HematologyLEC2Hematopoeisis (1).docx

**HEMATOPOIESIS** ----------------- **Erythropoiesis** ------------------ **TISSUE HOMEOSTASIS** Maintenance of an adequate number of cells through these functions: - **Proliferation** - **Differentiation** - **Death (apoptosis)** **CELL CYCLE** G1 S G2 M S phase - DNA synthesis M ph...

**HEMATOPOIESIS** ----------------- **Erythropoiesis** ------------------ **TISSUE HOMEOSTASIS** Maintenance of an adequate number of cells through these functions: - **Proliferation** - **Differentiation** - **Death (apoptosis)** **CELL CYCLE** G1 S G2 M S phase - DNA synthesis M phase -- mitosis **APOPTOSIS VS NECROSIS** - **Necrosis:** cell death by lethal chemical, biological or physical events - **Apoptosis**: programmed cell death regulated by the genetic material of the cell **HEMATOPOIESIS** - **Blood cell formation** -- production and development - Occurs bone marrow, liver, spleen, lymph nodes, thymus - **Bone marrow** -- sole site of effective hematopoiesis in normal adults - [6 billion cells/kg] of body **weight per day** - 2.5 billion red cells - 2.5 billion platelets - billion white cells - Rate adjusted to need, varies from nearly zero to many times the normal - Constant turnover of cells **TYPES OF HUMAN STEM CELLS** 1\. **Totipotential stem cells**. These cells are present in the [first few hours after an ovum is fertilized]. Totipotential stem cells, the most **versatile type of stem cell**, can develop into any [human cell type], including development [from embryo into fetus]. 2\. **Pluripotential stem cells**. These cells are present [several days after fertilization]. Pluripotent stem cells can develop into any cell type, except they [**cannot** develop into a fetus]. 3\. **Multipotential stem cells.** These cells are derived from [pluripotent stem cells]. They can be found **in adults**, but they are **limited** to specific types of cells to form tissues. For example, bone marrow stem cells can produce all types of blood cells, bone cartilage, and adipose (fat) cells. **DEFINITION OF HEMATOPOIESIS** - **Development of different cell lineages in blood** - **Differentiation** - Appearance of different properties in cells - **Commitment** - Cells derived from common precursors take separate routes - Maturation occurs from commitment to fully developed cell **ONTOGENY OF HEMATOPOEISIS** - Yolk sac \> fetal liver/spleen \> BM (bone marrow) Three developmental periods - Mesoblastic - Hepatic - Myeloid **MESOBLASTIC** - Blood islands of yolk sac - Primarily RBC production - Embryonic hemoglobin produced **HEPATIC** - At 6 weeks cell production in liver - Fetal hemoglobin produced - Spleen, thymus, and lymph nodes also active production **MYELOID** - At 5th month Bone Marrow becomes the site of cell production - Liver & spleen now Extramedullary - Hemoglobin A (α2β2) **HEMATOPOIETIC PRECURSOR CELLS** - Stem cells - Progenitor cells - Maturing cells **HEMATOPOIETIC GROWTH FACTOR** Hematopoietic GF Function: stimulate progenitor of the ff: ------------------------------------- ------------------------------------------- GM-CSF (granulocyte-macrophage CSF) Granulocyte-monocyte G-CSF (granulocyte CSF) Granulocyte M-CSF (macrophage CSF) Monocyte EPO (Erythropoietin) Erythrocyte IL-1,3,6 (Interleukin-3, 1, 6) Myeloid lineage TPO (Thrombopoietin) Platelet **STEM CELLS** - Very small group of cells - Multipotential cells that give rise to all lineages of blood cells - High self-renewal ability - Not morphologically distinguishable - Identified by flow cytometry with marker CD34 - Supporting research  **PROGENITOR CELLS** - Committed cells to differentiation into cell lines - Described as **colony-forming units (CFU)** - CFU-GEMM - CFU-GM - CFU-Meg - Population amplified by proliferation **MATURING CELLS** - Majority of precursor cells - Recognizable morphologic characteristics - Nomenclature unique for each cell line **CYTOKINES & GROWTH FACTORS** - **Cytokines** - Govern precursor cell survival, self-renewal, proliferation, differentiation - **Growth factor control** - Interleukins numbered according to discovery - **Growth factors promote cell survival by suppressing apoptosis** - **Growth factors promote proliferation** **LINEAGE-SPECIFIC CYTOKINES** - **Erythropoiesis** - BFU-E - CFU-E dependent on EPO - **Granulopoiesis and Monopoiesis** - CFU-GM supported by IL-3 - **Megakaryocytopoiesis** - CFU-Meg induced by IL-11 and TPO - **Lymphopoiesis** - Multiple GF in development of T & B cells **BONE MARROW** - Bone marrow/ medullary hematopoiesis - **Major** hematopoietic organ - Blood-forming tissue located between trabeculae - **Bone marrow stroma** is supporting tissue for hematopoietic cells - Red marrow/yellow marrow **THYMUS** - Lymphopoietic organ in **upper mediastinum** - Cortex densely packed with [small lymphocytes] - **Primary purpose** - Compartment for **maturation of T lymphocytes** - Precursor T cells leave the bone marrow and enter the thymus **SPLEEN** - **Upper left quadrant** of the abdomen - [Richly] supplied with blood - Functions include: - culling; filtering and destruction of old or damaged RBCs - Pitting: pluck our particles from RBCs - immune defense - storage: hold 1/3 of platelets **LYMPHATIC SYSTEM** - Lymph nodes and lymphatic vessels - Nodes **remove** foreign particles from lymph - Functions: - Immune defense - B cell production in germinal centers **ERYTHROPOIESIS** **ERYTHRON** - **Total population of erythrocytes** and precursors in peripheral blood and bone marrow - RBC production - RBC release - RBC destruction - Primary signal regulating RBC production is oxygen tension - ⇓ tissue oxygenation due to anemia or pulmonary insufficiency **ERYTHROPOIESIS** - Stimulated by **Erythropoietin (EPO),** a **glycoprotein hormone** produced in the kidney - EPO accelerates the commitment of pluripotent stem cells to CFU-E and erythroid development **MATURATION CHARACTERISTICS** - Cells accumulate hemoglobin - Lose their protein-synthesizing apparatus - Nuclear chromatin pattern changes - Cells become smaller - Nucleus to cytoplasm ratio decreases **SEQUENCE OF RBCS MATURATION** **ALL STAGES OF ERYTHROPOIESIS**    **NOMENCLATURE FOR RBC PRECURSORS** latin American-english ----------------- ------------------ ----------------- normoblastic rubriblastic Erythroblastic pronormoblastic Rubriblast proerythroblast **RBC STRUCTURE AND FUNCTION** - **RBC MEMBRANE COMPOSITION** **Trilaminar structure** - outer hydrophilic - central hydrophobic - inner hydrophilic **Proteins** - **integral:** Extend from outer surface to inner - **peripheral:** cytoplasmic surface beneath lipid bilayer **SCHEMATIC OF RBC MEMBRANE**  **RBC MEMBRANE LIPIDS** - **95% of lipid content** - Unesterified Cholesterol - Phospholipid bilayer - **Remaining 5%** - Glycolipids - Antigenic properties of the membrane - **Free fatty acids** **MEMBRANE PROTEINS: INTEGRAL** - Integral - Glycophorin A,B,C - Carry RBC antigens and give the RBC it's negative charge - Band 3 - Functions as anion exchange protein **MEMBRANE PROTEINS: PERIPHERAL** - Peripheral (form membrane **"skeleton"**) - Contribute to cell shape, membrane stability, and deformability and gives it the viscoelastic properties **RBC DEFORMABILITY** - Flexibility of the RBC to squeeze through capillaries - Increased conc of hgb or decreased fluidity = decreased deformability. - Accumulation of membrane calcium results in rigid, shrunken cells & reduced deformability **RBC PERMEABILITY** - Freely permeable to H2O, Cl-, - The cation pump regulates the balance of Na+ and K+ **RBC METABOLISM** - Limited because of the **absence** of a nucleus, mitochondria, and other organelles - Pathways described contribute energy to maintain: - high intracellular K+, low intracellular Na+, very low intracellular Ca++ - Hemoglobin in reduced form - Membrane integrity and deformability **PATHWAYS:** 1 - Embden-Meyerhof Pathway 2- Hexose Monophosphate Shunt 3- Methemoglobin reductase 4- Rapoport- Luebering Shunt **PATHWAYS:** **EMBDEN-MEYERHOF PATHWAY** - **90-95%** of **rbc glucose** consumption - **Glucose** enters the cell by diffusion and is metabolized to lactate net gain of **two moles of ATP/mole of glucose** - **Key enzymes:** pyruvate kinase, phosphofructokinase - Key role: ATP necessary for RBC shape, flexibility and membrane integrity **HEXOSE MONOPHOSPHATE SHUNT** - produces **reduced NADPH** and **reduced glutathione (GSH)** - Functionally dependent on G6PD - GSH protects cells from permanent oxidant damage - **Key enzymes**: glutathione reductase, G6PD - **Key role**: maintain reduced GSH and reduced NADP  **METHEMOGLOBIN REDUCTASE** - Pathway that maintains **heme iron** in reduced **ferrous (Fe2+)** - **Hgb in ferric state is methemoglobin (Fe3+)** - **Key enzyme:** methemoglobin reductase - **Key role:** prevent hypoxia **RAPOPORT- LUEBERING SHUNT** - causes accumulation of **2,3 DPG** thus regulating oxygen delivery to the tissues. - **Key enzyme:** DPG-synthetase - **Key role:** affects oxygen affinity of hemoglobin **ERYTHROCYTE DESTRUCTION** - RBC begins to undergo **senescence (a** process by which a cell ages and permanently stops dividing but does not die.) - Reticuloendothelial System (RES) daily removes 1% of old RBCs via macrophages - As RBC ages, glycolytic enzymes decrease activity resulting in less energy and less deformability **EXTRAVASCULAR HEMOLYSIS** - Occurs in **RES macrophages** - 90% of RBC destruction - iron returned to erythroid precursors - globin amino acids returned to AA pool - heme protoporphyrin ring disassembled. - Balances RBC number with production and use **INTRAVASCULAR HEMOLYSIS** - **5-10%** rbc destruction (within blood vessel) - Free hemoglobin in the blood - Iron bound to transferrin - Released Hgb complexed to haptoglobin therefore decreased haptoglobin in the plasma