Oxford Handbook of Clinical Haematology 3rd Edition PDF

Haematological emergencies Septic shock/neutropenic fever b p632 Transfusion reactions b p634 Immediate-type hypersensitivity reactions b p636 Febrile transfusion reactions b p636 Delayed transfusion reaction b p636 Bacterial contamination of blood products b p637 Post-transfusion purpura b p637 Hypercalcaemia b p638 Hyperviscosity b p640 Disseminated intravascular coagulation b p642 Overdosage of thrombolytic therapy b p645 Heparin overdosage b p646 Heparin-induced thrombocytopenia (HIT) b p648 Warfarin overdosage b p650 Massive blood transfusion b p652 Paraparesis/spinal collapse b p654 Leucostasis b p655 Thrombotic thrombocytopenic purpura b p656 Sickle crisis b p658 Tumour lysis syndrome (TLS) b p684 OXFORD MEDICAL PUBLICATIONS Oxford Handbook of Clinical Haematology Third edition Published and forthcoming Oxford Handbooks Oxford Handbook for the Foundation Programme 2/e Oxford Handbook of Acute Medicine 3/e Oxford Handbook of Anaesthesia 2/e Oxford Handbook of Applied Dental Sciences Oxford Handbook of Cardiology Oxford Handbook of Clinical and Laboratory Investigation 2/e Oxford Handbook of Clinical Dentistry 4/e Oxford Handbook of Clinical Diagnosis 2/e Oxford Handbook of Clinical Examination and Practical Skills Oxford Handbook of Clinical Haematology 3/e Oxford Handbook of Clinical Immunology and Allergy 2/e Oxford Handbook of Clinical Medicine – Mini Edition 7/e Oxford Handbook of Clinical Medicine 7/e Oxford Handbook of Clinical Pharmacy Oxford Handbook of Clinical Rehabilitation 2/e Oxford Handbook of Clinical Specialties 8e Oxford Handbook of Clinical Surgery 3/e Oxford Handbook of Complementary Medicine Oxford Handbook of Critical Care 3/e Oxford Handbook of Dental Patient Care 2/e Oxford Handbook of Dialysis 3/e Oxford Handbook of Emergency Medicine 3/e Oxford Handbook of Endocrinology and Diabetes 2/e Oxford Handbook of ENT and Head and Neck Surgery Oxford Handbook of Epidemiology for Clinicians Oxford Handbook of Expedition and Wilderness Medicine Oxford Handbook of Gastroenterology and Hepatology Oxford Handbook of General Practice 3/e Oxford Handbook of Genitourinary Medicine, HIV and AIDS Oxford Handbook of Geriatric Medicine Oxford Handbook of Infectious Diseases and Microbiology Oxford Handbook of Key Clinical Evidence Oxford Handbook of Medical Sciences Oxford Handbook of Nephrology and Hypertension Oxford Handbook of Neurology Oxford Handbook of Nutrition and Dietetics Oxford Handbook of Obstetrics and Gynaecology 2/e Oxford Handbook of Occupational Health Oxford Handbook of Oncology 2/e Oxford Handbook of Ophthalmology Oxford Handbook of Paediatrics Oxford Handbook of Palliative Care 2/e Oxford Handbook of Practical Drug Therapy Oxford Handbook of Pre-Hospital Care Oxford Handbook of Psychiatry 2/e Oxford Handbook of Public Health Practice 2/e Oxford Handbook of Reproductive Medicine and Family Planning Oxford Handbook of Respiratory Medicine 2/e Oxford Handbook of Rheumatology 2/e Oxford Handbook of Sport and Exercise Medicine Oxford Handbook of Tropical Medicine 3/e Oxford Handbook of Urology 2/e Oxford Handbook of Clinical Haematology THIRD EDITION Drew Provan Senior Lecturer in Haematology Barts and The London School of Medicine and Dentistry University of London, UK Charles R.J. Singer Consultant Haematologist Royal United Hospital Bath, UK Trevor Baglin Consultant Haematologist Addenbrookes NHS Trust Cambridge, UK Inderjeet Dokal Professor of Paediatrics Barts and The London School of Medicine and Dentistry University of London, UK 1 1 Great Clarendon Street, Oxford OX2 6DP Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide in Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With ofﬁces in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Published in the United States by Oxford University Press Inc., New York © Oxford University Press, 2009 The moral rights of the author have been asserted Database right Oxford University Press (maker) First edition published 1998 Second edition published 2004 Third edition published 2009 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this book in any other binding or cover and you must impose this same condition on any acquirer British Library Cataloguing in Publication Data Data available Library of Congress Cataloging-in-Publication-Data Data available Typeset by Cepha Imaging Private Ltd., Bangalore, India Printed in China on acid-free paper by Asia Paciﬁc Offset ISBN 978–0–19–922739–6 10 9 8 7 6 5 4 3 2 1 Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding. v Preface to the third edition It is hard to believe that at least three years have passed since the second edition of the handbook. As with all medical specialties, Haematology has seen major inroads with new diagnostic tests, treatments and a plethora of guidelines. In fact, Haematology has the largest collection of guidelines covering all aspects of haematology care ( http://www.bcshguidelines. com) and was the ﬁrst specialty to design guidelines in the 1980s. The book underwent a major revision with the second edition, most notably the sections dealing with malignant disease. For the new edition these have been brought right up to date by Charles Singer. Coagulation has been entirely rewritten by Trevor Baglin and now truly reﬂects the current investigation and management of coagulation disorders. Following the retirement of Professor Sir John Lilleyman we needed to ﬁnd a new author for the Paediatric Haematology component of the book. Thankfully, we were able to persuade Professor Inderjeet Dokal to take on this mantle and he has revised this section thoroughly. In addition to these signiﬁcant changes, we have gone through the entire book and attempted to ensure that obsolete tests have been removed and that the Handbook, in its entirety, reﬂects contemporary haematology practice. As ever, we are very keen to hear about errors or omissions, for which we are entirely responsible! We would also very much like readers to contact us if there are topics or subject areas which they would like to see included in the fourth edition (email [email protected]). We also need more trainee input so if there are any volunteer proof-readers or accuracy checkers among the haematology trainee community we would very much like to hear from you. DP CRJS TB ISD 2008 vi Preface to the second edition Haematology has seen many changes since 1998 when the ﬁrst edition of this small book was written. Most notably, there are major advances in the treatments of malignant blood disorders with the discovery of tyrosine kinase inhibitors which have transformed the outlook for patients with CML, the rediscovery of arsenic for AML, and many other new thera- pies. Progress has been slower in the non-malignant arena since there is still limited evidence on which to base decisions. We have attempted to update each section in the book in order to ensure that it reﬂects current practice. Although molecular diagnostics have seen huge changes through the Human Genome Project and other methodological developments, we have not included these in great detail here because of lack of space. We have attempted to focus more on clinical aspects of patient care. This edition welcomes two new authors: Professor Sir John Lilleyman, immediate Past-President of the Royal College of Pathologists, is a Paediatric Oncologist at Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London. John is a leading ﬁgure in the world of paediatric haematology with an interest in both malignant and non-malignant disease affecting children. He has extensively revised the Paediatric section of the book, in addition to Immunodeﬁciency. Dr Trevor Baglin, Consultant Haematologist at Addenbrookes Hospital, Cambridge is Secretary of the British Committee for Standards in Haematology Haemostasis and Thrombosis Task Force. Trevor is the author of many evidence-based guidelines and peer-reviewed scientiﬁc papers. He has rewritten the Haemostasis section of the book and brought this in line with modern management. Other features of this edition include the greater use of illustrations such as blood ﬁlms, marrows, and radiological images which we hope will enhance the text and improve readers’ understanding of the subject. We have increased the number of references and provided URLs for key web- sites providing easy access to organisations and publications. There will doubtless be omissions and errors and we take full respon- sibility for these. We are very keen to receive feedback (good or other- wise!) since this helps shape future editions. If there is something you feel we have left out please complete the Readers comment card. DP CRJS TB JL 2004 vii Preface to the ﬁrst edition This small volume is intended to provide the essential core knowledge required to assess patients with possible disorders of the blood, organize relevant investigations and initiate therapy where necessary. By reducing extraneous information as much as possible, and presenting key infor- mation for each topic, a basic understanding of the pathophysiology is provided and this, we hope, will stimulate readers to follow this up by consulting the larger haematology textbooks. We have provided both a patient-centred and disease-centred approach to haematological disease, in an attempt to provide a form of ‘surgical sieve’, hopefully enabling doctors in training to formulate a differential diagnosis before consulting the relevant disease-orientated section. We have provided a full review of haematological investigations and their interpretation, handling emergency situations, and included the com- monly used protocols in current use on Haematology Units, hopefully providing a uniﬁed approach to patient management. There are additional sections relating to patient support organizations and Internet resources for further exploration by those wishing to delve deeper into the subject of blood and its diseases. Obviously with a subject as large as clinical haematology we have been selective about the information we chose to include in the handbook. We would be interested to hear of diseases or situations not covered in this handbook. If there are inaccuracies within the text we accept full responsi- bility and welcome comments relating to this. DP MC ASD CRJS AGS 1998 viii Foreword to the ﬁrst edition The Concise Oxford Dictionary deﬁnes a handbook as ‘a short manual or guide’. Modern haematology is a vast ﬁeld which involves almost every other medical speciality and which, more than most, straddles the worlds of the basic biomedical sciences and clinical practice. Since the rapidly proliferating numbers of textbooks on this topic are becoming denser and heavier with each new edition, the medical student and young doctor in training are presented with a daunting problem, particularly as they try to put these ﬁelds into perspective. And those who try to teach them are not much better placed; on the one hand they are being told to decongest the curriculum, while on the other they are expected to introduce large slices of molecular biology, social science, ethics, and communication skills, not to mention a liberal sprinkling of poetry, music, and art. In this over-heated educational scene the much maligned ‘handbook’ could well stage a come-back and gain new respectability, particularly in the role of a friendly guide. In the past this genre has often been viewed as having little intellectual standing, of no use to anybody except the pan- icstricken student who wishes to try to make up for months of misspent time in a vain, one-night sitting before their ﬁnal examination. But given the plethora of rapidly changing information that has to be assimilated, the carefully prepared précis is likely to play an increasingly important role in medical education. Perhaps even that ruination of the decent paragraph and linchpin of the pronouncements of medical bureaucrats, the ‘bullet- point’, may become acceptable, albeit in small doses, as attempts are made to highlight what is really important in a scientiﬁc or clinical ﬁeld of enor- mous complexity and not a little uncertainty. In this short account of blood diseases the editors have done an excel- lent service to medical students, as well as doctors who are not specialists in blood diseases, by summarizing in simple terms the major features and approaches to diagnosis and management of most of the blood diseases that they will meet in routine clinical practice or in the tedious examina- tions that face them. And in condensing this rapidly expanding ﬁeld they have, remarkably, managed to avoid one of the great difﬁculties and pitfalls of this type of teaching; in trying to reduce complex issues down to their bare bones, it is all too easy to introduce inaccuracies. One word of warning from a battle-scarred clinician however. A précis of this type suffers from the same problem as a set of multiple-choice questions. Human beings are enormously complex organisms, and sick ones are even more complicated; during a clinical lifetime the self-critical doctor will probably never encounter a ‘typical case’ of anything. Thus the outlines of the diseases that are presented in this book must be used as approximate guides, and no more. But provided they bear this in mind, stu- dents will ﬁnd that it is a very valuable summary of modern haematology; the addition of the Internet sources is a genuine and timely bonus. D. J. Weatherall April 1998 ix Contents Acknowledgements xxiii Contributors xxv Symbols and abbreviations xxvii 1 Clinical approach 1 2 Red cell disorders 31 3 White blood cell abnormalities 109 4 Leukaemia 119 5 Lymphoma 179 6 Myelodysplasia 221 7 Myeloproliferative neoplasms (MPNs) 253 8 Paraproteinaemias 319 9 Haematopoietic stem cell transplantation (SCT) 387 10 Haemostasis and thrombosis 447 11 Immunodeﬁciency 541 12 Paediatric haematology 555 13 Haematological emergencies 631 14 Supportive care 659 15 Protocols and procedures 667 16 Haematological investigations 747 17 Blood transfusion 761 18 Phone numbers and addresses 787 19 Haematology online 793 20 Charts and nomograms 801 21 Normal ranges 807 Index 811 This page intentionally left blank xi Detailed contents Acknowledgements xxiii Contributors xxv Symbols and abbreviations xxvii 1 Clinical approach 1 History taking in patients with haematological disease 2 Physical examination 4 Splenomegaly 5 Lymphadenopathy 6 Unexplained anaemia 8 Patient with elevated haemoglobin 10 Elevated WBC 12 Reduced WBC 14 Elevated platelet count 16 Reduced platelet count 18 Easy bruising 20 Recurrent thromboembolism 22 Pathological fracture 23 Raised ESR 24 Serum or urine paraprotein 25 Anaemia in pregnancy 26 Thrombocytopenia in pregnancy 27 Prolonged bleeding after surgery 28 Positive sickle test (HbS solubility test) 30 2 Red cell disorders 31 The peripheral blood ﬁlm in anaemias 32 Anaemia in renal disease 34 Anaemia in endocrine disease 36 Anaemia in joint disease 38 Anaemia in gastrointestinal disease 40 Anaemia in liver disease 41 Iron (Fe) deﬁciency anaemia 42 xii DETAILED CONTENTS Vitamin B12 deﬁciency 46 Folate deﬁciency 48 Other causes of megaloblastic anaemia 50 Anaemia in other deﬁciency states 51 Haemolytic syndromes 52 Genetic control of haemoglobin production 54 Sickling disorders 56 HbS—new therapies 60 Sickle cell trait (HbAS) 62 Other sickling disorders 63 Other haemoglobinopathies 64 Unstable haemoglobins 66 Thalassaemias 68 A thalassaemia 69 B thalassaemia 70 Other thalassaemias 74 Hereditary persistence of fetal haemoglobin 75 Hb patterns in haemoglobin disorders 76 Non-immune haemolysis 78 Hereditary spherocytosis 80 Hereditary elliptocytosis 83 Glucose-6-phosphate dehydrogenase (G6PD) deﬁciency 84 Pyruvate kinase (PK) deﬁciency 87 Other red cell enzymopathies 88 Drug-induced haemolytic anaemia 90 Methaemoglobinaemia 91 Microangiopathic haemolytic anaemia (MAHA) 92 Acanthocytosis 93 Autoimmune haemolytic anaemia 94 Cold haemagglutinin disease (CHAD) 96 Leucoerythroblastic anaemia 97 Aplastic anaemia 98 Paroxysmal nocturnal haemoglobinuria 100 Pure red cell aplasia 102 Iron (Fe) overload 103 Transfusion haemosiderosis 106 DETAILED CONTENTS xiii 3 White blood cell abnormalities 109 Neutrophilia 110 Neutropenia 112 Lymphocytosis and lymphopenia 114 Eosinophilia 115 Basophilia and basopenia 116 Monocytosis and monocytopenia 117 Mononucleosis syndromes 118 4 Leukaemia 119 Acute myeloblastic leukaemia (AML) 120 Acute lymphoblastic leukaemia (ALL) 132 Chronic myeloid leukaemia (CML) 140 Chronic lymphocytic leukaemia (B-CLL) 150 Cell markers in chronic lymphoproliferative disorders 158 Prolymphocytic leukaemia (PLL) 160 Hairy cell leukaemia and variant 162 Splenic marginal zone lymphoma (SMZL) 166 Mantle cell lymphoma (MCL) 168 Large granular lymphocyte leukaemia (LGLL) 172 Adult T-cell leukaemia-lymphoma (ATL) 176 Sézary syndrome (SS) 178 5 Lymphoma 179 Non-Hodgkin lymphoma (NHL) 180 Indolent lymphoma 186 Treatment of indolent lymphoma 188 Aggressive lymphomas 194 Initial treatment of aggressive lymphomas 196 CNS lymphoma 204 Hodgkin lymphoma (HL, Hodgkin’s disease) 206 6 Myelodysplasia 221 Myelodysplastic syndromes (MDS) 222 Classiﬁcation 224 Clinical features of MDS 228 xiv DETAILED CONTENTS Diagnostic criteria of MDS 232 Prognostic factors in MDS 234 Clinical variants of MDS 236 Management of MDS 238 Response criteria 244 Myelodysplastic/myeloproliferative diseases (MDS/MPD) 248 7 Myeloproliferative neoplasms (MPNs) 253 Myeloproliferative neoplasms (MPNs) 254 Pathogenesis of the MPNs 256 Polycythaemia vera (PV) 260 Natural history of PV 266 Management of PV 268 Secondary erythrocytosis 272 Relative erythrocytosis (RE) 273 Idiopathic erythrocytosis (IE) 274 Essential thrombocythaemia (ET) 276 Reactive thrombocytosis (RT) 285 Primary myeloﬁbrosis (PMF) 286 Chronic neutrophilic leukaemia (CNL) 298 Chronic eosinophilic leukaemia (CEL) and idiopathic hypereosinophilic syndrome (HES) 300 Mast cell disease (mastocytosis) 306 Systemic mastocytosis (SM) 310 MPNs-unclassiﬁable (MPN-U) 317 8 Paraproteinaemias 319 Paraproteinaemias 320 Monoclonal gammopathy of undetermined signiﬁcance (MGUS) 322 Smouldering multiple myeloma (syn. asymptomatic myeloma) 326 Multiple myeloma (MM) 330 Variant forms of myeloma 359 Cryoglobulinaemia 360 POEMS syndrome 362 Plasmacytoma 364 DETAILED CONTENTS xv Waldenström macroglobulinaemia (WM) 366 Heavy chain disease (HCD) 378 AL (1° systemic) amyloidosis 380 9 Haematopoietic stem cell transplantation (SCT) 387 Haemopoietic stem cell transplantation (SCT) 388 Indications for haemopoietic SCT 392 Allogeneic SCT 396 Autologous STC 399 Investigations for BMT/PBSCT 400 Pretransplant investigation of donors 402 Bone marrow harvesting 404 Peripheral blood stem cell mobilization and harvesting 406 Microbiological screening for stem cell cryopreservation 408 Stem cell transplant conditioning regimens 410 Infusion of cryopreserved stem cells 412 Infusion of fresh non-cryopreserved stem cells 414 Blood product support for STC 416 GvHD prophylaxis 420 Acute GvHD 424 Chronic GvHD 428 Veno-occlusive disease (syn. sinusoidal obstruction syndrome) 432 Invasive fungal infections and antifungal therapy 436 CMV prophylaxis and treatment 440 Post-transplant vaccination programme 442 Treatment of relapse post-allogeneic SCT 444 Discharge and follow-up 445 10 Haemostasis and thrombosis 447 Assessing haemostasis 448 The coagulation system 450 Laboratory tests 452 Platelets 456 Bleeding 460 Bleeding: laboratory investigations 463 Bleeding: therapeutic products 464 xvi DETAILED CONTENTS von Willebrand disease (vWD) 466 Haemophilia A and B 470 Rare congenital coagulation disorders 476 Congenital thrombocytopenias 479 Congenital platelet function defects 480 Congenital vascular disorders 481 Haemorrhagic disease of the newborn 482 Thrombocytopenia (acquired) 484 Speciﬁc thrombocytopenic syndromes 486 Disseminated intravascular coagulation (DIC) 488 Anticoagulant drug therapy 490 Liver disease 492 Renal disease 494 Acquired anticoagulants and inhibitors 495 Treatment of spontaneous FVIII inhibitor 496 Acquired disorders of platelet function 498 Henoch–Schönlein purpura 500 Peri-operative bleeding and massive blood loss 502 Massive blood loss 504 Heparin 506 Heparin induced thrombocytopenia/ with thrombosis (HIT/T) 508 Oral anticoagulant therapy (warfarin, VKAs) 510 Thrombosis 514 Risk assessment and thromboprophylaxis 520 Example of VTE Risk Assessment 524 Heritable thrombophilia 526 Acquired thrombophilia 530 Thrombotic thrombocytopenic purpura (TTP) 534 Haemolytic uraemic syndrome (HUS) 536 Heparin-induced thrombocytopenia (HIT) 538 11 Immunodeﬁciency 541 Congenital immunodeﬁciency syndromes 542 Acquired immune deﬁciencies 546 HIV infection and AIDS 548 Therapy of HIV infection 552 DETAILED CONTENTS xvii 12 Paediatric haematology 555 Blood counts in children 556 Red cell transfusion and blood component therapy—special considerations in neonates and children 558 Polycythaemia in newborn and childhood 562 Neonatal anaemia 564 Anaemia of prematurity 566 Haemolytic anaemia in the neonate 568 Congenital red cell defects 570 Acquired red cell defects 572 Haemolytic disease of the newborn (HDN) 574 Hyperbilirubinaemia 578 Neonatal haemostasis 580 Neonatal alloimmune thrombocytopenia (NAIT) 582 Congenital dyserythropoietic anaemias 584 Congenital red cell aplasia 586 Acquired red cell aplasia 588 Fanconi anaemia (FA) 590 Rare congenital marrow failure syndromes 592 Neutropenia in childhood 596 Disorders of neutrophil function 598 Childhood immune (idiopathic) thrombocytopenic purpura (ITP) 600 Haemolytic uraemic syndrome (HUS) 602 Childhood cancer and malignant blood disorders 604 Childhood lymphoblastic leukaemia 608 Childhood lymphomas 612 Childhood acute myeloid leukaemia (AML) 616 Childhood myelodysplastic syndromes and chronic leukaemias 620 Histiocytic syndromes 624 Haematological effects of systemic disease in children 628 13 Haematological emergencies 631 Septic shock/neutropenic fever 632 Transfusion reactions 634 xviii DETAILED CONTENTS Immediate-type hypersensitivity reactions 636 Febrile transfusion reactions 636 Delayed transfusion reaction 636 Bacterial contamination of blood products 637 Post-transfusion purpura 637 Hypercalcaemia 638 Hyperviscosity 640 Disseminated intravascular coagulation (DIC) 642 Overdosage of thrombolytic therapy 645 Heparin overdosage 646 Heparin-induced thrombocytopenia (HIT) 648 Warfarin overdosage 650 Massive blood transfusion 652 Paraparesis/spinal collapse 654 Leucostasis 655 Thrombotic thrombocytopenic purpura 656 Sickle crisis 658 14 Supportive care 659 Quality of life 660 Pain management 662 Psychological support 665 15 Protocols and procedures 667 Acute leukaemia—investigations 668 Platelet storage and administration 670 Platelet reactions and refractoriness 672 Prophylactic regimen for neutropenic patients 674 Guidelines for use of IV antibiotics in neutropenic patients 676 Treatment of neutropenic sepsis when source unknown 678 Treatment of neutropenic sepsis when source known/suspected 680 Prophylaxis for patients treated with purine analogues 682 Tumour lysis syndrome (TLS) 684 Management of chronic bone marrow failure 686 Venepuncture 688 Venesection 689 DETAILED CONTENTS xix Tunnelled central venous catheters 690 Bone marrow examination 692 Administration of chemotherapy 694 Antiemetics for chemotherapy 696 Intrathecal chemotherapy 698 Management of extravasation 700 Speciﬁc procedures following extravasation 702 Splenectomy 704 Plasma exchange (plasmapheresis) 706 Leucapheresis 712 Anticoagulation therapy—heparin 710 Oral anticoagulation 712 Management of needlestick injuries 714 Chemotherapy protocols: ABVD 716 BEACOPP & Escalated BEACOPP 717 BEAM 718 CHOP 21 & CHOP 14 720 ChlVPP 722 CODOX-M/IVAC 724 CTD & CTDa 727 DHAP ± R 728 EPOCH & DA-EPOCH ± R 729 ESHAP ± R 730 FC ± R 732 FMD ± R (FND ± R) 733 Hyper-CVAD ± R / MA± R 734 ICE ± R 736 MCP ± R 737 MINE 738 Mini-BEAM ± R 739 R-CHOP 740 R-CVP & CVP 741 Rituximab 742 Stanford V 744 VAPEC-B 746 xx DETAILED CONTENTS 16 Haematological investigations 747 Full blood count 748 Blood ﬁlm 748 Plasma viscosity 748 ESR 749 Haematinic assays 749 Haemoglobin electrophoresis 749 Haptoglobin 750 Schumm’s test 750 Kleihauer test 750 Reticulocytes 751 Urinary haemosiderin 752 Ham’s test 753 Immunophenotyping 754 Cytogenetics 756 Human leucocyte antigen (HLA) typing 758 17 Blood transfusion 761 Introduction 762 Using the blood transfusion laboratory 764 Transfusion of red blood cells 766 Platelet transfusion 768 Fresh frozen plasma (FFP) 770 Cryoprecipitate 772 Intravenous immunoglobulin (IVIg) 774 Transfusion transmitted infections (TTI) 776 TRALI and TA-GVHD 778 Irradiated and CMV-negative blood products 779 Autologous blood transfusion 780 Maximum surgical blood ordering schedule (MSBOS) 782 Jehovah’s Witnesses 784 18 Phone numbers and addresses 787 American Society of Hematology 788 Birmingham Clinical Trials Unit (BCTU) 788 British Society for Haematology 788 DETAILED CONTENTS xxi CancerBACUP 789 CTSU 789 European Hematology Association 790 Leukaemia Research Fund (LRF) 790 Medical Research Council 791 National Cancer Research Network 791 Northern and Yorkshire Clinical Trials and Research Unit 791 19 Haematology online 793 Haematology online 794 20 Charts and nomograms 801 Karnofsky performance status 802 WHO/ECOG performance status 802 WHO haematological toxicity scale 803 Body surface area nomogram 804 Gentamicin dosage nomogram 805 The Sokal Score for CML prognostic groups 806 21 Normal ranges 807 Adult normal ranges 808 Paediatric normal ranges 810 Index 811 This page intentionally left blank xxiii Acknowledgements We are indebted to many of our colleagues for providing helpful suggestions and for proofreading the text. In particular we wish to thank Dr Helen McCarthy, Specialist Registrar in Haematology; Dr Jo Piercy, Specialist Registrar in Haematology; Dr Tanay Sheth, SHO in Haematology, Southampton; Sisters Clare Heather and Ann Jackson, Haematology Day Unit, Southampton General Hospital; Dr Mike Williams, Specialist Registrar in Anaesthetics; Dr Frank Boulton, Wessex Blood Transfusion Service, Southampton; Dr Paul Spargo, Consultant Anaesthetist, Southampton University Hospitals; Dr Sheila Bevin, Staff Grade Paediatrician; Dr Mike Hall, Consultant Neonatologist; Dr Judith Marsh, Consultant Haematologist, St George’s Hospital, London; Joan Newman, Haematology Transplant Coordinator, Southampton; Professor Sally Davies, Consultant Haematologist, Imperial College School of Medicine, Central Middlesex Hospital, London; Dr Denise O’Shaughnessy, Consultant Haematologist, Southampton University Hospitals NHS Trust; Dr Kornelia Cinkotai, Consultant Haematologist, Barts and The London NHS Trust; Dr Mansel Haeney, Consultant Immunologist, Hope Hospital, Salford; Dr Adam Mead, Specialist Registrar Barts and The London; Dr Chris Knechtli, Consultant Haematologist, Royal United Hospital, Bath; Dr Toby Hall, Consultant Radiologist, Royal United Hospital Bath, Craig Lewis, Senior Biomedical Scientist, Royal United Hospital Bath, Bob Maynard, Senior Biomedical Scientist, Royal United Hospital Bath and Rosie Simpson, Senior Pharmacist, Royal United Hospital Bath. We would like to thank Alastair Smith, Morag Chisholm and Andrew Duncombe for their contributions to the ﬁrst edition of the handbook. Three Barts & The London SpRs helped edit some of the sections of 3e, namely Drs John de Vos, Tom Butler and Jay Pandya. Dr Jim Murray, Queen Elizabeth Hospital, Birmingham, corrected the Haematological Emergencies section, though he did this in error since he was supposed to be proof-reading something completely different but he was too polite to say anything (bless). We would like to acknowledge the patience and forbearance of our wives and families for the months of neglect imposed by the work on this edition. Warm thanks, as ever, are extended to Oxford University Press, and in particular Catherine Barnes, Senior Commissioning Editor for Medicine, Elizabeth Reeve, Commissioning Editor, Beth Womack, Managing Editor, and Kate Wilson, Production Manager. We fell behind schedule with this edition and are grateful to the whole OUP team for bearing with us so patiently and not harassing us! We apologize for anyone omitted but this is entirely unintentional. This page intentionally left blank xxv Contributors Tom Butler Specialist Registrar in Haematology, Barts and the London NHS Trust, London, UK Johannes de Vos Specialist Registrar in Haematology, Barts and the London NHS Trust, London, UK This page intentionally left blank xxvii Symbols and abbreviations b cross-reference d decreased i increased 2 important 3 very important n normal websites 5 female 4 male 1° primary 2° secondary 2,3 DPG 2,3 diphosphoglycerate 2-CDA 2-chlorodeoxyadenosine A2-M alpha2 microglobulin 6-MP 6-mercaptopurine 99mTc methoxyisobutyl-isonitride or 99mTc-MIBI 99mTc-MIBI scintigraphy AA aplastic anaemia or reactive amyloidosis Ab antibody ABVD adriamycin (doxorubicin), bleomycin, vinblastine, ACD acid-citrate-dextrose or anaemia of chronic disease ACE angiotensin converting enzyme ACL anticardiolipin antibody ACML atypical chronic myeloid leukaemia ADA adenosine deaminase ADE cytosine arabinoside (Ara-C) daunorubicin etoposide ADP adenosine 5-diphosphate AFB acid fast bacilli Ag antigen AIDS acquired immunodeﬁciency syndrome AIHA autoimmune haemolytic anaemia AIN autoimmune neutropenia AITL angio-immunoblastic T-cell lymphoma AL (p) amyloidosis ALB serum albumin ALCL anaplastic large cell lymphoma xxviii SYMBOLS AND ABBREVIATIONS ALG anti-lymphocyte globulin ALIPs abnormal localization of immature myeloid precursors ALL acute lymphoblastic leukaemia ALS advanced life support ALT alanine aminotransferase AML acute myeloid leukaemia AMP adenosine monophosphate ANA antinuclear antibodies ANAE alpha naphthyl acetate esterase ANCA anti-neutrophilic cytoplasmic antibody ANH acute normovolaemic haemodilution APC activated protein C APCR activated protein C resistance APL antiphospholipid antibody APML acute promyelocytic leukaemia APS antiphospholipid syndrome APTR activated partial thromboplastin ratio APTT activated partial thromboplastin time ARDS adult respiratory distress syndrome ARF acute renal failure ARMS ampliﬁcation refractory mutation system ASCT autologous stem cell transplantation AST aspartate aminotranferase AT (ATIII) antithrombin III ATCML adult-type chronic myeloid (granulocytic) leukaemia ATG anti-thymocyte globulin ATLL adult T-cell leukaemia/lymphoma ATP adenosine triphosphate ATRA all-trans retinoic acid A-V arteriovenous AvWS acquired von Willebrand syndrome B2-M beta-2-microglobuline BAL broncho-alveolar lavage B-CLL B-cell chronic lymphocytic leukaemia bd bis die (twice daily) BEAC BCNU, etoposide, cytosine, cyclophosphamide BEAM BCNU, etoposide, cytarabine (ara-C), melphalan BFU-E burst-forming unit-erythroid BJP Bence Jones protein BL Burkitt lymphoma SYMBOLS AND ABBREVIATIONS xxix BM bone marrow BMJ British Medical Journal BMM bone marrow mastocytosis BMT bone marrow transplantation BNF British National Formulary BP blood pressure BPL BioProducts Laboratory BSS Bernard–Soulier syndrome BTG B-thromboglobulin BU Bethesda Units C/I consolidation/intensiﬁcation Ca carcinoma Ca2+ calcium CABG coronary artery by pass graft cALL common acute lymphoblastic leukaemia CAMT congenital amegakaryocytic thrombocytopenia CaPO4 calcium phosphate CBA collagen binding activity CBV cyclophosphamide, carmustine (BCNU), etoposide CCF congestive cardiac failure CCR complete cytogenetic response CD cluster differentiation or designation CDA congenital dyserythropoietic anaemia cDNA complementary DNA CEL chronic eosinophilic leukaemia CGL chronic granulocytic leukaemia CHAD cold haemagglutinin disease CHOP cyclophosphamide, adriamycin, vincristine, prednisolone CJD Creutzfeldt–Jakob disease (v = variant) Cl- chloride CLD chronic liver disease CLL chronic lymphocytic (‘lymphatic’) leukaemia CM cutaneous mastocytosis CMC chronic mucocutaneous candidiasis CML chronic myeloid leukaemia CMML chronic myelomonocytic leukaemia CMV cytomegalovirus CNS central nervous system COAD chronic obstructive airways disease COC combined oral contraceptive xxx SYMBOLS AND ABBREVIATIONS COMP cyclophosphamide, vincristine, methotrexate, CR complete remission CRF chronic renal failure CRP C-reactive protein CRVT central retinal renous thrombosis CSF cerebrospinal ﬂuid CT computed tomography CTLp cytotoxic T-lymphocyte precursor assays CTZ chemoreceptor trigger zone CVA cerebrovascular accident CVP cyclophosphamide, vincristine, prednisolone; central CVS chorionic villus sampling CVS cardiovascular system CXR chest x-ray CyA ciclosporin A CytaBOM cytarabine, bleomycin, vincristine, methotrexate d day DAGT direct antiglobulin test DAT direct antiglobulin test daunorubicin, cytosine (Ara-C), dATP deoxy ATP DBA Diamond–Blackfan anaemia DC dyskeratosis congenita DCS dendritic cell system DCT direct Coombs’ test DDAVP desamino D-arginyl vasopressin DEAFF detection of early antigen ﬂuorescent foci DEB diepoxy butane DFS disease-free survival DHAP dexamethasone, cytarabine, cisplatin DI delayed intensiﬁcation DIC disseminated intravascular coagulation dL decilitre DLBCL diffuse large B-cell lymphoma DLI donor leucocyte/lymphocyte infusion DMSO dimethyl sulphoxide DNA deoxyribonucleic acid DOB date of birth DPG diphosphoglycerate DRVVT dilute Russell’s viper venom time/test DTT dilute thromboplastin time SYMBOLS AND ABBREVIATIONS xxxi DVT deep vein thrombosis DXT radiotherapy EACA epsilon aminocaproic acid EBV Epstein–Barr virus EBVP etoposide, bleomycin, vinblastine, prednisolone ECG electrocardiograph ECOG European Co-operative Oncology Group EDTA ethylenediamine tetraacetic acid EEC endogenous erythroid colonies EFS event-free survival EGF epidermal growth factor ELISA enzyme-linked immunosorbent assay EMEA European Medicines Agency EMH extramedullary haemopoietic EMU early morning urine EPO erythropoietin EPOCH etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone EPS electrophoresis ESHAP etoposide, methylprednisolone, cytarabine, platinum ESR erythrocyte sedimentation rate ET essential thrombocythaemia or exchange transfusion ETTL enteropathy type T-cell lymphoma FAB French–American–British FACS ﬂuorescence-activated cell sorter FBC full blood count FCM ﬂudarabine, cyclophosphamide, melphalan 18 FDG-PET ﬂuoro–D–2–deoxyglucose positron emission tomography FDP ﬁbrin degradation products Fe iron FEIBA factor eight inhibitor bypassing activity FEL familial erythrophagocytic lymphohistiocytosis FeSO4 ferrous sulphate FFP fresh frozen plasma FFS failure-free survival Fgn ﬁbrinogen FH family history FISH ﬂuorescence in situ hybridisation FITC ﬂuorescein isothiocyanate FIX factor IX xxxii SYMBOLS AND ABBREVIATIONS fL femtolitre FL follicular lymphoma FNA ﬁne needle aspirate FOB faecal occult blood FVIII factor VIII FVL factor V Leiden g gram G&S group, screen, and save G6PD glucose-6-phosphate dehydrogenase GA general anaesthetic GCS graded compression stockings G-CSF granulocyte colony stimulating factor GIT gastrointestinal tract GM-CSF granulocyte macrophage colony stimulating factor GP glycoprotein GPI glycosylphosphatidylinositol GPS gray platelet syndrome GT Glanzmann’s thrombasthenia GvHD graft versus host disease GvL graft versus leukaemia h hour H/LMW high/low molecular weight HAART highly active antiretroviral therapy HAV hepatitis A virus Hb haemoglobin HbA haemoglobin A HbA2 haemoglobin A2 HbF haemoglobin F (fetal Hb) HbH haemoglobin H HBsAg hepatitis B surface antigen HBV hepatitis B virus HC hydroxycarbamide or heavy chain HCD heavy chain disease HCG human chorionic gonadotrophin HCII heparin cofactor II HCL hairy cell leukaemia HCO3 bicarbonate Hct haematocrit HCV hepatitis C virus HD haemodialysis SYMBOLS AND ABBREVIATIONS xxxiii HDM high dose melphalan HDN haemolytic disease of the newborn HDT high dose therapy HE hereditary elliptocytosis HELLP haemolysis, elevated liver enzymes and low platelets HES hypereosinophilic syndrome HHT hereditary haemorrhagic telangiectasia HI haematological improvement HIT(T) heparin-induced thrombocytopenia (with thrombosis) HIV human immunodeﬁciency virus HL Hodgkin’s lymphoma (Hodgkin’s disease) HLA human leucocyte antigen HLH haemophagocytic lymphohistiocytosis HMP hexose monophosphate shunt HMWK high molecular weight kininogen HPA human platelet antigen HPF high power ﬁeld HPFH hereditary persistence of fetal haemoglobin HPLC high performance liquid chromatography HPP hereditary pyropoikilocytosis HRT hormone replacement therapy HS hereditary spherocytosis HTLV-1 human T-lymphotropic virus type 1 HTO high titre antibodies HUMARA human androgen receptor gene assay HUS haemolytic uraemic syndrome IAGT indirect antiglobulin test IAHS infection-associated haemophagocytic syndrome ICE ifosfamide, carboplatin, etoposide ICH intracranial haemorrhage ICUS idiopathic cytopenia of uncertain (undetermined) signiﬁcance IDA iron deﬁciency anaemia IF involved ﬁeld (radiotherapy) IFA intrinsic factor antibody IFN-A interferon alpha Ig immunoglobulin IgA immunoglobulin A IgD immunoglobulin D IgE immunoglobulin E IgG immunoglobulin G xxxiv SYMBOLS AND ABBREVIATIONS IgM immunoglobulin M IL-1 interleukin-1 IM intramuscular IMF idiopathic myeloﬁbrosis INR International normalized ratio inv chromosomal inversion IPC intermittent pneumatic compression devices IPF immature platelet fraction IPI International Prognostic Index IPSS International Prognostic Scoring System ISM Indolent systemic mastocytosis ISS International Sensitivity Index IT intrathecal ITP idiopathic thrombocytopenic purpura ITU Intensive Therapy Unit IU international units IUGR intrauterine growth retardation IUT intrauterine transfusion IV intravenous IVI intravenous infusion IVIg intravenous immunoglobulin JCMML juvenile chronic myelomonocytic leukaemia JML juvenile myelomonocytic leukaemia JVP jugular venous pressure KCT Kaolin clotting time kg kilogram L litre LA lupus anticoagulant LAP leucocyte alkaline phosphatase (score) LC light chain LCH Langerhans cell histiocytosis LDH lactate dehydrogenase LDHL lymphocyte depleted HL LFS leukaemia free survival LFTs liver function tests LGL large granular lymphocyte LLN lower limit of normal LMWH low molecular weight heparin LN lymph node(s) LP lumbar puncture SYMBOLS AND ABBREVIATIONS xxxv LPD lymphoproliferative disorder LRCHL lymphocyte rich classical HL LSCS lower segment Caesarian section LTC large transformed cells M&P melphalan and prednisolone MACOP-B methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisolone MAHA microangiopathic haemolytic anaemia MALT mucosa-associated lymphoid tissue m-BACOD methotrexate, bleomycin, adriamycin (doxorubicin), cyclophosphamide, vincristine, dexamethasone mc micro MC mast cell(s) MCH mean cell haemoglobin MCHC mean corpuscular haemoglobin concentration MCHL mixed cellularity HL MCL mast cell leukaemia or mantle cell lymphoma MCP mitoxantrone, chlorambucil, prednisolone MCR major cytogenetic response MCS mast cell sarcoma M-CSF macrophage colony stimulating factor MCV mean cell volume MDS myelodysplastic syndrome MetHb methaemoglobin MF myeloﬁbrosis mg milligram MGUS monoclonal gammopathy of undetermined signiﬁcance MHC major histocompatibility complex MI myocardial infarction min minute(s) mL millilitre MLC mixed lymphocyte culture MM multiple myeloma MMC mitomycin C MNC mononuclear cell(s) MoAb monoclonal antibody MP melphalan and prednisolone MPCM maculopapular cutaneous mastocytosis MPD myeloproliferative disease MPO myeloperoxidase MPS mononuclear phagocytic system xxxvi SYMBOLS AND ABBREVIATIONS MPT melphalan, prednisolone, and thalidomide MPV mean platelet volume MRD minimal residual disease MRI magnetic resonance imaging mRNA messenger ribonucleic acid MRSA meticillin-resistant Staphylococcus aureus MSBOS maximum surgical blood ordering schedule MSU midstream urine MT mass: thoracic MTX methotrexate MUD matched unrelated donor (transplant) MZL mantle zone lymphoma Na+ sodium NaCl sodium chloride NADP nicotinamide adenine diphosphate NADPH nicotinamide adenine diphosphate (reduced) NAIT neonatal alloimmune thrombocytopenia NAP neutrophil alkaline phosphatase NBT nitro blue tetrazolium NEJM New England Journal of Medicine NHL non-Hodgkin’s lymphoma NLPHL nodular lymphocyte predominant HL NRBC nucleated red blood cells NS nodular sclerosing NS non-secretory (myeloma) NSAIDs non-steroidal antiinﬂammatory drugs NSE non-speciﬁc esterase NSHL nodular sclerosing HL OAF OC-activating factor OB osteoblast OC osteoclast OCP oral contraceptive pill od omni die (once daily) OPG osteoprotogerin OPG orthopantomogram OR overall response OS overall survival OWR Osler–Weber–Rendu PA pernicious anaemia PAI plasminogen activator inhibitor SYMBOLS AND ABBREVIATIONS xxxvii PaO2 partial pressure of O2 in arterial blood PAS periodic acid–Schiff PB peripheral blood PBSC peripheral blood stem cell PC protein C PCC prothrombin complex concentrate PCH paroxysmal cold haemoglobinuria PCL plasma cell leukaemia PCP Pneumocystis carinii pneumonia PCR polymerase chain reaction PCV packed cell volume PD peritoneal dialysis PDGF platelet-derived growth factor PDW platelet distribution width PE pulmonary embolism PEP post-expoure prophylaxis PET pre-eclamptic toxaemia or position emission tomography PF platelet factor PFA platelet function analysis PFK phosphofructokinase PFS progression-free survival PGD2 prostaglandin D2 PGE1 prostaglandin E1 PGK phosphoglycerate kinase Ph Philadelphia chromosome PIG phosphatidylinositol glycoproteins PIVKA protein induced by vitamin K absence PK pyruvate kinase PLL prolymphocytic leukaemia PML promyelocytic leukaemia PNET primitive neuroectodermal tumour PO per os (by mouth) PPH post-partum haomorrhage PPI proton pump inhibitor PPP primary proliferative polycythaemia PRCA pure red cell aplasia PRN as required ProMACE prednisolone, doxorubicin, cyclophosphamide, etoposide PRV polycythaemia rubra vera PS protein S xxxviii SYMBOLS AND ABBREVIATIONS PSA pure sideroblastic anaemia or prostate-speciﬁc antigen PT prothrombin time PTCL peripheral T-cell lymphomas PTP pretest probability or post-transfusion purpura PUVA phototherapy with psoralen plus UV-A PV polycythaemia vera PVO pyrexia of unknown origin qds quater die sumendus (to be taken 4 times a day) QoL quality of life RA refractory anaemia RAEB refractory anaemia with excess blasts RAEB-t refractory anaemia with excess blasts in transformation RAR retinoic acid receptor RARS refractory anaemia with ring sideroblasts RBC red blood cell RCC red blood cell count RCM red cell mass RCMD refractory cytopenia with multilineage dysplasia RDS respiratory distress syndrome RDW red cell distribution width RE relative erythrocytosis; reticuloendothelial REAL Revised European American Lymphoma RES reticuloendothelial system RFLP restriction fragment length polymorphism Rh Rhesus rhAPC recombinant human activated protein C rhG-CSF recombinant human granulocyte colony stimulating factor rHuEPO recombinant human erythropoietin RI remission induction RIA radioimmunoassay RIC reduced-intensity conditioning RiCoF ristocetin cofactor RIPA ristocetin-induced platelet agglutination RS Reed–Sternberg or ringed sideroblasts RT reptilase time RT-PCR reverse transcriptase polymerase chain reaction s second(s) SAA serum amyloid A protein SAGM saline adenine glucose mannitol SaO2 arterial oxygen saturation SYMBOLS AND ABBREVIATIONS xxxix SAP serum amyloid P protein SBP solitary plasmacytoma of bone SC subcutaneous SCA sickle cell anaemia SCBU special care baby unit SCD sickle cell disease SCID severe combined immunodeﬁciency SCT stem cell transplantation or silica clot time SD standard deviation SE secondary erythrocytosis SEP extramedullary plasmacytoma SLE systemic lupus erythematosus SLL small lymphocytic lymphoma SLVL splenic lymphoma with villous lymphocytes SM systemic mastocytosis SM-AHNMD systemic mastocytosis with an associated clonal haemato logical non-mast cell lineage disease SmIg surface membrane immunoglobulin SMZL splenic marginal zone lymphoma SOB short of breath SPB solitary plasmacytoma of bone SPD storage pool disorders/deﬁciency stat statim (immediate; as initial dose) sTfR soluble transferrin receptor SVC superior vena cava SVCO superior vena caval obstruction T° (4T°) temperature (fever) t½ half-life T4 thyroxine TAM transient abnormal myelopoiesis TAR thrombocytopenia with absent radius TB tuberculosis TBI total body irradiation TCR T-cell receptor tds ter die sumendum (to be taken 3 times a day) TdT terminal deoxynucleotidyl transferase TEC transient erythroblastopenia of childhood TEG thromboelastography TENS transcutaneous nerve stimulation TF tissue factor TFT thyroid function test(s) xl SYMBOLS AND ABBREVIATIONS TGF-B transforming growth factor-B TI transfusion-independence TIAs transient ischaemic attacks TIBC total iron binding capacity tiw three times in a week TNF tumour necrosis factor topo II topoisomerase II TORCH toxoplasmosis, rubella, cytomegalovirus, herpes sim TPA tissue plasminogen activator TPI triphosphate isomerase TPN total parenteral nutrition TPO thrombopoietin TPR temperature, pulse, respiration TRAP tartrate-resistant acid phosphatase TRM treatment related mortality TSE transmissible spongiform encephalopathy TSH thyroid-stimulating hormone TT thrombin time TTP thrombotic thrombocytopenic purpura TXA tranexamic acid TXA2 thromboxane A2 U&E urea and electrolytes U unit(s) UC ulcerative colitis UFH unfractionated heparin URTI upper respiratory tract infection US ultrasound USS ultrasound scan UTI urinary tract infection VAD vincristine adriamycin dexamethasone regimen VBAP vincristine, carmustine (BCNU), doxorubicin, prednisolone VBMCP vincristine, carmustine, melphalan, cyclophosphamide, prednisolone VC vena cava VDRL Venereal Disease Research Laboratory VEGF vascular endothelial growth factor VF ventricular ﬁbrillation VIII:C factor VIII clotting activity Vit K vitamin K VMCP vincristine, melphalan, cyclophosphamide, prednisolone SYMBOLS AND ABBREVIATIONS xli VMP melphalan, prednisolone, bortezomib VOD veno-occlusive disease VTE venous thromboembolism vWD von Willebrand disease vWF von Willebrand factor vWFAg von Willebrand factor antigen WAS Wiskott–Aldrich syndrome WBC white blood cell WBRT whole brain radiotherapy WCC white cell count WM Waldenström macroglobulinaemia X match cross-match XDPs cross-linked ﬁbrin degradation products This page intentionally left blank Chapter 1 1 Clinical approach History taking in patients with haematological disease 2 Physical examination 4 Splenomegaly 5 Lymphadenopathy 6 Unexplained anaemia 8 Patient with elevated haemoglobin 10 Elevated WBC 12 Reduced WBC 14 Elevated platelet count 16 Reduced platelet count 18 Easy bruising 20 Recurrent thromboembolism 22 Pathological fracture 23 Raised ESR 24 Serum or urine paraprotein 25 Anaemia in pregnancy 26 Thrombocytopenia in pregnancy 27 Prolonged bleeding after surgery 28 Positive sickle test (HbS solubility test) 30 2 CHAPTER 1 Clinical approach History taking in patients with haematological disease Approach to patient with suspected haematological disease An accurate history combined with a careful physical examination are fun- damental parts of clinical assessment. Although the likely haematological diagnosis may be apparent from tests carried out before the patient has been referred, it is nevertheless essential to assess the clinical background fully—this may inﬂuence the eventual plan of management, especially in older patients. It is important to ﬁnd out early on in the consultation what the patient may already have been told prior to referral, or what he/she thinks the diagnosis may be. There is often fear and anxiety about diagnoses such as leukaemia, haemophilia, or HIV infection. Presenting symptoms and their duration A full medical history needs to be taken to which is added direct ques- tioning on relevant features associated with presenting symptoms: Non-speciﬁc symptoms such as fatigue, fevers, weight loss. Symptoms relating to anaemia e.g. reduced exercise capacity, recent onset of breathlessness and nature of its onset, or worsening of angina, presence of ankle oedema. Symptoms relating to neutropenia e.g. recurrent oral ulceration, skin infections, oral sepsis. Evidence of compromised immunity e.g. recurrent oropharyngeal infection. Details of potential haemostatic problems e.g. easy bruising, bleeding episodes, rashes. Anatomical symptoms e.g. abdominal discomfort (splenic enlargement or pressure from enlarged lymph nodes), CNS symptoms (from spinal compression). Past medical history i.e. detail on past illnesses, information on previous surgical procedures which may suggest previous haematological problems (e.g. may suggest an underlying bleeding diathesis) or be associated with haematological or other sequelae e.g. splenectomy. Drug history: ask about prescribed and non-prescribed medications. Allergies: since some haematological disorders may relate to chemicals or other environmental hazards speciﬁc questions should be asked about occupational factors and hobbies. Transfusion history: ask about whether the patient has been a blood donor and how much he/she has donated. May occasionally be a factor in iron (Fe) deﬁciency anaemia. History of previous transfusion(s) and their timing is also critical in some cases e.g. post-transfusion purpura. Tobacco and alcohol consumption is essential; both may produce signiﬁcant haematological morbidity. Travel: clearly important in the case of suspected malaria but also relevant in considering other causes of haematological abnormality, including HIV infection. HISTORY TAKING IN PATIENTS WITH HAEMATOLOGICAL DISEASE 3 Family history is also important, especially in the context of inherited haematological disorders. A complete history for a patient with a haematological disorder should provide all the relevant medical information to aid diagnosis and clinical assessment, as well as helping the haematologist to have a working assess- ment of the patient’s social situation. A well taken history also provides a basis for good communication which will often prove very important once it comes to discussion of the diagnosis. 4 CHAPTER 1 Clinical approach Physical examination This forms part of the clinical assessment of the haematology patient. Pay speciﬁc attention to: General examination—e.g. evidence of weight loss, pyrexia, pallor (the latter is not a reliable clinical measure of anaemia), jaundice, cyanosis or abnormal pigmentation or skin rashes. The mouth—ulceration, purpura, gum bleeding, or inﬁltration, and the state of the patient’s teeth. Hands and nails may show features associated with haematological abnormalities e.g. koilonychia in chronic Fe deﬁciency (rarely seen today). Record—weight, height, T°, pulse, and blood pressure; height and weight give important baseline data against which sequential measurements can subsequently be compared. In myeloﬁbrosis, for example, evidence of sig- niﬁcant weight loss in the absence of symptoms may be an indication of clinical progression. Examination—of chest and abdomen should focus on detecting the pres- ence of lymphadenopathy, hepatic and/or splenic enlargement. Node sizes and the extent of organ enlargement should be carefully recorded. Lymph node enlargement—often recorded in centimetres e.g. 3cm x 3cm x 4cm; sometimes more helpful to compare the degree of enlargement with familiar objects e.g. pea. Record extent of liver or spleen enlargement as maximum distance palpable from the lower costal margin. Erythematous margins of infected skin lesions—mark these to monitor treatment effects. Bones and joints—recording of joint swelling and ranges of movement are standard aspects of haemophilia care. In myeloma, areas of bony tender- ness and deformity are commonly present. Optic fundi—examination is a key clinical assessment in the haematology patient. May yield the only objective evidence of hyperviscosity in parap- roteinaemias (b Hyperviscosity, p.640) or hyperleucocytosis (b p.655) such as in e.g. CML. Regular examination for haemorrhages should form part of routine observations in the severely myelosuppressed patient; rarely changes of opportunistic infection such as candidiasis can be seen in the optic fundi. Neurological examination—ﬂuctuations of conscious level and confu- sion are clinical presentations of hyperviscosity. Isolated nerve palsies in a patient with acute leukaemia are highly suspicious of neurological involvement or disease relapse. Peripheral neuropathy and long tract signs are well recognized complications of B12 deﬁciency. SPLENOMEGALY 5 Splenomegaly Many causes. Clinical approach depends on whether splenic enlargement is present as an isolated ﬁnding or with other clinical abnormalities e.g. jaundice or lymphadenopathy. Mild-to-moderate splenomegaly has a much greater number of causes than massive splenomegaly. Table 1.1 Causes of splenomegaly Infection Viral EBV, CMV, hepatitis Bacterial SBE, miliary tuberculosis, Salmonella, Brucella Protozoal Malaria, toxoplasmosis, leishmaniasis Haemolytic Congenital Hereditary spherocytosis, hereditary elliptocytosis, sickle cell disease (infants), thalassaemia, pyruvate kinase deﬁciency, G6PD deﬁciency Acquired AIHA (idiopathic or 2°) Myeloproliferative and Myeloﬁbrosis, CML, polycythaemia leukaemic rubra vera, essential thrombocythaemia, acute leukaemias Lymphoproliferative CLL, hairy cell leukaemia, Waldenström’s, SLVL, other NHL, Hodgkin lymphoma, ALL and lymphoblastic NHL Autoimmune Rheumatoid arthritis, SLE, hepatic disorders and storage cirrhosis, Gaucher’s disease, disorders histiocytosis X, Niemann–Pick disease Miscellaneous Metastatic cancer, cysts, amyloid, portal hypertension, portal vein thrombosis, tropical splenomegaly Clinical approach essentially involves a working knowledge of the possible causes of splenic enlargement and determining the more likely causes in the given clinical circumstances by appropriate further investigation. There are fewer causes of massive splenic enlargement, i.e. the spleen tip pal- pable below the level of the umbilicus. Massive splenomegaly Myeloﬁbrosis. CML. Lymphoproliferative disease—CLL and variants including SLVL, HCL, and marginal zone lymphoma. Tropical splenomegaly. Leishmaniasis. Gaucher’s disease. Thalassaemia major. 6 CHAPTER 1 Clinical approach Lymphadenopathy Occurs in a range of infective or neoplastic conditions; less frequently enlargement occurs in active collagen disorders. May be isolated, affecting a single node, localized, involving several nodes in an anatomical lymph node grouping, or generalized, where nodes are enlarged at different sites. As well as enlargement in the easily palpable areas (cervical, axillary, and iliac) node enlargement may be hilar or retroperitoneal and identiﬁable only by imaging. Isolated/localized lymphadenopathy usually results from local infection or neoplasm. Generalized lymphadenopathy may result from systemic causes, especially when symmetrical, as well as infection or neoplasm. Rarely drug-associated (e.g. phenytoin). Table 1.2 Causes of lymphadenopathy Infective Bacterial Tonsillitis, cellulitis, tuberculous infections, and p syphilis usually produce isolated or localized node enlargement Viral EBV, CMV, rubella, HIV, HBV, HCV Other Toxoplasma, histoplasmosis, chlamydia, cat-scratch Neoplastic Hodgkin lymphoma (typically isolated or localized lymphadenopathy), NHL isolated, generalized or localized, CLL, metastatic carcinoma, acute leukaemia (ALL especially, but occasionally AML) Collagen and other E.g. rheumatoid arthritis, SLE, sarcoidosis systemic disorders History and examination—points to elicit Age. Onset of symptoms, whether progressing or not. Systemic symptoms, weight loss (>10% body weight loss in 50 x 109/L deﬁnes a neutrophilia with marked ‘left shift’ (band forms, metamyelocytes, myelocytes, and occasionally promyelocytes and myeloblasts in the blood ﬁlm). Differential diagnosis is CGL and in children, juvenile CML. Primitive granulocyte precursors are also frequently seen in the blood ﬁlm of the infected or stressed neonate, and any seriously ill patient e.g. on ITU. Leucoerythroblastic blood ﬁlm—contains myelocytes, other primitive granulocytes, nucleated red cells, and often tear drop red cells, is due to BM invasion by tumour, ﬁbrosis, or granuloma formation and is an indica- tion for a BM biopsy. Other causes include anorexia and haemolysis. Leucocytosis due to blasts—suggests diagnosis of acute leukaemia and is an indication for cell typing studies and BM examination. FBC, blood ﬁlm, white cell differential count, and the clinical context in which the leucocytosis is detected will usually indicate whether this is due to a 1° haematological abnormality or reﬂects a 2° response. 2 It is clearly important to seek a history of symptoms of infection and examine the patient for signs of infection or an underlying haematological disorder. Neutrophilia 2° to acute infection is most common cause of leucocytosis. Usually modest (uncommonly >30 x 109/L), associated with a left shift and occasionally toxic granulation or vacuolation of neutrophils. Chronic inﬂammation causes less marked neutrophilia often associated with monocytosis. Moderate neutrophilia may occur following steroid therapy, heatstroke, and in patients with solid tumours. Mild neutrophilia may be induced by stress (e.g. immediate postoperative period) and exercise. May be seen following a myocardial infarction or major seizure. Frequently found in states of chronic BM stimulation (e.g. chronic haemolysis, ITP) and asplenia. Primary haematological causes of neutrophilia are less common. CML is often the cause of extremely high leucocyte counts (>200 x 109/L), predominantly neutrophils with marked left shift, basophilia and occasional myeloblasts. A low LAP score (seldom used now) and the presence of the Ph chromosome on karyotype analysis are usually helpful to differentiate CGL from a leukaemoid reaction. ELEVATED WBC 13 Less common are juvenile CML, transient leukaemoid reaction in Down syndrome, hereditary neutrophilia, and chronic idiopathic neutrophilia. BM examination is rarely necessary in the investigation of a patient with isolated neutrophilia. Investigation of a leukaemoid reaction, leucoeryth- roblastic blood ﬁlm, and possible CGL or juvenile CML are ﬁrm indica- tions for a BM aspirate and trephine biopsy. BM culture, including culture for atypical mycobacteria and fungi, may be useful in patients with per- sistent pyrexia or leucocytosis. Lymphocytosis Lymphocytosis >4.0 x 109/L. Normal infants and young children 50 x 109/L). Acute infectious lymphocytosis also seen in children, usually associated with transient lymphocytosis and a mild constitutional reaction. Characteristic of infectious mononucleosis but these lymphocytes are often large and atypical and the diagnosis may be conﬁrmed with a heterophil agglutination test (Monospot®; Paul–Bunnell). Similar atypical cells may be seen in patients with CMV and hepatitis A infection. Chronic infection with brucellosis, tuberculosis, s syphilis, and congenital syphilis may cause lymphocytosis. Lymphocytosis is characteristic of CLL, ALL, and occasionally NHL. Where a p haematological cause is suspected, immunophenotypic anal- ysis of the peripheral blood lymphocytes will often conﬁrm or exclude a neoplastic diagnosis. BM examination is indicated if neoplasia is strongly suspected and in any patient with concomitant neutropenia, anaemia, or thrombocytopenia, or if there are constitutional symptoms e.g. sweats, weight loss. 14 CHAPTER 1 Clinical approach Reduced WBC It is uncommon for absolute leucopenia (WBC 30g/L of IgG or >20g/L of IgA or heavy Bence Jones proteinuria; BM >10% plasma cells; lytic bone lesions on x-ray. Minimum diagnostic cri- teria are at least 2 of italicized items. Plasma cell leukaemia—as myeloma but fulminant history. Plasma cells seen on blood ﬁlm. Heavy chain disease—rare, characterized by a single heavy chain only in serum or urine electrophoresis. Presence of any light chain excludes. Amyloid—myriad clinical features. Diagnosis on biopsy of affected site or, if inaccessible, by BM or rectal biopsy—characteristic ﬁbrils stain with Congo Red and show green birefringence in polarized light. CLL and NHL—systemic symptoms e.g. fever, night sweats, weight loss. Lymphadenopathy or hepatosplenomegaly likely. Conﬁrm on BM or node biopsy. Waldenström’s—as for CLL but with symptoms or signs of hyperviscosity (b Waldenström’s macroglobulinaemia, p366). Autoimmune disorders—suggested by joint pain, skin rashes, multisystem disease. Conﬁrm on autoimmune proﬁle including rheumatoid factor, ANA, ANCA. b See Multiple myeloma, p.330. 26 CHAPTER 1 Clinical approach Anaemia in pregnancy Physiological changes in red cell and plasma volume occur during preg- nancy. Red cell mass i by ≤30%. Plasma volume i ≤60%. Net effect to i blood volume by ≤50% with lowering of the normal Hb concentration to 10.0–11.0g/dL during pregnancy. MCV i during pregnancy. Fe deﬁciency is a common problem and cause of anaemia in pregnancy. Table 1.9 Iron utilization in pregnancy Cause of i requirements Amount of additional Fe i Red cell mass 7500mg Fetal requirements 7300mg Placental requirements 75mg Basal losses over pregnancy (1.0–1.5mg/d) 7250mg These result in a total requirement of ≤1000mg Fe requiring an average daily intake of 3.5–4.0mg/d. Average Western diet provides

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