Hematological emergencies Septic shock/neutropenic fever E p636 Acute transfusion reactions E p638 Delayed transfusio n reaction E p642 Post-transfusion purpura E p643 Hypercalcaemia E p644 Hyperviscosity E p6 46 Disseminated intravascular coagulation E p648 Overdosage of thrombolytic therapy E p651 Heparin overdosage E p652 Heparin-induced thrombocytopenia (HIT) E p654 Warfarin overdosage E p656 Massive blood transfusion E p658 Paraparesis/spinal collapse E p662 Leucostasis E p 663 Thrombotic thrombocytopenic purpura E p664 Sickle crisis E p666 Tumor lysis syndrome (T LS) E p690 oxford medical publications Oxford Handbook of Clinical Hematology Published and upcoming Oxford Handbooks Oxford Handbook for the Foundation Program 4/e Oxfo rd Handbook of Acute Medicine 3/e Oxford Handbook of Anesthesia 2/e Oxford Handbook of Appl ied Dental Sciences Oxford Handbook of Cardiology 2/e Oxford Handbook of Clinical and Labor atory Investigation 2/e Oxford Handbook of Clinical Dentistry 6/e Oxford Handbook of Clinic al Diagnosis 3/e Oxford Handbook of Clinical Examination and Practical Skills 2/e Oxford Ha ndbook of Clinical Hematology 4/e Oxford Handbook of Clinical Immunology and Allergy 3/e Ox ford Handbook of Clinical Medicine \200\224Mini Edition 9/e Oxford Handbook of Clinical Med icine 9/e Oxford Handbook of Clinical Drugstore Oxford Handbook of Clinical Rehabilitation 2/e Oxford Handbook of Clinical Specialties 9/e Oxford Handbook of Clinical Surgery 4/e Oxf ord 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 Me dicine 4/e Oxford Handbook of Endocrinology and Diabetes 3/e Oxford Handbook of ENT and Hea d and Neck Surgery Oxford Handbook of Epidemiology for Clinicians Oxford Handbook of Expedi tion and Wilderness Medicine Oxford Handbook of Gastroenterology and Hepatology Oxford Hand book of General Practice 4/e Oxford Handbook of Genitourinary Medicine, HIV and AIDS Oxford Handbook of Geriatric Medicine 2/e Oxford Handbook of Infectious Diseases and Microbiology Oxford Handbook of Key Clinical Evidence Oxford Handbook of Medical Sciences 2/e Oxford Ha ndbook of Nephrology and Hypertension 2/e Oxford Handbook of Neurology 2/e Oxford Handbook of Nutrition and Dietetics Oxford Handbook of Obstetrics and Gynecology 3/e Oxford Handbook of Occupational Health 2/e Oxford Handbook of Oncology 3/e Oxford Handbook of Ophthalmolog y 3/e Oxford Handbook of Pediatrics 2/e Oxford Handbook of Palliative Care 2/e Oxford Handb ook of Practical Drug Therapy Oxford Handbook of Pre-Hospital Care Oxford Handbook of Psych iatry 2/e Oxford Handbook of Public Health Practice 3/e Oxford Handbook of Reproductive Med icine and Family Planning 2/e Oxford Handbook of Respiratory Medicine 3/e Oxford Handbook o f Rheumatology 3/e Oxford Handbook of Sport and Exercise Medicine Oxford Handbook of Tropic al Medicine 4/e Oxford Handbook of Urology 3/e Oxford Handbook of Clinical Hematology FOURTH EDITION Drew Provan Reader in Hematology Barts & The London School of Medicine and Dentistry Queen Mary University of London, UK Trevor Baglin Consultant Hematologist Addenbrooke \200\231s NHS Trust Cambridge, UK Inderjeet Dokal Chair of Child Health and Center Lead Barts & The London School of Medicine and Dentistry Queen Mary University of London Honorary Consultant Barts Health NHS Trust L ondon, UK Johannes de Vos Consultant Hematologist Royal Surrey County Hospital NHS Foundation Trust G uildford, UK 1 1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the Univer sity \200\231s objective of excellence in research, scholarship, and education by publishin g worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Oxford University Press 2015 The moral rights of the authors have been asserted First Edition published in 1998 Second Edition published in 2004 Third Edition published in 2009 Fourth Edition published in 2015 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval s ystem, 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, by license or under terms ag reed with the appropriate reprographics rights organization. Enquiries concerning reproduct ion outside the scope of the above should be sent to the Rights Department, Oxford Universi ty Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, Ne w York, NY 10016, United States of America British Library Cataloging in Publication Data Data available Library of Congress Control Number: 2014943849 Typeset by Greengate Publishing Services, Tonbridge, UK ISBN 978-0-19-968330-7 Printed in China by C&C Off set Printing Co. Ltd 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 c linical procedures with the most up-to-date published product information and data sheets p rovided by the manufacturers and the most recent codes of conduct and safety regulations. T he authors and the publishers do not accept responsibility or legal liability for any error s in the text or for the misuse or misapplication of material in this work. Except where ot herwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breast-feeding. Links to third party websites are provided by Oxford in good faith and for information only . Oxford disclaims any responsibility for the materials contained in any third party websit e referenced in this work. v Preface to the fourth edition The world of hematology has been exciting over the past few years, and we have seen major a dvances since the third edition of the Oxford Handbook of Clinical Hematology was published . These are most obvious in haemato-oncology, with the development of new agents and regime ns for treating malignant hematology disorders. But there have also been advances in haemos tasis and red cell hematology with the arrival of the novel oral anticoagulation drugs and new oral chelators for the treatment of iron overload, in addition to a number of other adv ances. This edition sees a change of editorial team and we are very happy to have John de Vos, hae mato-oncologist, on board. He has overhauled the haemato-oncology sections bringing them th oroughly up to date. We have also sought the advice of Shubha Allard, consultant in transfu sion medicine, to make sure the blood transfusion section is accurate, in addi- tion to Ban u Kaya, a red cell hematologist who has brought the red cell material up to date. For the fi rst time, we have incorporated a new chapter on rare disor- ders which we hope readers will fi nd useful. We are very grateful to the editorial team at Oxford University Press for their patience an d hard work, especially Liz Reeve and Michael Hawkes. There may be errors or omissions from the book and we would welcome any comments or feedbac k (email drewprovan@mac.com). We will try to incorporate these in future editions. DP TB ID JdV January 2014 vi 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, Hematology has seen major inroads with new diag nostic tests, treatments and a plethora of guidelines. In fact, Hematology has the largest collection of guidelines covering all aspects of hematology care (M http://www. bcshguideli nes. com) and was the fi rst specialty to design guidelines in the 1980s. The book underwent a major revision with the second edition, most notably the sections deal ing 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 ref l ects the current investigation and management of coagulation disorders. Following the ret irement of Professor Sir John Lilleyman we needed to fi nd a new author for the Pediatric H ematology component of the book. Thankfully, we were able to persuade Professor Inderjeet D okal to take on this mantle and he has revised this section thoroughly. In addition to these signifi cant changes, we have gone through the entire book and attempt ed to ensure that obsolete tests have been removed and that the Handbook, in its entirety, refl ects contemporary hematology practice. As ever, we are very keen to hear about errors or omissions, for which we are entirely resp onsible! 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. We also need more traine e input so if there are any volunteer proof-readers or accuracy checkers among the hematolo gy trainee community we would very much like to hear from you. DP CRJS TB ISD 2008 vii Foreword to the fourth edition The Concise Oxford English Dictionary defi nes a handbook as \200\230a short manual or gui de \200\231. Modern hematology is a vast fi eld which involves almost every other medical s pecialty and which, more than most, straddles the worlds of the basic biomedical sciences a nd clinical prac- tice. 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 f i elds 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 expe cted to introduce large slices of molecular biology, social science, ethics, and communicat ion skills, not to mention a liberal sprin- kling of poetry, music, and art. In this over-heated educational scene the much maligned \200\230handbook \200\231 could we ll stage a comeback and gain new respectability, particularly in the role of a friendly gui de. In the past this genre has often been viewed as having little intellectual standing, of no use to anybody except the panic-stricken student who wishes to try to make up for month s of mis- spent time in a vain, one-night sitting before their fi nal examination. But give n the plethora of rapidly changing information that has to be assimi- lated, the carefully prepared pr cis is likely to play an increasingly impor- tant role in medical education. P erhaps even that ruination of the decent paragraph and linchpin of the pronouncements of me dical bureaucrats, the \200\230bullet point \200\231, may become acceptable, albeit in sma ll doses, as attempts are made to highlight what is really important in a scientifi c or cl inical fi eld of enormous complexity and not a little uncertainty. In the fourth edition of this short account of blood diseases the editors have continued to provide an excellent service to medical students, as well as doctors who are not specialis ts in blood diseases, by summarizing in simple terms the major features and approaches to d iagnosis and manage- ment of most of the blood diseases that they will encounter in routine clinical practice or in the tedious examinations that face them. And, of equal importance, they have been able to update and summarize some of the major advances that have been made in this rapidly moving fi eld since the appearance of the early editions of this handbook. As in previous edi- tions they have managed to avoid one of the major pitfalls of this typ e of teaching: in trying to reduce complex issues down to their bare bones it is all too ea sy to introduce inaccuracies. One word of warning from a battle-scarred clinician however. A pr cis of this type suff er s 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 \200\230typical case \200\231 of anyt hing. Thus the viii FOREWORD TO THE FOURTH EDITION 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, students will fi nd that it is a very v aluable summary of modern haema- tology; the addition of the Internet sources is a genuine and timely bonus. D. J. Weatherall Oxford, June 2014 ix Contents Acknowledgements x Contributors xi Symbols and abbreviations xiii 1 Clinical approach 2 Red cell disorders 3 White blood cell abnormalities 4 Leukemia 5 Lymp homa 6 Myelodysplasia 7 Myeloproliferative neoplasms 8 Paraproteinaemias 9 Haematopoietic s tem cell transplantation 10 Haemostasis and thrombosis 11 Immunodefi ciency 12 Pediatric he matology 13 Hematological emergencies 14 Supportive care 15 Protocols and procedures 16 Hem atological investigations 17 Blood transfusion 18 Rare diseases 1 31 113 123 181 227 257 325 387 453 545 559 635 667 675 745 759 783 Appendix 1 Hematology online Appendix 2 Charts and nomograms Appendix 3 Normal ranges 795 803 809 Index 813 x Acknowledgements We are indebted to many of our colleagues for providing helpful suggestions and for proofre ading the text. In particular we wish to thank Dr Helen McCarthy, Specialist Registrar in H ematology; Dr Jo Piercy, Specialist Registrar in Hematology; Dr Tanay Sheth, SHO in Hematol ogy, Southampton; Sisters Clare Heather and Ann Jackson, Hematology Day Unit, Southampton G eneral Hospital; Dr Mike Williams, Specialist Registrar in Anesthetics; Dr Frank Boulton, W essex Blood Transfusion Service, Southampton; Dr Paul Spargo, Consultant Anesthetist, South ampton University Hospitals; Dr Sheila Bevin, Staff Grade Pediatrician; Dr Mike Hall, Consu ltant Neonatologist; Dr Judith Marsh, Consultant Hematologist, St George \200\231s Hospital , London; Joan Newman, Hematology Transplant Coordinator, Southampton; Professor Sally Davi es, Consultant Hematologist, Imperial College School of Medicine, Central Middlesex Hospita l, London; Dr Denise O \200\231Shaughnessy, Consultant Hematologist, Southampton University Hospitals NHS Trust; Dr Kornelia Cinkotai, Consultant Hematologist, Barts and The London N HS Trust; Dr Mansel Haeney, Consultant Immunologist, Hope Hospital, Salford; Dr Adam Mead, Specialist Registrar Barts and The London; Dr Chris Knechtli, Consultant Hematologist, Roya l United Hospital, Bath; Dr Toby Hall, Consultant Radiologist, Royal United Hospital Bath, Craig Lewis, Senior Biomedical Scientist, Royal United Hospital Bath, Bob Maynard, Senior B iomedical 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 Du ncombe for their contributions to the fi rst edition of the handbook. Three Barts & The Lon don SpRs helped edit some of the sections of the third edition, namely Drs John de Vos, Tom Butler, and Jay Pandya. Dr Jim Murray, Queen Elizabeth Hospital, Birmingham, corrected the \200\230Hematological emergencies \200\231 section, though he did this in error since he was supposed to be proof- reading something completely diff erent 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 Kat e 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. xi Contributors Shubha Allard Consultant Hematologist Barts Health NHS Trust, and NHS Blood & Transplant, U K Banu Kaya Consultant Hematologist Barts Health NHS Trust, UK This page intentionally left blank xiii Symbols and abbreviations E d i 2 3 n M \231\200 \231\202 1 2 2,3 DPG 2-CDA A2-M 6-MP 99mTc-MIBI AA Ab ABVD cross-reference decreased increased important very important normal website female male pri mary secondary 2,3 diphosphoglycerate 2-chlorodeoxyadenosine alpha-2 microglobulin 6-mercap topurine 99mTc methoxyisobutyl-isonitride or 99mTc-MIBI scintigraphy aplastic anemia or rea ctive amyloidosis antibody adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine ac id-citrate-dextrose or anemia of chronic disease angiotensin converting-enzyme anticardioli pin antibody atypical chronic myeloid leukemia adenosine deaminase cytosine arabinoside (Ar a-C) daunorubicin etoposide adenosine 5-diphosphate acid-fast bacilli antigen acquired immu nodefi ciency syndrome autoimmune haemolytic anemia autoimmune neutropenia angio-immunoblas tic T-cell lymphoma (1 ) amyloidosis serum albumin ACD ACE ACL ACML ADA ADE ADP AFB Ag AIDS AIHA AIN AITL AL ALB xiv SYMBOLS AND ABBREVIATIONS ALCL ALG ALIPs ALL ALS ALT AML AMP ANA ANAE ANCA ANH APC APCR APL APML APS APTR APTT ARDS A RF ARMS ASCT AST AT (ATIII) ATCML ATG ATLL ATP ATRA A-V AvWS 2-M BAL B-CLL bd BEAC anaplastic large cell lymphoma antilymphocyte globulin abnormal localization of immature my eloid precursors acute lymphoblastic leukemia advanced life support alanine aminotransferas e acute myeloid leukemia adenosine monophosphate antinuclear antibodies alpha naphthyl acet ate esterase antineutrophilic cytoplasmic antibody acute normovolaemic haemodilution activa ted protein C activated protein C resistance antiphospholipid antibody acute promyelocytic leukemia antiphospholipid syndrome activated partial thromboplastin ratio activated partial thromboplastin time adult respiratory distress syndrome acute renal failure amplifi cation refractory mutation system autologous stem cell transplantation aspartate aminotranferase antithrombin III adult-type chronic myeloid (granulocytic) leukemia antithymocyte globulin adult T-cell leukemia/lymphoma adenosine triphosphate all-trans retinoic acid arteriovenous acquired von Willebrand syndrome beta-2-microglobulin broncho-alveolar lavage B-cell chron ic lymphocytic leukemia bis die (twice daily) BCNU (Carmustine), etoposide, cytosine, cyclo phosphamide BCNU (Carmustine), etoposide, cytarabine (ara-C), melphalan BEAM xv SYMBOLS AND ABBREVIATIONS BFU-E BJP BL BM BMJ BMM BMT BNF BP BPL BSS BTG BU C/I Ca Ca2+ CABG cALL CAMT CaPO4 CBA CBV CCF CCR CD CDA cDNA CEL CGL CHAD CHOP CJD Cl \210\222 CLD CLL CM CMC CML CMML CMV burst-forming unit-erythroid Bence Jones protein Burkitt lymphoma bone marrow British Medic al Journal bone marrow mastocytosis bone marrow transplantation British National Formulary blood pressure BioProducts Laboratory Bernard \200\223Soulier syndrome -thromboglobulin B ethesda units consolidation/intensifi cation carcinoma calcium coronary artery bypass graft common acute lymphoblastic leukemia congenital amegakaryocytic thrombocytopenia calcium ph osphate collagen binding activity cyclophosphamide, carmustine (BCNU), etoposide congestive cardiac failure complete cytogenetic response cluster diff erentiation or designation cong enital dyserythropoietic anemia complementary DNA chronic eosinophilic leukemia chronic gra nulocytic leukemia cold haemagglutinin disease cyclophosphamide, doxorubicin, vincristine, prednisolone Creutzfeldt \200\223Jakob disease (v = variant) chloride chronic liver disease chronic lymphocytic ( \200\230lymphatic \200\231) leukemia cutaneous mastocytosis chronic mucocutaneous candidiasis chronic myeloid leukemia chronic myelomonocytic leukemia cytomega lovirus xvi SYMBOLS AND ABBREVIATIONS CNS COAD COC CR CRF CRP CRVT CsA CSF CT CTLp CTZ CVA CVP central nervous system chronic obstructive airways disease combined oral contraceptive comp lete remission chronic renal failure C-reactive protein central retinal venous thrombosis c iclosporin A cerebrospinal fl uid computed tomography cytotoxic T-lymphocyte precursor assa ys chemoreceptor trigger zone cerebrovascular accident cyclophosphamide, vincristine, predn isolone; central venous pressure chorionic villus sampling cardiovascular system chest x-ra y ciclosporin A cytarabine, bleomycin, vincristine, methotrexate day direct antiglobulin te st direct antiglobulin test daunorubicin, cytosine (Ara-C), deoxy ATP Diamond \200\223Black fan anemia dyskeratosis congenita dendritic cell system direct Coombs \200\231 test desamin o D-arginyl vasopressin detection of early antigen fl uorescent foci diepoxy butane disease -free survival dexamethasone, cytarabine, cisplatin delayed intensifi cation disseminated i ntravascular coagulation decilitre diff use large B-cell lymphoma donor leucocyte/lymphocyt e infusion dimethyl sulphoxide deoxyribonucleic acid CVS CVS CXR CyA CytaBOM d DAGT DAT dATP DBA DC DCS DCT DDAVP DEAFF DEB DFS DHAP DI DIC dL D LBCL DLI DMSO DNA xvii SYMBOLS AND ABBREVIATIONS DOB DPG DRVVT DTT DVT DXT EACA EBV EBVP ECG ECOG EDTA EEC EFS EGF ELISA EMEA EMH EMU EPO EP OCH date of birth diphosphoglycerate dilute Russell \200\231s viper venom time/test dilute thro mboplastin time deep vein thrombosis radiotherapy epsilon aminocaproic acid Epstein \200 \223Barr virus etoposide, bleomycin, vinblastine, prednisolone electrocardiograph European Co-operative Oncology Group ethylenediamine tetraacetic acid endogenous erythroid colonies event-free survival epidermal growth factor enzyme-linked immunosorbent assay European Medi cines Agency extramedullary haemopoietic early morning urine erythropoietin etoposide, vinc ristine, doxorubicin, cyclophosphamide, prednisone electrophoresis etoposide, methylprednis olone, cytarabine, platinum erythrocyte sedimentation rate essential thrombocythaemia or ex change transfusion enteropathy type T-cell lymphoma French \200\223American \200\223British fl uorescence-activated cell sorter full blood count fl udarabine, cyclophosphamide, melph alan 18fl uoro \200\223D \200\2232 \200\223deoxyglucose positron emission tomography fi bri n degradation products iron factor eight inhibitor bypassing activity familial erythrophago cytic lymphohistiocytosis ferrous sulfate fresh frozen plasma failure-free survival fi brin ogen EPS ESHAP ESR ET ETTL FAB FACS FBC FCM FDG-PET FDP Fe FEIBA FEL FeSO4 FFP FFS Fgn xviii SYMBOLS AND ABBREVIATIONS FH FISH FITC FIX fL FL FNA FNHTR FOB FVIII FVL g G&S G6PD GA GCS G-CSF GI GIT GM-CSF GP GPI GPS GT GvHD GvL h HAART HAV Hb HbA HbA2 HbF HbH HBsAg HBV HC HCD HCG HCII family history fl uorescence in situ hybridization fl uorescein isothiocyanate factor IX fe mtolitre follicular lymphoma fi ne needle aspirate febrile non-haemolytic transfusion react ion fecal occult blood factor VIII factor V Leiden gram group, screen, and save glucose-6-p hosphate dehydrogenase general anesthetic graded compression stockings granulocyte colony s timulating factor gastrointestinal gastrointestinal tract granulocyte macrophage colony sti mulating factor glycoprotein glycosylphosphatidylinositol gray platelet syndrome Glanzmann thrombasthenia graft-versus-host disease graft versus leukemia hour highly active antiretro viral therapy hepatitis A virus hemoglobin hemoglobin A hemoglobin A2 hemoglobin F (fetal H b) hemoglobin H hepatitis B surface antigen hepatitis B virus hydroxycarbamide or heavy cha in heavy chain disease human chorionic gonadotrophin heparin cofactor II xix SYMBOLS AND ABBREVIATIONS HCL HCO3 Hct HCV HD HDM HDN HDT HE HELLP HES HHT HI HIT(T) HIV HL HLA HLH HMP HMW HMWH HMWK HPA HPF HPFH HPLC HPP HRT HS HTC HTLV-1 HTO HUMARA HUS IAGT IAHS ICE ICH ICUS hairy cell leukemia bicarbonate haematocrit hepatitis C virus haemodialysis high-dose melph alan haemolytic disease of the newborn high-dose therapy hereditary elliptocytosis haemolys is, elevated liver enzymes and low platelets hypereosinophilic syndrome hereditary haemorrh agic telangiectasia hematological improvement heparin-induced thrombocytopenia (with thromb osis) human immunodefi ciency virus Hodgkin lymphoma (Hodgkin disease) human leucocyte anti gen haemophagocytic lymphohistiocytosis hexose monophosphate shunt high molecular weight hi gh molecular weight heparin high-molecular-weight kininogen human platelet antigen high pow er fi eld hereditary persistence of fetal hemoglobin high-performance liquid chromatography hereditary pyropoikilocytosis hormone replacement therapy hereditary spherocytosis hospita l transfusion committee human T-lymphotropic virus type 1 high titre antibodies human andro gen receptor gene assay haemolytic uraemic syndrome indirect antiglobulin test infection-as sociated haemophagocytic syndrome ifosfamide, carboplatin, etoposide intracranial hemorrhag e idiopathic cytopenia of uncertain (undetermined) signifi cance xx SYMBOLS AND ABBREVIATIONS IDA IF IFA IFRT Ig IgA IgD IgE IgG IgM IL-1 IM IMF INR inv IPC IPF IPI IPSS ISM ISS IST IT ITP ITU IU IUGR IUT IV IVI IVIg JCMML JML JVP KCT kg L LA LAP LC iron defi ciency anemia involved fi eld (radiotherapy) intrinsic factor antibody involved f i eld radiotherapy immunoglobulin immunoglobulin A immunoglobulin D immunoglobulin E immuno globulin G immunoglobulin M interleukin-1 intramuscular idiopathic myelofi brosis internati onal normalized ratio chromosomal inversion intermittent pneumatic compression devices imma ture platelet fraction International Prognostic Index International Prognostic Scoring Syst em Indolent systemic mastocytosis International Sensitivity Index immune suppressive therap y intrathecal idiopathic thrombocytopenic purpura Intensive Therapy Unit international unit s intrauterine growth retardation intrauterine transfusion intravenous intravenous infusion intravenous immunoglobulin juvenile chronic myelomonocytic leukemia juvenile myelomonocyti c leukemia jugular venous pressure kaolin clotting time kilogram liter lupus anticoagulant leucocyte alkaline phosphatase (score) light chain xxi SYMBOLS AND ABBREVIATIONS LCH LDH LDHL LFS LFTs L&H LGL LLN LMWH LN LP LPD LRCHL LSCS LTC M&P MACOP-B methotrexate, d oxorubicin, cyclophosphamide, Langerhans cell histiocytosis lactate dehydrogenase lymphocyte depleted Hodgkin lymphoma le ukemia-free survival liver function tests lymphocytic and histiocytic large granular lympho cyte lower limit of normal low-molecular-weight heparin lymph node(s) lumbar puncture lymph oproliferative disorder lymphocyte-rich classical HL lower segment Caesarian section large transformed cells melphalan and prednisolone vincristine, bleomycin, prednisolone MAHA microangiopathic haemolytic anemia mucosa-associa ted lymphoid tissue MALT m-BACOD methotrexate, bleomycin, doxorubicin (adriamycin), cyclophosphamide, vincristine, dexamethasone microgram mast cell(s) mean cell hemoglobin me an corpuscular hemoglobin concentration mixed cellularity Hodgkin lymphoma mast cell leukem ia or mantle cell lymphoma mitoxantrone, chlorambucil, prednisolone major cytogenetic respo nse mast cell sarcoma microscopy, culture, and sensitivity macrophage colony stimulating fa ctor mean cell volume myelodysplastic syndrome methaemoglobin myelofi brosis milligram mono clonal gammopathy of undetermined signifi cance major histocompatibility complex mcg MC MCH MCHC MCHL MCL MCP MCR MCS MC&S M-CSF MCV MDS MetHb MF mg MGUS MHC xxii SYMBOLS AND ABBREVIATIONS MI min mL MLC MM MMC MNC MoAb MP MPCM MPD MPN MPO MPS MPT MPV MRD MRI mRNA MRSA MSBOS MSU M T MTX MUD MW MZL Na+ NaCl NADP NADPH NAIT NAP NBT NCCN NEJM NHL NLPHL NRBC NS myocardial infarction minute milliliter mixed lymphocyte culture multiple myeloma mitomycin C mononuclear cell(s) monoclonal antibody melphalan and prednisolone maculopapular cutaneo us mastocytosis myeloproliferative disease myeloproliferative neoplasm myeloperoxidase mono nuclear phagocytic system melphalan, prednisolone, and thalidomide mean platelet volume min imal residual disease magnetic resonance imaging messenger ribonucleic acid meticillin-resi stant Staphylococcus aureus maximum surgical blood ordering schedule midstream urine mass: thoracic methotrexate matched unrelated donor (transplant) molecular weight mantle zone lym phoma sodium sodium chloride nicotinamide adenine diphosphate nicotinamide adenine diphosph ate (reduced) neonatal alloimmune thrombocytopenia neutrophil alkaline phosphatase nitro bl ue tetrazolium National Comprehensive Cancer Network New England Journal of Medicine non-Ho dgkin lymphoma nodular lymphocyte predominant HL nucleated red blood cells nodular sclerosi ng xxiii SYMBOLS AND ABBREVIATIONS NS NSAID NSE NSHL OAF OB OC OCP od OPG OPG OR OS OWR PA PAI PaO2 PAS PB PBSC PBSCH PBSCT PC PCC PCH PCL PCP PCR PCV PD PDGF PDW PE PEP PET non-secretory (myeloma) non-steroidal anti-infl ammatory drug non-specifi c esterase nodula r sclerosing HL OC-activating factor osteoblast osteoclast oral contraceptive pill omni die (once daily) osteoprotogerin orthopantomogram overall response overall survival Osler \200 \223Weber \200\223Rendu pernicious anemia plasminogen activator inhibitor partial pressure of O2 in arterial blood periodic acid \200\223Schiff peripheral blood peripheral blood stem cell peripheral blood stem cell harvest peripheral blood stem cell transplant protein C pr othrombin complex concentrate paroxysmal cold haemoglobinuria plasma cell leukemia Pneumocy stis carinii (jirovecii) pneumonia polymerase chain reaction packed cell volume peritoneal dialysis platelet-derived growth factor platelet distribution width pulmonary embolism post -expoure prophylaxis pre-eclamptic toxemia or position emission tomography platelet factor platelet function analysis phosphofructokinase progression-free survival PF PFA PFK PFS xxiv SYMBOLS AND ABBREVIATIONS PGD2 PGE1 PGK Ph PIG PIVKA PK PLL PML PNET PO PPH PPI PPP PRCA PRN ProMACE PRV PS PSA PT PT CL PTP PUVA PV PVO qds QoL RA RAEB RAEB-t RAR RARS RBC RCC RCM RCMD RDS RDW RE prostaglandin D2 prostaglandin E1 phosphoglycerate kinase Philadelphia chromosome phosphati dylinositol glycoproteins protein induced by vitamin K absence pyruvate kinase prolymphocyt ic leukemia promyelocytic leukemia primitive neuroectodermal tumor per os (by mouth) post-p artum hemorrhage proton pump inhibitor primary proliferative polycythaemia pure red cell ap lasia as required prednisolone, doxorubicin, cyclophosphamide, etoposide polycythaemia rubr a vera protein S pure sideroblastic anemia or prostate-specifi c antigen prothrombin time p eripheral T-cell lymphomas pretest probability or post-transfusion purpura phototherapy wit h psoralen plus UV-A polycythaemia vera pyrexia of unknown origin quater die sumendus (to b e taken 4 times a day) quality of life refractory anemia refractory anemia with excess blas ts refractory anemia with excess blasts in transformation retinoic acid receptor refractory anemia with ring sideroblasts red blood cell red blood cell count red cell mass refractory cytopenia with multilineage dysplasia respiratory distress syndrome red cell distribution width relative erythrocytosis; reticuloendothelial xxv SYMBOLS AND ABBREVIATIONS REAL RES RFLP Rh rhAPC rhG-CSF rHuEPO RI RIA RIC RiCoF RIPA RS RT RT-PCR s SAA SAGM SaO2 SA P SB SBP SC SCA SCBU SCD SCID SCT SD SE SEP SLE SLL SLVL SM SM-AHNMD systemic mastocytosis with an associated clonal Revised European American Lymphoma reticuloendothelial system restriction fragment length p olymorphism Rhesus recombinant human activated protein C recombinant human granulocyte colo ny stimulating factor recombinant human erythropoietin remission induction radioimmunoassay reduced-intensity conditioning ristocetin cofactor ristocetin-induced platelet agglutinati on Reed \200\223Sternberg or ringed sideroblasts reptilase time reverse transcriptase polym erase chain reaction second serum amyloid A protein saline adenine glucose mannitol arteria l oxygen saturation serum amyloid P protein Sudan solitary plasmacytoma of bone subcutaneou s sickle cell anemia special care baby unit sickle cell disease severe combined immunodefi ciency stem cell transplantation or silica clot time standard deviation secondary erythrocy tosis extramedullary plasmacytoma systemic lupus erythematosus small lymphocytic lymphoma s plenic lymphoma with villous lymphocytes systemic mastocytosis hematological non-mast cell lineage disease surface membrane immunoglobulin splenic margina l zone lymphoma short of breath SmIg SMZL SOB xxvi SYMBOLS AND ABBREVIATIONS SPB SPD stat sTfR SVC SVCO T t1 \201\2042 T4 TA-GVHD TAM TAR TB TBI TCR tds TdT TEC TEG T ENS TF TFT TGF-B TI TIA TIBC tiw TKI TLS TNF topo II TORCH TPA TPI TPN TPO TPR TRAP TRM TSE solitary plasmacytoma of bone storage pool disorders/defi ciency statim (immediate; as init ial dose) soluble transferrin receptor superior vena cava superior vena caval obstruction t emperature half-life thyroxine transfusion-associated graft-versus-host disease transient a bnormal myelopoiesis thrombocytopenia with absent radius tuberculosis total body irradiatio n T-cell receptor ter die sumendum (to be taken 3 times a day) terminal deoxynucleotidyl tr ansferase transient erythroblastopenia of childhood thromboelastography transcutaneous nerv e stimulation tissue factor thyroid function test(s) transforming growth factor-B transfusi on-independence transient ischaemic attack total iron binding capacity three times in a wee k tyrosine kinase inhibitor tumor lysis syndrome tumor necrosis factor topoisomerase II tox oplasmosis, rubella, cytomegalovirus, herpes simplex tissue plasminogen activator triphosph ate isomerase total parenteral nutrition thrombopoietin temperature, pulse, respiration tar trate-resistant acid phosphatase treatment-related mortality transmissible spongiform encep halopathy xxvii SYMBOLS AND ABBREVIATIONS TSH TT TTP TXA TXA2 U&E U UC UFH ULN URTI US USS UTI VAD thyroid-stimulating hormone thrombin time thrombotic thrombocytopenic purpura tranexamic ac id thromboxane A2 urea and electrolytes unit ulcerative colitis unfractionated heparin uppe r limit of normal upper respiratory tract infection ultrasound ultrasound scan urinary trac t infection vincristine doxorubicin (adriamycin) dexamethasone regimen vincristine, carmust ine (BCNU), doxorubicin, prednisolone vincristine, carmustine, melphalan, cyclophosphamide, prednisolone vena cava Venereal Disease Research Laboratory vascular endothelial growth fa ctor ventricular fi brillation factor VIII clotting activity vitamin K vincristine, melphal an, cyclophosphamide, prednisolone melphalan, prednisolone, bortezomib veno-occlusive disea se venous thromboembolism volunteer unrelated donor von Willebrand disease von Willebrand f actor von Willebrand factor antigen Wiskott \200\223Aldrich syndrome white blood cell whole -brain radiotherapy white cell count Waldenstr m macroglobulinaemia cross-match cross-link ed fi brin degradation products zinc protoporphyrin VBAP VBMCP VC VDRL VEGF VF VIII:C Vit K VMCP VMP VOD VTE VUD vWD vWF vWFAg WAS WBC WBRT WCC WM X-match XDPs ZPP This page intentionally left blank 1 Chapter 1 Clinical approach History taking in patients with hematological disease 2 Physical examination 4 Splenomegaly 5 Lymphadenopathy 6 Unexplained anemia 8 Patient with elevated hemoglobin 10 Elevated whit e blood cell (WBC) count 12 Reduced WBC count 14 Elevated platelet count 16 Reduced platele t count 18 Easy bruising 20 Recurrent thromboembolism 22 Pathological fracture 23 Raised ES R 24 Serum or urine paraprotein 25 Anemia 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 hematological disease Approach to patient with suspected hematological disease An accurate history combined with a careful physical examination are fundamental parts of clinical assessment. Although the l ikely haema- tological diagnosis may be apparent from tests carried out before the patient has been referred, it is nevertheless essential to assess the clinical background fully \200\224this may infl uence the eventual plan of management, especially in older patients. It is important to fi nd 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 fe ar and anxiety about diagnoses such as leukemia, hemophilia, 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: \200 Non-specifi c symptoms such as fatigue, fevers, weight loss. \200 Symptoms relating to anemia, e.g. reduced exercise capacity, recent onset of breathlessness and nature of its on set, 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. \200 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 hematological problems (e.g. may suggest an underlying bleeding diathesis) or be associated with hematological or other seq uelae, e.g. splenectomy. Drug history: ask about prescribed and non-prescribed medications. \200 Allergies: since some hematological disorders may relate to chemicals or other environmental hazards specifi c 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) defi cienc y anemia. History of previous transfusion(s) and their timing is also critical in some case s, e.g. post- transfusion purpura. Tobacco and alcohol consumption is essential; both may produce signifi cant hematological morbidity. Travel: clearly important in the case of suspected malaria but also relevant in considering other causes of hematological abnormality, including HIV infection. 3 HISTORY TAKING IN PATIENTS WITH hematological DISEASE Family history is also important, especially in the context of inherited hematological disorders. A complete history for a patient with a hematological disorder should provide all the relev ant medical information to aid diagnosis and clinical assessment, as well as helping the he matologist to have a working assessment of the patient \200\231s social situation. A well-t aken history also provides a basis for good communication which will often prove very impor tant once it comes to discussion of the diagnosis. 4 CHAPTER 1 Clinical approach