V ETE r I narY H EM aTolog Y
SEVENTH EDITION
EDITED BY
MarjorY B. Brooks, DVM, DaCVIM
Director, Comparative Coagulation Section, Animal Health Diagnostic Center, Cornell University, Ithaca, New York, USA
kEnDal E. Harr, DVM, Ms, DaCVP
URIKA, LLC, Mukilteo, Washington, USA
DaVIs M. sEElIg, DVM, PHD, DaCVP
Associate Professor, Clinical Pathology Department of Veterinary Clinical Sciences University of Minnesota, College of Veterinary Medicine St. Paul, Minnesota, USA
k. janE WarDroP, DVM, Ms, DaCVP
Professor and Director, Clinical Pathology Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA
Douglas j. WEIss, DVM, PHD, DaCVP
Emeritus Professor, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, USA
This edition first published 2022 © 2022 John Wiley & Sons, Inc
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A Tribute to Oscar Schalm
Oscar W. Schalm was born in 1909 and reared in Sturgis, Michigan. Upon graduation from Michigan State University, he entered the College of Veterinary Medicine at the urging of fellow students. He married Dorothy Burns, also of Sturgis, in 1930 and after attaining his DVM degree in 1932, he joined the Department of Veterinary Science at Berkeley, California as a research associate. He remained on the Berkeley campus until 1948, earning an M.S. in 1933 and Ph.D. in 1935. In 1948, he relocated to Davis, California, as the Department of Veterinary Medicine became the new School of Veterinary Medicine at the Davis campus.
Early in his career, Oscar established himself as a leader in bovine mastitis research, a subject he continued at Davis. At the founding of the School of Veterinary Medicine, Oscar was assigned the responsibility for clinical pathology, a most fortuitous choice for the field and
generations of veterinary students. Oscar focused on the fledgling field of veterinary hematology. With his characteristic energy and productivity, within ten years he had written the first edition of the now classic Veterinary Hematology. The original and subsequent early editions represented compilations of materials that he had painstakingly collected and analyzed.
He became an authority in veterinary clinical hematology, and spread the gospel by a prodigious record of publications, national and international seminars, and through his classes at Davis to over 1500 veterinary students. He exemplified the teacher-researcher who can successfully share their expertise and motivate students. As evidence of his dedication to teaching and his students, he was selected three times to receive the School of Veterinary Medicine’s Outstanding Teacher Award. He was listed in Educators of America in 1971 and 1973, and in 1973, he received the Davis Division of the Academic Senate’s Outstanding Teaching Award.
Oscar’s honors, awards, and prizes were many; some among them are the Borden Award in Veterinary Medicine (1964), the Gaines Award for Veterinarian of the Year (1965 and 1972), Alumni Award of Michigan State University (1969), and the Alumni Achievement Award of the School of Veterinary Medicine, University of California, Davis (1980). He was a Fulbright Scholar at the University of Munich in 1959, a visiting scholar and consultant to Israel in 1967, and was named Honorary Life Member of the Israeli Veterinary Medical Association in 1968.
Oscar Schalm retired in 1976, after 44 years of service to the university. He remained an active scholar, speaker, consultant, and contributor to prestigious journals throughout his retirement. At the time of his death, on September 15, 1982, a fourth edition of Schalm’s Veterinary Hematology was in preparation. In recognition of Dr. Schalm’s fundamental contributions to the field, all subsequent editions of this authoritative textbook have included his name in the title.
Dedication
Contributors
Preface
Acknowledgments
SECTION I
Hemolymphatic Tissue
CHAPTER 1
Embryonic and Fetal Hematopoiesis 3
KELLI L. BOYD and BRAD BOLON
CHAPTER 2
Stem Cell Biology 9
DORI L. BORJESSON and JED A. OVERMANN
CHAPTER 3
Structure of the Bone Marrow 18
NICOLE I. STACY and JOHN W. HARVEY
CHAPTER 4
The Hematopoietic System 27
BRUCE D. CAR and DAVIS M. SEELIG
CHAPTER 5
Vasculogenesis and Endothelial Cell Production 37
JONG HYUK KIM
CHAPTER 6
Cluster of Differentiation (CD) Antigens 41
MELINDA J. WILKERSON and NORA L. SPRINGER
CHAPTER 7
Major Histocompatibility Complex Antigens 48
PAUL R. HESS
CHAPTER 8
Lymphocyte Biology and Functions 63
IAN TIZARD
CHAPTER 9
Structure and Function of Primary and Secondary Lymphoid Tissue 74
CLEVERSON D. SOUZA, MEREDETH McENTIRE, V.E. TED VALLI, and ROBERT M. JACOBS
CHAPTER 10
Design and Methods of Nonclinical Hematotoxicity Studies 87
WILLIAM J. REAGAN and ARMANDO R. IRIZARRY ROVIRA
CHAPTER 11
Interpretation of Hematologic Data in Nonclinical Studies 93
JEFFREY McCARTNEY
CHAPTER 12
Nonclinical Evaluation of Compound-Related Cytopenias 100
LAURIE G. O’ROURKE
CHAPTER 13
Nonclinical Evaluation of Compound‐Related Alterations in Hemostasis 108
F. POITOUT‐BELISSENT
CHAPTER 14
Preclinical Evaluation of Immunotoxicity 116
KRISTIN L. HENSON
CHAPTER 15
Blood and Bone Marrow Toxicity Induced by Drugs, Heavy Metals, Chemicals, and Toxic Plants 122
DOUGLAS J. WEISS
CHAPTER 16
Acute Myelotoxicity and Myelitis in Domestic and Laboratory Animals 133
ADAM D. AULBACH and DOUGLAS J. WEISS
CHAPTER 17
Chronic Inflammation and Secondary Myelofibrosis in Domestic and Laboratory Animals 138
ADAM D. AULBACH and DOUGLAS J. WEISS
CHAPTER 18
Infectious Injury to Bone Marrow 144
K. JANE WARDROP
SECTION III
Erythrocytes .................................................149
CHAPTER 19
Erythropoiesis 151
CHRISTINE SWARDSON OLVER
CHAPTER 20
Erythrocyte Structure and Function 158
CHRISTINE SWARDSON OLVER
CHAPTER 21
Erythrocyte Biochemistry 166
JOHN W. HARVEY
CHAPTER 22
Erythrokinetics and Erythrocyte Destruction 172
ANDREA PIRES DOS SANTOS, and JOHN A. CHRISTIAN
CHAPTER 23
Reticulocyte and Heinz Body Staining and Enumeration 181
HAROLD TVEDTEN and ANDREAS MORITZ
CHAPTER 24
Erythrocyte Morphology 188
ANNE M. BARGER
CHAPTER 25
Classification and Laboratory Evaluation of Anemia 198
HAROLD TVEDTEN
CHAPTER 26
Erythrocytosis 209
JOHN F. RANDOLPH, MARK E. PETERSON, and ERICA BEHLING-KELLY
CHAPTER 27
Iron and Copper Deficiencies, and Disorders of Iron Metabolism 215
LAUREN B. RADAKOVICH and CHRISTINE SWARDSON OLVER
CHAPTER 28
The Porphyrias—Disorders of Defective Heme Synthesis 221
ANDREA A. BOHN
CHAPTER 29
Hereditary Erythroenzymopathies 229
URS GIGER
CHAPTER 30
Erythrocyte Membrane Defects 238
MUTSUMI INABA and JOANNE B. MESSICK
CHAPTER 31
Congenital Dyserythropoiesis 248
DOUGLAS J. WEISS
CHAPTER 32
Anemia Associated with Oxidative Injury 252
ERICA BEHLING-KELLY and ASHLEIGH NEWMAN
CHAPTER 33
Anemia Caused by Rickettsia, Mycoplasma, and Protozoa 260
SUSAN FIELDER, ROBIN W. ALLISON, and JAMES H. MEINKOTH
CHAPTER 34
Anemia Associated with Bacterial and Viral Infections 273
GEORGE M. BARRINGTON and DEBRA C. SELLON
CHAPTER 35
Immune-Mediated Anemia in the Dog 278
JILLIAN M. HAINES, ANDREW MACKIN, and MICHAEL J. DAY
CHAPTER 36
Immune-Mediated Anemia in the Cat 292
ASHLEIGH NEWMAN and TRACY STOKOL
CHAPTER 37
Immune-Mediated Anemia in Ruminants and Horses 300
JENIFER R. GOLD
CHAPTER 38
Precursor-Targeted Immune-Mediated Anemia and Pure Red Cell Aplasia in Dogs and Cats 307
CYNTHIA A. LUCIDI
CHAPTER 39
Anemia of Inflammatory, Neoplastic, Renal, and Endocrine Diseases 313
AGATA K. GRZELAK and MICHAEL M. FRY
CHAPTER 40
Aplastic Anemia 318
JENNIFER L. BRAZZELL and DOUGLAS J. WEISS
SECTION IV
Leukocytes ....................................................323
CHAPTER 41
Granulopoiesis 325
M. JUDITH RADIN and MAXEY L. WELLMAN
CHAPTER 42
Neutrophil Structure and Biochemistry 333
CLAIRE B. ANDREASEN
CHAPTER 43
Neutrophil Function and Response 339
DANA N. LEVINE and CLAIRE B. ANDREASEN
CHAPTER 44
Neutrophil Function Disorders 347
STEFANO COMAZZI, LUCA ARESU, and DOUGLAS J. WEISS
CHAPTER 45
Clinical Evaluation of Neutrophil Function 354
STEFANO COMAZZI
CHAPTER 46
Eosinophils and Their Disorders 363
KAREN M. YOUNG and ELIZABETH A. LAYNE
CHAPTER 47
Basophils, Mast Cells, and Their Disorders 373
BRANDY C. KASTL and LISA M. POHLMAN
CHAPTER 48
Monocytes, Macrophages, and Dendritic Cell Production 381
CLEVERSON D. SOUZA and DOUGLAS J. WEISS
CHAPTER 49
Monocytes and Macrophages and Their Disorders 386
CLEVERSON D. SOUZA and MEAGHAN V. EREN
CHAPTER 50
Lymphocyte Ontogeny and Lymphopoiesis 395
AMY L. WARREN and ROBIN M. YATES
CHAPTER 51
Structure, Function, and Disorders of Lymphoid Tissue 402
AMY L. WARREN and ROBIN M. YATES
CHAPTER 52
Systemic Lupus Erythematosus 414
LUC CHABANNE
CHAPTER 53
Feline Immunodeficiency Virus 424
MARGARET J. HOSIE and HANS LUTZ
CHAPTER 54
T Cell, Immunoglobulin, and Complement
Immunodeficiency Disorders 431
PETER J. FELSBURG
CHAPTER 55
Severe Combined Immunodeficiencies 436
STEVEN E. SUTER
CHAPTER 56
Lymphadenopathy Not Caused by Lymphoma 442
HAROLD TVEDTEN
SECTION V
Hematologic Neoplasia
CHAPTER 57
Cell-Cycle Control in Hematopoietic Cells 451
JAIME F. MODIANO and CATHERINE A. ST. HILL
CHAPTER 58
Epidemiology of Hematopoietic Neoplasia 457
MICHELLE G. RITT
CHAPTER 59
Genetics of Hematopoietic Neoplasia 463
DIANA GIANNUZZI, JAIME F. MODIANO, and MATTHEW BREEN
CHAPTER 60
Transforming Retroviruses 471
MARY JO BURKHARD
CHAPTER 61
Cytochemical Staining and Immunocytochemistry 478
ROSE E. RASKIN, KELLY SANTANGELO, and KLAUDIA POLAK
CHAPTER 62
Determination of Clonality 500
YUKO GOTO-KOSHINO and HAJIME TSUJIMOTO
CHAPTER 63
Immunophenotyping 508
AUSTIN K. VIALL
CHAPTER 64
Flow Cytometry in Hematologic Neoplasia 515
JAIME L. TARIGO, DAVIS M. SEELIG, and ANNE C. AVERY
CHAPTER 65
Classification and General Features of Lymphoma and Leukemia 528
BARBARA C. RÜTGEN and JENNIFER BOUSCHOR
CHAPTER 66
Myeloproliferative Neoplasms 538
ERIC J. FISH
CHAPTER 67
Myelodysplastic Syndromes 548
DOUGLAS J. WEISS and RANCE K. SELLON
CHAPTER 68
Acute Myeloid Leukemia 557
TRACY STOKOL
CHAPTER 69
B‐Cell Tumors 570
LUCA ARESU, STEFANO COMAZZI, LAURA MARCONATO, and FRANCESCO BERTONI
CHAPTER 70
Plasma Cell Tumors 588
ANTONELLA BORGATTI
CHAPTER 71
Hodgkin and Hodgkin‐Like Lymphoma 599
DANIEL A. HEINRICH and ERIN N. BURTON
CHAPTER 72
T‐Cell Tumors 605
NARIMAN DERAVI, STEFAN KELLER, and DOROTHEE BIENZLE
CHAPTER 73
Mast Cell Neoplasia 626
MELINDA S. CAMUS
CHAPTER 74
Histiocytic Proliferative Diseases of Dogs and Cats 633
PETER F. MOORE
SECTION VI
Platelets
CHAPTER 75
Thrombopoiesis 651
MARY K. BOUDREAUX and PETE W. CHRISTOPHERSON
CHAPTER 76
Platelet Structure 658
MARY K. BOUDREAUX and PETE W. CHRISTOPHERSON
CHAPTER 77
Platelet Signal Transduction and Activation Response 667
PETE W. CHRISTOPHERSON and MARY K. BOUDREAUX
CHAPTER 78
Platelet Kinetics and Laboratory Evaluation of Thrombocytopenia 675
ADI WASSERKRUG‐NAOR
CHAPTER 79
Evaluation of Platelet Function 686
PETE W. CHRISTOPHERSON and MARJORY B. BROOKS
CHAPTER 80
Immune Thrombocytopenia 696
DANA N. LeVINE and MARJORY B. BROOKS
CHAPTER 81
Nonimmune‐Mediated Thrombocytopenia 709
JULIE ALLEN
CHAPTER 82
Thrombocytosis and Essential Thrombocythemia 721
JULIE ALLEN and TRACY STOKOL
CHAPTER 83
von Willebrand Disease 731
MARJORY B. BROOKS and JAMES L. CATALFAMO
CHAPTER 84
Inherited Platelet Disorders 739
MARY K. BOUDREAUX and PETE W. CHRISTOPHERSON
CHAPTER 85
Acquired Platelet Dysfunction 747
BENJAMIN M. BRAINARD
CHAPTER 86
Treatment of Disorders of Platelet Number and Function 755
MARY BETH CALLAN
SECTION VII
Hemostasis ...................................................763
CHAPTER 87
Overview of Hemostasis 765
MAUREEN A. McMICHAEL
CHAPTER 88
Laboratory Testing of Coagulation Disorders 787
MARJORY B. BROOKS
CHAPTER 89
Acquired Coagulopathies 804
MARJORY B. BROOKS and ARMELLE DE LAFORCADE
CHAPTER 90
Hereditary Coagulopathies 812
MARJORY B. BROOKS
CHAPTER 91
Thrombotic Disorders 821
ERICA BEHLING‐KELLY and ROBERT GOGGS
CHAPTER 92
Disseminated Intravascular Coagulation 837
TRACY STOKOL
CHAPTER 93
Vascular Diseases 848
SEAN P. McDONOUGH
CHAPTER 94
Treatment of Hemostatic Defects 855
ROBERT GOGGS and ALEX M. LYNCH
CHAPTER 95
Avian Hemostasis 865
KAREN E. RUSSELL and J. JILL HEATLEY
SECTION VIII
Transfusion Medicine ................................875
CHAPTER 96
Erythrocyte Antigens and Blood Groups 877
MARIE‐CLAUDE BLAIS and MARIA CECILIA T. PENEDO
CHAPTER 97
Granulocyte and Platelet Antigens 891
JENNIFER S. THOMAS
CHAPTER 98
Principles of Canine and Feline Blood Collection, Processing, and Storage 898
ANTHONY C. G. ABRAMS-OGG and SHAUNA L. BLOIS
CHAPTER 99
Red Blood Cell Transfusion in the Dog and Cat 908
MARY BETH CALLAN
CHAPTER 100
Transfusion of Plasma Products 914
MARJORY B. BROOKS
CHAPTER 101
Platelet and Granulocyte Transfusion 921
ANTHONY C. G. ABRAMS‐OGG, and SHAUNA L. BLOIS
CHAPTER 102
Blood Transfusion in Large Animals 927
MARGARET C. MUDGE
CHAPTER 103
Blood Transfusion in Exotic Species 933
ANNELIESE STRUNK and ANKE C. STÖHR
CHAPTER 104
Transfusion Reactions 940
NICOLE M. WEINSTEIN
CHAPTER 105
Cellular Therapy 948
STEVEN E. SUTER and STEVEN DOW
CHAPTER 106
Clinical Use of Hematopoietic Growth Factors 957
STEVEN E. SUTER
CHAPTER 107
Clinical Blood Typing and Crossmatching 964
K. JANE WARDROP
SECTION IX
Species-Specific Hematology ................969
CHAPTER 108
Hematology of Dogs 971
MAGGIE R. MCCOURT and THERESA E. RIZZI
CHAPTER 109
Hematology of Cats 983
DEANNA M. W. SCHAEFER
CHAPTER 110
Hematology of Equids 993
KATHLEEN P. FREEMAN, ALISON J. FARR, and ANNALISA BARRELET
CHAPTER 111
Hematology of Bovids 1004
R. DARREN WOOD
CHAPTER 112
Hematology of Sheep and Goats 1012
JASON STAYT
CHAPTER 113
Hematology of Pigs 1019
CATHERINE E. THORN, ANDREW S. BOWMAN, and DAVID ECKERSALL
CHAPTER 114
Hematology of Rodentia 1026
AMY L. MACNEILL
CHAPTER 115
Hematology of Mustelids 1034
STACY CLOTHIER and CATHY JOHNSON‐DELANEY
CHAPTER 116
Hematology of Cavies 1043
SAMANTHA J. M. EVANS and KURT L. ZIMMERMAN
CHAPTER 117
Hematology of Lagomorphs 1050
FRANCISCO O. CONRADO
CHAPTER 118
Hematology of Laboratory Animals 1058
KARYN E. ENOS and DAVID M. MOORE
CHAPTER 119
Hematology of Camelids 1073
SUSAN J. TORNQUIST
CHAPTER 120
Hematology of Cervids 1079
BRIDGET C. GARNER
CHAPTER 121
Hematology of Paenungulata: Elephants, Sirenians, and Hyraxes 1090
EMMA H. HOOIJBERG
CHAPTER 122
Hematology of Marine Mammals 1104
NICOLE I. STACY and HENDRIK H. NOLLENS
CHAPTER 123
Hematology of Galliformes 1114
JULIE PICCIONE and JESSICA HOKAMP
CHAPTER 124
Hematology of Psittacines 1127
DIANA SCHWARTZ and HUGUES BEAUFRÈRE
CHAPTER 125
Hematology of Anseriformes 1140
JESSICA HOKAMP and JULIE PICCIONE
CHAPTER 126
Hematology of Raptors 1148
JENNIFER JOHNS
CHAPTER 127
Hematology of Ratites 1159
PHILLIP CLARK
CHAPTER 128
Hematology of Elasmobranchs 1166
JILL E. ARNOLD and ALEXA DELAUNE
CHAPTER 129
Hematology of Salmonids 1176
JERE STERN
CHAPTER 130
Hematology of Ictaluridae 1182
PATRICIA GAUNT
CHAPTER 131
Hematology of Cyprinidae 1188
ILZE K. BERZINS and ALEXANDER E. PRIMUS
CHAPTER 132
Hematology of Lizards, Crocodilians, and Tuatara 1197
CHARLOTTE HOLLINGER and JEAN A. PARÉ
CHAPTER 133
Hematology of Serpentes 1209
LAURA J. BLACK and MARJORIE BERCIER
CHAPTER 134
Hematology of Testudines 1219
JENNIFER D. STEINBERG and STEPHEN J. DIVERS
CHAPTER 135
Hematology of Amphibians 1228
PERRY BAIN and KENDAL E. HARR
CHAPTER 136
Hematology of Invertebrates 1233
JILL E. ARNOLD
SECTION X
Quality Management and Laboratory Techniques ...................................................1241
CHAPTER 137
Quality Management of Hematology Techniques 1243
MARTINA STIRN and KATHLEEN P. FREEMAN
CHAPTER 138
Total Error and Proficiency Testing 1255
STEN WESTGARD and KATHLEEN P. FREEMAN
CHAPTER 139
Quantitative Diagnostic Test Validation 1263
BENTE FLATLAND
CHAPTER 140
Reference Intervals and Decision Limits 1273
KRISTEN R. FRIEDRICHS, ASGER LUNDORFF JENSEN, and MADS
KJELGAARD‐HANSEN
CHAPTER 141
Bone Marrow Evaluation 1285
NATALI B. BAUER and KENDAL E. HARR
CHAPTER 142
Flow Cytometry 1295
UNITY JEFFERY
CHAPTER 143
Testing for Immune‐Mediated Hematologic Disease 1311
K. JANE WARDROP, MELINDA J. WILKERSON, and CINZIA
MASTRORILLI
CHAPTER 144
Electrophoresis and Acute‐Phase Proteins 1320
ALESSIA GIORDANO
CHAPTER 145
Molecular Diagnostic Techniques 1331
ROBERT J. OSSIBOFF
CHAPTER 146
Genetic Evaluation of Inherited Hematologic Diseases 1337
NOA SAFRA and DANIKA BANNASCH
SECTION 10 GLOSSARY 1351
Index ................................................................1353
Julie Allen, BVMS, MS, MRCVS, DACVIM (SAIM), DACVP
Veterinary Information Network Davis, California, USA
Anthony C. G. Abrams‐Ogg, DVM, DVSc, DACVIM
Department of Clinical Studies Ontario Veterinary College University of Guelph Guelph, Ontario, Canada
Robin W. Allison, DVM, PhD
Department of Veterinary Pathobiology College of Veterinary Medicine Oklahoma State University Stillwater, Oklahoma, USA
Claire B. Andreasen, DVM, PhD, DACVP Department of Pathology College of Veterinary Medicine Iowa State University Ames, Iowa, USA
Luca Aresu, DVM, PhD
Dipartimento di Scienze Veterinarie Università degli Studi di Torino, Italy
Jill E. Arnold, MS, MLS (ASCP)CM ZooQuatic Laboratory, LLC Baltimore, MD, USA
Adam D. Aulbach, DVM, DACVP Charles River Laboratories Mattawan, Michigan, USA
Anne C. Avery, VMD, PhD
Department of Microbiology, Immunology, and Pathology Colorado State University Fort Collins, Colorado, USA
Perry Bain, DVM, PhD, DACVP
Department of Biomedical Sciences
Cummings School of Veterinary Medicine at Tufts University North Grafton, Massachusetts, USA
CONTRIBUTORS
Danika Bannasch, DVM, PhD Department of Population Health and Reproduction School of Veterinary Medicine University of California Davis Davis, California, USA
Anne M. Barger, DVM, MS, DACVP Department of Veterinary Clinical Medicine College of Veterinary Medicine University of Illinois Urbana, Illinois, USA
Annalisa Barrelet, BVetMed, MS, CertESM, MRCVS Rossdales Laboratories Newmarket, United Kingdom
George M. Barrington, DVM, PhD, DACVIM Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, Washington, USA
Natali B. Bauer, DVM, PhD Justus‐Liebig‐Universität Gießen Klinikum Veterinärmedizin ‐klinische Laboratoriumsdiagnostik und klinische Pathophysiologie‐Gießen, Germany
Hugues Beaufrère, DVM, PhD, DACZM, ABVP (Avian), ECZM (Avian) Department of Clinical Studies Ontario Veterinary College, University of Guelph Guelph, Ontario, Canada
Erica Behling‐Kelly, DVM, PhD, DACVP Department of Population Medicine and Diagnostic Sciences College of Veterinary Medicine Cornell University Ithaca, New York, USA
Marjorie Bercier, DMV, DACZM Department of Clinical Sciences
Cummings School of Veterinary Medicine at Tufts University North Grafton, Massachusetts, USA
Francesco Bertoni
Institute of Oncology Research Faculty of Biomedical Sciences USI, Bellinzona, Switzerland and Oncology and Institute of Southern Switzerland Bellinzona, Switzerland
Ilze K. Berzins, PhD, DVM, MPH One Water, One Health, LLC Golden Valley, Minnesota, USA
Dorothee Bienzle, DVM, MSc, PhD, DACVP Department of Pathobiology Ontario Veterinary College University of Guelph Guelph, Ontario, Canada
Laura J. Black, DVM, DACVP Specialty VETPATH Seattle, Washington, USA
Marie‐Claude Blais, DMV, DACVIM
Department of Clinical Sciences
Faculté de médecine vétérinaire Université de Montréal Saint‐Hyacinthe Quebec, Ontario, Canada
Shauna L. Blois, DVM, DVSc, DACVIM Department of Clinical Studies Ontario Veterinary College University of Guelph Guelph, Ontario, Canada
Andrea A. Bohn, DVM, PhD, DACVP Department of Microbiology, Immunology, and Pathology Colorado State University Fort Collins, Colorado, USA
Brad Bolon, DVM, PhD, DACVP, DABT GEMpath Inc. Cedar City, Utah, USA
Antonella Borgatti, DVM, MS, DACVIM (Oncology) DECVIM
Department of Veterinary Clinical Sciences College of Veterinary Medicine University of Minnesota St Paul, Minnesota, USA
Dori L. Borjesson College of Veterinary Medicine Washington State University Pullman, Wahington, USA
Mary K. Boudreaux, DVM, PhD Department of Pathobiology College of Veterinary Medicine Auburn University Auburn, Alabama, USA
Jennifer Bouschor, DVM Department of Veterinary Clinical Sciences College of Veterinary Medicine University of Minnesota St Paul, Minnesota, USA
Andrew S. Bowman, MS, DVM, PhD, DACVPM College of Veterinary Medicine Department of Veterinary Preventive Medicine Columbus, Ohio, USA
Kelli L. Boyd DVM, PhD, DACVP Department of Pathology, Microbiology, and Immunology Vanderbilt University Nashville, Tennessee, USA
Benjamin M. Brainard, VMD, DACVAA, DACVECC Department of Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia, USA
Jennifer L. Brazzell, DVM, MVetSc, MRCVS, DACVP Veterinary Services Marshfield Labs Marshfield, Wisconsin, USA
Matthew Breen, PhD, CBIOL, FIBIOL Department of Molecular Biomedical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina, USA
Marjory B. Brooks, DVM, DACVIM Comparative Coagulation Section Department of Population Medicine and Diagnostic Sciences College of Veterinary Medicine Cornell University Ithaca, New York, USA
Mary Jo Burkhard, DVM, PhD, DACVP Department of Veterinary Biosciences College of Veterinary Medicine The Ohio State University Columbus, Ohio, USA
Erin N. Burton, MS, DVM, DACVP Department of Veterinary and Biomedical Sciences College of Veterinary Medicine University of Minnesota St. Paul, Minnesota, USA
Mary Beth Callan, VMD, DACVIM Department of Clinical Sciences and Advanced Medicine School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA
Melinda S. Camus College of Veterinary Medicine Auburn University Auburn, Alabama, USA
Bruce D. Car, BVSc, MVS, PhD, DACVP, DABT Bristol‐Myers Squibb Company Princeton, New Jersey, USA
James L. Catalfamo, MS, PhD Department of Population Medicine & Diagnostic Sciences College of Veterinary Medicine Cornell University Ithaca, New York, USA
Luc Chabanne, DVM, PhD Laboratoire d’Hematologie, Clinique et Unité de Médécine Interne
Départment des Animaux de Compagnie École Nationale Vétérinaire de Lyon Lyon, France
John A. Christian, DVM, PhD Department of Comparative Pathobiology College of Veterinary Medicine Purdue University West Lafayette, Indiana, USA
Pete W. Christopherson, DVM, PhD, DACVP Department of Pathobiology
Auburn University, College of Veterinary Medicine Auburn, Alabama, USA
Phillip Clark, BVSc, PhD, DVSc, MANZCVS, DACVP, SFHEA, FFSc (RCPA) Curtin Medical School Faculty of Heath Sciences Curtin University Perth, Western Australia, Australia
Stacy Clothier, DVM, MS, DACVP
Department of Biomedical Sciences and Pathobiology Virginia‐Maryland College of Veterinary Medicine Blacksburg, Virginia, USA
Stefano Comazzi, DVM, PhD, DECVCP
Dipartimento di Medicina Veterinaria Università degli Studi di Milano, Italy
Francisco O. Conrado, DVM, MSc, DACVP
Cummings School of Veterinary Medicine at Tufts University North Grafton, Massachusetts, USA
Michael J. Day, BSc, BVMS, PhD, DSc, Dr (hc), DECVP, FASM, FRCPath, FRCVS* Emeritus Professor School of Veterinary and Life Sciences Murdoch University Western Australia, Australia *deceased
Armelle de Laforcade, DVM, DACVP
Department of Clinical Sciences/Emergency/Critical Care
Cummings School of Veterinary Medicine at Tufts University North Grafton, Massachusetts, USA
Alexa Delaune, DVM Vice President of Veterinary Services Mississippi Aquarium Gulfport, Mississippi, USA
Nariman Deravi, DVM, DVSc, DACVP IDEXX Laboratories Toronto, Canada
Stephen J. Divers, BVetMed, DZooMed, DECZM(Herp), DECZM(ZHM), DACZM, FRCVS Department of Small Animal Medicine & Surgery (Zoological Medicine) College of Veterinary Medicine University of Georgia Athens, Georgia, USA
Andrea Pires dos Santos, DMV, MSc, PhD College of Veterinary Medicine Purdue University West Lafayette, Indiana, USA
Steven Dow, DVM, PhD, DACVIM Department of Clinical Sciences Colorado State University Fort Collins, Colorado, USA
David Eckersall, BSc, MBA, PhD, FRCPath, MAE Institute of Biodiversity Animal Health and Comparative Medicine School of Veterinary Medicine University of Glasgow Glasgow, Scotland
Karyn E. Enos, DVM, MS, DACVP (Anatomic) Concord Biomedical Sciences and Emerging Technologies Lexington, Massachusetts, USA
Meaghan V. Eren, DVM, MS, DAVCP Antech Diagnostics Lake Success, New York, USA
Samantha J.M. Evans, DVM, PhD Department of Veterinary Biosciences College of Veterinary Medicine The Ohio State University Columbus, Ohio, USA
Alison J. Farr, BVetMed, FRCPath, MRCVS IDEXX Laboratories, Ltd Wetherby, West Yorkshire, United Kingdom
Peter J. Felsburg, VMD, PhD School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA
Susan Fielder, DVM, MS, DACVP Department of Pathobiology Center for Veterinary Health Sciences Oklahoma State University Stillwater, Oklahoma, USA
Eric J. Fish, DVM, PhD, DACVP IDEXX Laboratories
St. Petersburg, Florida, USA
Bente Flatland, DVM, MS, DACVP, DACVIM Department of Biomedical and Diagnostic Sciences College of Veterinary Medicine University of Tennessee Knoxville, Tennessee, USA
Kathleen P. Freeman, DVM, MS, PhD, DECVCP, FRCPath, MRCVS
SYNLAB‐VPG/Exeter Exeter, United Kingdom
Kristen R. Friedrichs, DVM, DACVP Department of Pathobiological Sciences School of Veterinary Medicine University of Wisconsin Madison, Wisconsin, USA
Michael M. Fry, DVM, MS, DACVP Department of Biomedical and Diagnostic Sciences College of Veterinary Medicine University of Tennessee Knoxville, Tennessee, USA
Bridget C. Garner, DVM, PhD, DACVP Department of Pathology University of Georgia College of Veterinary Medicine Athens, Georgia, USA
Patricia Gaunt, DVM, PhD, DABVT College of Veterinary Medicine Mississippi State University Stoneville, Mississippi, USA
Diana Giannuzzi, DVM, PhD Department of Agronomy, Food, Natural Resources, Animals, and Environment University of Padua Padua, Italy
Urs Giger, DMV, MS, FVH, DACVIM, DECVIM, DECVCP School of Veterinary Medicine, School of Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA
Alessia Giordano, DVM, PhD, DECVCP, EBVS (CP) Department of Veterinary Medicine Veterinary Teaching Hospital University of Milan Lodi, Italy
Robert Goggs, BVSc, PhD, DACVECC, DECVECC, MRCVS Department of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York USA
Jenifer R. Gold, DACVIM, DACVECC Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, Washington, USA
Yuko Goto‐Koshino, PhD Department of Veterinary Internal Medicine Graduate School of Agricultural and Life Sciences The University of Tokyo Tokyo, Japan
Agata K. Grzelak, DVM Department of Biomedical and Diagnostic Sciences College of Veterinary Medicine University of Tennessee Knoxville, Tennessee, USA
Jillian M. Haines, DVM, MS, DACVIM Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, Washington, USA
Kendal E. Harr, DVM, MS, DACVP URIKA, LLC Mukilteo, Washington, USA
John W. Harvey, DVM, PhD, DACVP Department of Physiological Sciences College of Veterinary Medicine University of Florida Gainesville, Florida, USA
J. Jill Heatley, DVM, MS, DABVP, DACZM Department of Small Animal Clinical Sciences College of Veterinary Medicine & Biomedical Sciences Texas A & M University College Station, Texas, USA
Daniel A. Heinrich, DVM, DACVP Department of Veterinary Clinical Sciences College of Veterinary Medicine University of Minnesota St. Paul, Minnesota, USA
Kristin L. Henson, DVM, MS, DACVP Novartis Institutes for Biomedical Research Cambridge, Massachusetts, USA
Paul R. Hess, DVM, PhD, DACVIM Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina, USA
Jessica Hokamp, DVM, PhD, DACVP Department of Veterinary Biosciences College of Veterinary Medicine The Ohio State University Columbus, Ohio, USA
Charlotte Hollinger, VMD, MS, DACVP Wildlife Conservation Society Bronx, New York, USA
Emma H. Hooijberg, BVSc, PhD, DECVCP Department of Companion Animal Clinical Studies and Veterinary Wildlife Centre University of Pretoria Pretoria, South Africa
Margaret J. Hosie, BVM&S, MRCVS, BSc, PhD MRC‐University of Glasgow Centre for Virus Research Glasgow, United Kingdom
Mutsumi Inaba, DVM, PhD Laboratory of Molecular Medicine Graduate School of Veterinary Medicine Hokkaido University Sapporo, Japan
Armando R. Irizarry Rovira, DVM, PhD, DACVP Director of Investigative Toxicology, Nonclinical Study Management and Pathology Lilly Research Laboratories—Toxicology, Drug Disposition, and PKPD Eli Lilly and Company Indianapolis, Indiana, USA
Robert M. Jacobs, DVM, PhD, DACVP Department of Pathobiology Ontario Veterinary College University of Guelph Guelph, Ontario Canada
Unity Jeffery, VetMB, PhD, DACVP Department of Veterinary Pathobiology College of Veterinary Medicine Texas A&M University College Station, Texas, USA
Asger Lundorff Jensen, DVM, PhD, MLP Department of Veterinary Clinical Sciences University of Copenhagen Frederiksberg, Denmark
Jennifer Johns, DVM, PhD, DACVP Department of Biomedical Sciences Oregon State University Carlson College of Veterinary Medicine Corvallis, Oregon, USA
Cathy A. Johnson‐Delaney, DVM, DABVP NW Zoological Supply Everett, Washington, USA
Brandy C. Kastl, DVM, DACV
Kansas State Veterinary Diagnostic Laboratory Kansas State University Manhattan, Kansas, USA
Stefan Keller, DVM, PhD, DECVP Department of Pathobiology
Ontario Veterinary College University of Guelph Guelph, Ontario, Canada
Jong Hyuk Kim, DVM, PhD Department of Veterinary Clinical Sciences College of Veterinary Medicine University of Minnesota St. Paul, Minnesota, USA
Mads Kjelgaard‐Hansen, DVM, PhD Department of Veterinary Clinical Sciences University of Copenhagen Frederiksberg, Denmark
Elizabeth A. Layne, DVM, DACVD Department of Medical Sciences School of Veterinary Medicine University of Wisconsin–Madison Madison, Wisconsin, USA
Dana N. LeVine, DVM, PhD, DACVIM (SAIM) Department of Clinical Sciences Auburn University College of Veterinary Medicine Auburn, Alabama, United States
Cynthia A. Lucidi, DVM, PhD, DACVP Veterinary Diagnostic Laboratory College of Veterinary Medicine Michigan State University East Lansing, Michigan, USA
Hans Lutz, DMV, PhD, FVH, FAMH Clinical Laboratory, Department of Clinical Diagnostic Services University of Zurich Zurich, Switzerland
Alex M. Lynch, BVSc, DACVECC, MRCVS Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina, USA
Andrew Mackin, BVMS, MVS, DVSc, FANZCVSc, DACVIM Department of Clinical Sciences College of Veterinary Medicine Mississippi State University Starkville, Mississippi, USA
Amy L. MacNeill, DVM, PhD, DACVP Microbiology, Immunology, and Pathology Department College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado, USA
Laura Marconato Department of Veterinary Medical Sciences University of Bologna Bologna, Italy
Cinzia Mastrorilli, DVM, PhD, DACVP Veterinary Clinical Pathologist Ferrara, Italy
Jeffrey McCartney, DVM, MVSc, DACVP, DABT Charles River Laboratories Montreal, Quebec, Canada
Maggie R. McCourt, DVM, DACVP Department of Veterinary Pathobiology Center for Veterinary Health Sciences Oklahoma State University Stillwater, Oklahoma, USA
Sean P. McDonough, DVM, PhD, DACVP Chief of Anatomic Pathology Department of Biomedical Sciences College of Veterinary Medicine
Cornell University Ithaca, New York, USA
Meredeth McEntire, DVM, MS, DACVP Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, Washington, USA
Maureen A. McMichael, DVM, M.Ed., DACVECC Department of Clinical Sciences College of Veterinary Medicine Auburn University Auburn, Alabama, USA
James H. Meinkoth, DVM, MS, PhD, DACVP Department of Veterinary Pathobiology College of Veterinary Medicine Oklahoma State University Stillwater, Oklahoma, USA
Joanne B. Messick, VMD, PhD, DACVP Department of Comparative Pathobiology College of Veterinary Medicine Purdue University West Lafayette, Indiana, USA
Jaime F. Modiano, VMD, PhD Department of Veterinary Clinical Sciences College of Veterinary Medicine Masonic Cancer Center University of Minnesota Minneapolis/St. Paul, Minnesota, USA
David M. Moore, MS, DVM, DACLAM Department of Biomedical Sciences and Pathobiology
Virginia‐Maryland College of Veterinary Medicine Blacksburg, Virginia, USA
Peter F. Moore, BVSc, PhD, DACVP Department Pathology Microbiology and Immunology University of California‐Davis School of Veterinary Medicine Davis, California, USA
Andreas Moritz, Dr. med. vet., Prof., DEVIM‐CA, Assoc. Memb. ECVCP Department of Veterinary Clinical Sciences
Justus‐Liebig‐University Giessen, Giessen, Germany
Margaret C. Mudge, VMD, DACVS, DACVECC Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus, Ohio, USA
Ashleigh Newman, VMD, DACVP Department of Population Medicine and Diagnostic Sciences College of Veterinary Medicine Cornell University Ithaca, New York, USA
Hendrik Nollens, DVM, MSc, PhD Pacific Marine Mammal Center Laguna Beach, California, USA
Christine Swardson Olver, DVM, PhD, DACVP Department of Microbiology, Immunology, and Pathology Colorado State University Fort Collins, Colorado, USA
Laurie G. O’Rourke, DVM, PhD, DACVP, DECVCP Friday Harbor, Washington, USA
Robert J. Ossiboff, DVM, PhD, DACVP Department of Comparative, Diagnostic, and Population Medicine College of Veterinary Medicine University of Florida Gainesville, Florida, USA
Jed A. Overmann, DVM, DACVP Abbott Laboratories St. Paul, Minnesota, USA
Jean A. Paré, DMV, DVSc, DACZM, DECZM (ZHM) Wildlife Conservation Society Bronx, New York, USA
Maria Cecilia T. Penedo, PhD Veterinary Genetics Laboratory School of Veterinary Medicine University of California Davis, California, USA
Mark E. Peterson, DVM, DACVIM
Animal Endocrine Clinic New York, USA and Department of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York, USA
Julie Piccione, DVM, MS, DACVP
Texas A&M Veterinary Medical Diagnostic Laboratory College Station, Texas, USA
Lisa M. Pohlman, BS, DVM, MS, DACVP
Veterinary Diagnostic Laboratory Department of Diagnostic Medicine/Pathobiology College of Veterinary Medicine Kansas State University Manhattan, Kansas, USA
F. Poitout‐Belissent, DVM, DACVP, DECVCP
Charles River Laboratories Montréal, Québec, Canada
Klaudia Polak, DVM
Department of Microbiology, Immunology, and Pathology College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado, USA
Alexander E. Primus, DVM, PhD Department of Veterinary Population Medicine College of Veterinary Medicine University of Minnesota Saint Paul, Minnesota, USA
Lauren B. Radakovich, DVM, PhD, DACVP Department of Microbiology, Immunology, and Pathology College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado, USA
M. Judith Radin, DVM, PhD, DACVP Department of Veterinary Biosciences College of Veterinary Medicine Columbus, Ohio, USA
John F. Randolph, DVM, DACVIM
Department of Clinical Sciences College of Veterinary Medicine
Cornell University Ithaca, New York, USA
Rose E. Raskin, DVM, PhD, DACVP Department of Comparative Pathobiology School of Veterinary Medicine Purdue University West Lafayette, Indiana, USA
William J. Reagan, DVM, PhD, DACVP, Research Fellow Pfizer Drug Safety Research and Development Eastern Point Rd 8274/1203 Groton, Connecticut, USA
Michelle G. Ritt DVM, DACVIM (Small Animal) Department of Veterinary Clinical Sciences College of Veterinary Medicine St. Paul, Minnesota, USA
Theresa E. Rizzi, DVM, DACVP Department of Veterinary Pathobiology Center for Veterinary Health Sciences Oklahoma State University Stillwater, Oklahoma, USA
Karen E. Russell, DVM, PhD, DACVP Department of Veterinary Pathobiology College of Veterinary Medicine & Biomedical Sciences Texas A & M University College Station, Texas, USA
Barbara C. Rütgen, DVM Institute of Immunology Department of Pathobiology University of Veterinary Medicine Vienna Vienna, Austria
Noa Safra DVM PhD DACVP (clinical pathology) Zoetis, Inc. Parsippany, NJ, USA
Kelly Santangelo, DVM, PhD, DACVP
Department of Microbiology, Immunology, and Pathology College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado, USA
Deanna M. W. Schaefer, DVM, MS, MT(ASCP), DACVP
Department of Biomedical and Diagnostic Sciences The University of Tennessee, College of Veterinary Medicine Knoxville, Tennessee, USA
Diana Schwartz, DVM, DACVP VDx Veterinary Diagnostics Davis, California, USA
Davis M. Seelig, DVM, PhD, DACVP Department of Veterinary Clinical Sciences University of Minnesota, College of Veterinary Medicine St. Paul, Minnesota, USA
Debra C. Sellon, DVM, PhD, DACVIM Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, Washington, USA
Rance K. Sellon Department of Veterinary Clinical Sciences College of Veterinary Medicine
Washington State University Pullman, Washington, USA
Cleverson D. Souza, DVM, PhD, DACVP Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, Washington, USA
Nora L. Springer
Department of Diagnostic Medicine and Pathobiology College of Veterinary Medicine Kansas State University Manhattan, Kansas, USA
Catherine A. St. Hill, DVM, PhD Allina Health Minneapolis, Minnesota, USA
Nicole I. Stacy, DVM, DMV, DACVP Department of Comparative, Diagnostic, and Population Medicine College of Veterinary Medicine University of Florida Gainesville, Florida, USA
Jason Stayt, BVSc, DACVP Vetpath Laboratory Services Ascot, Western Australia, Australia
Jennifer D. Steinberg, DVM, DACVP Lacuna Diagnostics, Inc. Baltimore, Maryland, USA
Jere Stern, DVM Department of Pathobiology Auburn University College of Veterinary Medicine Auburn, Alabama, USA
Martina Stirn, DMV, DECVCP Clinical Laboratory Vetsuisse Faculty University of Zurich Zurich, Switzerland
Anke C. Stöhr, med vet, MS, DECZM (Herpetology), ZB Reptilien
Department of Veterinary Clinical Sciences
School of Veterinary Medicine
Louisiana State University Baton Rouge, Louisiana, USA
Tracy Stokol, BVSc, PhD, DACVP
Department of Population Medicine and Diagnostic Sciences
College of Veterinary Medicine
Cornell University Ithaca, New York, USA
Anneliese Strunk, DVM, DABVP (Avian) Center for Bird and Exotic Animal Medicine Bothell, Washington, USA
Steven E. Suter, VMD, PhD, DACVIM Department of Clinical Sciences North Carolina State University, Raleigh, North Carolina, USA
Jaime L. Tarigo, DVM, PhD, DACVP Department of Pathology College of Veterinary Medicine University of Georgia Athens, Georgia, USA
Jennifer S. Thomas, DVM, PhD, DACVP Department of Pathobiology and Diagnostic Investigation College of Veterinary Medicine
Michigan State University East Lansing, Michigan, USA
Catherine E. Thorn, DVM, DVSc, MSc, DACVP Antech Diagnostics Atlanta, Georgia, USA
Ian Tizard, DVM, PhD, ACVM
Department of Veterinary Pathobiology College of Veterinary Medicine and Biomedical Sciences
Texas A&M University College Station, Texas, USA
Susan J. Tornquist, DVM, MS, PhD, DACVP
Carlson College of Veterinary Medicine
Oregon State University Corvallis, Oregon, USA
Hajime Tsujimoto, PhD
Department of Veterinary Internal Medicine
Graduate School of Agriculture and Life Sciences
The University of Tokyo Tokyo, Japan
Harold Tvedten, DVM, PhD, DACVP, DECVCP Clinical Chemistry Laboratory University Animal Hospital Swedish University of Agricultural Sciences Uppsala, Sweden
V.E. Ted Valli, DVM, MSc, PhD, DACVP VDx Pathology Davis, California, USA
Austin K. Viall, DVM, MS, DACVP Department of Veterinary Pathology College of Veterinary Medicine Iowa State University Ames, Iowa, USA
K. Jane Wardrop, DVM, MS, DACVP Department of Veterinary Clinical Sciences College of Veterinary Medicine Washington State University Pullman, Washington, USA
Amy L. Warren, BSc, BVSc. (Hons.), PhD, DACVP Department of Veterinary Clinical and Diagnostic Sciences Faculty of Veterinary Medicine University of Calgary Calgary, Alberta, Canada
Adi Wasserkrug‐Naor, DVM, DAVCP Novartis East Hanover, New Jersey, USA
Nicole M. Weinstein, DVM, DACVP Department of Veterinary Pathobiology School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania, USA
Douglas J. Weiss, DVM, PhD, DACVP, Emeritus Professor College of Veterinary Medicine University of Minnesota Saint Paul, Minnesota, USA
Maxey L. Wellman, DVM, PhD, DACVP Department of Veterinary Biosciences, The Ohio State University Columbus, Ohio, USA
Sten Westgard, MS Westgard QC, Inc. Madison, Wisconsin, USA
Melinda J. Wilkerson, DVM, PhD, DACVP Department of Pathobiology School of Veterinary Medicine St. George’s University Grenada, West Indies
R. Darren Wood, DVM, DVSc, DACVP Department of Pathobiology Ontario Veterinary College University of Guelph Guelph, Ontario, Canada
Robin M. Yates, BSc., BVSc (Hons.), PhD, MTEM Department of Comparative Biology and Experimental Medicine
Department of Biochemistry and Molecular Biology Faculty of Veterinary Medicine, and Faculty of Medicine University of Calgary Calgary, Alberta, Canada
Karen M. Young, VMD, PhD Professor of Clinical Pathology Department of Pathobiological Sciences School of Veterinary Medicine University of Wisconsin–Madison, Wisconsin, USA
Kurt L. Zimmerman, DVM, PhD, DACVP Department of Biomedical Sciences & Pathobiology Virginia‐Maryland College of Veterinary Medicine Blacksburg, Virginia, USA
Veterinary clinical pathology has changed considerably since publication of the 6th edition of Schalm’s Veterinary Hematology. No longer the practitioners of a discipline that deals primarily with the clinical evaluation of dog and cat samples, clinical pathologists are now called on to use their diagnostic skills for a broad variety of animal species. Current specialty areas encompass diverse fields such as pharmaceutical compound and device development and the management of zoo and free‐range wildlife. Beyond nontraditional species, clinical pathologists have broadened the scope of their diagnostic expertise to incorporate genomics, proteomics, and metabolomics, and use novel assay platforms such as expression arrays, microfluidic devices, and multiplex immunoassays. Significant advances have also been made in more traditional techniques including flow cytometry, blood typing serology, and platelet function testing.
We have assembled a team of editors capable of covering this exceptional diversity in species and subject areas that now comprise the field of clinical pathology. Dr. Marjory Brooks’ career has focused on comparative hemostasis and the development of translational
biomarkers for Dr. Kendal Harr provides expertise in nondomestic species and has devoted the past 15 years to making ASVCP’s quality assurance guidelines more r Dr. Davis Seelig provides expertise in basic molecular biology, research techniques, and in hematopoietic neo plasia. Dr. Jane Wardrop has expertise in hematological disorders and transfusion medicine. Dr. Douglas Weiss has expertise in bone marrow disorders, infectious disease, and molecular biology.
Specific changes in this edition include a new section titled “Hemolymphatic T basic pathophysiology and disease mechanisms, expanded “Species‐Specific Hematology” and “Hematotoxicity” sections, and more in‐depth molecu lar and genetics sively revised and rearranged chapters to address emerging topics and to provide a more logical sequence for the material. With recognition of the hard work of our contributing authors, we are proud to provide the reader with a comprehensive, coherent, and state of the art presentation of topics in clinical pathology.
To the teachers and mentors, who set me on the path of discovery, and to the students, clinicians, and colleagues, who continually bring new insights and challenges to the journey.
Marjory Brooks
Iwould like to express my gratitude to my whole family for their support and patience during the time it has taken to construct this tome. Especially my husband, Bob, who thankfully has fabulous cooking skills (among others) and my daughters, Lily and Maeve, who have, since the start of this work, matured to wonderful, fascinating adults. And, of course, my mom whose voice I still hear and provides guidance to this day. I also appreciate my co-editors, who have helped me become a better editor, reviewer, and author, especially Dr. K. Jane Wardrop.
Kendal E. Harr
To Catherine and Angela, who (in their own unique ways) provided much needed emotional support and relief. To my coworkers and resident trainees, who tolerated the many mornings and afternoons in which I was squirreled away in my office.
Davis Seelig
To my family for their continued support, and to my colleagues around the world, who contributed to the making of this edition. Your work inspires me to be a better author, researcher, teacher, and person.
K. Jane Wardrop
To my parents (Bud and Dorothy) for their strength, moral guidance, and work ethic, my family (Jane, Matthew, Kal) for their love and support, which was essential to my career as well as my well-being, and to Barb for partnering with me in undertaking a whole new vision of how to live in harmony with the earth and all living things.
Douglas
J. Weiss (FF)
Embryonic and Fetal Hematopoiesis
KELLI L. BOYD and BRAD BOLON
Basic Principles of Hematopoietic Development
Cell Structure and Function
Primitive Hematopoiesis
Erythroid Cells
Other Cells
Definitive Hematopoiesis
Hemoglobin Switching
Molecular Mechanisms Regulating Hematopoietic Development
Acronyms and Abbreviations
AGM, aorta-gonad-mesonephros; Bmp, bone morphogenetic protein; 2,3-DPG, 2,3-diphosphoglycerate; E#, day of embryonic development, where the number indicates age of the embryo in days after conception; EPO, erythropoietin; fL, femtoliter; Gata-1, -2, and -4, GATA-binding proteins 1, 2, and 4; HSC, hematopoietic stem cell; Ihh, Indian hedgehog; IL, interleukin; NK, natural killer; P#, day of postnatal development, where the number indicates age of the neonate in days after delivery; pg, picogram; PU.1, purine box-binding transcription factor 1; Scl/Tal-1, stem cell leukemia/T-cell acute leukemia factor 1.
The complexities of hematopoietic system development have been highly conserved throughout vertebrate evolution. Understanding the embryonic and fetal origins of hematopoiesis provides important insights regarding the function of the adult hematopoietic system. Hematopoiesis in embryonic and fetal animals has been studied intensively for several decades as a model for hematopoietic progression in humans. Recent technical advances have allowed researchers to characterize the spatial and temporal relationships as well as the cellular and molecular mechanisms of hematopoietic development. This chapter reviews the basic biology of hematopoietic development in the mouse (Mus musculus). This appraisal will emphasize hematopoietic events during the embryonic and fetal stages of development, but also will cover selected features of neonatal hematopoiesis.
BASIC PRINCIPLES OF HEMATOPOIETIC DEVELOPMENT
Cell Structure and Function
Blood cells produced at different stages of development differ in morphology and function. Thus, primitive (“fetal”) cells fabricated early in gestation have markedly different properties from their definitive (“adult”) counterparts produced during late gestation and in postnatal life. This principle has been characterized most completely in erythroid lineage cells. Primitive erythrocytes (RBCs) are formed in the yolk sac, whereas definitive RBCs are produced by the liver and later spleen and bone marrow. Primitive RBCs are nucleated in circulation until approximately day 12.5 (E12.5) of gestation, after which nuclei gradually become condensed before being shed between E14.5 and E16.5.35
Veterinary Hematology, Seventh Edition. Edited
Schalm’s
by Marjory B. Brooks, Kendal E. Harr, Davis M. Seelig, K. Jane Wardrop, and Douglas J. Weiss.
Enucleated primitive RBCs retain their large size and can remain in circulation until as late as postnatal day 5 (P5). Both primitive and definitive RBCs are released during most of the latter half of gestation (E10–E18), although the ratio shifts as time progresses from mainly primitive to mainly definitive RBCs.
Primitive and definitive RBCs can be distinguished by their size. The volume of primitive RBCs varies from 465 to 530 femtoliters (fL), which is approximately six times larger than that of definitive RBCs.35 The hemoglobin content of primitive RBCs, 80–100 picograms (pg)/cell, also is nearly six times the amount found in definitive RBCs.35 Both primitive and definitive RBCs have basophilic cytoplasm when first produced due to abundant rough endoplasmic reticulum, but basophilia recedes as maximal hemoglobin content is achieved.
Other hematopoietic lineages also differ in cell structure and function during the course of development. Primitive megakaryocytes from the yolk sac contain fewer nuclei of lower ploidy, are about half the size, and respond differently to cytokine stimulation relative to definitive megakaryocytes.47 Primitive macrophages that originate in the yolk sac42 lack certain enzyme activities, are capable of division, and survive for extended periods compared to definitive monocytederived macrophages. These functional differences are related to the roles that the two cell populations appear to play. Primitive macrophages are the source for many tissue macrophages in embryonic through juvenile stages of development, whereas definitive macrophages are the source for circulating monocytes and resident macrophages characteristic of the adult immune system.
PRIMITIVE HEMATOPOIESIS
The processes that drive primitive and definitive stages of hematopoiesis as well as the events that regulate transition between the two stages are mediated by a constellation of factors.1,30,45,46 Cell adhesion factors, growth factors, and transcription factors that participate in this process often support differentiation of multiple hematopoietic cell types,10,29,36 and the dependence of a given cell lineage on any particular molecule may differ between primitive and definitive hematopoiesis.
Erythroid Cells
Hematopoiesis occurs at multiple sites within the embryo and in extraembryonic tissues. The first phase of blood cell production, referred to as primitive hematopoiesis, is responsible for producing blood elements during the earliest stage of embryogenesis. Primitive hematopoiesis takes place in the visceral yolk sac beginning at approximately E7.15,34 Thus, primitive hematopoietic cells are among the earliest distinct tissues to differentiate in the embryo. Formation of primitive cells declines rapidly after E11. The visceral yolk sac or extraembryonic splanchnopleure (the term for a
structure in which mesoderm and endoderm are directly apposed) arises from the migration of extraembryonic mesoderm streaming from the caudal primitive streak along the inner surface of the visceral endoderm. The mesodermal cells committed to initiate and support hematopoiesis have been termed hemangioblasts because the contiguity of primitive hematopoiesis and vasculogenesis in both space and time suggests that primitive hematopoietic and endothelial cells in the yolk sac share a common ancestor.1,9 Hemangioblasts arise as undifferentiated cells at the primitive-streak stage and commit to producing a particular cell lineage before blood island formation.34,44 These pluripotent cells also can differentiate into other mesenchymederived tissues.
Between E7.5 and E9, hemangioblasts form multiple aggregates termed blood islands.35 Each blood island contains a central core of unattached inner hemangioblasts (hematopoietic progenitors) surrounded by a rim of spindle-shaped outer hemangioblasts (endothelial progenitors).15 Nucleated erythroid cells are first recognized in the cores of the blood islands at E8 and are evident circulating in the cardiovascular system starting at E8.25.18 At this stage embryonic erythroblasts enter the circulation, where they continue to divide until approximately E13.
The majority of cells produced during primitive hematopoiesis are of the erythroid lineage. Committed erythroid colony-forming cells arrive in the yolk sac at approximately E7.25. These cells expand until E8 and then differentiate into primitive erythroblasts; all colony-forming cells have regressed completely by E9,34 which corresponds approximately to the earliest phase of definitive erythropoiesis. Primitive erythroblasts serve as the sole source of RBCs in the early embryo from E8 to approximately E10.534 and remain an important source of RBCs until E13. Thus, embryos with a developmental age between E8 and E11 that are anemic suffer from a defect in primitive erythropoiesis.26,38 Interestingly, seemingly profound defects in primitive hematopoiesis leading to persistent functional defects in adulthood may not elicit an aberrant hematologic profile in the embryo.
Other Cells
Recent studies suggest that other hematopoietic cell lineages also are generated in the yolk sac during this primitive stage of hematopoietic development. Primitive lymphoid precursors and even some adult stem cells evolve at E7.5 and subsequently seed other sites of hematopoiesis, including the aorta-gonad-mesonephros (AGM) region, umbilical vessels, and liver.40 Primitive macrophages have been identified in the yolk sac by E84–E9.34 In vitro experiments have demonstrated that E7.5 yolk sac cells can give rise to functional megakaryocytic precursors by E10.5.47 Many hemangioblasts actually serve as bipotent or oligopotent progenitors, including those capable of commitment to erythrocytic/ myeloid,4 erythrocytic/megakaryocytic,27 granulocyte/ macrophage,34 and lymphoid (B cell and T cell)/myeloid
lineages. Stem cells for mast cells have also been reported to arise in the yolk sac during primitive hematopoiesis.34
DEFINITIVE HEMATOPOIESIS
The second stage of blood cell production, termed definitive hematopoiesis, is thought to arise primarily from the AGM.3,27 The AGM is an amorphous band of intraembryonic splanchnopleure that encompasses the dorsomedial wall of the abdominal cavity. The AGM domain is the main source of mesenchyme-derived, definitive hematopoietic stem cells (HSCs) that will serve the developing animal during late gestation and postnatal life. Initiation of definitive hematopoiesis ranges between E8.5 and E9.25, with definitive HSCs evident in the AGM by no later than E10. Peak production of HSCs in the AGM occurs between E10.5 and E11.5, at which time they comprise almost 10% of all AGM cells. Although controversial, some AGM-independent HSCs may also arise from the allantois, chorion, definitive placenta, umbilical arteries, and yolk sac. The actual contribution of these secondary sites to the overall HSC population has yet to be defined. However, the placenta appears to serve a particularly important role. The yolk sac also appears to be an essential secondary site because it is a source of multiple progenitor cell lineages and remains for at least a day after the AGM has halted HSC production.28
Regardless of their original site of de novo synthesis, HSCs migrate to seed other locations that support definitive hematopoiesis: embryonic liver, followed by embryonic thymus, fetal spleen, and bone marrow (in that order). These latter destinations do not produce HSCs de novo, but rather contain niches suitable for expansion of newly arrived HSCs.33 The suitability of such niches is controlled by specific characteristics of their stromal support cells.33 The embryonic liver is colonized first, apparently because it shares many molecular and functional similarities with the yolk sac.31 It provides the major locus for definitive hematopoiesis from E12 to E16.39 The HSCs enter the embryonic liver in several succeeding waves between E9/E10 and E12.12 The first HSCs to enter the liver are pluripotent and can form any type of hematopoietic cell. Their first step in intrahepatic maturation is to commit to a more limited range of lineage options, typically as either an erythromyeloid progenitor or a common myelolymphoid progenitor.22
Definitive erythroid precursors mature and become enucleated within erythroid islands in the liver before entering the circulation.27 Liver-derived myelolymphoid progenitors subsequently develop into bipotent cells (B cell and myeloid, or T cell and myeloid) before committing to produce a single-cell lineage.22 Some T-cell progenitors have a bipotent commitment to natural killer (NK) cell lineage. T-cell precursors destined for transfer to the embryonic thymus are produced even in athymic mice, indicating that the fetal liver may play a role in promoting early T-cell differentiation.20,21
Embryonic thymus and fetal spleen are seeded either from the liver or AGM, or both, beginning about E13 for thymus and E15 for spleen. The thymus typically accepts only those HSCs that are committed to make T cells, whereas other multipotent myelolymphoid elements are directed to other sites.20 The number of T-cell precursors in liver is abundant at E12, but decreases thereafter, whereas the population of intrahepatic B-cell progenitors exhibits a reverse trend.19 Most types of definitive hematopoietic cells in the spleen arise from precursor cells that commit to a specific lineage before leaving the liver. Multipotent HSCs entering the spleen cease proliferating and differentiate into mature macrophages. These cells may regulate intrasplenic erythropoiesis.
The bone marrow first receives HSCs from hepatic depots at about E16.39,45 Thereafter, the allocation of colony-forming hematopoietic precursors shifts from a primarily hepatocentric localization at E18 through a more dispersed distribution (bone marrow, liver, and spleen in approximately equal numbers) at P2 to a profile-favoring bone marrow and to a lesser-extent spleen at P4 and after.49 Thus, the bone marrow, liver, and spleen function cooperatively to regulate definitive hematopoiesis. While cooperating, each organ supports a molecularly distinct subset of hematopoietic progenitors.
Committed hematopoietic progenitors necessary to foster all lineages observed in adult animals arise during definitive hematopoiesis. The AGM-derived HSCs contribute to all major hematopoietic cell lineages. The HSC population from the placenta reportedly supports the genesis of erythroid, lymphoid (both B-cell and T-cell lineages), and myeloid elements. By comparison, the lineages sustained by yolk-sac-derived HSCs are limited to lymphoid and myeloid cells.40 Whether or not progenitors for a given definitive cell lineage arising from distinct HSC populations exhibit different functional and molecular properties during late fetal and/or postnatal life has yet to be determined.
Late-stage embryos (E13–E15), fetuses (E16 to birth), and neonates which present with anemia are afflicted with a defect in definitive erythropoiesis. Abnormalities associated with this presentation include the total absence of definitive hematopoiesis,25,41 and an inability of progenitor cells to properly colonize intraembryonic sites of hematopoiesis. Multiple cell lineages may be affected; such a combined effect suggests that the hematopoietic defect occurs in a bipotent or multipotent stem cell rather than in one committed to forming a specific cell lineage.43 Presentation with late-stage anemia also might result from a general delay in growth and development rather than a focused anomaly in the erythrocytic lineage.7
Young animals have circulating blood cell numbers that are different from that of adults.39 RBC numbers are more than double between birth and young adulthood. Circulating leukocyte counts at birth are approximately 20% of adult levels before increasing to adult numbers by 6–7 weeks of age. Platelet counts in neonates are approximately one-third numbers.
HEMOGLOBIN SWITCHING
Primitive and definitive RBCs bear a battery of seven α- and β-globins, the mix of which varies with the developmental stage. The α-globins are encoded by three genes (ζ, α1, and α2), whereas β-globins are encoded by four main genes (εγ, βH1, βmin, and βmaj). The globins of a given type (e.g., α- or β-globins) typically exist as a series of closely linked homologous genes and related pseudogenes located on the same chromosome;16,24 mouse globin genes are carried on chromosomes 7 (β-globins) and 11 (α-globins). All seven mouse globin genes are transcribed during erythroid development, but the production of three—ζ, εγ, and βH1—is limited to primitive RBCs.23 A consequence of this limitation is that mouse β-globin genes, although closely related to human globins in most respects, do not follow the human pattern of upregulation in the sequence of their chromosomal arrangement.23,24
The extent of individual globin gene expression and the blend of globin genes that are expressed vary over time. For example, enucleated primitive RBCs contain relatively more βmin than do definitive RBCs. At E11.5, βmin constitutes approximately 80% of the β-globin in circulation. This level is reduced by approximately 60% at birth. Primitive RBCs express increasing levels of adult globins as gestation progresses, whereas definitive RBCs harbor only the adult protein variants. This evolution indicates that the pattern of globin expression switches as the primitive RBCs are replaced by definitive RBCs. Molecular mechanisms which regulate the switching process are complex.17 The timing of this switch, between E10.5 and E12.5, coincides with the initial escalation in definitive erythropoiesis. Perturbed timing of this switch is a feature of some murine models of hematopoietic disease.6
Successful maintenance of the developing conceptus depends on preferential capture of oxygen in embryonic and fetal tissues. Therefore, primitive RBCs generally have a higher affinity for oxygen than do maternal RBCs, although domestic cats are an exception. This sequestration of oxygen is mediated by two primary mechanisms. The mechanism pertinent to the early embryonic period is the greater affinity of embryonic hemoglobin in primitive RBCs for oxygen relative to that of adult hemoglobin.2 Alternatively, definitive RBCs in the late embryo and fetus possess a lower concentration of 2,3-diphosphoglycerate (2,3-DPG) than do maternal RBCs. Higher levels of 2,3-DPG facilitate oxygen release into tissues. After birth, levels 2,3-DPG content of RBCs rise to adult levels within 10–15 days.
MOLECULAR MECHANISMS REGULATING HEMATOPOIETIC DEVELOPMENT
A wide spectrum of growth factors, hormones, and transcription factors are required to specify the various stages of hematopoietic development in mammals. The entire meshwork responsible for directing any given
event has not been completely characterized. Shifting levels of several transcription factors have been shown to modify blood cell production. Insufficiencies in many of these molecules act by forestalling primitive hematopoiesis in the yolk sac. For example, genesis of erythroid precursors is impacted by deficits in GATA-binding protein 1 (Gata-1),13 shown in vivo to prevent erythroid maturation; Gata-2,48 demonstrated in vivo to abort precursor expansion; and Gata-4,5 for which an in vitro shortage thwarts hemangioblast-mediated specification of blood islands and their associated vessels. These effects occur because the GATA consensus elements are critical regulatory regions in many erythroid-specific genes. All cell lineages are affected by stem cell leukemia/T-cell acute leukemia factor 1 (Scl/Tal-1).38 Abnormal levels of transcription factors can also act later in gestation to disrupt definitive hematopoiesis. For example, purine box-binding transcription factor 1 (PU.1) is required for production of definitive (monocyte-derived) macrophages, but not their primitive (yolk-sac-derived) counterparts. This disparity in response is intriguing in that PU.1 is highly expressed during early hematopoiesis, but fluctuates in various cell lineages as time progresses.10 Normal genesis of many progenitor cells, including bipotent erythroid/ megakaryocytic progenitors as well as B-cell and T-cell progenitors, requires that PU.1 levels be reduced, whereas production of myeloid progenitors necessitates an increase in PU.1.10
Secreted molecules also are important regulators of hematopoietic development during gestation. For example, erythropoietin (EPO) sustains both primitive and definitive erythropoiesis by stimulating proliferation and differentiation of immature primitive and definitive RBCs.25 Reduction in EPO activity within the yolk sac greatly reduces the number of colony-forming cells and erythroblasts via excessive apoptosis. Thrombopoietin fulfills a similar function for megakaryocytes, although other cytokines (interleukin-3 [IL-3], IL-6) and growth factors (granulocyte-colony stimulating factor, stem cell factor) also are required.47 Other ligand/receptor signaling pathways shown to affect hematopoietic development include the endoderm-derived molecule Indian hedgehog (Ihh)8 and bone morphogenetic protein 4 (Bmp4),11 both of which participate in blood island production and vasculogenesis in the yolk sac. In general, secreted molecules act via their interaction with a specific transcription factor.
Cell adhesion molecules of the integrin family are essential for the proper migration of hematopoietic precursors. For instance, β1-integrins are essential if HSC are to reach the embryonic liver, and later the fetal spleen and bone marrow, at the appropriate developmental stages.37 A loss of β1-integrins prevents adhesive interactions between HSCs and endothelial cells, thereby stranding the HSCs within vessels.32 Some integrins have functions in addition to their targeting role. For example, β4-integrins are required not only for correct homing but also for expansion and differentiation of erythroid and B-cell precursors in liver, spleen, and bone marrow. As with secreted factors, the activities of some
integrins relate more to late gestation and neonatal stages rather than earlier stages of hematopoietic development. This chronology has been documented for β 4-integrin with respect to lymphoid and myeloid differentiation.14
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