Hematology physiology PP.pptx

Structure and function of the Hematologic system Jody Miniard, DNP, ACNP-BC University of Cincinnati Blood • Blood volume is ~ 6 quarts (5.5L) in adults • Consists of fluid, cells, and protein • These circulate throughout the body via the vascular system • Electrolytes and proteins maintain the o...

Structure and function of the Hematologic system Jody Miniard, DNP, ACNP-BC University of Cincinnati Blood • Blood volume is ~ 6 quarts (5.5L) in adults • Consists of fluid, cells, and protein • These circulate throughout the body via the vascular system • Electrolytes and proteins maintain the osmolarity and acid-base balance of the blood • Functions of blood • Provide nutrition (protein, carbohydrates, lipids, and vitamins) to cells • Provide oxygen for cellular metabolism • Removes the by-products of cellular metabolism • Carries cells that protect the body again infection and invading organisms Plasma • Solution of protein and inorganic materials • Approximately 92% water, and 8% dissolved substances (solutes) • 50-55% of the blood volume • Contains plasma proteins which are mainly synthesized in the liver • Albumins function as carriers; and control plasma oncotic pressure • Globulins are carrier proteins and immunoglobulins (Ig) (antibodies); primarily IgG • Made by plasma cells and not synthesized in the liver • Clotting factors – mainly fibrinogen • Lipoproteins- triglycerides, cholesterol, and fatty acids • Serum • Serum • Plasma that has been allowed to clot in the laboratory in order to remove fibrinogen and other clotting factors • May interfere with some diagnostic tests Pluripotential cells • Pluripotential cells in the bone marrow differentiate into major blood cells; • Red cells - erythrocytes • White cells - leukocytes • Platelets - thrombocytes Example 1 Cellular Components of Blood • Erythrocytes • Most abundant cells of the blood (48% in men; 42% in women) • Responsible for tissue oxygenation • Contain hemoglobin • Have 120 day life cycle • Have biconcavity and reversible deformity. Cellular components of Blood 1 • Leukocytes • Defend the body against infection and remove debris • Classified by structure and function • Granulocytes: Phagocytes • Neutrophils, basophils, and eosinophils • Mast cells • Agranulocytes • Monocytes and macrophages: Phagocytes • Lymphocytes: Immunocytes Cellular Components of Blood • Platelets; Thrombocytes • 150,000 – 400,000/mm3 = normal • Are irregularly-shaped cytoplasmic fragments. • Are formed by the fragmentation of megakaryocytes. • Are essential for blood coagulation and the control of bleeding. • Are incapable of mitotic division. • Granules are generally proinflammatory. • Normal count is 140,000 to 340,000 platelets/mm3. • Live for 5-9 days and then are removed by the spleen Lymphoid Organs • Are the sites of residence, proliferation, differentiation, and function of lymphocytes and mononuclear phagocytes (monocytes and macrophages) • They are the link to the hematologic and immune systems • Primary lymphoid organs • Thymus • Bone marrow • Secondary lymphoid organs • Spleen • Lymph nodes • Tonsils • Peyer patches of the small intestine Lymphoid Organs 1 • Spleen • Largest secondary lymphoid organ • Functions • Is the site of fetal hematopoiesis. • Filters and cleanses the blood. • Mounts an immune response to bloodborne microorganisms. • Serves as a blood reservoir. Lymphoid Organs 2 • Lymph Nodes • Site of the development or activity of lymphocytes, monocytes, and macrophages. • Are structurally part of the lymphatic system. • Provide filtration of the lymph. • Are fibrous capsules, the branches of which (trabeculae) extend inward to partition the node into several compartments. • Transport lymphatic fluid back into the circulation • Are functionally part of the immune and hematologic systems. • Are the first encounter between antigen and lymphocytes. • Macrophages reside in the lymph nodes. • Filter the lymph of debris, foreign substances, and microorganisms. Hematopoiesis • Is the process of blood cell production in adult bone marrow or in the liver and/or spleen of the fetus. • Humans need 100 billion new blood cells per day. • Two stages: • Mitosis (proliferation) • Maturation (differentiation) • Continues throughout life to replace blood cells that grow old and die, are killed by disease, or are lost through bleeding. Hematopoiesis 1 • Bone marrow • Confined to cavity of bones • Primary site of residence of hematopoietic stem cells • Also called myeloid tissue • Red versus yellow bone marrow • Red produces RBCS • Yellow does not produce RBCs • Adult active bone marrow • Pelvic bones, vertebrae, cranium and mandible, sternum and ribs, humerus, and femur Example 2 15 Hematopoiesis Process Hematopoiesis 2 • Factors that increase hematopoiesis • Conversion of yellow bone marrow, which does not produce blood cells, to hematopoietic red marrow by actions of erythropoietin (hormone that stimulates erythrocyte production) • Faster differentiation of progenitor cells • Faster proliferation of stem cells into progenitor cells Erythropoiesis • Development of RBCs • Erythrocytes derived from erythroblasts • Maturation stimulated by erythropoietin • Stimulates stem cells to form proerythroblasts, which are committed into producing erythroid cells • This promotes release of reticulocytes • Sequence • In each step, the quantity of hemoglobin increases and the nucleus decreases in size Erythropoiesis 1 Erythropoietin • Hormone released from the kidney in response to low renal oxygenation • NOT the number of red cells but rather oxygen delivery • Produced in the peritubular interstitial cells of the kidney • Produced in the liver as well but only about 10% • The red blood cell production increases within 24 hours • Erythropoietin life span is 4-12 hours (short half life) • Causes an increased in red cell number in 5 days. • Erythropoietin is always present in the plasma Erythropoiesis 2 • Reticulocytes: • Last Immature form of erythroblast • Contains polyribosomes (globin synthesis) & mitochondria (heme synthesis) • 24-48 hours after leaving bone marrow for circulation, matures into an erythrocyte • Loses the polyribosomes and mitochondria • Make up about 1-2 % of total RBCs • Lasts about 2 days in the bone marrow, and 1 day in the blood continuing to fully mature • During time of low HCT the time in marrow decreased to as little as 1 day • Reticulocyte count • Indicates whether new RBCs are being produced • Reticulocyte count is a good indicator of erythropoiesis Negative Feedback Loop Hemoglobin Synthesis • Oxygen-carrying protein of the erythrocyte • Single erythrocyte, containing as many as 300 hemoglobin molecules • Each Hgb molecule has • 2 pairs of globin chains • 4 complexes of iron + heme • Heme: Large, flat, ironprotoporphyrin disk that is synthesized in the mitochondria and can carry one molecule of oxygen Hemoglobin Synthesis 1 • Formation of Globin • Polyribosomes in reticulocytes • Each Hgb molecule has 2 pairs of polypeptide globin chains • Alpha, beta, gamma, delta, epsilon or zeta • The combination of pairs that forms determines the type of globin chain • Most common is Hgb A: 2 alpha chains and 2 beta chains • Hgb F (fetal): 2 alpha chains and 2 gamma chains Hemoglobin Synthesis 2 • Formation of heme • Heme: can carry O2 • Synthesized in mitochondria of reticulocyte • Each Hgb molecule has 4 four hemes which can carry four molecules of O2 • Carbon monoxide competitively binds to heme • Affinity is 200 -300 x greater than oxygen • Therefore: even a small increase in CO can effect Hgb ability to carry/transport O2 Shape Matters • Must be able to squeeze through the tiniest capillaries • Membrane facilitates • Red cell is just a sac of hemoglobin: no nucleus, no mitochondria, only hemoglobin and some enzymes surrounded by a membrane • Since they lack mitochondria they rely on glycolysis for energy • Deficiencies is 2 enzymes resulting in anemia • G6PD and pyruvate kinase deficiency • Pyruvate kinase is necessary for glycolysis – its absence can result in damage and death to RBCs • G6PD is involved in protecting the RBC against oxidative stress Destruction of Senescent (Old) Erythrocytes • Lifespan of typical erythrocyte: 100-120 days • Changes on outer surface of old erythrocyte attract macrophages • Tissue macrophages in spleen digest the erythrocyte • heme and globin dissociate easily • globin is broken down into component amino acids • iron is liberated from heme, oxidized and recycled (transferrin to ferritin) • porphyrin of heme is metabolized to bilirubin • transported to liver and conjugated • excreted as bile into intestine • transformed to urobilinogen • most urobilinogen excreted with feces, some through kidneys Regulation of Red Cell Mass Regulation of Red Cell Mass Balance between production and destruction ~ 1% produced/day ~ 1% destroyed/day Production regulated by erythropoietin DEFINITIONS Definitions Hematocrit: % volume of blood that is red cells Men ~45% Women ~40% Hemoglobin: 34 gm/100 ml red cells 15-16 (male) gm Hb/100 ml blood 13-14 (female) gm Hb/100 ml blood Iron • ~67% of total body iron is bound to heme in erythrocytes (hemoglobin) and muscle cells (myoglobin) • ~30% is stored in mononucleur phagocytes (macrophages) • ~3% (less than 1mg) is lost daily in urine sweat, bile, and minor bleeding. • 25mg of iron is required daily for erythropoiesis; 1-2mg of iron is dietary; the remainder is obtained from iron recycling. Iron Cycle • Ferritin is the major iron storage protein • Apoferritin = ferritin without attached iron; (precursor) • Hemosiderin are ferritin micelles (normal in small amounts) • Transferrin is the iron bound to apotransferrin (precursor) • Transfers iron in circulation • Iron for hemoglobin production is carried by transferrin to the bone marrow where it binds to transferrin Iron Cycle 1 • Transferrin-iron complex binds to transferrin receptor on erythroblast’s plasma membrane • This complex moves into the cell by endocytosis • Iron is released (dissociated) from the transferrin • The dissociated transferrin is returned to the bloodstream for reuse Iron Cycle 2 Iron Metabolism • Iron absorption from intestines : ≈1-1.5 mg/day • duodenum and upper jejunum major site absorption • absorption enhanced by meat, poultry, fish • inhibited by carbonates, tannate (tea), oxalate (spinach, rhubarb), phosphates (vegetables) , clay • HCl promotes absorption • loss 1 mg/day males average • menstruating women additional 14 Iron Absorption • Liver secretes apotransferrin • Apotransferrin binds with free iron • Transferrin • Transferrin binds with receptors in intestinal epithelial cells • Released into blood capillaries • Plasma transferrin • Excess iron  liver & bone marrow • Apoferritin  ferritin • Hemosiderin: Small quantity (excess iron) collects in cells (insoluble) Hemostasis and Blood Coagulation Jody Miniard, ACNP-BC University of Cincinnati – College of Nursing Platelets • Thrombocytes develop from Megakaryocyte progenitor cells • Active & have many functions: • Actin, myosin, thrombosthenin allow platelet to contract • Synthesize enzymes, store calcium ions • Synthesize ATP and ADP • synthesize prostaglandins • Fibrin-stabilizing factor • Growth factor affecting vasc endothelial cells/ vasc smooth muscle/fibroblasts (eventually repairs damages vasc walls) Platelets 1 • Normal platelet count is 150,000 to 400,000/mm3. • If the platelet count drops below 100,000/mm3, then become thrombocytopenic (abnormally low numbers of platelets); prolongation of normal clotting may result. • If count fall below 50,000/mm3 • If the platelet count falls below 20,000/mm3, then spontaneous bleeding may occur. • If platelet numbers are elevated (thrombocytosis), then the risk for spontaneous blood clots (thrombosis), Platelets 2 • Cell Membrane: • Glycoproteins on surface repulse adherence to ‘normal’ endothelium AND promote adherence to injured endothelium • Contains phospholipids that activate several stages in the blood clotting cascade • Life expectancy: 8-10 days • Eliminated : tissue macrophage system Mechanisms of Hemostasis • Hemostasis is the arrest of bleeding • The components: • Vasculature • Platelets • Blood proteins (clotting factors) • Sequence • • • • • Vascular injury leads to vasoconstriction Formation of a platelet plug Tissue factor activates coagulation cascade Formation of a blood clot (secondary hemostasis) Clot retraction and clot dissolution (fibrinolysis) Mechanisms of Hemostasis 1 • Functions of platelets • Help regulate blood flow into a damaged site by inducing vasoconstriction. • Initiate platelet-to-platelet interactions, resulting in the formation of a platelet plug. • Activate the coagulation (or clotting) cascade to stabilize the platelet plug. • Initiate repair processes including clot retraction and clot dissolution (fibrinolysis). Hemostasis 1. Local constriction 2. Formation of the pure platelet plug 3. Formation of a blood clot 4. Wound repair with formation of fibrous tissue 42 Platelet Plug • Primary hemostasis • Important biochemicals released from platelet granules • Thromboxane A2 - prothrombotic • produced by activated platelets • stimulates activation of new platelets • increases platelet aggregation • Vasoconstriction • ADP - prothrombotic • platelet activation • stimulate shape change • Von Willebrand Factor - anchor • endothelial cells attached to collagen • acts as bridging molecule at sites of vascular injury for normal platelet adhesion • under high shear conditions - promotes platelet aggregation • carries factor VIII in circulation 4 3 Vascular Constriction • After injury: • Intravascular smooth muscle contracts reducing blood flow • Platelets are responsible for much of the vasoconstriction (thromboxane A2) • Constriction can last minutes to hours , allowing for • Platelet plug • Blood clot Platelet Plug Formation • Adhesion • Mediated by the binding of the platelet surface receptor glycoprotein-Ib (GPIb) to von Willebrand factor (vWF) • Activation • Smooth spheres change to spiny projections and degranulation (called platelet-release reaction), resulting in the release of various potent biochemicals. • Aggregation • Is facilitated by fibrinogen bridges between receptors on the platelets. • Clot retraction: Fibrin strands shorten and become denser and stronger to approximate Example 3 Injured vascular surface Platelet s swell Secrete ADP  Thromoxane A2 Change shape Activates nearby platelets Contractile proteins contract Adhere to collagen & von Willebrand factor se lea les e R nu gra Become sticky Question?????? von Willebrand factor is: 1. 2. 3. 4. Essential for platelet activation. Necessary for platelet adhesion. Needed to stimulate platelet aggregation. Required for Hageman factor to degrade platelets. Clotting factors • Factor I = Fibrinogen • synthesized by the liver and converted to fibrin during coagulation cascade • Factor II = Prothrombin • synthesized in liver in presence of vitamin K and converted to thrombin during coagulation • Factor III = Tissue thromboplastin • released from damaged tissue, required to initiate second phase = the extrinsic pathway • Factor IV = Calcium • required throughout the entire clotting sequence • Factor V = Proaccelerin • synthesized in liver, functions during common pathway phase • Factor VII = Proconvertin • protein synthesized in liver in presence of vitamin K, activated by factor III in extrinsic pathway 48 Clotting Factors 1 • Factor VIII = Antihemophilic factor A • Von Willebrand factor is the carrier for Factor VIII • required during intrinsic pathway • Factor IX = Antihemophilic factor B • synthesized in liver in presence of vitamin K; intrinsic pathway • Factor X = Stuart factor • synthesized in liver in presence in vitamin K; common pathway • Factor XI = Antihemophilic factor C • synthesized in liver; intrinsic pathway • Factor XII = Hageman factor • required in intrinsic pathway • Factor XIII - fibrin stabilizing factor • stabilizes fibrin strands in common pathway • HMW Kinogen = Fitzgerald factor • Platelets 49 What is important in clotting? •Calcium • required in multiple steps in the process to activate clotting factors •Vitamin K • essential in the synthesis of certain clotting factors in the liver 50 Sequence of events • Blood Clot • 1. Injury to the blood vessel wall or to blood induces formation of prothrombin activator • 2. Prothrombin activator changes prothrombin to thrombin • 3. Thrombin changes fibrinogen to fibrin • 4. Clot retraction, assisted by platelets, expresses serum • Remember serum is plasma minus clotting factors, such as fibrinogen • plasma can clot, serum cannot 51 Clotting Factors 2 • Function of clotting factors • Fibrin production • Intrinsic pathway (factors XII, XI, IX, and VIII) • Is activated when the Hageman factor (factor XII) contacts subendothelial substances exposed by vascular injury. • Extrinsic pathway (factor VII) • Is the most dominant. • Is activated when the tissue factor (tissue thromboplastin) is released by damaged endothelial cells. • Both pathways lead to a common pathway (factors X, V, II) • Prothrombin to thrombin • Fibrinogen to fibrin Synthesis of the Blood Clot • Begins in seconds (≈ 15) if trauma is severe • 1-2 minutes for minor injury • Three essential steps: 1. After injury, a chemical cascade resulting in the activation of prothrombin activator 2. Prothrombin activator causes prothrombin to be converted to thrombin • Dependent on adequate calcium • Prothrombin attaches to Platelets adherent to injured area 3. Thrombin converts fibrinogen to fibrin • Fibrin meshes with blood cells, platelets and plasma to form the clot Control of Hemostatic Mechanisms • Major regulatory factors are located on the endothelial cell surface. • Endothelium prevents the formation of spontaneous clots in normal vessels by several anticoagulant mechanisms. • Production of nitric oxide (NO) and prostacyclin I2 (PGI2), thrombin inhibitors (antithrombin III), tissue factor inhibitors (tissue factor pathway inhibitors), and degrading activated clotting factors (thrombomodulinprotein C). Control of Clotting • Fibrin in clot absorbs excess thrombin • Anti-thrombin III inactivates excess thrombin • Heparin is produced by mast cells and basophils • Enhances activity of antithrombin III • Coumadin acts by competing with vitamin K and inhibits the production in the liver of prothrombin and other clotting factors. • Plasminogen (profibrinolysin) is activated and becomes plasmin (fibrinolysin) • Plasminogen activator is released by damaged tissues; which then activates the plasmin • Plasminogen activators are used clinically to dissolve coronary artery clots in pts with acute MI. Clinical Evaluation of the Hematologic System • Tests of bone marrow function • Bone marrow aspiration from sternum or pelvis • Bone marrow biopsy • Provides the most reliable and complete information. • Is painful and expensive. • Bone marrow iron stores can be measured. • Can determine differential cell count. Clinical Evaluation of the Hematologic System • Blood tests • Provide information about the absolute and relative numbers of blood cells and their structural and functional characteristics. • Usually provide the initial justification for performing a bone marrow aspiration. • Large variety of blood tests are available. Blood tests of Intrinsic Pathway • Whole blood clotting time • Measure time take for blood to clot in glass test tube • Normally 9-15 minutes • PTT (partial thromboplastin time) • Clotting in a test tube is initially prevented by removing calcium • Measures time for recalcified citrated plasma to clot in the test tube Blood Tests of the Extrinsic pathway • PT (prothrombin time) – is the time needed for recalcified citrated plasma to clot in the presence of tissue thromboplastin • “protime” adds the critical tissue ingredient (tissue thromboplastin) that is necessary to start off the extrinsic pathway • Normal PT is 11-15 seconds • INR (International normalized ratio) INR = PT test PT normal INR= 0.9-1.3 for normal people INR= 2-3 people on anticoagulation therapy (Warfarin) Other coagulation tests • Platelet function assesses number of platelets. • Bleeding time assesses platelet function • Normal (depends on method) may be 2-7 min • Tends to be normal in coagulation disorders of the extrinsic and intrinsic pathway • If it is prolonged it usually suggests a defect in platelet function • PTT and PT tests are useful to distinguish extrinsic from intrinsic coagulation disorders • In liver failure, Coumadin or heparin therapy both the PT and the PTT will be abnormal Pediatrics and the Hematologic System • Blood cell counts increase above adult levels at birth; they decline during childhood. • Cause: Trauma of birth and cutting the umbilical cord • Hypoxic intrauterine environment stimulates erythropoietin production. • Result: Polycythemia of the newborn • Large number of immature erythrocytes (reticulocytes) are in full-term neonates. • In full-term and premature infants, the erythrocyte lifespan is 60 to 80 days and 20 to 30 days, respectively. Pediatrics and the Hematologic System 1 • Differences in clotting factors result in a decreased risk for thrombotic diseases and complications. • Children have more atypical lymphocytes as a result of frequent viral infections. • Neutrophil count is high at birth and rises during the first days of life. • After 2 weeks, the neutrophil count falls to within or below the normal adult range. • By approximately 4 years of age, the neutrophil count is the same as that of an adult. Pediatrics and the Hematologic System • Eosinophil count is high in the first year of life and higher in children than in teenagers or adults. • Monocyte counts also are high in the first year of life but then decrease to adult levels. • Platelet counts in full-term neonates are comparable with platelet counts in adults and remain so throughout infancy and childhood. Pediatrics and the Hematologic System Question 5 Which information is correct regarding an infant or child’s hematologic system? 1. Blood cell counts decrease at birth from the loss of blood and then increase throughout childhood. 2. Immediately after birth of a full-term neonate, the reticulocyte count decreases. 3. Platelets increase at birth and then decrease to adult levels. 4. Polycythemia of the newborn occurs from the hypoxic intrauterine environment. Aging and the Hematologic System • Blood composition changes little with age. • Erythrocyte lifespan is normal, but erythrocytes are replaced more slowly. • Possible causes • Iron depletion • Decreased total serum iron, iron-binding capacity, and intestinal iron absorption • Platelet adhesiveness may increase with age. • Lymphocyte function decreases with age. • T-cell function (cellular immunity) declines somewhat. • Humoral immune system is less responsive.