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Blood and Hematopoiesis TA: Breann Yanagisawa Johns Hopkins Pathobiology Program September 8, 2014 Lecture Overview • Blood Physiology – FuncIons, components, cell types, hematopoiesis, homeostasis, hemostasis • Blood Pathology – Techniques, Red blood cell disorders, white blood cell disorders Blood Physiology – FuncIons • Blood is important in many funcIons including: – TransportaIon of: • Oxygen and nutrients • Metabolic waste for eliminaIon • Hormones – RegulaIon of: • Body temperature • Body Issue pH • Fluid volume – PrevenIon of: • Blood loss through cloPng mechanisms • InfecIon through immune mechanisms Blood Physiology – Components • Blood is made up of two main parts: – Plasma – liquid • Mostly water and dissolved solutes – Proteins » Albumin » CloPng factors – Non-‐protein substances » Nutrients, metabolic byproducts, hormones, etc. – Formed elements – cells • Buffy coat • Erythrocytes Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology – Cell Types Erythrocytes (Red Blood Cells) • Most abundant (45% of blood volume – hematocrit) • Males: 47% ± 5%, Females 42% ± 5% • Biconcave disc • Anucleate • Main funcIon: oxygen transport Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb ASH Teaching Slides: Blood Cells The appearance of normal circulating blood is relatively uniform with little variation in size and shape. Red blood cells will have an area of paleness in the center, which is approximately one-third the diameter of the cell. Maslak, P. ASH Image Bank 2008;2008:8-00044. Copyright ©2008 American Society of Hematology. Blood Physiology – Red Blood Cells • High surface area to volume raIo • Hemoglobin – Globin: two α, two β chains – Heme: four heme groups containing iron (Fe) – Bind easily to oxygen – Carbon dioxide transport back to lungs Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology – White Blood Cells • Leukocytes – White blood cells – Less abundant (<1% of blood volume) • 4,800-‐10,800/uL of blood – Main funcIon: immune response – Two categories: • Granulocytes • Agranulocytes Blood Physiology – White Blood Cells Granulocytes Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology -‐ Granulocytes • Neutrophil – Acute bacterial infecIons – Chemically adracted to sites of inflammaIon – PhagocyIc – Life span: hours -‐ days Peter Maslak, ASH Image Bank 2011; 2011-3776 • Appearance – MulIlobed nucleus – Small cytoplasmic granules; pink and purple – Pinkish cytoplasm Peter Maslak, ASH Image Bank 2011; 2011-3608 Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. Blood Physiology -‐ Granulocytes • Eosinophil – ParasiIc worm infecIons – Lysosome filled granules – Life span: days • Appearance: Peter Maslak, ASH Image Bank 2011; 2011-3776 – Bilobed nucleus – Large cytoplasmic granules; red – Reddish cytoplasm Peter Maslak, ASH Image Bank 2011; 2011-2677 Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. Blood Physiology – Granulocytes • Basophil – Inflammatory response and vasodilaIon – Histamine containing granules – Life span: hours to days Peter Maslak, ASH Image Bank 2011; 2011-1590 • Appearance: – Bilobed nucleus – Large cytoplasmic granules; purple and black – Purplish cytoplasm Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. Peter Maslak, ASH Image Bank 2011; 2011-2582 Blood Physiology – White Blood Cells Agranulocytes Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology -‐ Agranulocytes • Lymphocyte – Immune response – T cells: act directly against enemies – B cells: anIbody producIon – Life span: hours to years Peter Maslak, ASH Image Bank 2011; 2011-2046 • Appearance – Small; low cytoplasm to nucleus raIo – Spherical nucleus – Pale blue cytoplasm John Lazarchick, ASH Image Bank 2011; 2011-1049 Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. Blood Physiology -‐ Agranulocytes • Monocyte – CirculaIng macrophages – PhagocyIc – Life span: months • Appearance Peter Maslak, ASH Image Bank 2011; 2011-1591 – “Kidney bean” shaped nucleus – Gray-‐blue cytoplasm Peter Maslak, ASH Image Bank 2011; 2011-1662 Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. Blood Physiology -‐ Hematopoiesis • FormaIon of blood cells – Approx 100 billion new cells turned out each day! • Occurs in bone marrow – Red bone marrow • All blood cells arise from the hematopoieIc stem cell (HSC) – RelaIvely rare • 1-‐4 HSCs per 100,000 nucleated marrow cells – Erythropoiesis = red blood cells – Leukopoiesis = white blood cells "603 Anatomy of Long Bone" by OpenStax College -‐ Anatomy & Physiology, Connexions Web site. hdp://cnx.org/content/col11496/1.6/, Jun 19, 2013.. Licensed under CreaIve Commons AdribuIon 3.0 via Wikimedia Commons -‐ hdp://commons.wikimedia.org/wiki/File:603_Anatomy_of_Long_Bone.jpg#mediaviewer/File:603_Anatomy_of_Long_Bone.jpg Blood Physiology -‐ Erythropoiesis • ErythropoieIn (EPO) – Glycoprotein hormone – Mainly synthesized in the kidneys; some in liver • Hypoxia-‐inducible factor (HIF) – Increases EPO producIon – Degraded by oxygen-‐sensiIve enyzmes • Accumulates in low oxygen concentraIons Blood Physiology – Leukopoiesis • Appearance of surface receptors that respond to specific hormones and growth factors • Released by supporIng cells in red bone marrow or mature leukocytes: – Interleukins • IL-‐2, IL-‐3, etc. – Colony-‐sImulaIng factors (CSFs) • G-‐CSF = granulocyte colony-‐sImulaIng factor Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology -‐ Platelets • Megakaryocytes – Myeloid stem cell • Undergo repeated mitoses with no cytokinesis • Regulatory hormone = thrombopoieIn Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology – Homeostasis • Red blood cell destrucIon – 100-‐120 day lifespan – DegeneraIng red cells get caught in spleen (smaller circulatory channels) • Engulfed and degraded by macrophages – Globin chains broken down to amino acids à reused – Iron porIon is stored for reuse – Remaining heme degraded to bilirubin » Binds to albumin for transport and eventual excreIon Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology -‐ Hemostasis • “Stoppage of bleeding” • Requires cloPng factors and released substances • 3 major steps: – Vascular spasm – Platelet plug formaIon – CoagulaIon Primary CloPng Secondary CloPng Blood Physiology – Hemostasis • Vascular Spasm – VasoconstricIon induced by: • Direct injury to vascular smooth muscle • Chemicals released by surrounding endothelial cells and platelets • Reflexes iniIated by local pain receptors – Main outcome: reduced blood flow Blood Physiology -‐ Hemostasis • Platelet Plug FormaIon – Nitric oxide and prostacyclin • Normally released from endothelial cells; prevents platelet aggregaIon – Damaged endothelium • Exposed collagen fibers; platelets sIck • von Willebrand factor (VWF) forms stable bridge between collagen and platelets • Platelets release chemical messengers that recruit more platelets and increase the vascular spasm Blood Physiology -‐ Hemostasis • CoagulaIon – FormaIon of a clot via fibrin threads – Carried out by cloPng factors • Exist in blood in inacIve form – Protein cleavage acIvates them – 3 Phases of coagulaIon: • 1. FormaIon of prothrombin acIvator – Extrinsic vs. Intrinsic pathways • 2. Conversion of prothrombin to thrombin • 3. Fibrinogen molecules joined into fibrin mesh Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology -‐ Hemostasis • Liver – Most cloPng factors synthesized here • Vitamin K (green leafy vegetables) – Factor II (Prothrombin) – Factor VII – Factor IX – Factor X • Calcium – Plays a major role in many of the cloPng cascade reacIons Adapted from Human Anatomy and Physiology 2nd Edi8on, Marieb Blood Physiology -‐ Hemostasis • Fibrinolysis – Plasminogen (inacIve) integrated into clot • Fibrin digesIng – Endothelial cells secrete Issue plasminogen acIvator (tPA) • AcIvated Factor XII, thrombin – Plasmin (acIvated Plasminogen) • AnIcoagulants – AnIthrombin III present in plasma – Protein C Lecture Overview • Blood Physiology – FuncIons, components, cell types, hematopoiesis, homeostasis, hemostasis • Blood Pathology – Techniques, Red blood cell disorders, white blood cell disorders Blood Pathology -‐ Techniques • Blood Smears (Wright’s Giemsa) – hdps://www.youtube.com/watch?v=R1DU_N6eazg • Complete Blood Count (CBC) – Cell counts – Hemoglobin – Hematocrit – Red cell specific tests • Bone Marrow ExaminaIon – Trephine biopsy – Bone marrow aspiraIon • Flow Cytometry ASH Teaching Slides: Blood Cells Normal blood smear. The four larger cells shown are called granulocytes, a type of white blood cell. Maslak, P. ASH Image Bank 2008;2008:8-00067. Copyright ©2008 American Society of Hematology. Bone Marrow ExaminaIon Bone marrow biopsy (gross specimen) - 1. Peter Maslak, ASH Image Bank 2011; 2011-1715 Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. Bone Marrow ExaminaIon Normal Bone Marrow Aspirate - 1. Peter Maslak, ASH Image Bank 2011; 2011-3158 Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. Flow Cytometry Copyright © 2000 by Eric Martz; BD Biosciences Blood Pathology – Erythroid Disorders • Anemias – “lacking blood” – Too few red blood cells • HemolyIc anemia – Mismatched blood transfusion – Too lidle hemoglobin • Iron-‐deficiency anemia à microcytes – Abnormal hemoglobin • Sickle-‐cell anemia – Single base mutaIon in normal hemoglobin β chain HemolyIc Anemia Microangiopathic hemolytic anemia - 1. Peter Maslak; Lisa Southern;, ASH Image Bank 2013; 2013-4048 Copyright © 2013 American Society of Hematology. Copyright restrictions may apply. Sickle Cell Anemia Sickle cell disease – RBC morphology - 1. John Lazarchick, ASH Image Bank 2011; 2011-3958 Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. Blood Pathology – Erythroid Disorders • Polycythemia – “many blood cells” – Polycythemia vera • Bone marrow cancer; increased blood viscosity Blood Pathology – Leukocyte Disorders • Leukopenia – low white blood cell count • Leukemia – high white blood cell count – Acute: quickly advancing; blast-‐type cells – Chronic: slowly advancing; more mature cells Class QuesIons • Why is Wright’s Giemsa stain used instead of H&E? – I couldn’t find a definiIve answer, but it appears that the stain offers beder differenIaIon potenIal between different blood cell types: – hdp://en.wikipedia.org/wiki/Wright's_stain
