blood physiology
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blood physiology
- 1. DR. WILMA BUNAYOG KOU BLOOD PHYSIOLOGY
- 2. Blood By the end of the lecture you should be able to: State the composition of Blood State the function of red blood cells and plasma Explain the function of hemoglobin in the transport of oxygen State the function of macrophages and lymphocytes To understand the value of blood as an important factor in homeostasis
- 3. INTRODUCTION: GENERAL CHARACTERISTICS OF BLOOD: 1. color: bright red oxygenated (systemic) dark red/purple deoxygenated (venous) 2. pH: 7.35 -7.45 3. 0smolality : 285 -295 mOsm 4. Viscosity 3-4x more viscous than water 5. Almost all blood cells are found red bone marrow.
- 4. BLOOD FUNCTIONS: Transport function - nutrients glucose, AA, etc - waste products urea, lactic acid , creatinine - gases O2 , CO2 - electrolytes Na+ K+ Cl- Ca++ regulation - ph buffers - temperature protection - infection WBC , antibodies - blood loss platelets, clotting factors
- 5. 5 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Centrifuged Blood Sample Peripheral Blood Smear Liquid (plasma) “Buffy coat” (white blood cells and platelets) Red blood cells Red blood cells Platelets White blood cells
- 6. 6 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Plasma = 55% Capillary tube Plug Buffy coat Red cells = 45% (hematocrit)
- 7. Blood Volume and Composition Volume varies with size. Blood is about 8% of the total body weight. Average adult has 5 liters of blood Blood is 40-45% cells This is also known as the percent packed cell volume 95% are red blood cells, remainder white blood cells and blood platelets The hematocrit is an indicator of anemia, polycythemia, and other conditions. Blood is 55 -60% plasma water, amino acids, proteins, carbohydrates, lipids, vitamins, hor mones, electrolytes, wastes
- 8. 8 Blood (4.8%) (95.1%) (0.1%) Plasma Hormones MonocytesBasophilsEosinophilsNeutrophils (54–62%) (1–3%) (<1%) (3–9%) (25–33%) GlobulinsAlbumins (92%) (7%) N2 O2 CO2 Platelets Red blood cells Proteins Nutrients Gases 45% 55% WastesWaterWhite blood cells Electrolytes Vitamins Lymphocytes Fibrinogen Formed elements Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
- 10. PLASMA CHARACTERISTICS: 1. Straw colored 2. mainly water (92%), plasma CHONs, nutrients, gases, non-CHON nitrogen subs, and electrolytes FUNCTIONS 1. transport of nutrients, gases and vitamins 2. regulate fluid and electrolyte balance 3. maintain pH
- 11. PLASMA PLASMA PROTEINS 1. most abundant dissolved substances in plasma 2. Three main plasma proteins: a. albumin – 60% of plasma CHONs, made in the liver and they help to maintain oncotic pressure, and transport certain molecules such as bilirubin and fatty acids. b. globulins – 36% of plasma CHONs i. alpha and beta – produced in the liver, transport lipids and fat soluble vitamins ii. Gamma globulins – made by lymph tissue, a type of antibody c. fibrinogen - 4% of plasma CHONs, made in the liver, help in blood coagulation
- 12. PLASMA NUTRIENTS AND GASES 1. Nutrients : amino acids, simple sugars, 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. CHON digestion amino acids 4. CHON & nucleic acid catabolism uric acid & urea 5. creatine metabolism creatinine
- 13. PLASMA 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.
- 14. Blood Cells 14 • Blood cells originate in red marrow from hemocytoblasts or hematopoietic stem cells • Stem cells can then: • Give rise to more stem cells • Specialize or differentiate HEMATOPOIESIS - making of blood cells ERYTHROPOIESIS - making of RBC LEUKOPOIESIS - making of WBC
- 16. Hematopoiesis
- 17. Blood vessel Red blood cell platelet Plasma White blood cell
- 18. PRODUCTION OF RBC: Early embryonic life : nucleated RBC yolk sac Middle trimester: liver main organ for production, some are produced in the spleen and lymph nodes Last month of gestation and after birth: exclusively produced in the bone marrow Bone marrow of essentially all bones produces RBCs until 5 years old Bone marrow of the long bones, except proximal portions of the humeri and tibiae no RBCs after 20 yrs old >20 yo membranous bones , like vertebrae, sternum, ribs, ilia less productive as age increases.
- 20. GENESIS OF RBC
- 21. FUNCTIONS OF RBC To transport Hemoglobin, which carries oxygen from the lungs to the tissues As an enzyme that catalyzes the reversible reaction between carbon dioxide (CO2) and water to form carbonic acid (H2CO3) carbonic anhydrase As an excellent acid-base buffer
- 22. Characteristics of Red Blood Cells Red blood cells are: • Erythrocytes • Biconcave discs • Able to readily squeeze through capillaries • Lack nuclei and mitochondria •average volume: 90 -95 cubic micrometers •Normal men: 5,200,00 cubic mm •Normal women: 4,700,00 cubic mm Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Top view 2.5 micrometers 7.8 micrometers Sectional view (a) (b)
- 23. RED BLOOD CELLS Concentrate Hemoglobin (Hgb) in the cell fluid: 34 grams in each 100 milliliters of cells Hematocrit ( % of blood that is cells – normally , 40- 45%) and the quantity of Hgb men : 15 grams of Hgb/100ml of cells women: 14 grams Hgb/100ml of cells Each gram of pure Hgb 1.34 ml of Oxygen Normal man: 20ml of O2/100ml of blood Normal woman: 19 ml of O2/100 ml of blood
- 24. REGULATION OF RBC Regulated within narrow limits: 1. adequate number is always available to provide sufficient transport of O2 2. cells do not become so numerous that they impede blood flow Tissue oxygenation is the most essential regulator of RBC
- 25. Red Blood Cell Production & Its Control 25 • Low blood oxygen causes the kidneys and the liver to release erythropoietin (EPO) which stimulates RBC production • This is a negative feedback mechanism • Within a few days many new blood cells appear in the circulating blood Low blood oxygen Liver Kidney Erythropoietin Red bone marrow + – Bloodstream Stimulation Inhibition Release into bloodstream Increased oxygen- carrying capacity Increased number of red blood cells
- 27. ERYTHROPOIETEN A glycoprotein, molecular wt 34,000 90% kidneys; 10% liver Epi or norepi will also stimulate erythropoietin Maximum production within 24hours 5 days Stimulation of the erythroblast
- 28. Dietary Factors Affecting Red Blood Cell Production • Vitamin B12 and folic acid are necessary • They are required for DNA synthesis making them necessary for the growth and division of all cells • Iron is also necessary • It is required for hemoglobin synthesis
- 29. Formation of hemoglobin Synthesis of hemoglobin begin in the proerythroblast and continues into Reticulocyte Hemoglobin molecule compose of 4 hemoglobin chains There are four different chains of hemoglobin (alpha, beta, gamma and delta chain) Hemoglobin A is a combination of two alpha and two beta chain
- 31. Heme 8 8 Succinyl CoA Glycine** HEME SYNTHESIS ** Amino acid (building blocks of protein) synthesized in your body
- 33. STRUCTURE OF HEME Ferrous iron (Fe2+) Protoporphyrin IX: contains 4 pyrrole rings linked together by methenyl bridges
- 34. Fig. 14.8 Note that, in muscle, myoglob (Mb) binds oxygen. Mb consis of only 1 protein chain. Note the 4 protein chains that make up 1 molecule of Hb.
- 35. Mechanism of Transport * 4 Heme Molecules = * 4 Oxygen Molecules *Oxygenated Hemoglobin Bright Red (systemic) *Deoxygenated Hemoglobin Blue (venous circulation) HEMOGLOBIN
- 36. Formation of hemoglobin There are 4 iron atom in each hemoglobin molecule. Each can bind one molecule of oxygen that can be transported in each hemoglobin molecule
- 38. Normal iron metabolism: -The primary function is oxygen transport. -Iron is absorbed by duodenum and jejunim -Average total body iron content 4000-5000 mg. - 65% in the form of HGB, 4% myoblogin, 1% heme cpd -Iron is also stored in RE cells (BM, Spleen and liver) as hemosiderin and ferritin. -Also iron found in myglobin and myeloperoxidase and in certain electron transfer. -Iron is more stable in ferric state (Fe+++) than in ferrous state (Fe++).
- 39. Overview of Normal Iron Metabolism Iron Tansport Via transferrin Iron Storage (Hepatic - major site) Hepatic uptake of transferrin bound Fe via classic transferrin receptor TfR1 (& homologous TfR2) Hepatocytes are storage reservoir for iron Taking up dietary iron from portal blood Releasing iron into the circulation via ferroportin in times of increased demand Iron Utilisation Erythropoiesis for haem synth / general cellular respiration
- 40. Normally the body stores iron but women need to consume more iron than men. Why?
- 42. Absorption, transport, and storage of iron
- 43. BLOOD CELLS LIVER Bilirubin diglucuronide (water-soluble) 2 UDP-glucuronic acid via bile duct to intestines Stercobilin excreted in feces Urobilinogen formed by bacteria KIDNEY Urobilin excreted in urine CO Biliverdin IX Heme oxygenase O2 Bilirubin (water-insoluble) NADP+ NADPH Biliverdin reductase Heme Globin Hemoglobin reabsorbed into blood Bilirubin (water-insoluble) via blood to the liver INTESTINE Figure 2. Catabolism of hemoglobin
- 44. 44 Bilirubin Bone Blood Liver Globin + Heme 3 2 1 Absorption 4 5 Macrophage Hemoglobin Iron + Biliverdin 8 6 7 Bile Red bone marrow Red blood cells produced Red blood cells circulate in bloodstream for about 120 days Old red blood cells Blood transports absorbed nutrients Nutrients from food Vitamin B12 Folic acid Iron Small intestine Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
- 45. Too few, Too many Anemia – low hematocrit (below-normal oxygen- carrying capacity of the blood) Nutritional, pernicious, aplastic, renal, hemorrhagic, hemolytic Polycythemia- abnormally high hematocrit (too many RBCs in circulation) Primary, secondary
- 46. ANEMIAS Blood Loss Anemia - after hemorrhage , replaces the fluid portion of the plasma in 1 to 3 days. - cell concentration usually returns to normal within 3 to 6 weeks. - chronic blood loss - microcytic,hypochromic anemia Aplastic Anemia - Bone marrow aplasia means lack of functioning bone marrow. Megaloblastic Anemia - deficiency of vitamin B12, folic acid, and intrinsic factor from the stomach mucosa - atrophy of the stomach mucosa, as occurs in pernicious anemia, or loss of the entire stomach after surgical total gastrectomy
- 47. ANEMIAS HEMOLYTIC ANEMIA 1. hereditary spherocytosis the red cells are very small and spherical rather than being biconcave discs. 2. sickle cell anemia present in 0.3 to 1.0 % of West African and American blacks the cells have an abnormal type of hemoglobin called hemoglobin S, containing faulty beta chains in the hemoglobin molecule 3. erythroblastosis fetalis Rh-positive red blood cells in the fetus are attacked by antibodies from an Rh-negative mother.
- 48. GENESIS OF RBC
- 49. Effects of Anemia on Function of the Circulatory System Increased cardiac output Increased pumping workload of the heart during exercise, which greatly increases tissue demand for oxygen, extreme tissue hypoxia results, and acute cardiac failure ensues.
- 50. POLYCYTHEMIA Secondary Polycythemia > too little oxygen in the breathed air, such as at high altitudes, or because of failure of oxygen delivery to the tissues, such as in cardiac failure, the blood-forming organs automatically produce large quantities of extra red blood cells. > RBC counts 6 to 7 million/mm3, about 30 % above normal. >physiologic polycythemia, occurs in natives who live at altitudes of 14,000 to 17,000 feet, where the atmospheric oxygen is very low.
- 51. POLYCYTHEMIA Polycythemia Vera (Erythremia) > pathological condition known in which the red blood cell count may be 7 to 8 million/mm3 and the hematocrit may be 60 to 70 per cent. > caused by a genetic aberration in hemocytoblastic cells that produce the blood cells. > not only does the hematocrit increase, but the total blood volume also increases, on some occasions to almost twice normal. > the viscosity of the blood increases from the normal of 3 times the viscosity of water to 10 times that of water.
- 52. Effect of Polycythemia on Function of the Circulatory System increased viscosity of the blood , blood flow through the peripheral blood vessels is often very sluggish decreases the rate of venous return to the heart. Conversely, the blood volume is greatly increased in polycythemia, which tends to increase venous return. cardiac output in polycythemia is not far from normal
- 53. (b) (a) a: © The McGraw-Hill Companies, Inc./Al Telser, photographer :b © Ed Reschke Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 53
- 55. Blood Cell Origin and Production Bone Marrow Circulation Figure 11-8
- 56. 5 - Types of WBC’s Each WBC has a specific function GranulocytesAgranulocytes
- 57. White Blood Cells (Leukocytes) Mobile units of body’s defense system: “Seek and Destroy” Functions: 1. Destroy invading microorganisms 2. Destroy abnormal cells (ie: cancer ) Clean up cellular debris (phagocytosis) 3. Assist in injury repair
- 58. Phagocytosis WBC function is phagocytosis which means cellular ingestion of the offending agent Phagocytes is selective of the material that is phagocytized and depends on: 1. Tissue surface structure 2. Protein coats 3. Development of antibodies This selection of phagocytosis called opsonization
- 59. Characteristics of WBC White Blood Cells enter the tissue spaces by Diapedesis. Neutrophils and monocytes can squeeze through the pores of the blood capillaries by diapedesis. White Blood Cells move through tissue spaces by Ameboid Motion. White Blood Cells are attracted to inflamed tissue areas by Chemotaxis
- 61. Epithelia Protect against infection: phagocytize bacteria; produce proteins that destroy foreign particles Diapedesis: leukocytes can squeeze between cells and leave the circulation Fig. 14.14
- 62. Infection
- 63. Characteristics of WBC The adult human 7000 WBC/ ml of bld (in comparison with 5 million red blood cells).(NV: 5,000 – 6,000) The normal percentages of the different types are Polymorphonuclear neutrophils 62.0% (54 -62%) Polymorphonuclear eosinophils 2.3% (1 -3%) Polymorphonuclear basophils 0.4% ( 0.5 - 1%) Monocytes 5.3% (3 – 8%) Lymphocytes 30.0% ( 25- 35%)
- 64. Characteristics of WBC The life of the granulocytes normally 4 to 8 hours circulating in the blood and another 4 to 5 days in tissues . The monocytes short transit time, 10 to 20 hours in the blood, before wandering through the capillary membranes into the tissues. Once in the tissues, they swell to much larger sizes to become tissue macrophages, and, in this form, can live for months
- 65. Types of WBC’s Polymorphonuclear Granulocytes 1.Neutrophils 2.Eosinophils 3.Basophils
- 66. 1. NEUTROPHILS * 54 -62% of all leukocytes (most abundant of WBC’s) * Phagocytes that engulf bacteria and Debris * Important in inflammatory responses
- 67. 2. EOSINOPHILS * 1 -3 % of the WBC's * Attack parasitic worms * Control inflammation and allergic reactions
- 68. 3. BASOPHILS •Releases histamine and heparin * 0.5 - 1% of the WBC's * Important in Allergic Reactions * Heparin anticoagulant and helps clear fat from
- 69. Types of WBC’s Mononuclear Agranulocytes 4. Monocytes 5. Lymphocytes (B and T cells)
- 70. 4. MONOCYTES * Exit blood (diapedesis) to become macrophages * 3 - 8 % of the WBC's * Phagocytic = defend against viruses and bacteria
- 71. 5. LYMPHOCYTES * B-lymphocytes: Produce Antibodies * T-lymphocytes: Directly destroy virus- invaded cells and cancer cells * 25-35 % of the WBC's
- 72. Charateristics Both Neutrophils and Macrophages can kill bacteria. - contain bactericidal agents that kill most bacteria Some bacteria have protective coats or other factors that prevent destruction, killing results from oxidizing agents formed by enzymes in the membrane These oxidizing agents include large quantities of superoxide (O2–), hydrogen peroxide (H2O2), and hydroxyl ions (–OH–), all of which are lethal to most bacteria, even in small quantities. Also, lysosomal enzymes, myeloperoxidase, catalyzes the reaction between H2O2 and chloride ions to form hypochlorite, which is exceedingly bactericidal.
- 73. Monocyte-Macrophage Cell System (Reticuloendothelial System) The total combination of monocytes,mobile, macrophages, fixed tissue macrophages, and a few specialized endothelial cells in the bone marrow, spleen, and lymph nodes is called the reticuloendothelial system. all or almost all these cells originate from monocytic stem cells; therefore, the reticuloendothelial system is almost synonymous with the monocyte- macrophage system.
- 74. Tissue macrophages in the skin and subcutaneous tissues Histiocytes Macrophages (Kupffer Cells) in the liver sinusoids
- 75. Inflammation: Role of Neutrophils & Macrophages Tissue macrophages is the First Line of defense against infection Neutrophil invasion of the inflamed area is a Second Line of Defense. Second Macrophage invasion into the inflamed tissue is a Third Line of Defense. Along with the invasion of neutrophils. Increased production of granulocytes and monocytes by the Bone Marrow Is a Fourth Line of Defense
- 76. Blood vessel Red blood cell Plasma White blood cell Platelets
- 77. 3. Platelets (Thrombocytes) * Cell fragments bound to megakaryocytes * “Bud Off” and are released into the blood
- 78. CHARACTERISTICS OF PLATELETS CHARACTERISTICS: 1. Fragment of cells 2. round cell that lacks a nucleus 3. half size of the RBC 4. life span = around 10 days Platelet count: NV 140,000 – 440,000/cumm FUNCTION: 1. Release serotonin which contracts smooth muscle in the blood vessel reducing the flow of blood and will begin the formation of a blood clot
- 79. Function of Platelets Stop bleeding from a damaged vessel * Hemostasis Three Steps involved in Hemostasis 1. Vascular Spasm 2. Formation of a platelet plug 3. Blood coagulation (clotting)
- 80. Steps in Hemostasis • Immediate constriction of blood vessel • Vessel walls pressed together – become “sticky”/adherent to each other • Minimize blood loss *DAMAGE TO BLOOD VESSEL LEADS TO: 1. Vascular Spasm:
- 81. Steps in Hemostasis a. PLATELETS attach to exposed collagen b. Aggregation of platelets causes release of chemical mediators (ADP, Thromboxane A2) c. ADP attracts more platelets d. Thromboxane A2 (powerful vasoconstrictor) * promotes aggregation & more ADP 2. Platelet Plug formation: (figure 11-10) Leads to formation of platelet plug !
- 82. Figure 11-10 (+) Feedback promotes formation of platelet Plug
- 83. Final Step in Hemostasis a. Transformation of blood from liquid to solid b. Clot reinforces the plug c. Multiple cascade steps in clot formation d. Fibrinogen (plasma protein) Fibrin Thrombin 3. Blood Coagulation (clot formation): “Clotting Cascade”
- 84. COMPLETE BLOOD COUNT RBC 4.5 – 6 MILLION/cumm HEMOGLOBIN 12 – 16 gm/dl HEMATOCRIT 40 – 48 % RETICULOCYTE < 1% WBC 5,000 – 10,0000/ cumm NEUTROPHIL 54 - 62% EOSINOPHIL 1 – 3% BASOPHILS <1% LYMPHOCYTES 25 – 35% MONOCYTES 3 – 9% PLATELETS 140,000 –
- 85. THANK YOU!
Editor's Notes
- Remain stable within the plasma however an increase could mean a problem with the kidneys or a possible infection.
- The blood cells begin their lives in the bone marrow from a single type of cell called the pluripotential hematopoietic stem cell, from which all the cells of the circulating blood are eventually derived. Figure 32–2 shows the successive divisions of the pluripotential cells to form the different circulating blood cells. As these cells reproduce, 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. Most of the reproduced cells,however, differentiate to form the other cell types shown to the right in Figure 32–2. The intermediate stagecells are very much like the pluripotential stem cells, even though they have already become committed to a particular line of cells and are called committed stem cells. The different committed stem cells, when grown inculture, will produce colonies of specific types of blood cells. A committed stem cell that produces erythrocytesis called a colony-forming unit–erythrocyte, and the abbreviation CFU-E is used to designate this typeof stem cell. Likewise, colony-forming units that form granulocytes and monocytes have the designationCFU-GM, and so forth. Growth and reproduction of the different stem cells are controlled by multiple proteins called growth Inducers. Four major growth inducers have been described, each having different characteristics. One ofthese, interleukin-3, promotes growth and reproduction of virtually all the different types of committed stem cells, whereas the others induce growth of only specific types of cells. The growth inducers promote growth but not differentiation of the cells.This is the function of another set of proteins called differentiation inducers. Each ofthese causes one type of committed stem cell to differentiate one or more steps toward a final adult blood cell.Formation of the growth inducers and differentiation inducers is itself controlled by factors outside the bone marrow. For instance, in the case of erythrocytes (red blood cells), exposure of the blood to low oxygen for a long time results in growth induction, differentiation, and production of greatly increased numbers of erythrocytes, as discussed later in the chapter. In the case of some of the white blood cells, infectious diseases cause growth, differentiation, and eventual formation of specific types of white blood cells that are needed to combat each infection.
- Areas of the Body That Produce Red Blood Cells. In the earlyweeks of embryonic life, primitive, nucleated red blood cells are produced in the yolk sac. During the middle trimester of gestation, the liver is the main organ forproduction of red blood cells, but reasonable numbers are also produced in the spleen and lymph nodes.Then,during the last month or so of gestation and after birth, red blood cells are produced exclusively in the bonemarrow. As demonstrated in Figure 32–1, the bone marrow of essentially all bones produces red blood cells untila person is 5 years old.The marrow of the long bones, except for the proximal portions of the humeri and tibiae, becomes quite fatty and produces no more red blood cells after about age 20 years. Beyond this age, most red cells continue to be produced in the marrow of the membranous bones, such as the vertebrae, sternum, ribs, and ilia. Even in these bones, the marrow becomes less productive as age increases.
- The first cell that can be identified as belonging to the red blood cell series is the proerythroblast, shown at the starting point. Under appropriate stimulation, large numbers of these cells are formed from the CFU-E stem cells. Once the proerythroblast has been formed, it divides multiple times, eventually forming many mature red blood cells. The first-generation cells are called basophil erythroblasts because they stain with basic dyes; the cell at this time has accumulated very little hemoglobin. In the succeeding generations, as shown in Figure 32–3, the cells become filled with hemoglobin to a concentration of about 34 per cent, 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. The cell at this stage is called a reticulocytebecause it still contains a small amount of basophilic material, consisting of remnants of the Golgi apparatus, mitochondria, and a few other cytoplasmic organelles. During this reticulocyte stage, the cells pass from the bone marrow into the blood capillaries by diapedesis (squeezing through the pores of the capillary membrane). The remaining basophilic material in the reticulocyte normally disappears within 1 to 2 days, and the cell is then a mature erythrocyte. Because of the short life of the reticulocytes, their concentration among all the red cells of the blood is normally slightly less than 1 per cent.
- The major function of red blood cells, also known as erythrocytes, is to transport hemoglobin, which in turn carries oxygen from the lungs to the tissues.for hemoglobin to remain in the human blood stream, it must exist inside red blood cells. they contain a large quantity of carbonic anhydrase, an enzyme that catalyzes the reversible reaction between carbon dioxide (CO2) and water to form carbonic acid (H2CO3), increasing the rate of this reaction several thousandfold. The rapidity of this reaction makes it possible for the water of the blood to transport enormous quantities of CO2 in the form of bicarbonate ion (HCO3 –) from the tissues to the lungs, where it is reconverted to CO2 and expelled into the atmosphere as a body waste product. The hemoglobin in thecells is an excellent acid-base buffer (as is true of most proteins), so that the red blood cells are responsible for most of the acid-base buffering power of whole blood.
- Normal red blood cells, shown in Figure 32–3,are biconcave discs having a mean diameter of about 7.8 micrometers anda thickness of 2.5 micrometers at the thickest point and 1 micrometer or lessin the center. The average volume of the red blood cell is 90 to 95 cubicmicrometers.The shapes of red blood cells can change remarkably as the cells squeezethrough capillaries.Actually, the red blood cell is a “bag” that can be deformedinto almost any shape. Furthermore, because the normal cell has a great excessof cell membrane for the quantity of material inside, deformation does notstretch the membrane greatly and, consequently, does not rupture the cell, aswould be the case with many other cells.Concentration of Red Blood Cells in the Blood. In normal men, the average numberof red blood cells per cubic millimeter is 5,200,000 (±300,000); in normal women,it is 4,700,000 (±300,000). Persons living at high altitudes have greater numbersof red blood cells.
- Quantity of Hemoglobin in the Cells. Red blood cells have the ability to concentratehemoglobin in the cell fluid up to about 34 grams in each 100 milliliters of cells.The concentration does not rise above this value, because this is the metabolic limit of the cell’s hemoglobin-forming mechanism. Furthermore, in normal people, the percentage of hemoglobin is almost alwaysnear the maximum in each cell. However, when hemoglobin formation is deficient, the percentage of hemoglobinin the cells may fall considerably below this value, and the volume of the red cell may also decreasebecause of diminished hemoglobin to fill the cell. When the hematocrit (the percentage of blood thatis cells—normally, 40 to 45 per cent) and the quantity of hemoglobin in each respective cell are normal, thewhole blood of men contains an average of 15 grams of hemoglobin per 100 milliliters of cells; for women,it contains an average of 14 grams per 100 milliliters. As discussed in connection with blood transport ofoxygen in Chapter 40, each gram of pure hemoglobin is capable of combining with 1.34 milliliters of oxygen.Therefore, in a normal man, a maximum of about 20 milliliters of oxygen can be carried in combinationwith hemoglobin in each 100 milliliters of blood, and in a normal woman, 19 milliliters of oxygen can becarried.
- The total mass of red blood cells in the circulatory system is regulated within narrow limits, so that (1) anadequate number of red cells is always available to provide sufficient transport of oxygen from the lungsto the tissues, yet (2) the cells do not become so numerous that they impede blood flow.Tissue Oxygenation Is the Most Essential Regulator of RedBlood Cell Production. Any condition that causes the quantity of oxygen transported to the tissues todecrease ordinarily increases the rate of red blood cell production. Thus, when a person becomes extremelyanemic as a result of hemorrhage or any other condition, the bone marrow immediately begins to produce large quantities of red blood cells.Also, destruction of major portions of the bone marrow by any means, especially by x-ray therapy, causes hyperplasia of the remaining bone marrow, thereby attempting to supply the demand for red blood cells in the body. At very high altitudes, where the quantity of oxygen in the air is greatly decreased, insufficient oxygen is transported to the tissues, and red cell production is greatly increased. In this case, it is not the concentration of red blood cells in the blood that controls red cell production but the amount of oxygen transported to the tissues in relation to tissue demand for oxygen. Various diseases of the circulation that causedecreased blood flow through the peripheral vessels, and particularly those that cause failure of oxygen absorption by the blood as it passes through the lungs, can also increase the rate of red cell production. This is especially apparent in prolonged cardiac failure and in many lung diseases, because the tissue hypoxia resulting from these conditions increases red cell production, with a resultant increase in hematocrit and usually total blood volume as well.
- The principal stimulus for red blood cell production in low oxygen states is a circulating hormone called erythropoietin, a glycoprotein with a molecular weight of about 34,000. In the absence of erythropoietin, hypoxia has little or no effect in stimulating red blood cell production. But when the erythropoietin system is functional, hypoxia causes a marked increase in erythropoietin production, and the erythropoietin in turn enhances red blood cell production until the hypoxia is relieved. In the normal person, about 90 per cent of all erythropoietin is formed in the kidneys; the remainder is formed mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is formed. One likely possibility is that the renal tubular epithelial cells secrete the erythropoietin, because anemic blood is unable to deliver enough oxygen from the peritubular capillaries to the highly oxygen-consuming tubular cells, thus stimulating erythropoietin production. At times, hypoxia in other parts of the body, butnot in the kidneys, stimulates kidney erythropoietin secretion, which suggests that there might be some nonrenal sensor that sends an additional signal to the kidneys to produce this hormone. In particular, both norepinephrine and epinephrine and several of the prostaglandins stimulate erythropoietin production. When both kidneys are removed from a person or when the kidneys are destroyed by renal disease, the person invariably becomes very anemic because the 10 per cent of the normal erythropoietin formed in other tissues (mainly in the liver) is sufficient to cause only one third to one half the red blood cell formation needed by the body.
- The principal stimulus for red blood cell production in low oxygen states is a circulating hormone called erythropoietin, a glycoprotein with a molecular weight of about 34,000. In the absence of erythropoietin, hypoxia has little or no effect in stimulating red blood cell production. But when the erythropoietin system is functional, hypoxia causes a marked increase in erythropoietin production, and the erythropoietin in turn enhances redblood cell production until the hypoxia is relieved. Role of the Kidneys in Formation of Erythropoietin. Inthe normal person, about 90 per cent of all erythropoietin is formed in the kidneys; the remainder is formed mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is formed. One likely possibility is that the renal tubular epithelial cells secrete the erythropoietin, because anemic blood is unable to deliver enough oxygen from the peritubular capillaries to the highly oxygen-consuming 9tubular cells, thus stimulating erythropoietin
- Maturation of Red Blood Cells—Requirementfor Vitamin B12 (Cyanocobalamin) andFolic Acid Because of the continuing need to replenish red blood cells, the erythropoietic cells of the bone marrow are among the most rapidly growing and reproducing cells in the entire body. Therefore, as would be expected, their maturation and rate of production are affected greatly by a person’s nutritional status. Especially important for final maturation of the red blood cells are two vitamins, vitamin B12 and folic acid. Both of these are essential for the synthesis of DNA,because each in a different way is required for the formation of thymidinetriphosphate.the erythroblastic cells of the bone marrow, in addition to failing to proliferate rapidly, produce mainly largerthan normal red cells called macrocytes, and the cell itself has a flimsy membrane and is often irregular,large, and oval instead of the usual biconcave disc. These poorly formed cells, after entering the circulatingblood, are capable of carrying oxygen normally, but their fragility causes them to have a short life, one halfto one third normal.Therefore, it is said that deficiency of either vitamin B12 or folic acid causes maturationfailure in the process of erythropoiesis.
- Synthesis of hemoglobin begins in the proerythroblasts and continues even into the reticulocyte stage ofthe red blood cells.Therefore, when reticulocytes leave the bone marrow and pass into the blood stream, theycontinue to form minute quantities of hemoglobin for another day or so until they become mature erythrocytes.Figure 32–5 shows the basic chemical steps in the formation of hemoglobin. First, succinyl-CoA, formed in the Krebs metabolic cycle (as explained in Chapter 67), binds with glycine to form a pyrrole molecule. Inturn, four pyrroles combine to form protoporphyrin IX, which then combines with iron to form the hememolecule. Finally, each heme molecule combines with a long polypeptide chain, a globin synthesized by ribosomes, forming a subunit of hemoglobin called a hemoglobin chain (Figure 32–6). Each chain has a molecular weight of about 16,000; four of these in turn bind together loosely to form the whole hemoglobin molecule. There are several slight variations in the different subunit hemoglobin chains, depending on the amino acid composition of the polypeptide portion. The different types of chains are designated alpha chains, beta chains, gamma chains, and delta chains. The most common form of hemoglobin in the adult human being, hemoglobin A, is a combination of two alphachains and two beta chains. Hemoglobin A has a molecular weight of 64,458. Because each hemoglobin chain has a heme prosthetic group containing an atom of iron, and because there are four hemoglobin chains in each hemoglobin molecule, one finds four iron atoms in each hemoglobin molecule; each of these can bind loosely with one molecule of oxygen, making a total of four molecules of oxygen (or eight oxygen atoms) that can be transported by each hemoglobin molecule. The types of hemoglobin chains in the hemoglobin molecule determine the binding affinity of the hemoglobin for oxygen. Abnormalities of the chains can alter the physical characteristics of the hemoglobin molecule as well. For instance, in sickle cell anemia, the amino acid valine is substituted for glutamic acid a
- Absorption, transport, and storage of iron. Intestinal epithelial cells actively absorb inorganic iron and heme iron (H). Ferrous iron that is absorbed or released from absorbed heme iron in the intestine (1) is actively transported into the blood or complexed with apoferritin (AF) and stored as ferritin (F). In the blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) (2) or to hepatocytes for storage as ferritin (3). The transferrin-iron complexes bind to transferrin receptors (TfR) in erythroid precursors and hepatocytes and are internalized. After release of the iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4). Hepatocytes use several mechanisms to take up iron and store the iron as ferritin. DMT1, divalent metal transporter; FP, ferroportin; FR, ferrireductase; HCP1, heme carrier protein 1.
- The principal stimulus for red blood cell production in low oxygen states is a circulating hormone called erythropoietin, a glycoprotein with a molecular weight of about 34,000. In the absence of erythropoietin, hypoxia has little or no effect in stimulating red blood cell production. But when the erythropoietin system is functional, hypoxia causes a marked increase in erythropoietin production, and the erythropoietin in turn enhances red blood cell production until the hypoxia is relieved. In the normal person, about 90 per cent of all erythropoietin is formed in the kidneys; the remainder is formed mainly in the liver. It is not known exactly where in the kidneys the erythropoietin is formed. One likely possibility is that the renal tubular epithelial cells secrete the erythropoietin, because anemic blood is unable to deliver enough oxygen from the peritubular capillaries to the highly oxygen-consuming tubular cells, thus stimulating erythropoietin production. At times, hypoxia in other parts of the body, butnot in the kidneys, stimulates kidney erythropoietin secretion, which suggests that there might be some nonrenal sensor that sends an additional signal to the kidneys to produce this hormone. In particular, both norepinephrine and epinephrine and several of the prostaglandins stimulate erythropoietin production. When both kidneys are removed from a person or when the kidneys are destroyed by renal disease, the person invariably becomes very anemic because the 10 per cent of the normal erythropoietin formed in other tissues (mainly in the liver) is sufficient to cause only one third to one half the red blood cell formation needed by the body.
- Blood Loss Anemia. After rapid hemorrhage, the body replaces the fluid portion of the plasma in 1 to 3 days,but this leaves a low concentration of red blood cells. If a second hemorrhage does not occur, the red blood cell concentration usually returns to normal within 3 to 6 weeks. In chronic blood loss, a person frequently cannotabsorb enough iron from the intestines to form hemoglobin as rapidly as it is lost. Red cells are then producedthat are much smaller than normal and have too little hemoglobin inside them, giving rise to microcytic,hypochromic anemia, which is shown in Figure 32–3.
- The first cell that can be identified as belonging to the red blood cell series is the proerythroblast, shown at the starting point. Under appropriate stimulation, large numbers of these cells are formed from the CFU-E stem cells. Once the proerythroblast has been formed, it divides multiple times, eventually forming many mature red blood cells. The first-generation cells are called basophil erythroblasts because they stain with basic dyes; the cell at this time has accumulated very little hemoglobin. In the succeeding generations, as shown in Figure 32–3, the cells become filled with hemoglobin to a concentration of about 34 per cent, 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. The cell at this stage is called a reticulocytebecause it still contains a small amount of basophilic material, consisting of remnants of the Golgi apparatus, mitochondria, and a few other cytoplasmic organelles. During this reticulocyte stage, the cells pass from the bone marrow into the blood capillaries by diapedesis (squeezing through the pores of the capillary membrane). The remaining basophilic material in the reticulocyte normally disappears within 1 to 2 days, and the cell is then a mature erythrocyte. Because of the short life of the reticulocytes, their concentration among all the red cells of the blood is normally slightly less than 1 per cent.
- chemotaxis depends on the concentration gradient of the chemotactic substance. The concentration is greatest near the source, which directs the unidirectional movement of the white cells. Chemotaxis is effective up to 100 micrometers away from an inflamed tissue.Therefore, because almost no tissue area is more than 50 micrometersaway from a capillary, the chemotactic signal can easily move hordes of white cells from the capillaries into theinflamed area.