Rossi’s Principles of Transfusion Medicine

Rossi’s Principles ofTransfusion MedicineFifth Edition

Edited by

Toby L. Simon, MDSenior Medical Director, Plasma Product Development and CSL Plasma, CSL Behring, King of Prussia, Pennsylvania; andClinical Professor of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA

Jeffrey McCullough, MDProfessor, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

Edward L. Snyder, MD, FACPProfessor, Department of Laboratory Medicine, Yale University School of Medicine; andDirector, Blood Bank/Apheresis Service, Yale-New Haven Hospital, New Haven, Connecticut, USA

Bjarte G. Solheim, MD, PhD, MHAProfessor Emeritus, Institute of Immunology, Oslo University Hospital–Rikshospitalet, and University of Oslo, Oslo, Norway

Ronald G. Strauss, MDProfessor Emeritus, Departments of Pathology and Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa, USA;Associate Medical Director, LifeSource/Institute for Transfusion Medicine, Chicago, Illinois, USA

This edition first published 2016 2016 by John Wiley & Sons, Ltd.Previous edition 2009 by AABB, published by Blackwell Publishing Ltd.

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Library of Congress Cataloging-in-Publication Data

Rossi’s principles of transfusion medicine / edited by Toby L. Simon, Jeffrey McCullough, Edward L. Snyder, Bjarte G. Solheim,Ronald G. Strauss. – Fifth edition.

p. ; cm.Principles of transfusion medicineIncludes bibliographical references and index.ISBN 978-1-119-01299-3 (cloth)I. Simon, Toby L., editor. II. McCullough, Jeffrey, 1938- , editor. III. Snyder, Edward L. (Edward Leonard), 1946- ,

editor. IV. Solheim, Bjarte G., editor. V. Strauss, Ronald G., editor. VI. Title: Principles of transfusion medicine.[DNLM: 1. Blood Transfusion. 2. Blood Banks–organization & administration. 3. Blood Grouping and Crossmatching.

WB 356]RM171615.3'9–dc23

2015031868

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available inelectronic books.

Set in 9/11pt, MinionPro-Regular by Thomson Digital, Noida, India

1 2016

Contents

Contributors, vii

Preface, xi

List of abbreviations, xiii

About the companion website, xix

1 Transfusion in the new millennium, 1Ennio C. Rossi and Toby L. Simon

Section I: Contemporary issues in donationand transfusion

2 Patient blood management, 13Darrell J. Triulzi, Mark H. Yazer, and Jonathan H. Waters

3 Clinical and technical aspects of blood administration, 23Eric A. Gehrie, Jocelyn Chandler, and Edward L. Snyder

4 Recruitment and screening of donors and the collection,processing, and testing of blood, 30Kendall P. Crookston, Aaron E. Pritchard, andToby L. Simon

5 Adverse reactions and iron deficiency after blood donation, 43Anne F. Eder and Joseph E. Kiss

6 Donor vigilance and hemovigilance, 58Øystein Flesland and Johanna C. Wiersum-Osselton

7 Global perspective on ensuring blood and blood productsafety and availability, 69

Part I: Red blood cells

Paul D. Mintz and Mark J. Weinstein

Section II: Blood components and derivatives

8 Red blood cell production and kinetics, 87Mark J. Koury

9 Red blood cell metabolism, preservation,and oxygen delivery, 97John R. Hess and Bjarte G. Solheim

10 Anemia and red blood cell transfusion, 110Jeffrey L. Carson and Paul Hébert

11 Sickle cell anemia, thalassemia, and congenitalhemolytic anemias, 126Keith Quirolo and Elliott Vichinsky

12 Autoimmune hemolytic anemias and paroxysmalnocturnal hemoglobinuria, 144Andrea M. McGonigle, Paul M. Ness, and Karen E. King

13 Carbohydrate blood groups, 159Laura Cooling

14 Rh and LW blood group antigens, 176Connie M. Westhoff and Don L. Siegel

15 Other protein blood groups, 185Jill R. Storry

16 Red cell immunology and compatibility testing, 193Connie M. Westhoff

Part II: Platelets

17 Platelet production and kinetics, 206Christopher A. Tormey and Henry M. Rinder

18 Platelet immunology and alloimmunization, 215Janice G. McFarland

19 Preparation, preservation, and storage of plateletconcentrates, 227Ralph R. Vassallo, Jr.

20 Thrombocytopenia and platelet transfusion, 235Michael F. Murphy, Simon J. Stanworth, and Lise Estcourt

21 Management of immune-mediated thrombocytopenia, 245Donald M. Arnold, Ishac Nazi, James W. Smith, and TheodoreE. Warkentin

Part III: White blood cells

22 Neutrophil production and kinetics: neutropeniaand neutrophilia, 265Lawrence Rice and Miho Teruya

23 Neutrophil collection and transfusion, 271Ronald G. Strauss

24 Leukocyte-reduced blood components: laboratoryand clinical aspects, 278Tor Hervig and Jerard Segatchian

25 Composition of plasma, 286

Part IV: Plasma

Peter Hellstern

26 Plasma and cryoprecipitate for transfusion, 295Simon J. Stanworth and Alan T. Tinmouth

27 The purification of plasma proteins for therapeutic use, 302Joseph Bertolini

28 Recombinant products for the treatment of hemophilia:recent advances, 321Michael Wilson, Andrew Nash, Iris Jacobs, and Arna Andrews

29 Coagulation factor concentrates for inherited bleedingdisorders, 328Gary M. Woods and Amy L. Dunn

30 Coagulation factor concentrates and pharmacologic therapiesfor acquired bleeding disorders, 344Neil Shah and Lawrence Tim Goodnough

v

vi Contents

31 Immunoglobulin products, 358Melvin Berger

Section III: Apheresis, transplantation,and new therapies

32 Apheresis: principles and technology of hemapheresis, 373Edwin A. Burgstaler and Jeffrey L. Winters

33 Therapeutic apheresis, 388Shanna Morgan and Jeffrey McCullough

34 Therapeutic phlebotomy and specialized hemapheresis, 407Jeffrey A. Bailey and Robert Weinstein

35 Hematopoietic growth factors, 418David J. Kuter

36 Hematopoietic stem cells and cord blood, 430Jeffrey McCullough

37 Hematopoietic stem cell transplantation, 440Sameh Gaballa, Amin Alousi, Sergio Giralt,and Richard Champlin

38 Gene therapy applications to transfusion medicine, 452Eric A. Gehrie, Alexey Bersenev, Emanuela Bruscia,Diane Krause, and Wade L. Schulz

39 HLA antigens and alleles, 456Christian Naper and Bjarte G. Solheim

40 Tissue banking, 464Ralph M. Powers and Jeanne V. Linden

41 Adoptive immunotherapy, 479Sarah M. Drawz, Jeffrey S. Miller, and David H. McKenna

42 Tissue engineering and regenerative medicine, 488Sumati Sundaram, Joshua Siewert, Jenna Balestrini, AshleyGard, Kevin Boehm, Elise Wilcox, and Laura Niklason

Section IV: Specialized clinical practice

Part I: Obstetrics and pediatrics

43 Obstetric transfusion practice, 507Marieke B. Veenhof, Jos J.M. van Roosmalen,and Anneke Brand

44 Fetal and neonatal hematopoiesis, 516Robert D. Christensen and Martha C. Sola-Visner

45 Hemolytic disease of the fetus and newborn, 528Bjarte G. Solheim, Morten Grönn, and Thor Willy RuudHansen

46 Red blood cell transfusions for neonates and infants, 535Ronald G. Strauss

47 Platelet and plasma transfusions for infants and children, 542Jeanne E. Hendrickson and Cassandra D. Josephson

Part II: Surgery and trauma

48 Perioperative transfusion needs, 549Leanne Clifford, Daryl J. Kor, and James R. Stubbs

49 Transfusion therapy in the care of trauma and burnpatients, 562John R. Hess, John B. Holcomb, Steven E. Wolf,and Michael W. Cripps

Part III: Oncology

50 Transfusion support for the oncology patient, 574

Part I: Infectious hazards

Wade L. Schulz and Edward L. Snyder

Section V: Hazards of transfusion

51 Transfusion-transmitted virus infections, 583Erhard Seifried and Michael Schmidt

52 Transfusion transmission of parasites, 599Bryan R. Spencer

53 Bacterial contamination of blood components, 608Richard J. Benjamin

54 Prion diseases, 620Marc L. Turner

55 Testing for pathogens in donors, 626Tho D. Pham and Susan A. Galel

56 Pathogen reduction of blood components and plasmaderivatives, 632Nathan J. Roth

Part II: Other hazards

57 Hemolytic transfusion reactions, 642Robertson D. Davenport and Martin H. Bluth

58 Febrile, allergic, and nonimmune transfusion reactions, 652Emmanuel A. Fadeyi and Gregory J. Pomper

59 Transfusion-related lung injury, 667Ulrich J. Sachs and Jonathan P. Wallis

60 Transfusion-associated graft-versus-host disease, 680Eric A. Gehrie, Edward L. Snyder, and Alex B. Ryder

61 Transfusional iron overload, 685Sujit Sheth

62 Immunomodulatory and pro-inflammatory effects ofallogeneic blood transfusion, 695Eleftherios C. Vamvakas, José O. Bordin, and Morris A.Blajchman

Index, 711

Contributors

Amin Alousi, MDAssociate Professor of MedicineDepartment of Stem Cell Transplantationand Cellular TherapyThe University of TexasMD Anderson Cancer CenterHouston, TX, USA

Arna Andrews, PhDDirector, Cell Line Development, CSL BehringBroadmeadows, VIC, Australia

Donald M. Arnold, MD, MSc, FRCPCAssociate Professor, Division of Hematology andThromboembolism, Department of Medicine, MichaelG. DeGroote School of Medicine, McMasterUniversity, Hamilton, ON, Canada

Jeffrey A. Bailey, MD, PhDAssistant Professor, Departments of Medicineand Pathology, Division of Transfusion Medicine;Program in Bioinformatics and Integrative BiologyUniversity of Massachusetts Medical School; and UMassMemorial Medical Center, Worcester, MA, USA

Jenna Balestrini, PhDPostdoctoral Fellow in AnesthesiologyDepartment of Biomedical Engineering, Department ofAnesthesiology, Yale University School of MedicineNew Haven, CT, USA

Richard J. Benjamin, MD, PhD,

FRCPathChief Medical Officer, Cerus Corp, Concord CA, USA

Melvin Berger, MD, PhDSenior Director, Medical Research StrategyCSL Behring, King of Prussia, PA, USA

Alexey Bersenev, MD, PhDAssociate Research Scientist, Department of LaboratoryMedicine, Yale University School of Medicine, andBlood Bank, Yale-New Haven Hospital, New HavenCT, USA

Joseph Bertolini, PhDR&D Director, CSL BehringBroadmeadows, VIC, Australia

Morris A. Blajchman, MD, FRCP(C)Professor Emeritus, Departments of Pathology andMedicine, McMaster University, HamiltonON, Canada

Martin H. Bluth, MD, PhDProfessor, Department of PathologyWayne State University School of MedicineDetroit, MI, USA

Kevin Boehm, MDStudent, Department of Biomedical EngineeringDepartment of Anesthesiology, Yale University Schoolof Medicine, New Haven, CT, USA

José O. Bordin, MDAssociate Professor, Department of Hematology andTransfusion Medicine, Universidade Federal de SãoPaulo, São Paulo, Brazil

Anneke Brand, MD, PhDProfessor of Transfusion Medicine, Sanquin Blood Bankand Department of ImmunoHematology and BloodTransfusion, Leiden University Medical Center, LeidenThe Netherlands

Emanuela Bruscia, PhDAssistant Professor of Pediatrics, Yale University Schoolof Medicine and Blood Bank, Yale-New Haven HospitalNew Haven, CT, USA

Edwin A. Burgstaler,MT, HP(ASCP)Development Technologist, Therapeutic ApheresisTreatment Unit, Mayo Clinic, RochesterMN, USA

Jeffrey L. Carson, MDRichard C. Reynolds Professor of MedicineChief, Division of General Internal Medicine; andProvost— New Brunswick, Rutgers Robert WoodJohnson Medical School, Rutgers Biomedical HealthSciences, Rutgers University, New Brunswick, NJ, USA

Richard Champlin, MDProfessor and Chairman, Department of Stem CellTransplantation and Cellular Therapy, University ofTexas-MD Anderson Cancer Center, Houston, TX, USA

Jocelyn Chandler, MDChief Resident, Department of PathologyYale University School of Medicine; and Blood BankYale-New Haven Hospital, New Haven, CT, USA

Robert D. Christensen, MDPresidential Professor and Chief, Division ofNeonatology, University of Utah School of MedicineSalt Lake City, UT, USA

Leanne Clifford, BM, MScResident, Department of Anesthesiology, Mayo ClinicRochester, MN, USA

Laura Cooling, MDAssociate ProfessorDepartment of PathologyUniversity of MichiganAnn Arbor, MI, USA

Michael W. Cripps, MDAssistant Professor of Surgery, Department of SurgeryDivision of Burn/Trauma/Critical Care, University ofTexas Southwestern Medical Center, Dallas, TX, USA

Kendall P. Crookston, MD, PhDProfessor, Departments of Pathology and MedicineUniversity of New Mexico School of Medicine; RegionalMedical Director, United Blood Services ofNew Mexico; and Associate Medical Director, TriCoreReference Laboratories, Albuquerque, NM, USA

Robertson D. Davenport, MDAssociate Professor, Department of PathologyThe University of Michigan Medical SchoolAnn Arbor, MI, USA

Sarah M. Drawz, MDFellow, Department of Laboratory Medicine andPathology, University of MinnesotaMinneapolis, MN, USA

Amy L. Dunn, MDAssociate Professor, Department of PediatricsThe Ohio State University; and Director, Hemophiliaand Bleeding Disorder Program, Hemophilia TreatmentCenter, Division of Hematology/Oncology/BMTColumbus, OH, USA

Anne F. Eder, MD, PhDVice President, National Medical Affairs; BiomedicalServices, American Red Cross, Adjunct AssociateProfessor, Georgetown University Medical CenterWashington DC, USA

Lise Estcourt, MA(MEL), MSc, DPhil,

MRCP, FRCPathConsultant Hematologist, NHS Blood and Transplantand The National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, Oxford UniversityHospitals, NHS Foundation Trust and the University ofOxford, Oxford, UK

Emmanuel A. Fadeyi, MDAssociate Professor, Department of PathologyWake Forest University School of MedicineWinston-Salem, NC, USA

vii

viii Contributors

Øystein Flesland, MD, PhDHead of Section, Patient Reporting and LearningSystems Unit, Norwegian Knowledge Centre for theHealth Services, Oslo, Norway

Sameh Gaballa, MDAssistant Professor of Medical OncologyDivision of Hematological Malignancies andBone Marrow TransplantationThomas Jefferson UniversityPhiladelphia, PA, USA

Susan A. Galel, MDSenior Director of Scientific Affairs, Blood ScreeningRoche Molecular Systems, Pleasanton, CA; andAssociate Professor Emeritus, Department of PathologyStanford University School of Medicine, Palo AltoCA, USA

Ashley Gard, PhD cand.Department of Biomedical Engineering, Department ofAnesthesiology, Yale University School of MedicineNew Haven, CT, USA

Eric A. Gehrie, MDInstructor, Department of Laboratory MedicineYale University School of Medicineand Blood Bank, Yale-New Haven HospitalNew Haven, CT, USA

Sergio Giralt, MDProfessor of Medicine, Weill Cornell Medical CollegeChief, Adult BMT Service, Memorial Sloan KetteringCancer Center, New York, NY, USA

Lawrence Tim Goodnough, MDProfessor of Pathology and Medicine, Co-DirectorTransfusion Medicine Program, Director, TransfusionMedicine Fellowship Program, Associate MedicalDirector, Stanford Blood CenterStanford University Medical CenterStanford, CA, USA

Morten Grönn, MDConsultant Neonatologist, Department of Child andAdolescent Medicine, Akershus University HospitalNordbyhagen, Norway

Thor Willy Ruud Hansen, MD, PhDProfessor of Pediatrics, Consultant NeonatologistNeonatal Intensive Care, Women and Children’sDivision, Oslo University Hospital; and Institute forClinical Medicine, Faculty of Medicine, University ofOslo, Oslo, Norway

Paul Hébert, MDProfessor of Medicine, University of Montreal; andPhysician-in-Chief, Centre Hospitalier de L’Universitéde Montréal (CHUM), Montreal, Canada

Peter Hellstern, MDDirector and Professor, Institute of Hemostaseology andTransfusion Medicine, Academic City HospitalLudwigshafen, Germany

Jeanne E. Hendrickson, MDAssociate Professor, Departments of LaboratoryMedicine and of Pediatrics, Yale University School ofMedicine, and Associate Director, TransfusionMedicineService, Yale-New Haven Hospital, New HavenCT, USA

Tor Hervig, MD, PhDProfessor, Department of Clinical ScienceDepartment of Immunology and Transfusion MedicineHaukeland University Hospital, Bergen, Norway

John R. Hess, MD, MPHProfessor, Department of Laboratory Medicine andHematology, University of WashingtonSchool of Medicine; and Medical Director, TransfusionService, Harborview Medical CenterSeattle, WA, USA

John B. Holcomb, MDProfessor of Surgery; Chief, Division of Acute CareSurgery; and Director, Center for Translational InjuryResearch, University of Texas Health Science CenterHouston, TX, USA

Iris Jacobs, MDGlobal Clinical Program Director, CSL BehringKing of Prussia, PA USA

Cassandra D. Josephson, MDProfessor, Pathology and Pediatrics, Emory UniversitySchool of Medicine, Medical Director, Children’sHealthcare of Atlanta, Blood Tissue & ApheresisServices, Atlanta, GA, USA

Karen E. King, MDAssociate Professor, Department of Pathology andOncology, Director, Hemapheresis and TransfusionSupport, Associate Director, Transfusion Medicine, TheJohns Hopkins University School of MedicineBaltimore, MD, USA

Joseph E. Kiss, MDMedical Director, Hemapheresis and Blood ServicesThe Institute for Transfusion Medicine; and AssociateProfessor of Medicine, Division of Hematology-Oncology, Department of Medicine, The University ofPittsburgh, Pittsburgh, PA, USA

Daryl J. Kor, MD, MScAssociate Professor, Department of AnesthesiologyMayo Clinic, Rochester, MN, USA

Mark J. Koury, MDProfessor of Medicine, Division of Hematology/Oncology, Vanderbilt University, Nashville, TN, USA

Diane Krause, MD, PhDProfessor, Laboratory Medicine, Pathology and CellBiology, Yale University School of Medicine and BloodBank, Yale-New Haven Hospital, New Haven, CT, USA

David J. Kuter, MD, DPhilChief of Hematology, Massachusetts General HospitalProfessor of Medicine, Harvard Medical School, BostonMA, USA

Jeanne V. Linden, MD, MPHDirector, Blood and Tissue Resources, WadsworthCenter, New York State Department of HealthAlbany, NY, USA

Jeffrey McCullough, MDProfessor, Department of Laboratory Medicine andPathology, University of Minnesota Medical SchoolMinneapolis, MN, USA

Janice G. McFarland, MDMedical Director, Platelet and Neutrophil ImmunologyLaboratory, Blood Center of Wisconsin; and ProfessorDepartment of Medicine, Medical College of WisconsinMilwaukee, WI, USA

Andrea M. McGonigle, MDAssistant Professor, Department of Pathology andLaboratory Medicine, Associate Medical DirectorTransfusion Medicine, David Geffen School of Medicineat UCLA, Los Angeles, CA USA

David H. McKenna, MDAssociate Professor of Laboratory Medicine andPathology, Director, Division of Transfusion MedicineUniversity of Minnesota Medical SchoolMinneapolis, MN, USA

Jeffrey S. Miller, MDDepartment of MedicineDivision of Hematology, Oncology and TransplantationBlood and Marrow Transplantation ProgramUniversity of Minnesota, Minneapolis, MN, USA

Paul D. Mintz, MDDirector, Division of Hematology Clinical ReviewOffice of Blood Research and Review, Center forBiologics Evaluation & Research, US Food and DrugAdministration, Silver Spring, MD, USA

Shanna Morgan, MDMedical Director,American Red Cross-North Central RegionAdjunct Assistant ProfessorLaboratory Medicine and PathologyDivision of Transfusion MedicineUniversity of MinnesotaAssistant Medical Director Blood BankVeterans Affairs Hospital, Minneapolis, MN, USA

Michael F. Murphy, MD, FRCP,

FRCPathProfessor of Transfusion Medicine and ConsultantHaematologist, NHS Blood & Transplant, NationalInstitute of Health Research (NIHR)Oxford Biomedical Research CentreOxford University Hospitals and theUniversity of Oxford, UK

Christian Naper, MD, PhD, MHASenior Consultant, Institute of ImmunologyOslo University Hospital–Rikshospitalet andUniversity of Oslo, Oslo, Norway

Andrew Nash, PhDSenior Vice President, Research, CSL BehringBroadmeadows, VIC, Australia

Contributors ix

Ishac Nazi, PhDAssistant Professor, Department of Medicine, Michael G.DeGroote School of Medicine, McMaster UniversityHamilton, ON, Canada

Paul M. Ness, MDProfessor, Pathology, Medicine and Oncology, DirectorTransfusion Medicine Division, The Johns HopkinUniversity School of Medicine Baltimore, MD, USA

Laura Niklason, PhD, MDProfessor of Anesthesiology and BiomedicalEngineering, Department of Anesthesiology, YaleUniversity School of Medicine, New Haven, CT, USA

Tho D. Pham, MDAssistant Medical Director of Clinical Services, StanfordBlood Center; and Clinical Instructor, Department ofPathology, Stanford University School of Medicine, PaloAlto, CA, USA

Gregory J. Pomper, MDAssociate Professor, Department of PathologyWake Forest School of Medicine, Winston-SalemNC, USA

Ralph M. Powers, DDSSenior Manager, Scientific Affairs, Institute ofRegenerative Medicine, LifeNet HealthVirginia Beach, VA, USA

Aaron E. Pritchard, MDAssistant Professor of Pathology, University of NewMexico School of Medicine, Albuquerque, NM, USA

Keith Quirolo, MDFormerly Department of Hematology/Oncology, UCSFBenioff Children’s Hospital, Oakland, Oakland, CAUSA

Lawrence Rice, MDChief, Division of Hematology, Houston MethodistHospital; Professor of Medicine, Weill Cornell MedicalCollege; and Adjunct Professor of Medicine, BaylorCollege of Medicine, Houston, TX, USA

Henry M. Rinder, MDProfessor of Laboratory Medicine and Internal Medicine(Hematology), Yale University School of Medicine andDirector, Hematology Laboratories, Yale-New HavenHospital, New Haven, CT, USA

Ennio C. Rossi, MDProfessor Emeritus of Medicine, NorthwesternUniversity School of Medicine, Chicago, IL, USA

Nathan J. Roth, PhDDirector, Global Pathogen Safety, CSL BehringKing of Prussia, PA, USA

Alex B. Ryder, MDAssistant Professor, Departments of Pediatricsand Pathology, University of Tennessee HealthScience Center, Le Bonheur Children’s HospitalMemphis, TN, USA

Ulrich J. Sachs, MD, PhDHead and Professor, The Platelet and GranulocyteLaboratory, Institute for Clinical Immunology andTransfusion Medicine, Justus Liebig UniversityGiessen, Germany

Michael Schmidt, MDProfessor, Institute of Transfusion Medicine andImmunohematology, German Red Cross, Frankfurt/MGermany

Wade L. Schulz, MD, PhDResident, Department of Laboratory MedicineYale University School of Medicine and Blood BankYale-New Haven Hospital, New Haven, CT, USA

Jerard Seghatchian, MDSenior Consultant, International Consultancy in BloodComponents Quality/Safety Improvement, Audit/Inspection and DDR Strategies, London, UK

Erhard Seifried, MD, PhDDirector and ProfessorInstitute of Transfusion Medicine andImmunohematology, German Red Cross, Frankfurt/MGermany

Neil Shah, MDClinical Assistant Professor of Pathology andTransfusion Medicine, Medical Director of ReferralTesting, Departments of Pathology and MedicineStanford School of Medicine Stanford, CA, USA

Sujit Sheth, MDProfessor of Clinical Pediatrics, Department ofPediatrics, Weill Cornell Medical CollegeNew York, NY, USA

Don L. Siegel, PhD, MDProfessor, Pathology and Laboratory Medicine; andDirector, Division of Transfusion Medicine andTherapeutic Pathology, Department of Pathology andLaboratory Medicine, Perelman School of Medicine atthe University of Pennsylvania, Philadelphia, PA, USA

Joshua Siewert, MScSchool of Management, Department of BiomedicalEngineering, Yale University; Department ofAnesthesiology, Yale University School of MedicineNew Haven, CT, USA

Toby L. Simon, MDSenior Medical Director, Plasma Product Developmentand CSL Plasma, CSL Behring, King of PrussiaPA; Clinical Professor of Pathology, University of NewMexico School of Medicine,Albuquerque, NM, USA

James W. Smith, MT, BScTechnical Director, Platelet Immunology LaboratoryMichael G. DeGroote School of MedicineMcMaster University, Hamilton, ON, Canada

Edward L. Snyder, MDProfessor, Department of Laboratory MedicineYale University School of Medicine, DirectorBlood Bank/Apheresis Service, Yale-New HavenHospital, New Haven, CT, USA

Martha C. Sola-Visner, MDAssociate Professor of Pediatrics, Harvard MedicalSchool, Harvard University; and AttendingNeonatologist, Division of Newborn Medicine, BostonChildren’s Hospital, Boston, MA, USA

Bjarte G. Solheim, MD, PhD, MHAProfessor Emeritus, Institute of ImmunologyOslo University Hospital–Rikshospitalet andUniversity of Oslo, Oslo, Norway

Bryan R. Spencer, MPHResearch Scientist, American Red CrossDedham, MA, USA

Simon J. Stanworth, MA, FRCP,

DPhil, FRCPathConsultant Haematologist, NHS Blood and Transplantand The National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, Oxford UniversityHospitals, NHS Foundation Trust and the University ofOxford, Oxford, UK

Jill R. Storry, PhDBlood Group Immunology, Clinical Immunology andTransfusion Medicine, University and RegionalLaboratories Region Skåne, Lund UniversityHospital; and Associate Professor, Division ofHematology and Transfusion Medicine, Department ofLaboratory Medicine, Lund UniversityLund, Sweden

Ronald G. Strauss, MDProfessor Emeritus, Departments of Pathology andPediatrics, University of Iowa College of Medicine, IowaCity, IA, USA, Associate Medical Director, Life Source/Institute for Transfusion Medicine, Chicago, IL, USA

James R. Stubbs, MDChairman, Division of Transfusion Medicine,Department of Laboratory Medicine and PathologyMayo Clinic, Rochester, MN, USA

Sumati Sundaram, PhDPost Doctorate Associate in Cell Biology, Department ofBiomedical Engineering, Yale University; Department ofAnesthesiology, Yale University School of MedicineNew Haven, CT, USA

Miho Teruya, MD, MPHPostdoctoral Fellow, Department of Hematology/Oncology, Baylor College of Medicine, Houston, TXUSA

Alan T. Tinmouth, MD, MSc (Clin

Epi), FRCPCAssistant Professor, Departments of Medicine, andLaboratory Medicine & Pathology, University ofOttawa; Head, General Hematology and TransfusionMedicine, Division of Hematology, The OttawaHospital; andUniversity ofOttawaCentre forTransfusionResearch Ottawa Hospital Research InstituteOttawa, ON, Canada

Christopher A. Tormey, MDAssociate Professor, Department of LaboratoryMedicine, Yale University School of Medicine, NewHaven, CT; and Director of Transfusion MedicineVeterans Affairs Medical CenterWest Haven, CT, USA

x Contributors

Darrell J. Triuzi, MDProfessor of PathologyDirector, Division of Transfusion MedicineUniversity of Pittsburgh Medical CenterMedical DirectorInstitute for Transfusion MedicinePittsburgh, PA, USA

Marc L. Turner, PhDProfessor, Department of Cellular Therapy, Universityof Edinburgh; and Medical Director, Scottish NationalBlood Transfusion Service, Edinburgh, Scotland, UK

Eleftherios C. Vamvakas,MD, PhDFormerly, Rita and Taft Schreiber Chair in TransfusionMedicine; Professor of Pathology and Director ofClinical Pathology, Department of PathologyCedars-Sinai Medical Center Los Angeles, CA, USA

Jos J.M. van Roosmalen, MD, PhDProfessor of International Safe Motherhood and HealthSystems, Department of Obstetrics, Leiden UniversityMedical Center, Leiden; and Section of Health Care andCulture, Athena Institute, VU University, AmsterdamThe Netherlands

Ralph R. Vassallo, Jr., MDEVP/Chief Medical and Scientific OfficerBlood Systems, Inc., Scottsdale AZ, USA andAdjunct Associate Professor of Medicine, University ofPennsylvania School of Medicine, Philadelphia, PAUSA

Marieke B. Veenhof, MDSenior Resident, Obstetrics and GynaecologyDepartment of Obstetrics, Leiden University MedicalCenter, Leiden, The Netherlands

Elliott Vichinsky, MDMedical Director, Hematology/Oncology, UCSF BenioffChildren’s Hospital Oakland, Oakland, CA; andProfessor of Pediatrics, University of California SanFrancisco, San Francisco, CA, USA

Jonathan P. Wallis, BA oxon, MB.

BS. lond., FRCP(UK), FRCPathConsultant Haematologist, Department ofHaematology, Freeman Hospital, Newcastle uponTyne, UK

Theodore E. Warkentin, MD, BSc

(Med), FRCPC, FACP, FRCP(Edin)Professor, Departments of Pathology, Medicine andMolecular Medicine, Michael G. DeGroote School ofMedicine, McMaster University, Hamilton, ON, Canada

Jonathan H. Waters, MDChief, Department of AnesthesiologyMagee-Womens Hospital of UPMC, Professor ofAnesthesiology and Bioengineering, University ofPittsburgh, Medical Director, Patient BloodManagement Program of UPMCPittsburgh, PA, USA

Mark J. Weinstein, PhDAssociate Deputy Director for Science, Office of BloodResearch and Review, Center for Biologics Evaluation &Research, US Food and Drug Administration, SilverSpring, MD, USA

Robert Weinstein, MDProfessor, Departments of Medicine and Pathology, andChief, Division of Transfusion Medicine, University ofMassachusetts Medical School; and UMass MemorialMedical Center, Worcester, MA, USA

Connie M. Westhoff, SBB, PhDDirector, Laboratory of Immunohematology andGenomics, New York Blood Center, New YorkNY, USA

Johanna C. Wiersum-Osselton,PhDTRIP National Hemovigilance and Biovigilance OfficeLeiden, The Netherlands

Elise WilcoxStudent, Department of Biomedical EngineeringYale University; Department of AnesthesiologyYale University School of Medicine, New Haven, CTUSA

Michael Wilson, PhDSenior Director, Molecular Biology, CSL BehringBroadmeadows, VIC, Australia

Jeffrey L. Winters, MDMedical Director, Therapeutic Apheresis TreatmentUnit, Mayo Clinic, Rochester, MN, USA

Steven E. Wolf, MDProfessor of Surgery and Chairman for ResearchDepartment of Surgery, Division of Burn/Trauma/Critical Care, University of Texas Southwestern MedicalCenter, Dallas, TX, USA

Gary M. Woods, MDAssistant Professor, Department of PediatricsEastern Virginia Medical School, Division of PediatricHematology/Oncology, Children’s Hospital of theKing’s Daughters, Norfolk VA, USA

Mark H. Yazer, MDProfessor of Pathology, University of PittsburghAssociate Medical Director, Centralized TransfusionService, Institute for Transfusion MedicinePittsburgh, PA, USA

Preface

After an interval of six years, we have again focused on the task ofupdating Rossi’s Principles of Transfusion Medicine in order tosupport the continually evolving disciplines of transfusion medi­cine, blood banking, and cellular therapies. Many of the trends weidentified and covered in the last edition have continued to evolve.More extensive use of molecular techniques, increased focus onhemovigilance and donor vigilance, continued maturation of path­ogen inactivation technologies, and advances in cellular therapy arebut some examples. Many controversies remain, such as the impactof red cell storage on patient well-being and the best approach tofollow for the treatment of severe bleeding, particularly in the acutetrauma setting.As before, we welcome back authors from the prior editions as

well as introduce new authors to strategically deal with changes inthe field, including as a new editor Dr. Jeffrey McCullough. Keepingabreast of changing technology in publishing, we have provided aweb connection for all purchasers of the book—both the print andelectronic editions. To keep the size of the book manageable, the fulllist of numbered references is available on the web. Additionally,after each chapter, authors have provided a short list of majorreviews or key articles.We have made one significant organizational change. We

removed the section at the end that was called “Delivery ofTransfusion and Transplantation Services.” Instead, the first sectionof the book is titled “Contemporary issues in donation andtransfusion.” After the historical perspective, a new chapter onpatient blood management explores in greater detail than beforewhat has been arguably the most transformative movement in thefield since the last edition. Teaching the responsible and cautioususe of blood components has long been a major part of the role ofthe transfusion medicine expert. But, somehow in the last five years,the message has resonated as never before and the resulting declinein blood utilization has revolutionized the business model ofcommunity and national blood programs as well as reduced dra­matically the frequency of blood shortages in the developed world.Recruitment techniques have been refined so that the right numberof donors for the right component with the right blood type at theright time has become more important than total numbers. Ofcourse, we do need to remember that the situation in countries withunderdeveloped economies is much different. There, the lack ofadequate quantities of safe blood components and transfusionservices for lifesaving needs is still all too common.In this same section, there is a new chapter on the technical

aspects of transfusion as well as an updated chapter on collectionof blood. In consideration of the increased attention focused onboth preventing the acute problem of loss of consciousness after

donation and the chronic problem of iron depletion in red celldonors, a new separate chapter on adverse effects of donation hasbeen added. Chapters on hemovigilance and donor vigilance andregulatory oversight complete the section. The latter chapter com­bines material from several chapters in the prior edition coveringquality and regulation from both the manufacturing and hospitalperspectives on a global basis.In the second section on transfusion medicine practice, new

data on blood components are added and the restrictive use of redcells is further documented. In addition, the chapters on plasmaare expanded given the growth in use of plasma derivatives—atrend opposite to the declining use of most cellular components.The third section on apheresis, transplantation, and new thera­pies has been expanded to keep up with increased activity,particularly in cell and gene therapy. Section IV is devoted tospecialized clinical practice, with coverage of the new approachesto treatment of trauma and massive bleeding. The last sectioncovers the hazards of transfusion. As the “big three” viruses(hepatitis B and C and HIV) have come under better control,that material has been placed in one chapter. A new chapter ontesting for pathogens complements an expanded chapter onpathogen reduction to highlight approaches to containing infec­tious threats. The book concludes with chapters on non-infec­tious hazards of transfusion.Our publisher, Wiley-Blackwell, was able to provide full support

for the coordination and production of this edition. We appreciateall of their efforts, which they have provided efficiently and withhigh quality.As we publish the fifth edition, we simultaneously celebrate both

the continuity in the field and the new developments and once againemphasize the teamwork of the transfusion medicine professionalsat all levels, including medical specialists in all fields who utilizetransfusion medicine, technologists, administrators, nurses, anddonors. We hope that a new upcoming generation of transfusionmedicine specialists will carry on its proud traditions and bringabout exciting innovation.Most importantly, it is our ability to provide help to the patient—

who, as the recipient of transfusion medicine products and services,is better able to extend his or her life, improve the quality of that life,or both—that constantly motivates us to move the field forwardthroughout the world.We, as an editorial group, recognize the contribution of our

invaluable authors and thank our families, colleagues, employers,teachers, and students for their understanding and support duringthe intense period of time needed for preparation and execution ofthis, the fifth edition of Rossi’s Principles of Transfusion Medicine.

xi

List of abbreviations

2-ME 2-mercaptoethanol2RBC double red cell collectionAA aplastic anemiaAABB (Not spelled out; originally founded as the

American Association of Blood Banks)AAP American Academy of PediatricsaAPC artificial antigen presenting cellAAV adeno-associated virusAb antibodyABC America’s Blood CentersABLE Age of Blood Evaluation (trial)ABT allogeneic blood transfusionACCP American College of Chest PhysiciansACD acid–citrate–dextroseACE angiotensin-converting enzymeACEI angiotensin-converting enzyme inhibitorACh acetylcholineAChR acetylcholine receptor moleculeACI anemia of chronic inflammationACOG American College of Obstetricians and

GynecologistsADCC antibody-dependent cellular cytotoxicityADF actin depolymerizing factorADP adenosine diphosphateADSC adipose-derived stem cellAFSA American Society for ApheresisAGM aortogonadomesonephrosAHF antihemophilic factorAHG antihuman globulinAHRQ Agency for Healthcare Research and QualityAHSP alpha-hemoglobin stabilizing proteinaHUS atypical hemolytic uremic syndromeAIDS acquired immune deficiency syndromeAIHA autoimmune hemolytic anemiaAIS absent iron storesALAS2 5-aminolevulinic acid synthaseALCL anaplastic large-cell lymphomaALK anterior lamellar keratoplastyALL acute lymphoblastic leukemiaALT alanine aminotransferaseAMKL acute megakaryoblastic leukemiaAML acute myelogenous leukemiaAMP adenosine monophosphateAMR Ashwell–Morell receptorANC absolute neutrophil countANCA anti-neutrophil cytoplasmic antibodyANH acute normovolemic hemodilutionAPC antigen-presenting cellAPI alpha1-proteinase inhibitor

aPCC activated prothrombin complex concentrateAPS antiphospholipid antibody syndromeaPTT activated partial thromboplastin timeARDS acute respiratory distress syndromeARITI Age of Red Blood Cell in Premature InfantsASP antibody specificity predictionASRI American Society for Reproductive

ImmunologyAtf4 activating transcription factor-4ATG antithymocyte globulinATP adenosine triphosphateAUC area under the ROC curveAvWS acquired von Willebrand syndromeBAGP bicarbonate, adenine, glucose, and phosphateB-ALL B-cell acute lymphoblastic leukemiaBART Blood Conservation Using Antifibrinolytics

in a Randomized TrialBasoEB basophilic erythroblastB-CAM basal cell adhesion moleculeBDD B-domain-deletedBECS blood establishment computer softwareBFU-E(s) burst-forming unit(s)-erythroidBFU-MK MK burst-forming unitBiKE bispecific killer engagerBMD Becker muscular dystrophyBMP bone morphogenetic proteinBMSC bone marrow stem cellBNP B-type natriuretic peptideBOS bronchiolitis obliterans syndromeBRN Blood Regulators NetworkBSA body surface areaBSS Bernard Soulier syndromeBTHC butyryl-tri-hexyl citrateBVDV bovine viral diarrhea virusCABG coronary artery bypass graftCAD cold agglutinin diseaseCAEV arthritis-encephalitis virus of goatsCAFC cobblestone area-forming cellCAP College of American PathologistsCAR CXCL12 abundant reticular (cell)CARS compensatory anti-inflammatory response

syndromeCAR-T cell T cell expressing a chimeric antigen receptorCBC complete blood countCBER Center for Biologics Evaluation and

ResearchCCAD Central Cardiac Audit DatabaseCCI corrected count incrementCCPD complement control protein domain

xiii

xiv List of abbreviations

CDA congenital dyserythropoietic anemiaCDC Centers for Disease Control and PreventionCDER Center for Drug Evaluation and ResearchCDR complementarity-determining regionCDRH Center for Devices and Radiologic HealthCD–P–TS European Committee on Blood TransfusionCDSS clinical decision support softwarecffDNA cell-free fetal DNACFR US Code of Federal RegulationsCFU-GM progenitor cells with the capacity to generate

neutrophils in vitroCGD chronic granulomatous diseasecGMP current good manufacturing practiceCH2-THF methylenetetrahydrofolateCH3-THF methyltetrahydrofolateCHCM cell hemoglobin concentration meanChLIA chemiluminescent immunoassayCHMP Committee for Medicinal Products for

Human UseCHO-THF formyltetrahydrofolateCHr cellular hemoglobin in reticulocytesCI confidence intervalCIBMTR Center for International Blood and Marrow

Transplant ResearchCIDP chronic inflammatory demyelinating

polyneuropathyCJD Creutzfeldt–Jakob diseaseCLET cultured limbal epithelial transplantationCLIA Clinical Laboratory Improvement

AmendmentsCM carboxymethylCML chronic myelogenous leukemiaCMP common myeloid precursorCMS Centers for Medicare and Medicaid ServicesCMV cytomegalovirusCNS central nervous systemCOBLT Cord Blood Transplant (study)COM All Common ChecklistCPB cardiopulmonary bypassCPD citrate–phosphate–dextroseCPDA citrate–phosphate–dextrose–adenineCPOE computerized physician order entryCPSI Canadian Patient Safety InstituteCRASH-2 Clinical Randomization of an Antifibrino­

lytic in Significant Hemorrhage trialCREG cross-reactive groupCRM cross-reactive materialCRISPR clustered regularly interspaced short palin­

dromic repeatCRPS II chronic regional pain syndrome type 2CSA cyclosporineCSF circulating steel factorCTA cancer-testis antigenCTL cytotoxic T-cellCVAD central venous access deviceCXCL12 stromal-cell derived factor 1DAF decay accelerating factorDARC Duffy antigen receptor for chemokinesDART Danish Registration of Transfusion

AccidentsDAT direct antiglobulin test

DBADCDCASGPRDDAVPDEADEAEDEHPDFPPDFSDDHFDHFRDHStDICDITPDMDDMSdsDNAdsRNADTTDVTEACAEBAEBIECBS

ECMECPEDQM

EDTAEFICEIAELISAEMPEPOEPO-αEPO-REEAEIAEIAVELISAEMAERMAPESCETEUEUHASSEVAEXMFACT

FADHFASTFBSFCRFcRnFDAFDAAAA

FDAMA

Diamond–Blackfan anemiadendritic celldendritic cell asialoglycoprotein receptordesmopressin acetatediethyleneaminedietlylaminoethyldiethylhexyl phthalatedouble-membrane filtration plasmapheresisdry fibrin sealant dressingdihydrofolatedihydrofolate reductasedehydrated stomatocytosisdisseminated intravascular coagulationdrug-induced immune thrombocytopeniaDuchenne muscular dystrophydemarcation membrane systemdouble-stranded DNAdouble-stranded RNAdithiothreitoldeep vein thrombosisε-aminocaproic acidEuropean Blood Allianceerythroblastic islandExpert Committee on BiologicalStandardizationextracellular matrixextracorporeal photopheresisEuropean Directorate for the Quality ofMedicinesethylenediaminetetraacetic acidexception from informed consentenzyme immunoassayenzyme-linked immunosorbent assayerythroblast–macrophage proteinerythropoietinerythropoietin alphaerythropoietin receptorEuropean Economic Areaenzyme immunoassayinfectious anemia virus of horsesenzyme-linked immunosorbent assayEuropean Medicines Agencyerythrocyte membrane-associated proteinembryonic stem cellessential thrombocythemiaEuropean UnionEuropean Hemophilia Safety Surveillanceethylene vinyl acetateelectronic crossmatchFoundation for the Accreditation of CellularTherapyreduced flavin adenine dinucleotidefocused ultrasonographic survey for traumafetal blood samplingfraction of cells remainingneonatal Fc receptorUS Food and Drug AdministrationFood and Drug Administration Amend­ments ActFood and Drug Administration Moderniza­tion Act

List of abbreviations xv

FDA cGMP US Food and Drug Administration currentgood manufacturing practice

FDASIA Food and Drug Administration Safety andInnovation Act

FDC follicular dendritic cellFDP fibrin degradation productFEIBA factor VIII inhibitory bypass activityFEP free erythrocyte protoporphyrinFFP fresh frozen plasmaFGS focal glomerulosclerosisFH familial hypercholesterolemiaFLAER fluorescent aerolysinFNAIT fetal/neonatal alloimmune

thrombocytopeniaFNHTR febrile nonhemolytic transfusion reactionFT/RA first-time and reactivated (donors)G6PD glucose-6-phosphate dehydrogenaseGABA γ-amino butyric acidGAD-65 65-kD isoform of glutamic acid

decarboxylaseGAG glycoslyaminoglycanGBM glomerular basement membraneG-CSF granulocyte colony-stimulating factorGDP guanosine diphosphateGEN Laboratory General ChecklistGI gastrointestinalGLUT1 glucose transporter 1GM-CSF granulocyte macrophage colony-stimulating

factorGMP good manufacturing practiceGP glycoproteinGPA glycophorin AGPB glycophorin BGPI glycosylphosphatidylinositolGPS Goodpasture syndromeGRADE Grading of Recommendations Assessment,

Development and EvaluationGSH glutathioneGSL glycospingolipidGSS Gerstmann–Sträusler–Scheinker (disease)GTP guanosine triphosphateGTX granulocyte transfusionGVHD graft-versus-host diseaseGVL graft-versus-leukemiaGWA genome-wide associationHA hydroxyapatiteHAM (test) (Not an abbreviation; named after its

creator, Thomas Ham)HBc hepatitis B core (antigen)HBcAg hepatitis B core antigenHBeAg hepatitis B e antigenHBSAg hepatitis B virus surface antigenHBV hepatitis B virusHCEC human corneal endothelial cellHCT hematopoietic cell transplantHCT/P human cells, tissues, and cellular and tissue-

based productHCV hepatitis C virusHDL high-density lipoproteinHDFN hemolytic disease of the fetus and newbornHDV hepatitis D virus

HEHELLP

HEShESCHEVHFMEAHHHHVHIFHIPAHITHIVHIV-1HIV-2HLAHMWHO1HPCHRIHSCHSCTHSVHTAHTLV-IHTLV-IIHTRHUS%HYPOm

%HYPOrIATIBCTIBRICAM4ICH

ICHICUIDAIDEIDSAIDTIFATIFNIGF1IgGIgSFIHNILINDiNKTIPDINRIPFA

iPSCIPSSIQPPIREIRP

hereditary elliptocytosissyndrome of hemolysis, elevated liverenzymes, and low platelet counthydroxyethyl starchhuman embryonic stem cellhepatitis E virusHealthcare FailureMode and Effect Analysishereditary hemochromatosishuman herpesvirushypoxia-inducible transcription factorheparin-induced platelet activation assayheparin-induced thrombocytopeniahuman immunodeficiency virushuman immunodeficiency virus type 1human immunodeficiency virus type 2human leukocyte antigenhigh molecular weightheme oxygenase-1hematopoietic progenitor cellheme-regulated inhibitorhematopoietic stem cellhematopoietic stem cell transfusionherpes simplex virushealth technology assessmenthuman T-cell lymphotropic virus, type Ihuman T-cell lymphotropic virus, type IIhemolytic transfusion reactionhemolytic uremic syndromepercentage of hypochromic mature redblood cellspercentage of hypochromic red blood cellsindirect antiglobulin testingincorrect blood component transfusedintraoperative blood recoveryinterstitial cell adhesion molecule-4International Conference on Harmoniza­tion (of Technical Requirements)intracranial hemorrhageintensive care unitiron-deficiency anemiairon-deficient erythropoiesisInfectious Disease Society of Americaindividual testingimmunofluorescent antibody testinterferoninsulin-like growth factor-1immunoglobulin Gimmunoglobulin superfamilyInternational Hemovigilance Networkinterleukininvestigational new druginvariant natural killer T cellindividual-patient datainternational normalized ratioInternational Plasma FractionationAssociationinduced pluripotent stem cellInternational Prognostic Scoring SystemInternational Quality Plasma Programiron-responsive elementiron regulatory protein

xvi List of abbreviations

ISBT International Society of Blood TransfusionISTARE International Surveillance Database for

Transfusion Adverse Reactions and EventsISTH International Society on Thrombosis and

HemostasisIT information technologyITI immune tolerance inductionITP immune thrombocytopenic purpuraIV intravenousIVD in vitro diagnosticIVIG intravenous immunoglobulinJAK2 Janus tyrosine kinase-2KIR killer immunoglobulin-like receptorKLF1 Krüppel-like factor-1LAK lymphokine-activated killerLCL lymphoblastoid lineLCR locus control regionLCT lymphocytotoxicityLDL low-density lipoproteinLEMS Lambert–Eaton myasthenic syndromeLESC limbal epithelial stem cellLGL large granular lymphocyteLHR long homologous repeatLIC liver iron concentrationLISS low-ionic-strength salineLMAN lectin mannose bindingLMW low molecular weightLR leukocyte-reduced or leukoreductionLSC limbal stem cellMAG myelin-associated glycoproteinMAHA microangiopathic hemolytic anemiaMAIPA monoclonal antibody-specific

immobilization of platelet antigensMAP mean arterial pressureMAPK mitogen-activated protein kinaseMART melanoma antigen recognized by T cellsMBP myelin basic proteinMCFD multiple coagulation factor deficiency geneMCH mean cell hemoglobinMCHC mean corpuscular hemoglobin

concentrationMCP macrophage chemoattractant proteinMCV mean corpuscular volumeMDS myelodysplastic syndromeMEP megakaryocytic-erythroid progenitorMGSA melanocyte growth-stimulating activityMGUS monoclonal gammopathy of undetermined

significanceMHC major histocompatibility complexMIRL membrane inhibitor of reactive lysisMK megakaryocyteMMP matrix metalloproteinaseMODS multiple-organ dysfunction syndromeMOF multiple-organ failureMOG myelin oligodendrocyte glycoproteinMPP multipotent progenitorMPV mean platelet volumeMRI magnetic resonance imagingMSC mesenchymal stem (or stromal) cellMTP massive transfusion protocolMTX methotrexate

NAATNADNADHNADP

NAITNAPTTNATNATA

NBCUS

NCANCINETNHLBINIBSC

NICUNIHNODNPONSAIDNTBINYHAOBIOBRROCSOHIOHStOMCLOROrthoEBPAI-1PAIgGPANDAS

PASPASSPORT

PBMPBMCPBPCPBRPBSCPCPCAM

PCCPCHPCLPCPPCRPDMPPEGPEG-rHuMGDF

PEIPFPF24

nucleic acid amplification testingnicotinamide adenine dinucleotidereduced nicotinamide adenine dinucleotidenicotinamide adenine dinucleotidephosphateneonatal alloimmune thrombocytopenianon-activated partial thromboplastin timenucleic acid testingNetwork for Advancement of TransfusionAlternatives(AABB) National Blood Collection and Uti­lization Surveynational competent authorityNational Cancer Instituteneutrophil extracellular trapNational Heart, Lung, and Blood InstituteNational Institute of Biological Standardsand Controlneonatal intensive care unitNational Institutes of Healthnon-obese diabeticnil per osnonsteroidal anti-inflammatory drugnon-transferrin-bound ironNew York Heart Associationoccult hepatitis B infectionOffice of Blood Research and Reviewopen canalicular systemoccult hepatitis infectionoverhydrated stomatocytosisOfficial Medicines Control Laboratoryodds ratioorthochromatic erythroblastplasminogen activator inhibitor type 1platelet-associated IgGpediatric autoimmune neuropsychiatric dis­orders associated with streptococcalinfectionsplatelet additive solutionPost Approval Surveillance Study of PlateletOutcomes, Release Tested (protocol)patient blood managementperipheral blood mononuclear cellperipheral blood progenitor cellpostoperative blood recoveryperipheral blood stem cellplatelet concentrateplatelet-endothelial cell adhesion molecule­1prothrombin complex concentrateparoxysmal cold hemoglobinuriapolycaprolactonePneumocystis cariniipolymerase chain reactionplasma-derived medicinal productpolyethylene glycolpegylated recombinant human megakaryocyte growth and development factorPaul Ehrlich Instituteplatelet factor24-hour frozen plasma

List of abbreviations xvii

PFA-100 platelet function analyzer 100PfEMP Plasmodium falciparum erythrocyte mem­

brane proteinPGA polyglycolic acidPhEur European PharmacopeiaPHSA Public Health Service ActPICC peripherally inserted central catheterPIC/S Pharmaceutical Inspection Co-operation

Scheme and Pharmaceutical InspectionConvention

PIG-A phosphatidylinosital glycan class APIVKA proteins induced in vitamin K absence or

antagonismPK penetrating keratoplastyPKD pyruvate kinase deficiencyPLA polylactic acidPLADO Optimal Platelet Dose Strategy to Prevent

Bleeding in Thrombocytopenia PatientsPLGA polylactic-co-glycolic acidPMMA polymethylmethacrylatePMN neutrophilPNH paroxysmal nocturnal hemoglobinuriaPNM polymorphonuclearPOEMS polyneuropathy, organomegaly, endocrin­

opathy, monoclonal protein, and skinchanges (syndrome)

POISE Perioperative Ischemic Evaluation (trial)PolyEB polychromatophilic erythroblastPPH postpartum hemorrhagePPi pyrophosphatePPTA Plasma Protein Therapeutics AssociationPRA panel-reactive antibodyPRAC Pharmacovigilance Risk Assessment

CommitteeProEB pro-erythroblastPRP platelet-rich plasmaPRPP phosphoribosyl pyrophosphatePRV pseudorabies virusPS phosphatidylserinePSA prostate-specific antigenPSGL1 platelet sialoglycoprotein ligand-1PSO patient safety organizationPT prothrombin timePTFE polytetrafluoroethylenePTLD posttransplant lymphoproliferative diseasePTP posttransfusion purpuraPTR platelet transfusion refractorinessPT/PTT prothrombin time and partial thromboplas­

tin timePUP previously untreated patientPVC polyvinyl chloridepVHL von Hippel–Lindau proteinQA quality assuranceQAE quaternary amino ethylQALY quality-adjusted life yearQC quality controlRA rheumatoid arthritisRANTES regulated on activation, normal T-cell

expressed and secretedRBC red blood cellRBC(s), LR red blood cell(s), leukocytes reduced

RBM15RCAS1

RECESSREFRFLPRhAGRhIGRING

RIPARIRRISERLSROCROSRPRSVSAASABM

SAGSAG-MSCDSCFscFvSCLSCNsc-TPAsc-UPA

S/DSDS-PAGE

serpinSIRSSLESMCSNPSoGAT

SOPSPSPRCASPSSQUID

SRASRFssDNASSOPH

ssRNASTAT5

sTfRTACOTAD

RNA binding motif protein 15receptor-binding cancer antigen expressedon SiSo cellsRed Cell Duration Studyfebrile nonhemolytic transfusion reactionrestriction fragment length polymorphismRh-associated glycoproteinRh immune globulinSafety and Effectiveness of GranulocyteTransfusion in Resolving Infection in Peoplewith Neutropenia (study)radioimmunoprecipitation assayreplication-incompetent retrovirusREDS-II Donor Iron Status Evaluationreporting and learning systemsreceiver operating characteristicreactive oxygen speciesreticulated plateletrespiratory syncytial virussevere aplastic anemiaSociety for the Advancement of BloodManagementsaline, adenine, and glucosesaline, adenine, glucose, and mannitolsickle cell diseasestem cell factorsingle-chain variable fragmentstem cell leukemiasevere congenital neutropeniasingle-chain tissue plasminogen activatorsingle-chain urokinase plasminogenactivatorsolvent and detergent (or solvent–detergent)sodium dodecyl sulfate–polyacrylamide gelelectrophoresisserine protease inhibitorsystemic inflammatory response syndromesystemic lupus erythematosussmooth muscle cellsingle nucleotide polymorphismInternational Working Group on theStandardization of Genomic AmplificationTechniques for the Virological SafetyTesting of Blood and Blood Productsstandard operating proceduresulfopropylsolid-phase red cell adherencestiff-person syndromesuperconducting quantum interferencedeviceserotonin release assayserum response factorsingle-stranded DNAsequence-specific oligonucleotide probehybridizationsingle-stranded RNAsignal transduction and activator of tran­scription-5soluble transferrin receptortransfusion-associated circulatory overloadtransfusion-associated dyspnea

xviii List of abbreviations

TAFI thrombin-activatable fibrinolysis inhibitorTA-GVHD transfusion-associated graft-versus-host

diseaseTALENS transcription activator–like effector

nucleasesTA-MC transfusion-associated microchimerismTAMMv timed average mean maximum velocityTAPS twin anemia–polycythemia sequenceTCD transcranial DopplerTCP tricalcium phosphatetc-TPA two-chain tissue plasminogen activatortc-UPA two-chain urokinase plasminogen activatorTEE thromboembolic eventTEG thromboelastographyTEVG tissue-engineered vascular graftTFPI tissue factor pathway inhibitorTGA thrombin generation assayTh T helper (cell)THA total hip arthroplastyTHF tetrahydrofolateTI tincture of iodineTIL tumor-infiltrating lymphocyteTLR toll-like receptorTM thalassemia majorTMA thrombotic microangiopathyTMAA thrombotic micro-angiopathic anemiaTNC total nucleated cell countTNF tumor necrosis factorTNF-α tumor necrosis factor alphaTOP Transfusion of PrematuresTOTM triethyl hexyl trimellitatetPA tissue plasminogen activatorTPMT thiopurine methyltransferaseTPO thrombopoietinTRAIL TNF-related apoptosis-inducing ligandTRALI transfusion-related acute lung injuryTRAP Trial to Reduce Alloimmunization

to Platelets

TRICCTRICKTRIMTRSTSOTTTTITTPTTTSTWEAKTXAUDHQULRUTRVATSVCAM1vCJDVEGFVEGFRVGKCVKAVLBWVLDLVMVVWDWAIHAWASWBCWBDWBITWCCWFHWHIM (syndrome)

WHOZFNZnPP

Transfusion Requirements in Critical Caretransfusion-related inhibition of cytokinestransfusion-related immunomodulation(WHO) Technical Report SeriesTransfusion Safety Officethrombin timetransfusion-transmissible infectionthrombotic thrombocytopenic purpuratwin-to-twin transfusion syndromeTNF-like weak inducer of apoptosistranexamic acidUniform Donor History Questionnaireuniversal leukocyte reductionuntranslated regionViral Activation by Transfusion Studyvascular cell adhesion molecule 1variant Creutzfeldt–Jakob diseasevascular endothelial growth factorvascular endothelial growth factor receptorvoltage-gated potassium channelvitamin K antagonistvery-low-birthweightvery-low-density lipoproteinvisna-maedi virus of sheepvon Willebrand diseasewarm-type autoimmune hemolytic anemiaWiskott–Aldrich syndromewhite blood cellwhole blood derivedwrong blood in tubeWHO Collaborating CenterWorld Federation of Hemophiliawarts, hypogammaglobulinemia, infections,and myelokathexisWorld Health Organizationzinc finger nucleasezinc protoporphyrin

About the companion website

This book has a companion website:

www.wiley.com/go/simon/transfusion

The website features the figures from the book, the full text of the book, and all references.

The password for the website is the first word of Chapter 2. Please use all lowercase.

xix

CHAPTER 1

Transfusion in the new millennium

Ennio C. Rossi1 & Toby L. Simon2

1Northwestern University School of Medicine, Chicago, IL, USA2Plasma Product Development and CSL Plasma, CSL Behring, King of Prussia, PA; and Department of Pathology, University of New Mexico School of Medicine,Albuquerque, NM, USA

Prehistoric man left drawings of himself pierced by arrows.1 Thismeans he was as aware of blood as he was of his own limbs. The flintimplements he used as tools and weapons distinguished him fromother creatures and contributed to the violence of his era. As hehunted food and fought enemies, he observed bleeding and theproperties of blood. A cut, received or inflicted, yielded a vivid redcolor. If the cut was shallow, there was little blood. But if the cut wasdeep, a red torrent flowing from the stricken victim quickly led todeath, with shed blood congealed and darkening in the sun. Fatalhemorrhage was commonplace. Nonetheless, the sight must havebeen fearful and possibly existential as life flowed red out of thebody of an enemy or a wounded animal.2 It is no wonder, then, thatat the dawn of recorded history, blood was already celebrated inreligious rites and rituals as a life-giving force.The cultural expressions of primitive and ancient societies,

although separated by time or space, can be strikingly similar.Whether these expressions emerged independently or were diffusedabout the world by unknown voyagers will probably always remainclouded in mystery.2 Nonetheless, there is a common thread in theancient rituals that celebrate blood as a mystical vital principle. InLeviticus 17:11, “the life of the flesh is in the blood,” and the ChineseNeiching (ca. 1000 BC) claims the blood contains the soul.2 Pre-Columbian North American Indians bled their bodies “of its great­est power” as self-punishment,3 Egyptians took blood baths as arecuperative measure, and Romans drank the blood of fallengladiators in an effort to cure epilepsy.4 The Romans also practiceda ceremony called taurobolium—a blood bath for spiritual restora­tion. A citizen seeking spiritual rebirth descended into a pit, or fossasanguinis. Above him on a platform, a priest sacrificed a bull, andthe animal’s blood cascaded down in a shower upon the beneficiary.Then, in a powerful visual image, the subject emerged up from theother end of the pit, covered with blood and reborn.1

The legend of Medea and Aeson taken from Ovid’s Metamor­phoses and quoted in Bulfinch’s Mythology 5 also ascribed rejuve­nating powers to blood. Jason asked Medea to “take some years offhis life and add them to those of his father Aeson.”Medea, however,pursued an alternative course. She prepared a cauldron with theblood of a sacrificed black sheep. To this, she added magic herbs,hoarfrost gathered by moonlight, the entrails of a wolf, and manyother things “without a name.” The boiling cauldron was stirredwith a withered olive branch, which became green and full of leavesand young olives when it was withdrawn. Seeing that all was ready,

Medea cut the throat of the old man and let out all his blood, and pouredinto his mouth and into his wound the juices of her cauldron. As soon ashe had imbibed them, his hair and beard laid by their whiteness andassumed the blackness of youth; his paleness and emaciation were gone;his veins were full of blood, his limbs of vigour and robustness. Aeson isamazed at himself and remembers that such as he now is, he was in hisyouthful days, 40 years before.

This legend seems to echo the apocryphal story of Pope InnocentVIII, who is said to have received the blood of three young boys in1492 while on his deathbed. As the story goes, a physician attemptedto save the pope’s life by using blood drawn from three boys 10 yearsof age, all of whom died soon thereafter. Some 19th-centuryversions of this tale suggest the blood was transfused. However,earlier renditions more plausibly suggest that the blood wasintended for a potion to be taken by mouth. In any event, thereis no evidence the pope actually received any blood in any form.6,7

The folklore that flowed with blood was not accompanied by agreat deal of accurate information. The ancient Greeks believed thatblood formed in the heart and passed through the veins to the rest ofthe body, where it was consumed. Arteries were part of an inde­pendent system transporting air from the lungs. Although Erasis­tratos (circa 270 BC) had imagined the heart as a pump, his idea wasahead of its time. As long as veins and arteries were dead-endchannels transporting blood and air, there was little need for apump in the system. Although Galen (131–201 AD) finally provedthat arteries contain blood, communication with the venous systemwas not suspected. Blood, formed in the liver, merely passedthrough the blood vessels and heart on its way to the periphery.1

These teachings remained in place for 1400 years until they wereswept away in 1628 by Harvey’s discovery of the circulation.The realization that blood moved in a circulating stream opened

the way to experiments on vascular infusion. In 1642, George vonWahrendorff injected wine8—and, in 1656, Christopher Wren andRobert Boyle injected opium and other drugs9— intravenously intodogs. The latter studies, performed at Oxford, were the inspirationfor Richard Lower’s experiments in animal transfusion.

The first animal transfusionRichard Lower (1631–1691) was a student at Oxford when Chris­topherWren and Robert Boyle began their experiments on infusion.In due course, Lower joined their scientific group and studied the

Rossi’s Principles of Transfusion Medicine, Fifth Edition. Edited by Toby L. Simon, Jeffrey McCullough, Edward L. Snyder, Bjarte G. Solheim, andRonald G. Strauss.© 2016 John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd.

1

2 Chapter 1: Transfusion in the new millennium

intravenous injection of opiates, emetics, and other substances intoliving animals.10 In time, the transfusion of blood itself became theobjective. The announcement of the first successful transfusion,performed by Richard Lower at Oxford in February 1665, waspublished on November 19, 1666, in the Philosophical Transactionsof the Royal Society in a short notation titled, “The Success of theExperiment of Transfusing the Blood of One Animal intoAnother.”11 The entire notation is as follows:11

This experiment, hitherto look’d upon to be of an almostinsurmountable difficulty, hath been of late very successfully perform’dnot only at Oxford, by the directions of that expert anatomist Dr. Lower,but also in London, by order of the R. Society, at their publick meeting inGresham Colledge: the Description of the particulars whereof, and theMethod of Operation is referred to the next opportunity.

The December 17, 1666, issue of the Transactions contained thefull description as promised.12 It was taken from a letter13 written byLower to Robert Boyle on July 6, 1666, in which Lower describeddirect transfusion from the carotid artery of one dog to the jugularvein of another. After describing the insertion of quills into theblood vessels of the donor and recipient dogs, Lower wrote:13

When you have done this you may lay the dogs on their side and fastenthem densely together as best you may to insure the connection of thetwo quills. Quickly tighten the noose around the neck of the receivinganimal as in venasection, or at all events compress the vein on theopposite side of the neck with your finger, then take out the stopperand open the upper jugular quill so that while the foreign blood isflowing into the lower quill, the animal’s own blood flows out from theupper into suitable receptacles—until at last the second animal, amidhowls, faintings, and spasms, finally loses its life together with its vitalfluid.

When the tragedy is over, take both quills out of the jugular vein of thesurviving animal, tie tightly with the former slipknots, and divide thevein. After the vessel has been divided, sew up the skin, slacken the cordsbinding the dog, and let it jump down from the table. It shakes itself alittle, as though aroused from sleep, and runs away lively and strong,more active and vigorous perhaps, with the blood of its fellow than itsown.

These studies inevitably led to the transfusion of animal blood tohumans. In England, this occurred on November 23, 1667, whenLower and Edmund King transfused sheep blood into a man namedArthur Coga.14 Described by Samuel Pepys as “a little frantic,” Cogawas paid 20 shillings to accept this transfusion, with the expectationthat it might have a beneficial “cooling” effect. One week later, Cogaappeared before the Society and claimed to be a new man, althoughPepys concluded he was “cracked a little in the head.”13 However,this was not the first transfusion performed in a human. The creditfor that accomplishment belongs to Jean-Baptiste Denis(1635–1704), who had performed the first human transfusionseveral months earlier in Paris.

The first animal-to-human transfusionThe founding of the Royal Society in London in 1662 was followedin 1666 by the establishment of the Academie des Sciences in Parisunder the patronage of King Louis XIV. The new Academiereviewed the English reports on transfusion with great interest.Denis probably read of Lower’s experiments in the Journal desSavants on January 31, 1667, and he began his own studiesapproximately one month later.15,16 The first human transfusionwas then performed on June 15, 1667, when Denis administered theblood of a lamb to a 15-year-old boy (Figure 1.1).

Figure 1.1 The first human transfusion. Source: Denis (1967). 17

Although discovery of the circulation had suggested the idea oftransfusion, indications for the procedure remained uninformed.Transfusion was still thought to alter behavior and possibly achieverejuvenation. The blood of young dogs made old dogs seem frisky;the blood of lions was proposed as a cure for cowardice; and, fivemonths later, Arthur Coga would receive a transfusion of sheepblood because of its presumed “cooling” effect. Denis used animalblood for transfusion because he thought it was “less full ofimpurities”:17

Sadness, Envy, Anger, Melancholy, Disquiet and generally all thePassions, are as so many causes which trouble the life of man, andcorrupt the whole substance of the blood: Whereas the life of Brutes ismuch more regular, and less subject to all these miseries.

It is thus ironic that the symptoms of the first transfusion recipientmay have been explained in part by profound anemia; the singletransfusion of lamb blood may have produced temporary amelio­ration owing to increased oxygen transport. Denis described thecase as follows:17

On the 15 of this Moneth, we hapned upon a Youth aged between 15 and16 years, who had for above two moneths bin tormented with acontumacious and violent fever, which obliged his Physitians to bleedhim 20 times, in order to asswage the excessive heat.

3Chapter 1: Transfusion in the new millennium

Before this disease, he was not observed to be of a lumpish dullspirit, his memory was happy enough, and he seem’d chearful andnimble enough in body; but since the violence of this fever, his witseem’d wholly sunk, his memory perfectly lost, and his body so heavyand drowsie that he was not fit for anything. I beheld him fall asleep ashe sate at dinner, as he was eating his Breakfast, and in all occurrenceswhere men seem most unlikely to sleep. If he went to bed at nine of theclock in the Evening, he needed to be wakened several times before hecould be got to rise by nine the next morning, and he pass’d the rest ofthe day in an incredible stupidity.

I attributed all these changes to the great evacuations of blood, thePhysitians had been oblig’d to make for saving his life.

Three ounces of the boy’s blood were exchanged for 9 ounces oflamb arterial blood. Several hours later the boy arose, and “for therest of the day, he spent it with muchmore liveliness than ordinary.”Thus the first human transfusion, which was heterologous, wasaccomplished without any evident unfavorable effect.This report stimulated a firestorm of controversy over priority of

discovery.18,19The letterbyDeniswaspublished in theTransactionsonJuly22,1667,while theeditor,HenryOldenburg,was imprisoned in theTower of London. Oldenburg, following some critical commentsconcerning the Anglo-Dutch War then in progress (1665–1667),had been arrested under a warrant issued June 20, 1667. After hisrelease 2 months later, Oldenburg returned to his editorial post andfound the letter published in his absence. He took offense at Denis’sopening statement, which claimed that the French had conceived oftransfusion “about ten years agoe, in the illustrious Society ofVirtuosi”(Figure 1.1). This seemed todeny theEnglish contributions to thefield.Oldenburg cited these omissions in an issue of the Transactionspublished September 23, 1667, “for the Months of July, August, andSeptember.”Bynumbering this issue27andbeginningpaginationwith489, Oldenburg attempted to suppress the letter by Denis.18 However,as is evident, this did not ultimately succeed. Nonetheless, subsequentevents created even greater difficulties for Denis.Although the first two subjects who underwent transfusion by

Denis were not adversely affected, the third and fourth recipientsdied. The death of the third subject was easily attributable to othercauses. However, the fourth case initiated a sequence of events thatput an end to transfusion for 150 years.Anthony du Mauroy was a 34-year-old man who suffered from

intermittent bouts of maniacal behavior. On December 19, 1667,Denis and his assistant Paul Emmerez removed 10 ounces of theman’s blood and replaced it with 5 or 6 ounces of blood from thefemoral artery of a calf. Failing to note any apparent improvement,they repeated the transfusion 2 days later. After the second trans­fusion, du Mauroy experienced a classic transfusion reaction:20

His pulse rose presently, and soon after we observ’d a plentiful sweatover all his face. His pulse varied extremely at this instant, and hecomplain’d of great pains in his kidneys and that he was not well in hisstomach.

Du Mauroy fell asleep at about 10 o’clock in the evening. He awokethe following morning and “made a great glass full of urine, of acolour as black, as if it had been mixed with the soot of chimneys.”20

Two months later, the patient again became maniacal, and his wifeagain sought transfusion therapy. Denis was reluctant but finallygave in to her urgings. However, the transfusion could not beaccomplished, and du Mauroy died the next evening.The physicians of Paris strongly disapproved of the experiments

in transfusion. Three of them approached du Mauroy’s widow andencouraged her to lodge a malpractice complaint against Denis. She

instead went to Denis and attempted to extort money from him inreturn for her silence. Denis refused and filed a complaint before theLieutenant in Criminal Causes. During the subsequent hearing,evidence was introduced to indicate that Madame du Mauroy hadpoisoned her husband with arsenic. In a judgment handed down atthe Chatelet in Paris on April 17, 1668, Denis was exonerated, andthe woman was held for trial. The court also stipulated “that for thefuture no Transfusion should be made upon any Human Body butby the approbation of the Physicians of the Parisian Faculty.”21

At this point, transfusion research went into decline, and within10 years it was prohibited in both France and England.

The beginnings of modern transfusionAfter the edict that ended transfusion in the 17th century, thetechnique lay dormant for 150 years. Stimulated by earlier experi­ments by Leacock, transfusion was “resuscitated” and placed on arational basis by James Blundell (1790–1877), a London obstetricianwho had received his medical degree from the University ofEdinburgh.22 Soon after graduation, Blundell accepted a post inphysiology and midwifery at Guy’s Hospital. It was there that hebegan the experiments on transfusion that led to its rebirth. Thefrequency of postpartum hemorrhage and death troubled Blundell.In 1818, he wrote:23

A fewmonths ago I was requested to visit a womanwhowas sinking underuterine hemorrhage. . . . Her fate was decided, and notwithstanding everyexertion of the medical attendants, she died in the course of two hours.

Reflecting afterwards on this melancholy scene . . . I could notforbear considering, that the patient might very probably have beensaved by transfusion; and that . . . the vessels might have been replen­ished by means of the syringe with facility and prompitude.

This opening statement introduced Blundell’s epoch-making studytitled “Experiments on the Transfusion of Blood by the Syringe”23

(see Figure 1.2). Blundell described in detail a series of animal

Figure 1.2 The beginnings of modern transfusion. Source: Blundell (1818). 23

4 Chapter 1: Transfusion in the new millennium

experiments. He demonstrated that a syringe could be used effec­tively to perform transfusion, that the lethal effects of arterialexsanguination could be reversed by the transfusion of eithervenous or arterial blood, and that the injection of 5 drams(20 cc) of air into the veins of a small dog was not fatal buttransfusion across species ultimately was lethal to the recipient.23

Thus, Blundell was the first to state clearly that only human bloodshould be used for human transfusion. The latter conclusion wasconfirmed in France by Dumas and Prevost, who demonstrated thatthe infusion of heterologous blood into an exsanguinated animalproduced only temporary improvement and was followed by deathwithin 6 days.24 These scientific studies provided the basis forBlundell’s subsequent efforts in clinical transfusion.The first well-documented transfusion with human blood took

place on September 26, 1818.25 The patient was an extremelyemaciated man in his mid-thirties who had pyloric obstructioncaused by carcinoma. He received 12 to 14 ounces of blood in thecourse of 30 or 40 minutes. Despite initial apparent improvement,the patient died two days later. Transfusion in the treatment ofwomen with postpartum hemorrhage was more successful. In all,Blundell performed 10 transfusions, of which five were successful.Three of the unsuccessful transfusions were performed on mori­bund patients, the fourth was performed on a patient with puerperalsepsis, and the fifth was performed on the aforementioned patientwith terminal carcinoma. Four of the successful transfusions weregiven for postpartum hemorrhage, and the fifth was administered toa boy who bled after amputation.22 Blundell also devised variousinstruments for the performance of transfusion. They included an“impellor,” which collected blood in a warmed cup and “impelled”the blood into the recipient via an attached syringe, and a “grav­itator”26 (Figure 1.3), which received blood and delivered it bygravity through a long vertical cannula.The writings of Blundell provided evidence against the use of

animal blood in humans and established rational indications fortransfusion. However, the gravitator (Figure 1.3) graphically dem­onstrated the technical problems that remained to be solved. Bloodfrom the donor, typically the patient’s husband, flowed into afunnel-like device and down a flexible cannula into the patient’svein “with as little exposure as possible to air, cold and inanimatesurface.”25 The amount of blood transfused was estimated from theamount spilled into the apparatus by the donor. In this clinicalatmosphere, charged with apprehension and anxiety, the amount ofblood issuing from a donor easily could be overstated. Clottingwithin the apparatus then ensured that only a portion of that bloodactually reached the patient. Thus, the amount of blood actuallytransfused may have been seriously overestimated. This mayexplain the apparent absence of transfusion reactions. Alternatively,reactions may have been unrecognized. Patients who underwenttransfusion frequently were agonal. As Blundell stated, “It seemsright, as the operation now stands, to confine transfusion to the firstclass of cases only, namely, those in which there seems to be no hopefor the patient, unless blood can be thrown into the veins.”26 Underthese circumstances, “symptoms” associated with an “unsuccessful”transfusion might be ascribed to the agonal state rather than thetransfusion itself. For a time, the problem of coagulation duringtransfusion was circumvented by the use of defibrinated blood. Thisundoubtedly increased the amount of blood actually transfused.However, there were numerous deaths. Interestingly, these deathswere attributed to intravascular coagulation when in actuality theywere probably fatal hemolytic reactions caused by the infusion ofincompatible blood.27

Figure 1.3 Blundell’s gravitator. Source: Blundell (1828). 26

Transfusion at the end of the 19th century, therefore, was neithersafe nor efficient. The following description, written in 1884,illustrates this point:28

Students, with smiling faces, are rapidly leaving the theatre of one of ourmetropolitan hospitals. The most brilliant operator of the day has justperformed immediate transfusion with the greatest success. By means ofa very beautiful instrument, the most complex and ingenious thatmodern science has yet produced, a skilful surgeon has transfusedhalf a pint, or perhaps a pint, of blood from a healthy individual to afellow creature profoundly collapsed from the effects of severe hemor­rhage. Some little difficulty was experienced prior to the operation, asone of the many stop-cocks of the transfusion apparatus was found towork stiffly; but this error was quickly rectified by a mechanic inattendance. Towards the close of the operation the blood-donor, apowerful and heavy young man, swooned. Two porters carried himon a stretcher into an adjoining room.

In the latter half of the 19th century, there were many attempts torender transfusion a more predictable and less arduous procedure.In 1869, Braxton-Hicks,29 using blood anticoagulated with phos­phate solutions, performed a number of transfusions on womenwith obstetric bleeding. Many of the patients were in extremis, andultimately all died. Unfortunately, a detailed description of terminalsymptoms was not provided.29 Some investigators attempted torejuvenate animal-to-human transfusion, and Oscar Hasse per­sisted in this approach despite disastrous results. Studies by Emil

5

Ponfick and by Leonard Landois finally put an end to this practice.Ponfick, in carefully controlled studies, confirmed the lethality ofheterologous transfusion and identified the resulting hemoglobin­uria along with its donor erythrocyte source. Landois documentedthe poor results of animal-to-human transfusion and demonstratedthe lysis of sheep erythrocytes by human serum in vitro.8

Frustration with blood as a transfusion product led to even morebizarre innovations. From 1873 to 1880, cow, goat, and even humanmilk was transfused as a blood substitute.30 The rationale derivedfrom an earlier suggestion that the fat particles of milk could beconverted into blood cells. Milk transfusion was particularly popu­lar in the United States,30 where the practice of animal-to-humantransfusion was recorded as late as 1890.31 Fortunately, theseastonishing practices were discontinued when saline solutionswere introduced as “a life-saving measure” and “a substitute forthe transfusion of blood.”32 A passage from an article written by Bullin 188432 is particularly instructive:

The danger from loss of blood, even to two-thirds of its whole volume,lies in the disturbed relationship between the calibre of the vessels andthe quantity of the blood contained therein, and not in the diminishednumber of red blood-corpuscles; and. . . . This danger concerns thevolume of the injected fluids also, it being a matter of indifferencewhether they be albuminous or containing blood corpuscles or not.

Mercifully, volume replacement with saline solutions deflectedattention from the unpredictable and still dangerous practice ofblood transfusion. Accordingly, transfusions were abandoned untilinterest was rekindled by the scientific and technical advances of theearly 20th century.

The 20th centuryThe 20th centurywas ushered in by a trulymonumental discovery. In1900, Karl Landsteiner (1868–1943) observed that the sera of somepersons agglutinated the red blood cells of others. This study, pub­lished in 1901 in theWiener Klinische Wochenschrift 33 (Figure 1.4),showedfor thefirst time thecellulardifferences in individuals fromthesame species. In his article, Landsteiner wrote:34

In a number of cases (Group A) the serum reacts on the corpuscles ofanother group (B), but not, however, on those of group A, while, again,the corpuscles of A will be influenced likewise by serum B. The serum ofthe third group (C) agglutinates the corpuscles of A and B, while thecorpuscles of C will not be influenced by the sera of A and B. Thecorpuscles are naturally apparently insensitive to the agglutinins whichexist in the same serum.

With the identification of blood groups A, B, and C (subse­quently renamed group O) by Landsteiner and of group AB byDecastello and Sturli,35 the stage was set for the performance of safetransfusion. For this work, Landsteiner somewhat belatedlyreceived the Nobel Prize in 1930. But even that high recognitiondoes not adequately express the true magnitude of Landsteiner’sdiscovery. His work was like a burst of light in a darkened room. He

Figure 1.4 Landsteiner’s description of blood groups. Source: Landsteiner(1901). 33

Chapter 1: Transfusion in the new millennium

gave us our first glimpse of immunohematology and transplantationbiology and provided the tools for important discoveries in genetics,anthropology, and forensic medicine. Viewed from this perspective,the identification of human blood groups is one of only a fewscientific discoveries of the 20th century that changed all of ourlives.34 Yet the translation of Landsteiner’s discovery into transfu­sion practice took many years.At the turn of the 20th century, the effective transfer of blood

from one person to another remained a formidable task. Clotting,still uncontrolled, quickly occluded transfusion devices and frus­trated most efforts. In 1901, the methods used in transfusion weretoo primitive to demonstrate the importance of Landsteiner’sdiscovery. Indeed, the study of in vitro red cell agglutinationmay have seemed rather remote from the technical problemsthat demanded attention. An intermediate step was needed beforethe importance of Landsteiner’s breakthrough could be perceivedand the appropriate changes could be incorporated into practice.This process was initiated by Alexis Carrel (1873–1944), anotherNobel laureate, who developed a surgical procedure that alloweddirect transfusion through an arteriovenous anastomosis.Carrel36 introduced the technique of end-to-end vascular anas­

tomosis with triple-threaded suture material. This procedurebrought the ends of vessels in close apposition and preservedluminal continuity, thus avoiding leakage or thrombosis. Thistechnique paved the way for successful organ transplantationand brought Carrel the Nobel Prize in 1912. It was also adaptedby Carrel37 and others38,39 to the performance of transfusion.Crile38 introduced the use of a metal tube to facilitate placementof sutures, and Bernheim39 used a two-piece cannula to unite theartery to the vein (Figure 1.5). Because all of these proceduresusually culminated in the sacrifice of the two vessels, they were notperformed frequently. Direct transfusion was also fraught withdanger. In a passage written two decades later, the procedurewas recalled in the following manner:40

The direct artery to vein anastomosis was the best method available butwas often very difficult or even unsuccessful. And, what was almost asbad, one never knew howmuch blood one had transfused at anymomentor when to stop (unless the donor collapsed). (I remember one suchcollapse in which the donor almost died—and the surgeon needed to berevived.)

Figure 1.5 Direct transfusion by means of arteriovenous anastomosisthrough the two-pieced cannula of Bernheim. Source: Bernheim (1917). 39

6 Chapter 1: Transfusion in the new millennium

Figure 1.6 Report of a fatal transfusion reaction. Source: Pepper andNisbet (1907). 41

Figure 1.8 Apparatus for Unger’s two-syringe, four-way stopcock methodof indirect transfusion. Source: Unger (1915). 49

Despite these many difficulties, direct transfusion through anarteriovenous anastomosis for the first time efficiently transferredblood from one person to another. The process also disclosed fatalhemolytic reactions that were undeniably caused by transfusion41

(Figure 1.6). However, the relation of these fatal reactions toLandsteiner’s discovery was not recognized until Reuben Ottenberg(1882–1959) demonstrated the importance of compatibility testing.Ottenberg’s interest in transfusion began in 1906 while he was

an intern at German (now Lenox Hill) Hospital in New York.There, Ottenberg learned of Landsteiner’s discovery and in 1907began pretransfusion compatibility testing.42 Ottenberg acceptedan appointment at Mount Sinai Hospital the next year andcontinued his studies on transfusion. In 1913, Ottenberg pub­lished the report that conclusively demonstrated the importanceof preliminary blood testing for the prevention of transfusion“accidents”43 (Figure 1.7). This was not Ottenberg’s only contri­bution. He observed the Mendelian inheritance of blood groups,44

and he was the first to recognize the relative unimportance ofdonor antibodies and consequently the “universal” utility of typeO blood donors.45

Further advances in immunohematology were to occur insucceeding decades. The M, N, and P systems were describedin the period between 1927 and 1947.46 The Rh system wasdiscovered in connection with an unusual transfusion reaction.In 1939, Levine and Stetson47 described an immediate reaction ina group O woman who had received her husband’s group O bloodsoon after delivery of a stillborn fetus with erythroblastosis. This

Figure 1.7 Report of the importance of testing before transfusion. Source:Ottenberg and Kaliski (1913). 43

sequence of events suggested that the infant had inherited a redcell agglutinogen from the father that was foreign to the mother.At about the same time, Landsteiner and Wiener48 harvested arhesus monkey red cell antibody from immunized guinea pigs andrabbits. This antibody agglutinated 85% of human red cell sam­ples (Rh-positive) and left 15% (Rh-negative) unaffected. Whenthe experimentally induced antibody was tested in parallel withthe serum from Levine’s patient, a similar positive and negativedistribution was observed, and the Rh system had been discov­ered. Other red cell antigen systems were subsequently described,but when Rh immunoglobulin was introduced as a preventivemeasure for hemolytic disease of the newborn, it became one ofthe major public health advances of the century.

Despite the introduction of compatibility testing by Ottenberg,transfusion could not be performed frequently as long as arterio­venous anastomosis remained the procedure of choice. Using thismethod, Ottenberg needed five years (Figure 1.7) to accumulate the128 transfusions he reported in his study on pretransfusion test­ing.43 New techniques, such as Unger’s two-syringe method intro­duced in 191549 (Figure 1.8), eventually put an end to transfusion bymeans of arteriovenous anastomosis. However, transfusions did notbecome commonplace until anticoagulants were developed anddirect methods of transfusion were rendered obsolete.

Anticoagulants, the blood bank, andcomponent therapyTheanticoagulantactionof sodiumcitrate completely transformedthepractice of transfusion. Early reports from Belgium50 and Argentina51

were followed by the work of Lewisohn52 that established the optimalcitrate concentration for anticoagulation. The work of Weil53 thendemonstrated the feasibility of refrigerated storage. Subsequently,Rous and Turner54 developed the anticoagulant solution that wasusedduringWorldWar I.55Despite its very large volume, this solutionremained the anticoagulant of choice untilWorldWar II, when Loutitand Mollison56 developed an acid–citrate–dextrose (ACD) solution.Used in a ratio of 70 mL ACD to 450 mL blood, ACD provided 3 to4weeks of preservation of amore concentrated red cell infusion. Thus,the two world wars were the stimuli for the development of citrateanticoagulants and the introduction of indirect transfusion.46 Forthe first time, the donation process could be separated, in time andplace, from the actual transfusion. Blood drawn and set aside nowawaited the emergence of systems of storage anddistribution.Again, itwas the provision of medical support during armed conflict thatstimulated these developments.A blood transfusion service, organized by the Republican Army

during the Spanish Civil War (1936–1939), collected 9000 L of

7Chapter 1: Transfusion in the new millennium

blood in citrate–dextrose anticoagulant for the treatment of battlecasualties.57 At about that same time, Fantus58 began operation ofthe first hospital blood bank at Cook County Hospital in Chicago.His interest had been stimulated by Yudin’s report59 on the use ofcadaveric blood in Russia. Apart from certain scruples attached tothe use of cadaveric blood, Fantus reasoned that a transfusionservice based on such a limited source of supply would beimpractical. Accordingly, he established the principle of a “bloodbank” from which blood could be withdrawn, provided it hadpreviously been deposited. As Fantus58 himself stated, “[J]ust asone cannot draw money from a bank unless one has depositedsome, so the blood preservation department cannot supply bloodunless as much comes in as goes out. The term ‘blood bank’ is not amere metaphor.” The development of anticoagulants and theconcept of blood banks provided an infrastructure upon which amore elaborate blood services organization could be built. WorldWar II was the catalyst for these further developments.At the beginning of World War II, blood procurement programs

were greatly expanded.46 In Great Britain, an efficient system hadbeen developed through the organization of regional centers. Whenthe war started, these centers, already in place, were able to increasetheir level of operation. In the United States, the use of plasma in themanagement of shock had led to the development of plasmacollection facilities.60 The efficient long-term storage of plasmahad been further facilitated by the process of lyophilization devel­oped by Flosdorf and Mudd and the introduction of ABO-inde­pendent “universal” plasma produced by pooling several thousandunits of plasma.61 In 1940, the United States organized a programfor the collection of blood and the shipment of plasma to Europe.The American Red Cross, through its local chapters, participated inthe project, which collected 13 million units by the end of the war.46

The national program of the American Red Cross ceased at theend of the war. However, many of the local chapters continued tohelp recruit donors for local blood banks, and in 1948, the firstregional Red Cross blood center was begun in Rochester, New York.By 1949–1950 in the United States, the blood procurement systemincluded 1500 hospital blood banks, 1100 of which performed allblood bank functions. There were 46 nonhospital blood banks and31 Red Cross regional blood centers. By 1962, these numbers hadgrown to 4400 hospital blood banks, 123 nonhospital blood banks,and 55 American Red Cross regional blood centers, and the numberof units collected had grown to between 5 and 6 million per year.62

During this time, blood was collected through steel needles andrubber tubing into rubber-stoppered bottles. After washing andresterilization, the materials were reused. On occasion, “vacuumbottles” were used to speed up the collection. However, the highincidence of pyrogenic reactions soon led to the development ofdisposable plastic blood collection equipment.In a classic article written in 1952, Walter and Murphy63

described a closed, gravity technique for whole blood preservation.They used a laminar flow phlebotomy needle, an interval donortube, and a collapsible bag of polyvinyl resin designed so that theunit could be assembled and ready for use after sterilization withsteam. The polyvinyl resin was chemically inert to biologic fluidsand nonirritating to tissue. Soon thereafter, Gibson et al. 64 dem­onstrated that plastic systems were more flexible and allowedremoval of plasma after sedimentation or centrifugation. In time,glass was replaced with plastic, and component therapy began toemerge. This development was enhanced by the US military’s needto reduce the weight and breakage of blood bottles during shipmentin the Korean War.

Component and derivative therapy began during World War II,when Edwin J. Cohn and his collaborators developed the coldethanol method of plasma fractionation.65 As a result of theirwork, albumin, globulin, and fibrinogen became available forclinical use. As plastic equipment replaced glass, component sepa­ration became a more widespread practice, and the introduction ofautomated cell separators provided even greater capabilities in thisarea.Clotting factor concentrates for the treatment of patients with

hemophilia and other hemorrhagic disorders also were developedduring the postwar era. Although antihemophilic globulin had beendescribed in 1937,66 unconcentrated plasma was the only thera­peutic material until Pool discovered that Factor VIII could beharvested in the cryoprecipitable fraction of blood.67 This resultedin the development of cryoprecipitate, which was introduced in1965 for the management of hemophilia. Pool showed that cry­oprecipitate could be made in a closed-bag system and urged itsharvest from as many donations as possible. The development ofcryoprecipitate and other concentrates was the dawn of a golden agein the care of patients with hemophilia. Self-infusion programs,made possible by technologic advances in plasma fractionation,allowed early therapy and greatly reduced disability andunemployment. This golden age came abruptly to an end withthe appearance of the AIDS virus.

Transfusion in the age of technologyIn contrast to the long ledger of lives lost in previous centuriesbecause of the lack of blood, transfusion in the 20th century savedcountless lives. In 1937, during those early halcyon days of trans­fusion, Ottenberg wrote:40

Today transfusion has become so safe and so easy to do that it is seldomomitted in any case in which it may be of benefit. Indeed the chiefproblem it presents is the finding of the large sums of money needed forthe professional donors who now provide most of the blood.

It is ironic that Ottenberg’s statement should refer to paid donorsand foreshadow difficulties yet to come. However, experience to thatpoint had not revealed the problem of viral disease transmission.More transfusions would have to be administered before thatproblem would be perceived.After the introduction of anticoagulants, blood transfusions were

given in progressively increasing numbers. At Mount Sinai Hospitalin New York, the number of blood transfusions administeredbetween 1923 and 1953 increased 20-fold68,69 (Table 1.1). Thisincrease was particularly notable after the establishment of bloodbanks. It was during this period that Beeson wrote his classicdescription of transfusion-transmitted hepatitis.70 He had beenalerted to the problem by the outbreaks of jaundice that followedinoculation programs with human serum during World War II.Thus blood transfusion entered a new era. Blood components notonly saved lives but also transmitted disease. The discovery of theAustralian antigen71 and the subsequent definition of hepatitis Avirus and B virus (HBV) still left residual non-A and non-Bdisease,72 a gap that has been largely filled by the discovery ofthe hepatitis C virus (HCV).73 However, it was the outbreak ofAIDS that galvanized public attention to blood transfusion.The AIDS epidemic was first recognized in the United States, and

the first case of AIDS associated with transfusion was observed in a20-month-old infant.74 Subsequently, the suspicion that AIDScould be transmitted by means of transfusion was confirmed.75

8 Chapter 1: Transfusion in the new millennium

Table 1.1 Increase in the Number of Blood Transfusions at Mount Sinai Hospital, NewYork, 1923–1953

Year Number of Transfusions

1923 1431932 4771935 7941938 (Blood bank started)1941 20971952 28741953 3179

Source: Lewisohn (1955).68 Adapted with permission of Elsevier.

The human immunodeficiency virus (HIV) was identified,76 and aneffective test to detect the HIV antibody was developed.76

Concern for blood safetySince 1943, transfusion therapy has been shadowed by the specter ofdisease transmission. In that year, Beeson described posttransfusionhepatitis and unveiled a problem that has grown with time. Astransfusion increased, so did disease transmission. In 1962, theconnection between paid donations and posttransfusion hepatitiswas made.77 A decade later, the National Blood Policy mandated avoluntary donation system in the United States. And yet, bloodusage continued to increase.Concern about posttransfusion hepatitis was not sufficient to

decrease the number of transfusions. Although the use of wholeblood declined as blood components became more popular, totalblood use in the United States doubled between 1971 and 1980(Table 1.2).78–85 This pattern changed as the emergence of AIDSexposed all segments of society to a revealing light.AIDS probably arose in Africa in the 1960s and spread quietly for

years before it was detected. By 1980, an estimated 100,000 personswere infected, and by 1981, when the first cases were reported, aworldwide pandemic lay just beneath the surface. The initialresponse of the public and officials seemed trifling and insufficientas the outbreak grew to proportions few had foreseen. Criticism waslevied against the news media for initially ignoring the story, thegovernment for delay in acknowledging the problem, gay civil rights

Table 1.2 Transfusions in the United States (in Millions of Units)78–85

Year Whole Blood and Red BloodCells

Platelets Plasma Total∗∗

1971 6.32 0.41 0.18 6.911979 9.47 2.22 1.29 12.981980 9.99 3.19 1.54 14.721982 11.47 4.18 1.95 17.601984 11.98 5.53 2.26 19.771986 12.16 6.30 2.18 20.641987 11.61 6.38 2.06 20.051989 12.06 7.26 2.16 21.481992 11.31 8.33 2.26 21.901994 11.11 7.87 2.62 21.601997 11.52 9.04 3.32 23.881999 12.39 9.05 3.32 24.762001 13.90 10.20 3.93 28.032004 14.18 9.88 4.09 28.152006 14.65 10.39 4.01 29.052008 15.02 2.28∗ 4.48 23.242011 13.79 3.16∗ 3.88 20.93

∗ Platelets reported in apheresis units.∗∗ Includes other components.

groups for resistance to epidemiologic measures, research scientistsfor unseemly competition, blood services for delayed response in atime of crisis, and the US Food and Drug Administration (FDA) forinadequate regulatory activity. Historians with the perspective oftime will determine whether there really were more villains than thevirus itself.86

The realization that transfusion can transmit an almostinvariably fatal disease had a chilling effect on the public. Twomajor changes in blood services have occurred in the aftermath ofthe AIDS epidemic. The FDA, using pharmaceutical manufacturingcriteria not “tailored to . . . blood banks,” became more aggressivein regulatory actions against blood collection establishments.87

And, finally, blood use moderated for approximately 10 years.Through the 1980s and early 1990s, red cell and plasma transfusionpeaked and began to stabilize (Table 1.2). Only platelet use andhuman progenitor cell transplantation, driven by the demands ofcancer chemotherapy, continued to increase.78–85 Educational pro­grams to encourage judicious use of blood have been initiated, andthey have been favorably received by practicing physicians. Use ofred cells and plasma fell from 2008 to 2011. This was a combinedimpact of the great recession reducing healthcare utilization and thewidespread use of patient blood management programs intended toreduce blood transfusion. This represents the first time since the endof the Second World War that the growth in transfusion of bloodproducts in the United States and other developed countriesstopped and was reversed for a sustained period.Relentless public pressure for a “zero-risk” blood supply

resulted in dividends through continued scientific and techno­logic improvements. Enhanced sensitivity and better use of sero­logic testing, along with improved scrutiny of donors, resulted inmajor reductions in risk of transmitted disease by the mid­1990s.88 Discovery that pools of units subjected to nucleic acidtesting almost closed the window for HIV and HCV virus resultedin application of this testing for both whole blood and plasmadonations beginning between 1998 and 2000.88,89 This, combinedwith virus reduction and inactivation of the final product, resultedin plasma derivatives that have not transmitted AIDS or hepatitissince 1994.90 For whole blood and platelet components, risks havebecome low. A solvent/detergent-treated fresh frozen plasmacomponent has been used in Europe and recently became availa­ble in the United States.With the reduction in the risk of viral transmission, the focus in

the developed world has shifted to transfusion-related acute lunginjury (TRALI)—possibly from recipient-directed leukocyte anti­bodies and lipid mediators in transfused plasma—and bacterialinfection primarily occurring in room-temperature stored platelets.So that incremental gains can be made against these risks, the use ofmale plasma only and the culture of platelets before they arereleased have been implemented. The 2011 blood utilization surveyindicated a 28.8% reduction in TRALI, suggesting a significantbreakthrough with regard to this risk.85 Geographic exclusions havebeen aimed at reducing the potential for variant Creutzfeldt–Jakobdisease (vCJD) transmission by transfusion, although in the UnitedStates such occurrence seems highly unlikely. In many countries,universal leukocyte reduction has been a response to the vCJD risk.Ironically, universal application of leukocyte reduction is probablyineffective for vCJD but has stimulated controversy over its use forpreventing other problems.91

Finally, focus on the understanding, management, and preven­tion of medical errors in general might lead to progress againstremaining nemesis hemolytic transfusion reactions caused by