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Physiology of the Blood Dr. Mohamamd Alqudah, BDS, Ph.D Department of physiology and biochemistry Office location M2, fifth floor Office hours 2-3 Monday- Thursday Email: [email protected] Outline General overview of the blood Hematopoiesis Guyton 32 Physiology of Red Blood Cells (RBCs) Guyton 32 Physiology of White Blood Cells (WBCs) Guyton 33&34 Blood coagulation and homeostasis Guyton 35 Blood groups and transfusion Guyton 36 Lecture # 1 General overview of blood Blood characteristics Components of blood General functions of blood Characteristics of Blood Blood is the only fluid tissue in the body Blood is a complex connective tissue in which living cells, the formed elements, are suspended in the nonliving fluid called plasma. Cells of the body are served by two fluids 1) The blood transports nutrients and wastes 1) The interstitial flood bathes the cells of the body http://facweb.northseattle.edu/ Characteristics of Blood Volume: A person has 4 to 6 liters of blood, depending on his or her size. Of the total blood volume in the human body, 38% to 48% is composed of the various blood cells, also called formed elements. The remaining 52% to 62% of the blood volume is plasma, the liquid portion of blood. Color: Arterial blood is bright red because it contains high levels of oxygen. Venous blood has given up much of its oxygen in tissues, and has a darker, dull red color. pH: The normal pH range of blood is 7.35 to 7.45, which is slightly alkaline. Venous blood normally has a lower pH than does arterial blood because of the presence of more carbon dioxide. Viscosity: Blood is about three to five times thicker than water so flows more slowly than water Blood volume Volume of the blood The average blood volume of an adult is about 7% of body weight, or about 5 litters Adult male - 5-6 liters Adult female - 4-5 liters 55% of blood is plasma and 45% is red blood cells, these percentage vary with many factors such as gender, weight and other factors. Determination of blood volume Direct method: removal of all blood in experimental conditions with animals. Indirect method: (dye dilution) injection of known amount of radio-labeled albumin or Evans blue dye to measure plasma volume and you know the Hematocrit, the blood volume will be: Total blood volume = Plasma volume 1- Hematocrit Blood viscosity • It is the inherent resistance of blood to flow due to internal friction of adjacent blood layers sliding past each other. • Factors that contribute to blood plasma 1. Plasma proteins and electrolytes (specifically; albumin and fibrinogen), Plasma is about 1.8 more viscous than water. 2. Blood cells( especially red blood cells) 3. Temperature, cold blood is thicker and flows slowly. 4. Blood velocity 5. Vessel radius Blood viscosity **Plasma is about 1.8 more viscous than water this is due mainly to presence of plasma protein. Whole blood viscosity is 3-4 times of that of water. This is due to presence of RBCs. Viscosity is increased when hematocrit value or no. of RBCs rise. **Increased viscosity will decrease blood flow through blood vessels. Plasma osmotic pressure is 300 mmol/L or 770kPa (1) Crystal osmotic pressure results from NaCl and modulates water distribution between inside and outside of cells. (2) Colloid osmotic pressure results from albumin and regulates water distribution between inside and outside of capillary. Components of the blood Components of Blood (Hematocrit) Components of Blood 1.Formed elements 45% of whole blood • Known as percent packed cell volume granular leukocytes neutrophils eosinophils basophils agranular leukocytes lymphocytes = T cells, B cells, and natural killer cells monocytes Platelets (special cell fragments) In the buffy coat Red blood cells ( erythrocytes ) Hematocrit White blood cells ( leukocytes ) Blood smear Formed elements of the blood Components of Blood 2. Plasma ( blood without cells) 55% about 3 litters water, amino acids, proteins, carbohydrates, lipids, vitamins, hormones, electrolytes, wastes ***Plasma is obtained when unclotted blood is centrifuged. The fluid above cellular elements is PLASMA. Characteristics of Plasma 1. Straw-colored liquid 2. Mainly water 90% 3. Includes many dissolved substances Nutrients, Salts (metal ions) Respiratory gases Hormones Proteins, Waste products Source: DiverDave, CC-BY-SA, via Wikimedia Commons Plasma proteins: you can separate plasma protein by electrophoresis 1) Albumin: 60% synthesized in the liver, main function is to provide colloid osmotic pressure in the plasma 2) Globulin: 36% of plasma proteins, made in the liver except gamma globulins 1-globulins e.g. antitrypsin 2-globulins e.g. Angiotensinogen -globulins e.g. Transferrin -globulins immunoglobulins IgA, IgD, IgE, and IgM: made in plasma cells 3) Fibrinogen: fibrin, fibers (4% of plasma proteins), produced from the liver Blood Coagulation Plasma proteins Most plasma proteins are produced by the liver, except for hormones and gamma globulins. Gamma globulins are formed by plasma cells. 8% by weight of plasma volume Plasma proteins serve a variety of functions, but they are not taken up by cells to be used as fuels or metabolic nutrients as are most other plasma solutes, such as glucose, fatty acids, and amino acids. Note: hypoproteinemia is seen in a. liver diseases….less formation b. kidneys disease….loss of protein PLASMA ELECTROLYTES 1. Electrolyte release ions when dissolved in water 2. include: sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate and sulfate ions 3. Function: maintain osmotic pressure and the pH of the plasma. NUTRIENTS AND GASES 1. Nutrients : simple sugars, amino acids,, nucleotides and lipids 2. Blood gases: oxygen and carbon dioxide NONPROTEIN NITROGEN SUBSTANCES 1. contain nitrogen but are not proteins 2. include: urea, uric acid, creatine & creatinine 3. digestion amino acids 4. nucleic acid catabolism uric acid & urea 5. creatine metabolism creatinine Plasma VS Serum Serum is plasma from which fibrinogen and other coagulation proteins have been removed as a result of clotting. It contains high level of serotonin (released from platelets during clotting). ***It is obtained when clotted blood is centrifuged. The fluid above clotted blood is SERUM General functions of the blood 1. Transportation Gases: O2 & CO2 Nutrients: Amino acids, lipids, glucose, etc. Hormones: pituitary, thyroid, pancreas, ovary, and testes, synthesize hormones brought by blood to tissu requiring them. waste products: urea, lactic acid , creatinine Electrolytes: Na+ K+ Cl- Ca++ 2. Regulation Blood pH: H2CO3, lactic acid, citric acid, NH3, HCO3- tend to lower or raise blood pH. Buffer systems help maintain pH within limits. Fluid balance: plasma colloid osmotic pressure Body temperature: coolant properties of water and vasodilatation of surface vessels dump heat 3. Protection Infection Blood loss WBC , antibodies platelets, clotting factors Hematology lab tests The complete blood count (CBC) include a hemogram and differential white blood cell (WBC) count. The hemogram includes the enumeration of WBCs, red blood cells (RBCs), and platelets The WBC count with differential enumerates the different WBC types Tests designed to assist the accuracy of RBCs number, structure and function RBC count Hgb concentration hematocrit(Hct) RBC indices. RBC count: is the part of the CBC that determines the number of RBCs found in a cubic centimeter of blood. Hemoglobin Hgb : 300 million molecules of Hgb in one RBC. Hematocrit: Hct represents the percentage of the total volume of RBCs relative to the total volume of whole blood in a sample Note: Hgb and Hct levels parallel, in that Hct levels are 3 times the Hgb level This relationship is altered if RBCs are abnormal in size or shape or if the synthesis of Hgb is defective. RBC Indices RBC indices are calculated mean values that are used to define the size, weight, and Hgb content of the RBC. They are mainly used to classify anemias. RBC indices consist: Mean Corpuscular volume (MCV) Mean corpuscular volume. MCV describes the RBC by size or volume. The MCV classifies RBCs as microcytic, normocytic, and macrocytic MCV is a calculated value obtained by dividing the Hct by the RBC count. Mean corpuscular hemoglobin (MCH) This This value is the index that measures the average weight of Hgb in the RBC. Mean corpuscular hemoglobin concentration This index is a measure of the average concentration of Hgb in the RBC per unit volume. (Normochromic, hypochromic and hyperchromic Hematopoiesis Hematopoietic process Regulation of Hematopoiesis Chronological Sites for Hematopoiesis Nutritional requirement for hematopoiesis Hematopoiesis Hematopoiesis is the process of blood cells (erythrocyte (red blood cell, RBC), leukocyte (white blood cell, WBC) and thrombocyte (platelet, P)) formation in the bone marrow from hematopoietic stem cells. All blood cells are derived from a common stem cell called Pluripotent hematopoietic stem cell (PHSC) Hemopoietic process 1: Hemopoietic stem cells- Pluripotent hematopoietic stem cell (PHSC) Unlimited self renewal, steady numbers, active differentiation. 2: committed progenitors directional differentiation (CFU-GEMM, CFU-E, CFUGM, CFU-MK, CFU-TB). [CFU: colony- forming unit 3: precursors morphologic occurrence of various original blood cells. PHSC differentiates to become: either a) Myeloid progenitor cell or b) Lymphoid progenitor cell Myeloid Myeloid RBC’s and WBC’s and platelets Lymphoid B and T cells and Lymphoid Hematopoiesis Proliferative potential differentiation www.freelivedoctor.com Pluripotent hematopoietic stem cell (PHSC) features Self renewal in high degree, a small portion of them remains exactly like the original pluripotential cells and is retained in the bone marrow to maintain a supply of these, although their numbers diminish with age. Multi- directional differentiation High proliferative capacity, Hematopoietic stem cells produce about 1×1011 blood cells releasing to blood for use. Surface sign According to CFU (colony forming unit), using fluorescenceactivated cell sorting (FACS), its main surface sign is CD34+CD38-Lin-and CD34-CD38-Lin-. Note CD: cluster of differentiation of antigen on the white blood cells; Lin: systemic specific antigen on the hematopoietic cells. Hematopoietic Microenvironment 1) stem cell(s) 1) stromal cells 2) growth factors endothelial cells, fibroblasts, adipocytes, macrophages, Hematopoietic Microenvironment Stromal cells: fibroblasts endothelial cells adipocytes Growth Factors www.freelivedoctor.com Regulation of hematopoiesis The process of hematopoiesis is under tight control by multiple proteins called growth factors Growth factors control the growth and reproduction of different stem cells Another group of growth factors ( differentiation inducers) control the differentiation process. Each of the differentiation inducers cause the one type of committed stem cells to differentiate one or more step towards the final cell type responsible for basal hematopoiesis and maintaining blood counts in normal ranges Hematopoiesis ERYTHROPOIESIS GRANULOPOIESIS GROWTH FACTORS MEGAKARYOPOIESIS LYMPHOPOIESIS generation of each specific lineage of mature blood cells is regulated by a specific set of hematopoietic growth factors. Hematopoietic growth factors Growth Factors Function: stimulate progenitor of the followings: GM-CSF (granulocytemacrophage 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 Sites of Hemopoietic Activity Bone marrow Yolk sac Vertebra Liver Sternum Rib Spleen Femur Tibia 1 3 FETAL MONTHS 20 ADULT Nutritional requirement of hematopoiesis Blood cell production (hematopoiesis) is a dynamic process that requires the replenishment of more than 7 × 109 blood cells (leukocytes, erythrocytes and platelets) per kg body weight per day Therefore, as would be expected, their maturation and rate of production are affected greatly by a person’s nutritional status. o o o Especially important to our discussion are : Vitamin B12 Folic acid Iron Role of vitamin B12 and folic acid in synthesis of cellular DNA** **Bone marrow cellular elements are among the most rapidly dividing cells in the body (because of continuous needed for RBCs and WBCs). Dividing cells needs continuous formation of DNA. Both vit B12 and folic acid are needed for formation of thymidine triphosphate (one of four nitrogen bases that form the DNA). thymine Role of vitamin B12 and folic acid in synthesis of cellular DNA (cont.)** **Because both Vitamin B12 and folic acid are needed for normal formation of DNA, therefore nuclear maturation and cell division of bone morrow cells (hematopoiesis) is not rapid and this leads to larger cells (macrocytes). The macrocytes have irregular ,oversized (large than normal) and oval shape with fragile cell membrane. Macrocytes are red cells with an increased size, 912µm in diameter Abnormal cell membrane of RBCs leads to short life of RBCs. Facts regarding Vitamin B12 (Cyanocobalamin )** • Water soluble vitamin • Vit B12 in diet can be destroyed by digestive enzymes. It is protected by intrinsic factor • Prolonged deficiency leads to irreversible neurological damage • Its absorption from gatrointestinal tract (terminal ileum) needs presence of intrinsic factor • It is absorbed from terminal ileum with intrinsic factor by pinocytosis. Sources of Vitamin B12 1. 2. 3. 4. Fish Eggs Meat and liver Dairy Products ** Dietary deficiency is rare except in vegetarians Absorption of vitamin B12 (Cbl) Dietary Cbl in the presence of acid and pepsin in the stomach is liberated from binding to protein and then quickly binds to R factors (Cbl -binding proteins) in saliva and gastric juice R factor- Cbl complex is freed in the alkaline milieu of the duodenum by the action of pancreatic proteases and then binds specifically and rapidly to gastric-derived intrinsic factor (IF). IF is a 45 kDa glycoprotein with very high affinity for Cbl. The IF-Cbl complex binds to a specific ileal receptor, cubilin, from which it will be absorbed into ileal enterocytes. Then it will exit into blood and bind to transcobalamins II This complex enters cells by receptor-mediated endocytosis. Reference Stanley L Schrier, MD The minimum amount of vitamin Cbl required each day to maintain normal red cell maturation is only 1 to 3 micrograms Total body stores of Cbl are 2 to 5 milligrams, approximately one-half of which is in the liver Therefore, 3 to 4 years of defective B12 absorption are usually required to cause maturation failure anemia. Folic acid The daily folate requirement for unstressed adults is estimated to be approximately 50mg/day Folate occurs in animal products and in leafy vegetables in the polyglutamate form Dietary folate in the form of the polyglutamates is cleaved to the monoglutamate in the jejunum where it is absorbed Body stores are 5-10 mg (liver) Folate deficiency take place in a disease called sprue Reference Stanley L Schrier, MD Megaloblastic anemia** Both vitamin B12 and folate deficiency cause an identical megaloblastic anemia Pernicious anemia is due to primary deficiency of vitamin B12 secondary to failure of vitamin B12 absorption from gastrointestinal tract. This absorption failure is due to absence of intrinsic factor (atrophic gastric mucosa). Megaloblastic anemia due to Deficiency of vitamin B12 Causes of vitamin B12 deficiency: 1. Impaired absorption a. Gastric atrophy: Auto immune disease can destroys the parietal cells that secrete the I.F. required for absorption of vit. B12. b. Gastrectomy c. Intestinal disease like ileal resection in these cases treatment is life long injections of vitamin B12 (oral administration wouldn't be effecient!) d. Infestation with Fish tapeworm (Diphyllobothrium latum) 2. Decreased vitamin B12 intake- seen in vegetarian Iron metabolism Iron is very important to our body: Hemoglobin synthesis It is an essential element of myoglobin, cytochromes, cytochrome oxidase, peroxidase, catalase Iron distribution in our body, total body Iron is 4-5 g: 65% of which is in the form of hemoglobin 4% myoglobin 1% various heme compounds .1% plasma transferrin 15-30% is stored in reticuloendothelial cells and liver parenchymal cells mainly in the form of ferritin Daily iron loss average 1-2 mg Man .6mg female about 1.3 Copyright © Cornell University Iron absorption, transport and storage Copyright © Cornell University Iron uptake by erythroid progenitors Copyright © Cornell University Regulation of total body iron Copyright © Cornell University Physiology of Red Blood Cells (RBCs) Erythrocytes Structural characteristics Hemoglobin Erythropoiesis Erythrocytes destruction Anemia Polycythemia Shape and Size of Red Blood Cells. 1 µm No nucleus (anucleate) or organelles (no mitochondria, no endoplasmic reticulum) biconcave discs having a mean diameter of about 7.8 micrometers and a thickness of 2.5 micrometers at the thickest point and 1 micrometer or less in the center. The average volume (MCV) of the red blood cell is 90 to 95 cubic micrometers (fL). The red blood cell is a “bag” that can be deformed into almost any shape Filled with hemoglobin Concentration of Red Blood Cells in the Blood Men 5,200,000 (±300,000); women, it is 4,700,000 (±300,000) 7.8 Quantity of Hemoglobin Hb in the Cells. RBCs concentrate Hb in their cytoplasm Each 100 ml of RBCs , the concentration of Hb is about 34g (MCHC) - This is the maximum metabolic limit and normal people always Hb near the maximum value - If hematocrit (Hct) is normal, then Hb is one third of Hct value Hct =45% then Hb = 15 Each gram of Hb can bind 1,34 ml of O2 So 100 ml of blood carry 20 ml of O2 in man Women the amount is less. Production of Red Blood Cells Erythropoiesis • • • In early weeks of pregnancy, a primitive nucleated RBC are formed in yolk sac Middle trimester of fetal life- Liver (mainly), spleen, lymph nodes. Last month of pregnancy and after birthexclusively from Bone marrow Sites of RBC formation in different ages 0-5 Y …..all bones of the body 5-20 Y…. The shaft of long bones become fatty and its contribution to form RBC reduced gradually and stops completely after 20 y. Heads of long bones continue to form RBC After 20 Y….. Almost in membranous bones Relative rates of RBC production in bone marrow of different bones at different ages Production of Red Blood Cells Erythropoiesis Stages of Differentiation of Red Blood Cells The first cell that can be identified as belonging to the red blood cell series is the proerythroblast The first-generation cells are called basophil erythroblasts, very little hemoglobin At the satge of reticulocytes, the nucleus condenses to a small size, and its final remnant is absorbed or extruded from the cell. At the same time, the endoplasmic reticulum is also reabsorbed Reticulocytes pass from bone marrow into blood capillaries by diapedesis In the blood stream the remaining basophilic material will disappear in 1-2 days and mature erythrocytes will developed Regulation of Red Blood Cell The total mass of red blood cells in the circulatory system is regulated within narrow limits, so (1) adequate red cells are always available to provide sufficient transport of oxygen from the lungs to the tissues, yet (2) the cells do not become so numerous that they impede blood flow. Any condition that causes the quantity of oxygen transported to the tissues to decrease ordinarily increases the rate of red blood cell production - Anemia These conditions produce tissues hypoxia leading to increase - Bone marrow destruction in RBCs production, Hct & total blood volume will increase - Very high altitude - Cardiac failure - Lung disease Regulation of Red Blood Cell Production—Role of Erythropoietin How does hypoxia induce erythropoiesis? Erythropoietin Erythropoietin is a glycoprotein with a molecular weight of about 34,000. Produced mainly by the kidneys (90%) but the liver produces some (10%). Produced in response to tissue hypoxia Renal tissue hypoxia leads to hypoxia inducible factor-1 (HIF-1 HIF-1 stimulates erythropoietin production Another factors increases erythropoietin production: 1. Androgen 2. alkalosis 3. Catecholamine Effect of Erythropoietin in Erythrogenesis. Binding of erythropoietin on its receptors activates the transcription of antiapoptotic molecules and inactivates the proapoptotic proteins Erythropoietin receptors are expressed on CFU-E and the subsequent cells but are not expressed on reticulocytes and RBCs S. Elliott et al./ Experimental Hematology 2008;36:1573– 1584 Effect of Erythropoietin in Erythrogenesis. Erythropoietin will stimulate the production of proerythroblasts Will facilitate the passage of the RBC precursors from one stage to another There will be a negative feed back mechanism for erythropoietin production when the O2 carrying capacity of the blood is back to normal Normal erythropoiesis requires amino acids, Vit. B12, Iron and folate in proper amounts Formation of Hemoglobin Hb formation begins at the stage of proerythroblasts and continues to the stage of reticulocytes Hemoglobin molecule compose of 4 hemoglobin chains There are four different chains of hemoglobin (alpha, beta, gamma and delta chain) Hemoglobin A (64,458) is a combination of two alpha and two beta chain About 300 million molecules of HB in every red cell. Each molecule of HB carries 4 oxygen O2 molecules. Normal values: Females: 14 g/100ml blood Males: 15 g/100 ml blood Oxygenated Hemoglobin Bright Red (systemic) *Deoxygenated Hemoglobin dull (venous circulation) Life Span of Red Blood Cells is About 120 Days Even erythrocytes are anucleated they have many cytoplasmic enzymes: (1)maintain flexibility of the cell membrane (2) maintain membrane transport of ions (3) keep the iron of the cells’ hemoglobin in the ferrous form rather than ferric form (4) prevent oxidation of the proteins in the red cells In old RBCs the enzymatic activity of these cells will drop dramatically, they lose their flexibility and become increasingly rigid and fragile, and their contained hemoglobin begins to degenerate. Erythrocyte Destruction • Macrophages in spleen, liver and red bone marrow phagocytize dying RBC. • Globin – breaks into amino acids, which can be reused to produce other proteins • Heme – iron and porphyrin • Fe – removed and recycled in spleen • Porphyrin – converted to bilirubin (bile pigment) • Yellow pigment secreted by liver into bile, which is excreted in urine and feces Anemias Anemia means deficiency of hemoglobin in the blood, which can be caused by either too few red blood cells too little hemoglobin in the cells decrease in blood’s oxygen-carrying capacity Examples of Anemia : 1. Blood loss anemia: acute and chronic blood loss 2. Aplastic anemia lack of functioning bone marrow (aplasia) radiation, chemotherapy, toxin material such as insecticides, autoimmune and idiopathic 3. Megaloplastic anemia vit. B12, folic acid, pernicious anemia, sprue 4. Hemolytic anemia: hereditary spherocytosis, sickle cell anemia and erythroblastosis fetalis Effect of anemia on cardiovascular system** Decreased viscosity anemia Decreased resistance to blood flow hypoxia Dilatation of blood vessels What will happen during exercise? More blood returns to the heart More cardiac output Polycythemia** Primary polycythemia (polycythemia vera) polycythemia (Means increased RBCs no.( Due to increased activity of hemocytoblastic cell of bone marrow Secondary polycythemia Due to hypoxia, high altitudes and heart failure Effects of polycythemia on CVS* Increased cardiac output Blood volume Polycythemia Leads to Increased venous return Hematocrit viscosity decreased blood flow Decreased venous return to the heart Decreased cardiac output Increased blood pressure More O2 is extracted from Hb and thus deoxygenated blood is increased leading to bluish discoloration of the skin (cyanosis)