Ain-Shams University Hematology Lecture 1 2024/2025 PDF

Ain-Shams University Faculty of Veterinary Medicine Physiology and Biochemistry Department Hematology (lecture 1) By Dr. Heba Hozyen Associate Professor of Physio...

Ain-Shams University Faculty of Veterinary Medicine Physiology and Biochemistry Department Hematology (lecture 1) By Dr. Heba Hozyen Associate Professor of Physiology 2024/2025  Components of blood o Cellular portion, called formed elements, include erythrocytes (red blood cells), leukocytes (white blood cells) and platelets. o Fluid portion, called plasma (act as transport medium) composed of: - 90-92% water - 6-7% proteins - 2-3% (fats, carbohydrates (glucose), electrolytes, gases (O2, CO2) and chemical messengers)  Colour Bright red Volume Consistency 7–8% Viscous & sticky Physical properities Specific PH (7.35) gravity Slightly 1058 : 1060 Taste alkaline saltish  Function of blood Transport Defensive Hemostatic Homeostatic function function function function Blood acts as through: Blood cloting Keeping the carrier for: Phagocytic activity through: composition of internal Gases (O2 and CO2 ) of neutrophile & environment constant Absorbed food monocytes Coagulation through: (amino acids, sugar Antibodies factors Regulation of body water, &minerals) Enzymes & hormones production &platelets interstitial fluid and urine volumes Wast products (urea Regulation of body temp. & creatinine) Regulation of O.P. Regulation of PH  Hematopoiesis (Hemopoiesis): * Definition: Formation of blood cells (RBCs, WBCs & platelets). Site of Hematopoiesis: * After birth, hematopoiesis occurs in two classes of tissues: Myeloid tissue: is the red bone marrow of long bones, ribs, sternum, bodies of vertebrae and portions of the skull. It produces all different types of blood cells. Lymphoid tissue: includes the lymph nodes, tonsils, spleen and thymus. It produces one type of lymphocytes only. ❖ Site of hematopoiesis (three developmental periods): The hematopoietic Mesoblastic Hepatic Myeloid stem cells—those that give rise to blood Origin Blood islands Liver Bone marrow cells— originate in the yolk sac of the embryo of yolk sac and then migrate to the Period Till 6 weeks At 6 weeks At 5th month liver. Hematopoiesis thus occurs Cells Primarily All types of All types of in the liver of the fetus. The produced nucleated blood cells blood cells stem cells then migrate to RBCs with and fetal and the bone marrow, and embryonic hemoglobin is hemoglobin A shortly after birth the liver hemoglobin produced (α2 – β2) is produced ceases to be a source of blood cell production.  Erythrocytes 1. Structure and metabolism. 2. Functions and types of hemoglobin 3. Erythropoiesis & factors affecting it. 4. Functions and types of hemoglobin 5. Fate of RBCs Structure A nucleate, no granules to allow more space for hemoglobin. Filled with hemoglobin (Hb) as each cell contains 30 pg. Shape is maintained by a protein framework (spectrin) & other proteins that give RBCs their shape and flexibility. The red blood corpuscle is composed of: 1. Water (62-72%). 2. Total solids (28-37%): which is composed of a) Solids and organic materials including: Inorganic salts: potassium, calcium and magnesium. Organic material: as lipoproteins and phospholipids (lecithin, kephalin and cholesterol). Waste material: as urea and creatine. b) Hemoglobin (95% of total solids or 28-35% of whole cell): this is the coloring matter to which the blood owes its tint (red color). It is present in red cells to extent of 14 gm/100 ml blood. Metabolism (no mitochondria): Anaerobic respiration – glycolysis Pentose phosphate pathway Role of 2,3,Diphosphoglycerate (2,3,DPG): It is a side product of anaerobic glycolysis of glucose inside RBCs In anemia or decreased PO2 (high altitude), the production of 2,3,DPG increases 2,3,DPG + deoxy Hb : more stable compound / decrease Hb affinity to O2 / increase amount of oxy Hb in tissue capillary to be converted to deoxy Hb / lead to unloading and release of O2 to tissue.  Hemoglobin (Hb) Each Hb molecule consists of 2 parts Globin Heam group (protein part) ❑ 4 iron containing protoporphyrin ❑ Consist of four chains. (cyclic tetrapyrrole) ❑ Functions of hemoglobin: 1 carries O2 and CO2 2 Acts as buffer system More powerful than that of plasma proteins because of : High concentration Contain large amount (38 histidine residue) which is basic a.a that acts as week acid  Structure of Hb Globin Heam group (protein part) ❑ In the center of each heme group, ❑Basic protein rich in histidine a.a. there is one atom of iron in ferrous ❑Each molecule of globin form (F+2, reduced form) composed of 4 polypeptide ❑ Ferrous iron can share on electron chains with O2 to form oxyhemoglobin ❑According to sequence of amino (no oxidation). acids in the primary structure of ❑ There are 4 heme groups each each chain, there are four types attached to on globin chain. So one of chains; α, β, γ and δ. Hb molecule can carry up to 4 O2 molecules. Synthesis of hemoglobin : - Synthesis begins in proerythroblast: 65% at erythroblast stage. 35% at reticulocyte stage. - Haem and globulin are produced at two different sites of the cell: Haem in mitochondria. Globulin in polyribosomes. Types of Hb: Hb A or HbA1: is the normal Hb in adults represents about 97% of total Hb. it is composed of 2 α and 2 β chains. HbA2: minor adult Hb, comprised 3% of normal adult Hb. Composed of 2 α and 2 δ chains HbF(fetal Hb): is the main Hb during fetal life and about 60% of normal Hb at birth then disappear gradually. It is composed of 2α and 2 γ chains. Hb F has greater affinity for O2 than HbA so ensure O2 transfer from maternal circulation to fetus RBCs through placenta. Erythropoiesis (RBC Production)  Factors affecting erythropoiesis: 1- Tissue hypoxia 2- other factors: Occurred in : 1 healthy bone marrow 2 healthy liver and kidney Anemia, 3 hormones (specific and non High Altitudes, specific) Cardiac failure, 4- diatery factors Respiratory problem Hemorrage athletes Erythropoiesis (RBC Production): 1- Tissue hypoxia proliferation and maturation of RBCS through increased secretion of 1 interleukin (IL1 &IL3) from Uncommitted stem cells (bone marrow) macrophages and T (IL1 IL3) lymphocyte mediate 2 2 erythropoietin H. (from committed stem cell liver of fetus or kidney of Erythropoietin adult) steps 3 granulocyte macrophages Erythropoietin sensitive committed colony stimulating factor stem cell (GM-CSF) from macrophages, T- cells and (GM-CSF) fibroblast erythroblast Erythropoietin: Sources: - In fetus: almost formed by liver. In adult: 85% is formed by the kidney (by the endothelial cells of peritubular capillaries in the kidneys). So, anemia is a constant feature of renal failure. 15% is formed by liver (Kupffer cells i.e. tissue macrophages). Mechanism of action: it increases the number of erythropoietin sensitive committed stem cells. II. Other factors than tissue oxygenation: 1) Healthy bone marrow. 2) Healthy liver: Forms globulin, 15% of erythropoietin and stores iron, Vit. B12 3) Healthy kidney: Forms 85% of erythropoietin. 4) Hormones: Specific like erythropoietin and non- specific like thyroid hormones, androgens & glucocorticoids. 5) Diet ❑ Proteins (of high biological value) Formation of Globin Cell membrane formation ❑ Fats For Cell membrane formation ❑ Minerals and trace elementes Iron (for heme formation) 65% of Fe stored in Hb: Intracellular Fe stored in protein-Fe complexes (ferritin & hemosiderin) in liver & spleen Fe is transported on transferrin (transport protein)  Copper Ceruloplasmin Necessary for Iron transfer from storage sites Cobalt Forms a part of Vitamin B12 Nickel and Manganese Vitamins Vit. B12 & folate : Essential for formation of thymidine triphosphate important unit in DNA syntheces help in RBCs division and maturation. Called antiperinecious anemia factor Vitamin C ▪ Potentiate the effect of Folic acid ▪ Also helpful in Iron Absorption and Reducing Ferric to ferrous form Riboflavin and Pantothenic acid ▪ Heme formation ▪ Cell growth and division  Fate of red blood cells (Extravascular and intravascular hemolysis) Life span in blood stream is 60-120 days. Senescent RBCs are phagocytosed and/or lysed. Normally, lysis occurs extravascularly in the reticuloendothelial system subsequent to RBC phagocytosis. Lysis can also occur intravascularly (in blood stream).  Fate of red blood cells (Extravascular and intravascular hemolysis) Extravascular Pathway for RBC Destruction Extravascular Pathway for RBC Destruction Extravascular Pathway for RBC Destruction Intravascular Pathway for RBC Destruction Intravascular Pathway for RBC Destruction  Handling of Free (Intravascular) Hemoglobin Purposes: 1. Scavenge iron 2. Prevent major iron losses 3. Complex free heme (very toxic) Haptoglobin: hemoglobin-haptoglobin complex is readily metabolized in the liver and spleen forming an iron-globin complex and bilirubin. Prevents loss of iron in urine. Hemopexin: binds free heme. The heme-hemopexin complex is taken up by the liver and the iron is stored bound to ferritin. Methemalbumin: complex of oxidized heme and albumin. Heme is degraded to bilirubin (yellow) Bilirubin is secreted by the liver into the intestine as bile The intestines metabolize it into urobilinogen (green) then to stercobilin (brown)  Thrombocytes Mature Platelet 1. Thrombopoiesis & Structure of platelets. Megakaryocyte 2. Hemostasis. 3. Clot retraction and lysis. Bone 4. Function of platelets. Marrow Developmental pathway of platelets Structure of platelets  Structure of platelets 1- Membrane structures: ❑ Plasma membrane contains glycoproteins serve as receptors for collagen, vessel wall von-willebrand factor and fibrinogen so, facilitate platelet adhesion & contraction. (prevent adherence of platelet to normal endothelium but helps adherence to injured endothelium). ❑ The platelet membrane also contains phospholipids which provide a catalytic surface for coagulation (i.e platelet factor-3 (PF3) and yield arachidonic acid for synthesis of prostaglandins. ❑ Canalicular system: numerous invaginations of the platelet surface which serves as a pathway for both the uptake of extracellular calcium and release of intracellular substances. 2- Cytoplasm: System of contractile proteins : are present beneath the plasma membrane and include filaments and micofilamentes of actin and myosin which enable activated platelets to change their shape. Microtubules: keep disc shape of platelets. Residual of both endoplasmic reticulum and golgi apparatus Mitochondria: for synthesis of ATP & ADP. Dense tubular system: Prostaglandin converting enzymes, contractile calcium Peroxisomes: Catalase Lysosomes: Acid hydrolase. Platelet granules Dense body: contain non protein substances (ADP, ATP, GTP, GDP, serotonin, and Ca++) Alpha granules: contain secreted proteins as fibrin stabilizing factor (factor ), platelet derived growth factor (PDGF) and platelet activating factor (PAF). Hemostasis: - It is the stoppage of bleeding, which is vitally important when blood vessels are damaged to prevent blood loss including 3 steps: 1st step: vasoconstriction of the injured and surrounding blood vessels. It takes seconds. 2nd step: temporary hemostatic plug of platelets (platelets plug formation). 3rd step: blood coagulation, which converts the temporary plug to definitive hemostatic plug. It takes 4-8 min. 1- Local vasoconstriction Myogenic reflex Nervous reflex (pain reflex) can be maintained by platelet vasoconstrictors (ADP, serotonine and thromboxane A2)  2-platelet plug formation (temperory) ❑It is aggregation and fusion of platelets at the site of injury to form : A sealing plug Activator mechanism of blood clotting. Injured blood vessel releases ADP, which attracts platelets (PLT) PLT comming in contact with exposed collagen release: serotonin, ADP, TXA2, which accelerate vasoconstriction and cause activation to more platelets (where it swell, change its shape and become more sticky) and aggregate to form sealing plug  3-Formation ofblood clot (blood coagulation) Is convertion of soluble fibrinogen into insoluble protein, fibrin by an enzyme called thrombin Fibrin aggregates to form a meshlike network at the site of vascular damage. ❖ coagulation factors: Chemical nature and site of formation of coagulation factors: Coagulation factors are plasma proteins mainly β globulins that are synthetized in the liver except : FactorVIII platelets and endothelial cells. Factor XIII platelets and liver. Function: They act as proteolytic enzymes activates each other in a step like reaction (e.g. cascade, waterfall reaction).  Blood clotting factors Factor I Fibrinogen. Factor II Prothrombin. Factor III Tissue factor/ Tissue thromboplastin. Factor IV Calcium. FactorV Labile factor/ proaccelerin. FactorVII Stable factor/ proconvertin. FactorVIII Antihemophilic globulin/factor A. FactorIX Christmas factor/ antihemophilic factor B. Factor X Stuart‐Prower factor Factor XI Plasma thromboplastin antecedent. FactorXII Hageman factor, contact factor. Factor XIII fibrin stabilizing factor.