucleus, fine lacy chromatin, small amount of deeply basophilic cytoplasm, one or more nucleoli. • Also called as Basophilic normoblast • 12-16 µm, N/C ratio decreased as compared to normoblast • Abundant deeply basophilic cytoplasm • Coarser chromatin. 2 1
- 20. • Polychromatic normoblast • 12-15 µm , N/C ratio further dec, irregular and coarsely clumped nuclear chromatin. • Abundant grey blue cytoplasm. • Large amount of hemoglobin is synthesized during this stage. This is the last stage capable of mitosis. • Orthochromatic normoblast • 8-12 µm , nucleus occupies 1/4th of cell volume, condensed chromatin • Cytoplasm is pink or orange • These cells can’t synthesize DNA or divide. • Hemoglobinization is increased. 3 4
- 21. • Reticulocyte • 8-10 µm, • Identified by using supravital. stains such as new methylene blue or brilliant cresyl blue which cause. precipitation of RNA. • Seen as punctate purplish blue inclusion. • 7-7.5 µm, non-nucleated, pink to orange • Life span 100-120 days • Biconcave disc • Center of RBC has pallor which is 1/3rd of total volume 5 6
- 22. Duration • From the stage of proerythroblast to reticulocyte, it takes 3-8 days. • Reticulocytes mature in 2-3 days in BM and released in circulation. • The normal lifespan of red cells is 100 to120 days and about 1% of the red cells are replaced daily.
- 23. RBC Functions • Transport of Oxygen from the Lungs to the Tissue. • Transport of Carbon Dioxide from the Tissues to the Lungs. • Buffering Action in Blood • RBCs carry the blood group antigens like A antigen, B antigen and Rh factor. This helps in determination of blood group and enables to prevent reactions due to incompatible blood transfusion
- 24. Regulation of erythropoiesis Amino acids Iron Vitamin B12 & Folic acid Vitamin B6 Cobalt Zinc Vitamin C Hormones
- 25. Regulation of erythropoiesis • Erythropoiesis is regulated by erythropoietin (EPO) synthesized in the kidney. EPO production is increased in response to hypoxia/reduced oxygen tension (e.g. due to anemia, lung disease). • Erythropoietin acts on EPO receptors present on erythroid precursors. • Failure of erythropoietin production is a major causative factor for anemia of chronic renal failure. Excessive EPO results in polycythemia secondary to renal tumors.
- 26. Dyserythropoiesis • Defective erythropoiesis in which abnormal red cells are produced which are either destroyed in the marrow before their release or enter circulation but have a shortened life span. • Morphological abnormalities in normoblasts are Nuclear budding Abnormal mitosis Nuclear bridges Basophilic stippling and Howell Jolly bodies in red cells • Ineffective erythropoiesis: The term ineffective erythropoiesis is used when developing erythroid precursors die within the marrow without producing mature cells.
- 28. Granulopoiesis
- 29. Granulopoiesis • Myelopoiesis (granulopoiesis) results in production of neutrophils, eosinophils, basophils and monocytes
- 31. • MYELOBLAST : 14-20 µm, high N/C ratio, round to oval nucleus, • Evenly stain lacy chromatin, • 2-5 nucleoli, small amount of agranular • Deep blue cytoplasm • PROMYELOCYTE : 15-20 µm, • Cytoplasm contains blue black primary granules (azurophilic), • larger than Myeloblast. • Chromatin is coarser and 2-3 nucleoli are seen. 1 2
- 32. • MYELOCYTE – 16-20 µm, • Secondary granules appear, • Small sand like specific granules purple - pink. • Cytoplasm light pink, • Nucleus is round. • Condensed chromatin, nucleoli absent. • Last stage capable of mitotic division • METAMYELOCYTE – 12-18 µm, • indented nucleus (horse shoe-shaped shaped), • Dense and clumped chromatin stains dark purple, absent nucleoli. • cytoplasm is pink with predominance of secondary granules 3 4
- 33. • BAND FORM – 9-15 µm, pinkish cytoplasm. • U-shaped nucleus. • Heavily clumped chromatin • Juvenile granulocyte •NEUTROPHIL – 10-12 µm, • segmented nucleus with 2-5 lobes. • purple-pink cytoplasmic granules • life span of only 1 to 2 days in circulation 5 6
- 34. Neutrophil Functions • Neutrophils play an important role in the defense mechanism of the body. • Granules of neutrophils contain enzymes like proteases, myeloperoxidases, elastases and metalloproteinases. These enzymes destroy the microorganisms. • Neutrophils also secrete platelet-activating factor (PAF), which is a cytokine. It accelerates the aggregation of platelets during injury to the blood vessel, resulting in prevention of excess loss of blood.
- 35. • EOSINOPHIL – 15-16 µm • Bilobed nucleus. • Bright orange red granules in cytoplasm. • Maturation time for eosinophils in bone marrow is 2 to 6 days and half-life in blood is less than 8 hours. •BASOPHIL – 9-12 µm, • S shaped nucleus . • Purple black cytoplasmic granules and obscure the nucleus.
- 36. Eosinophil functions • Eosinophils play an important role in the defense mechanism of the body against the parasites. • Eosinophils are responsible for detoxification, disintegration and removal of foreign proteins. • Eosinophils attack Parasites by some special type of cytotoxic substances present in their granules. When released over the invading parasites from the granules, these substances become lethal and destroy the parasites.
- 37. Basophil Functions • Basophils play an important role in healing processes. • Heparin is essential to prevent the intravascular blood clotting. • Histamine, slow-reacting substances of anaphylaxis, bradykinin and serotonin: These substances produce the acute hypersensitivity reactions by causing vascular and tissue responses. • Proteases and myeloperoxidase: These enzymes destroy the microorganisms
- 38. Monopoiesis
- 39. • MONOBLAST : abundant granular blue grey cytoplasm. • Nucleus is round to oval , folded or indented. • Finely dispersed blue purple nuclear chromatin. • Several nucleoli. • PROMONOCYTE : 12-20 µm , abundant blue grey cytoplasm • Nucleus is deeply indented, coarser chromatin. • MONOCYTE : 12-18 µm , blue grey cytoplasm (ground glass appearance), indented nucleus (bean shaped), chromatin has lacy appearance. Monocytes circulate in blood for about 1 day. 1 3 2
- 41. Monocyte Functions • Monocytes play an important role in phagocytosis. • Immunologic function as antigen presenting cells and present the antigen to lymphocytes to deal further. • Monocytes secrete: 1. Interleukin-1 (IL-1). 2. Colony stimulating factor (M-CSF). 3. Platelet-activating factor (PAF).
- 42. Lymphopoiesis
- 43. • LYMPHOBLAST – 16 - 18 µm, • Scanty Blue Cytoplasm. • Nucleus 4/ 5th of cell size. • 1 – 2 indistinct nucleoli. •Prolymphocyte : slightly smaller than lymphoblast, • clumped nuclear chromatin, • nucleoli can be present, cytoplasm is light blue • Lymphocyte : small – 8-10 µm, nucleus of the size of RBC. condensed dark purple chromatin, scanty sky blue cytoplasm. • Large : 11-16 µm, cytoplasm is more abundant as compared to small lymphocyte. 1 3 2
- 45. Megakaryopoiesis
- 46. Megakaryopoiesis • Megakaryopoiesis (thrombopoiesis) is the process of platelet formation. • The megakaryocyte is an easily identifiable cell in megakaryopoiesis because of its large size. • They undergo nuclear division without cytoplasmic division (endomitosis). • In the bone marrow megakaryocytes are situated close to the marrow sinusoids.
- 47. Early Megakaryocyte • MEGAKARYOBLAST : • 30 – 35 µm. • Nucleus is large with multiple nucleoli. • cytoplasm is Basophilic. • EARLY MEGAKARYOCYTE : • Larger than blast 70 – 80 µm. • Deeply basophilic cytoplasm. • Nucleus may be lobulated. • Chromatin is deeply basophilic. • Cytoplasm abundant, projections may be present. 1 2
- 48. Late Megakaryocyte • LATE MEGAKARYOCYTE : • 90 – 100 µm. • Nucleus lobulated, nucleoli absent. • Abundant granular cytoplasm. • MATURE MEGAKARYOCYTE : •Large Cell seen in bone marrow. • Nucleus is more lobulated. • Abundant granular cytoplasm. • Granules present in periphery. • PLATELETS : • Very tiny cells 1 – 4 µm . • Pink granular cytoplasm. • Cells are seen in clumps 5 3 4
- 50. Platelets • Platelets are the fragments of the cytoplasm of megakaryocytes and are formed by pinching off their cytoplasm. • They are released in groups (called proplatelets) into the sinusoids and reach circulation. Each megakaryocyte releases 1000 to 4000 anucleate platelets. • In a Romanowsky (Leishman, Giemsa) stained smear, platelets appear as pale blue colored structures of varying sizes having purple granules. • Normal platelet count: 150-450 × 109/L • Normal lifespan: About 4-10 days
- 51. Platelet Functions • Hemostasis • Coagulation • Thrombosis. • Platelet-derived growth factor (PDGF) formed in cytoplasm of platelets is useful for the repair of the endothelium and other structures of the ruptured blood vessels.
- 52. References 1. Kawthalkar SM. Essentials of Haematology. Second edition, New Delhi: Jaypee Brothers Medical Publishers (P) Ltd, 2013. 2. Dr Tejinder Singh. Text and Practical Haematology for MBBS. First edition, H.P: Arya Publications, 2010