Hematopoiesis production and Disorders.pptx

Hematopoiesis is the process by which blood cells are formed. It occurs primarily in the bone marrow, which is a spongy tissue found within the cavities of certain bones, such as the sternum, ribs, pelvis, and long bones. Hematopoiesis involves the differentiation and proliferation of hematopoietic stem cells (HSCs) into various types of blood cells.
Differentiation and Lineage Commitment:

HSCs can differentiate into two main lineages: the myeloid lineage and the lymphoid lineage.
Myeloid lineage: Gives rise to red blood cells (erythrocytes), platelets (thrombocytes), and white blood cells (leukocytes) such as granulocytes (neutrophils, eosinophils, and basophils) and monocytes.
Lymphoid lineage: Gives rise to lymphocytes, including T cells, B cells, and natural killer (NK) cells.


Proliferation and Maturation:

Once committed to a specific lineage, progenitor cells undergo proliferation and differentiation into mature blood cells. This process is tightly regulated by various growth factors, cytokines, and hormones.
Erythropoiesis: The process of erythrocyte (red blood cell) production.
Thrombopoiesis: The process of platelet production.
Granulopoiesis: The process of granulocyte (neutrophil, eosinophil, basophil) production.
Monocytopoiesis: The process of monocyte production.
Lymphopoiesis: The process of lymphocyte production.

Regulation:

Hematopoiesis is tightly regulated by various factors, including:
Growth factors and cytokines such as erythropoietin (EPO), thrombopoietin (TPO), granulocyte colony-stimulating factor (G-CSF), and interleukins.
Hormones such as cortisol, thyroid hormones, and sex hormones.
Microenvironmental signals within the bone marrow niche.
Migration and Circulation:

Once matured, blood cells are released into the bloodstream and circulate throughout the body, performing their respective functions. Red blood cells carry oxygen to tissues, white blood cells participate in the immune response, and platelets are involved in blood clotting.

1. Hematopoiesis DR.S.Sundaresan tagore medical college

2. Hematopoietic Stem Cells (HSCs): Undifferentiated cells with the potential to give rise to all blood cell types. Two main types: Multipotent Progenitor Cells (MPPs): Can differentiate into multiple cell types. Hematopoietic Stem Cells Proper: Have the potential to differentiate into any blood cell type.

3. Steps in Hematopoiesis: Proliferation (Mitosis): HSCs undergo mitosis to produce more stem cells. Some cells remain as stem cells, while others become committed progenitor cells. Differentiation: Progenitor cells differentiate into specific cell lineages (erythroid, myeloid, lymphoid). Maturation: Cells undergo maturation to become fully functional blood cells.

4. Regulation: Cytokines and Growth Factors: Various signaling molecules regulate the proliferation and differentiation of hematopoietic cells. Some cytokines that regulates haematopoiesis are: Granulocyte macrophage-colony stimulating factor (GM-CSF): It enhances the myeloid lineage, finally leading to the differentiation of granulocytes and macrophages. Such cytokines are termed as growth factors. These growth factors are needed throughout the process of hematopoiesis functioning in order to activate transcription factors. Transcription factor GATA-2 : It is required for the development of all hematopoietic lineages; in its absence animals die during embryogenesis. Transcriptional regulator Bmi-1: It is required for the self-renewal of HSCs, and in its absence animals die within 2 months of birth because of the failure to repopulate their red and white blood. .

5. Other Examples of cytokines involved in haematopoiesis are: Colony-stimulating factors (CSFs) Erythropoietin (EPO) Thrombopoietin (TPO) Granulocyte colony-stimulating factor (G-CSF) Monocyte colony-stimulating factor (M-CSF) Tumor necrosis factor (TNF) Transforming growth factor (TGF) Stem cell factor (SCF) Leukemia inhibitory factor (LIF) Hormonal Control: Erythropoietin (EPO) regulates erythropoiesis. Thrombopoietin (TPO) regulates thrombopoiesis

6. Hematopoietic stem cells (HSCs) are multipotent cells with critical functions in the maintenance and replenishment of the blood and immune system. 1. Self-Renewal HSCs have the ability to undergo self-renewal, meaning they can divide and give rise to identical daughter cells. 2. Differentiation They give rise to committed progenitor cells, which further differentiate into mature blood cells, including red blood cells, white blood cells, and platelets. 3. Production of Blood Cells HSCs are the source of all blood cells, contributing to the continuous production and replenishment of erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets). functions

7. 4. Immune System Support: HSCs play a pivotal role in supporting the immune system by generating lymphoid progenitor cells, which differentiate into T lymphocytes (T cells), B lymphocytes (B cells), and natural killer (NK) cells. 5. Hematopoietic Microenvironment Regulation HSCs interact with the bone marrow microenvironment, which includes stromal cells, endothelial cells, and extracellular matrix components. 6. Response to Environmental Signals: HSCs respond to signals from the surrounding environment, including cytokines, growth factors, and hormones 7. Maintenance of Hematopoietic Homeostasis: HSCs contribute to the maintenance of hematopoietic homeostasis by balancing the production of different blood cell lineages. This ensures a proper ratio of red blood cells, white blood cells, and platelets to meet the body's physiological needs. 8. Adaptation to Physiological Demands: HSCs can adjust their activity in response to changing physiological demands, such as during periods of increased blood cell production in response to injury, infection, or other stressors

8. Hematopoietic Tissues: Bone Marrow: The primary site for hematopoiesis in adults. Red bone marrow is involved in the production of blood cells. Liver and Spleen (in fetus): These organs are involved in hematopoiesis during embryonic and fetal development.

9. Bone Marrow: Red Bone Marrow: Found in the spongy bone tissue of flat bones (e.g., pelvis, sternum, ribs, skull). Primary site for hematopoiesis in adults. Composed of hematopoietic stem cells (HSCs), which give rise to all blood cell types. Yellow Bone Marrow: Contains more fat cells and fewer hematopoietic cells. Can convert back to red bone marrow in response to increased demand for blood cell production. Liver (During Embryonic and Fetal Development): In the early stages of development, the liver plays a crucial role in hematopoiesis. As development progresses, the liver's hematopoietic function decreases, and the bone marrow takes over. Spleen (During Embryonic and Fetal Development): Like the liver, the spleen is involved in hematopoiesis during early development. As the bone marrow becomes the primary site for hematopoiesis, the spleen's hematopoietic function diminishes.

10. 4. Lymphatic Tissues: Lymph nodes, tonsils, and other lymphatic tissues may contribute to certain aspects of immune cell production. While not the primary sites, they play a role in the development and maturation of lymphocytes (a type of white blood cell). 5. Thymus: The thymus is involved in the maturation of T-lymphocytes (T cells), an essential component of the immune system. It is not a site for the production of hematopoietic stem cells but is critical for the development of functional immune cells. Regulation of Hematopoiesis: Hematopoiesis is tightly regulated by various signaling molecules, including cytokines and growth factors. Hormones such as erythropoietin (EPO) and thrombopoietin (TPO) play key roles in the regulation of specific blood cell lineages.

11. Types of Blood Cells: Erythropoiesis: Formation of red blood cells (erythrocytes). Controlled by the hormone erythropoietin, which is produced by the kidneys in response to low oxygen levels. Leukopoiesis: Formation of white blood cells (leukocytes). Differentiation into various types of leukocytes: neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Thrombopoiesis: Formation of platelets (thrombocytes). Regulated by thrombopoietin.

12. Myeloid cells:  It consists of- Monocytes Eosinophils Basophils Neutrophils Macrophages Erythrocytes Megakaryocytes Platelets. Lymphoid cells:  It consists of- B cells T cells Natural killer cells Innate lymphoid cells.

13. erythrocyte production

14. Hematopoietic Stem Cell (HSC): Size: Variable Shape: Undifferentiated, round Color: N/A Mechanism: HSCs are pluripotent stem cells capable of differentiating into various blood cell types. Time: A few days. Proerythroblast: Size: Large (12-20 μ m) Shape: Round Color: Blue-purple cytoplasm (basophilic) Mechanism: Initiates synthesis of hemoglobin. Time: About 1-2 days. Basophilic Erythroblast: Size: Slightly smaller than proerythroblasts Shape: Round Color: Basophilic cytoplasm due to ongoing hemoglobin synthesis Mechanism: Continued hemoglobin synthesis; nucleus begins to condense. Time: About 1 day.

15. Polychromatic Erythroblast: Size: Further reduced Shape: Round Color: Pinkish cytoplasm (polychromatic) due to increased hemoglobin Mechanism: Intense hemoglobin synthesis; further nuclear condensation. Time: About 1 day. Orthochromatic Erythroblast: Size: Smaller than previous stages Shape: Round Color: Cytoplasm becomes even more eosinophilic (orthochromatic) as hemoglobin synthesis peaks Mechanism: Final nuclear condensation and extrusion of the nucleus. Time: About 1 day. .

16. Reticulocyte: Size: Slightly larger than mature RBCs Shape: Slight central pallor; biconcave shape Color: Bluish-gray tint due to residual ribosomal RNA Mechanism: Nucleus is expelled; the cell enters the bloodstream; ribosomal remnants visible under certain stains. Time: 1-2 days in the bone marrow before entering circulation Mature Erythrocyte (Red Blood Cell): Size: 7-8 μ m in diameter Shape: Biconcave disc Color: Red (due to hemoglobin) Mechanism: No nucleus or organelles; flexible biconcave shape facilitates gas exchange; primary function is oxygen transport. Time: Lifespan in circulation is about 120 days. Regulation by Erythropoietin (EPO): Mechanism: EPO, produced in response to low oxygen levels, stimulates the differentiation, proliferation, and survival of erythroid progenitor cells.

17. leukocyte production

18. Granulopoiesis (Development of Granulocytes): Myeloblast: Size: Larger than mature granulocytes Shape: Round or oval Color: Blue-purple cytoplasm (basophilic) Mechanism: Initiates synthesis of specific granules. Promyelocyte: Size: Slightly smaller than myeloblasts Shape: Round or oval Color: Cytoplasm becomes more distinct; specific granules develop. Mechanism: Continued granule synthesis.

19. Myelocyte: Size: Smaller than promyelocytes Shape: Round or slightly indented Color: Specific granules are prominent, and cytoplasm takes on a distinct color. Mechanism: Granules mature; nucleus undergoes changes. Metamyelocyte: Size: Further reduced Shape: Kidney-shaped nucleus Color: Distinctive cytoplasmic coloration Mechanism: Nucleus continues to change shape; cell prepares for final stages of maturation. Band Neutrophil: Size: Slightly smaller than mature neutrophils Shape: Nucleus is horseshoe or band-shaped Color: Distinctive cytoplasmic coloration Mechanism: Nucleus becomes elongated and horseshoe-shaped.

20. Segmented Neutrophil (Mature Neutrophil): Size: 10-12 μ m Shape: Segmented nucleus; multi-lobed Color: Distinctive cytoplasmic coloration Mechanism: Final maturation; ready for immune response. Time: Several days to a week.

21. b. Eosinophil Development: Myeloblast to Metamyelocyte: Similar stages as neutrophils. Mechanism: Synthesis of specific granules containing enzymes. Mature Eosinophil: Size: 12-17 μ m Shape: Bilobed nucleus; often bi-lobed or tri-lobed. Color: Eosinophilic granules give a reddish-orange color. Mechanism: Granules contain enzymes involved in combating parasitic infections. Time: About 2 weeks.

22. c. Basophil Development: Myeloblast to Metamyelocyte: Similar stages as neutrophils. Mechanism: Synthesis of specific granules containing histamine and other mediators. Mature Basophil: Size: 12-15 μ m Shape: Bilobed nucleus; may be obscured by granules. Color: Dark purple or blue due to large basophilic granules. Mechanism: Granules release histamine and other inflammatory mediators. Time: Variable.

23. Monopoiesis (Development of Monocytes): a. Monoblast : Size: Larger than mature monocytes Shape: Round or oval Color: Blue-purple cytoplasm (basophilic) Mechanism: Initiates synthesis of specific granules. b. Promonocyte: Size: Slightly smaller than monoblasts Shape: Round or oval Color: Cytoplasm becomes more distinct; specific granules develop. Mechanism: Continued granule synthesis. c. Monocyte: Size: Larger than neutrophils Shape: Kidney-shaped or amoeboid nucleus Color: Abundant pale blue-gray cytoplasm Mechanism: Final maturation; migrates into tissues to become macrophages or dendritic cells. Time: A few days.

24. 3. Lymphopoiesis (Development of Lymphocytes): a. Lymphoblast: Size: Variable Shape: Round Color: Blue-purple cytoplasm (basophilic) Mechanism: Initiates synthesis of specific proteins. b. Prolymphocyte: Size: Slightly smaller than lymphoblasts Shape: Round Color: Cytoplasm becomes more distinct. Mechanism: Continued differentiation and maturation. c. Mature Lymphocyte (T Cell, B Cell, NK Cell): Size: Variable (small to medium-sized) Shape: Round or irregular Color: Scant cytoplasm, may be pale or basophilic. Mechanism: Specific functions depending on the type (e.g., T cells, B cells, NK cells). Time: Variable, can range from days to weeks.

25. Erythropoiesis: The process of formation of red blood cells termed as erythrocytes is known as erythropoiesis. It is enhanced by decreased levels of oxygen in the blood, which signals for the secretion of erythropoietin. Erythropoietin is a hormone central to the formation of red blood cells. Erythropoiesis takes on average 2 days to be completed from to form mature red blood cell from unipotential hematopoietic cell. 2 million erythrocytes are produced every second in our bodies. Hematopoietic cells determined to become red blood cells usually get smaller and more condensed as they mature until there is finally loss of their nuclei. The unipotential cell becomes proerythroblast, which has uncondensed nucleus and has basophilic or blue cytoplasm.  Then the cell becomes a basophilic erythroblast, which is followed by a polychromatophilic erythroblast stage. In  polychromatophilic erythroblast stage, the nucleus becomes more condensed than the latter two stages and the cytoplasm is reduced.  In the succeeding orthochromatophilic erythroblast stage, the nucleus is much smaller than that of the prior stages having a pinker cytoplasm. Then comes the reticulocyte stage, where the red blood cell lacks nucleus, but still stains somewhat blue because of the remnants of polyribosomes within the cell. Ultimately, the erythrocyte is the mature red blood cell, with no nucleus and no polyribosome remnants and as a result stains pink.

26. Granulopoiesis The process of formation of granulocytes is termed as granulopoiesis. Granulocytes are white blood cells having multi-lobular nuclei and cytoplasmic granules. The unipotential hematopoietic cell which forms a myeloblast is large.  It has a cytoplasm that stains blue with a large nucleus. This cell gives rise into a promyelocyte that contains azurophilic granules. Then it becomes a myelocyte, which has a non-indented still rather large nucleus. This cell then gives rise to a metamyelocyte, which is alike in size to a mature granulocyte and the nucleus starts to become indented. After this stage is the band cell stage, where the nucleus resembles a horseshoe and has definitive indentation. Ultimately, there is the mature granulocytes having a lobed nucleus and cytoplasmic granules. The entire process occurs over a period of 2 weeks.

27. Monopoiesis: The process by which monocytes are formed is termed as monopoiesis. The monoblast is the committed progenitor cell, found only in the bone marrow. Also, monoblast has a basophilic cytoplasm without granules. These monoblasts give rise to promonocytes, which are smaller in size with nuclei that become slightly indented, before becoming monocytes.  Monocytes have kidney-shaped nuclei and can develop into dendritic cells or macrophages.

28. Lymphopoiesis: The formation of lymphocytes, starts from their first committed progenitor cells, lymphoblasts, this process is called Lymphopoiesis. These cells after maturation, are able to differentiate into either B, T or natural killer cells.   Thrombopoiesis: Megakaryocytes, which are extremely large cells within the bone marrow forms the platelets, this process is termed as thrombopoiesis. When the plasma membranes of megakaryocytes are fragmented, the origin of individual platelets take place, thus generating platelets containing many granules.

29. Disorders of Hematopoiesis: Anemia : Iron-deficiency anemia Vitamin B12 deficiency anemia (pernicious anemia) Folate deficiency anemia Sickle cell anemia Thalassemia Hemolytic anemia (e.g., autoimmune hemolytic anemia, hereditary spherocytosis) Aplastic anemia Anemia of chronic disease

30. Leukopenia : Neutropenia Lymphopenia Monocytopenia Eosinopenia Basopenia Thrombocytopenia : Immune thrombocytopenic purpura (ITP) Thrombotic thrombocytopenic purpura (TTP) Drug-induced thrombocytopenia Heparin-induced thrombocytopenia (HIT) Hypersplenism Disseminated intravascular coagulation (DIC) Congenital thrombocytopenia syndromes

31. Myelodysplastic Syndromes (MDS) : Refractory anemia Refractory cytopenia with multilineage dysplasia Refractory anemia with excess blasts Refractory cytopenia with multilineage dysplasia and ring sideroblasts Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) Myeloproliferative Neoplasms (MPNs) : Polycythemia vera Essential thrombocythemia Primary myelofibrosis Chronic myeloid leukemia (CML) Chronic neutrophilic leukemia Chronic eosinophilic leukemia Mast cell disease

32. Bone Marrow Failure Syndromes : Aplastic anemia Diamond- Blackfan anemia Fanconi anemia Shwachman -Diamond syndrome Dyskeratosis congenita Paroxysmal nocturnal hemoglobinuria (PNH) Hemophagocytic Lymphohistiocytosis (HLH) : Primary HLH Secondary HLH (e.g., infection-associated HLH, malignancy-associated HLH)

33. Hemoglobinopathies : Sickle cell disease Thalassemia Erythrocytosis : Secondary erythrocytosis (e.g., due to chronic hypoxia, renal disease) Polycythemia vera Pure Red Cell Aplasia : Acquired pure red cell aplasia Diamond- Blackfan anemia (a congenital form of pure red cell aplasia)

34. Paroxysmal Nocturnal Hemoglobinuria (PNH) : Acquired hemolytic anemia Congenital Disorders of Hematopoiesis : Congenital neutropenia syndromes Congenital thrombocytopenia syndromes Congenital amegakaryocytic thrombocytopenia Congenital dyserythropoietic anemias Congenital sideroblastic anemia Marrow Infiltrative Disorders : Leukemia Lymphoma Metastatic cancer Myeloma Gaucher disease