Oxford Handbook of Clinical Hematology, Second edition Drew Provan, et al. OXFORD UNIVERSITY PRESS 00-Prelims i-viii 10.12.2003 03.51 PM Page i Oxford Handbook of Clinical Hematology 00-Prelims i-viii 10.12.2003 03.51 PM Page ii 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 provided by the manu- facturers and the most recent codes of conduct and safety regulations . The authors and the publishers do not accept responsibility or legal liability for any er rors in the text or for the misuse or misapplication of material in this work. (cid:2) Except where otherwise stated (e.g. Pediatric Hematology), drug doses and recommend ations are for the non-pregnant adult who is not breast-feeding. 00-Prelims i-viii 10.12.2003 03.51 PM Page iii Oxford Handbook of Clinical Hematology Second edition Drew Provan Senior Lecturer in Hematology, Barts and The London, Queen Mary \200\231s Schoo l of Medicine and Dentistry, University of London Charles R. J. Singer Consultant Hematologist, Royal United Hospital, Bath, UK Trevor Baglin Consultant Hematologist, Addenbrookes NHS Trust, Cambridge, UK John Lilleyman Professor of Pediatric Oncology & Consultant Pediatric Hematologist, Barts a nd The London, Queen Mary \200\231s School of Medicine and Dentistry, University of London 1 00-Prelims i-viii 10.12.2003 03.51 PM Page iv 1 Great Clarendon Street, Oxford OX2 6DP Oxford University Press is a department of the University of Oxford. It furthers the Univer sity s objective of excellence in research, scholarship, and education by publishing worldw ide in Oxford New York Auckland Bangkok Buenos Aires Cape Town Chennai Dar es Salaam Delhi Hong Ko ng Istanbul Karachi Kolkata Kuala Lumpur Madrid Melbourne Mexico City Mumbai Nairobi S o P aulo Shanghai Taipei Tokyo Toronto Oxford is a trade mark of Oxford University Press Published in the United States by Oxford University Press, Inc., New York Oxford University Press 2004 The moral rights of the author have been asserted Database right Oxford University Press (maker) First edition published 1998 Reprinted 1999, 2000, 2003 Second edition published 2004 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, or under terms agreed with t he appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, a t the address above. This book is sold subject to the condition that it shall not, by way of trade or otherwise, be lent, re-sold, hired out, or otherwise circulated without the publisher \200\231s prior consent in any form of binding or cover other than that in which it is published and witho ut a similar condition including this condition being imposed on the subsequent purchaser. British Library Cataloging in Publication Data Data available 1 3 5 7 9 10 8 6 4 2 ISBN 0 19 852652 0 Typeset by Drew Provan and EXPO, Malaysia Printed by 00-Prelims i-viii 10.12.2003 03.51 PM Page v Foreword to the first edition The Concise Oxford Dictionary defines a handbook as \200\230a short manual or guide \200 \231. Modern hematology is a vast field which involves almost every other medical specialty and which, more than most, straddles the worlds of the basic biomedical sciences and clini cal practice. Since the rapidly pro- liferating numbers of textbooks on this topic are beco ming denser and heavier with each new edition, the medical student and young doctor in trai ning are presented with a daunting problem, particularly as they try to put these fields in to 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 i ntroduce 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 \200\230handbook \200\231 could we ll stage a come-back and gain new respectability, particularly in the role of a friendly gu ide. In the past this genre has often been viewed as having little intellectual standing, o f no use to anybody except the panic- stricken student who wishes to try to make up for mon ths of mis-spent time in a vain, one-night sitting before their final examination. But give n the plethora of rapidly changing information that has to be assimilated, the carefully pr epared pr cis is likely to play an increasingly important role in medical education. Perha ps even that ruination of the decent paragraph and linchpin of the pronouncements of medica l bureaucrats, the \200\230bullet- point \200\231, may become acceptable, albeit in small doses, as attempts are made to highlight what is really important in a scientific or clinic al field of enormous complexity and not a little uncertainty. In this short account of blood diseases the editors have done an excel- lent service to med ical 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 t he blood diseases that they will meet in routine clinical practice or in the tedious examin a- tions that face them. And in condensing this rapidly expanding field they have, remarkab ly, managed to avoid one of the great difficulties and pitfalls of this type of teaching; i n 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 pr cis of this type suffers from the same problem as a set of multiple-choice questions. Human beings are enormously c omplex organisms, and sick ones are even more complicated; during a clinical lifetime the s elf-critical doctor will probably never encounter a \200\230typical case \200\231 of anyth ing. Thus the outlines of the diseases that are presented in this book must be used as appr oximate guides, and no more. But provided they bear this in mind, students will find that i t is a very valuable summary of modern haema- tology; the addition of the Internet sources is a genuine and timely bonus. D. J. WEATHERALL April 1998 00-Prelims i-viii 10.12.2003 03.51 PM Page vi Preface to the second edition Hematology has seen many changes since 1998 when the first edition of this small book was w ritten. Most notably, there are major advances in the treatments of malignant blood disorde rs 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 therapies. Progres s 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 t hrough 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 cl inical aspects of patient care. This edition welcomes two new authors: Professor Sir John Lilleyman, immediate Past-Preside nt of the Royal College of Pathologists, is a Pediatric Oncologist at Barts and The London, Queen Mary \200\231s School of Medicine and Dentistry, University of London. John is a lea ding figure in the world of pediatric hematology with an interest in both malignant and non -malignant disease affecting children. He has extensively revised the Pediatric section of the book, in addition to Immunodeficiency. Dr Trevor Baglin, Consultant Hematologist at Add enbrookes Hospital, Cambridge is Secretary of the British Committee for Standards in Hemato logy Haemostasis and Thrombosis Task Force. Trevor is the author of many evidence-based gui delines and peer-reviewed scientific papers. He has rewritten the Haemostasis section of th e 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 \200\231 understanding of the subject. We have increased the number of references and provi ded URLs for key web- sites providing easy access to organizations and publications. There will doubtless be omissions and errors and we take full responsi- bility for these. W e are very keen to receive feedback (good or other- wise!) since this helps shape future ed itions. If there is something you feel we have left out please complete the Readers comment card. DP CRJS TB JL January 2004 00-Prelims i-viii 10.12.2003 03.51 PM Page vii Preface to the first edition This small volume is intended to provide the essential core knowledge required to assess pa tients with possible disorders of the blood, organize relevant investigations and initiate therapy where necessary. By reducing extraneous information as much as possible, and presen ting key informa- tion for each topic, a basic understanding of the pathophysiology is pro- vided and this, we hope, will stimulate readers to follow this up by consulting the larger hematology textbooks. We have provided both a patient-centered and disease-centered approach to hematological dis ease, in an attempt to provide a form of \200\230surgical sieve \200\231, hopefully enabli ng doctors in training to formulate a differ- ential diagnosis before consulting the releva nt disease-orientated section. We have provided a full review of hematological investigations and their interpretation, ha ndling emergency situations, and included the com- monly used protocols in current use on H ematology Units, hopefully providing a unified approach to patient management. There are additional sections relating to patient support organizations and Internet resour ces 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 hematology we have been selective about the i nformation 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 ac cept full respon- sibility and welcome comments relating to this. DP MC ASD CRJS AGS 1998 00-Prelims i-viii 10.12.2003 03.51 PM Page viii Acknowledgements We are indebted to many of our colleagues for providing helpful sugges- tions and for proof reading the text. In particular we wish to thank Dr Helen McCarthy, Specialist Registrar in Hematology; Dr Jo Piercy, Specialist Registrar in Hematology, Southampton; Sisters Clare H eather and Ann Jackson, Hematology Day Unit, Southampton General Hospital; Dr Mike Williams , Specialist Registrar in Anesthetics; Dr Frank Boulton, Wessex Blood Transfusion Service, Southampton; Dr Paul Spargo, Consultant Anesthetist, Southampton University Hospitals; Dr S heila Bevin, Staff Grade Pediatrician; Dr Mike Hall, Consultant Neonatologist; Dr Judith Ma rsh, Consultant Hematologist, St George \200\231s Hospital, London; Joan Newman, Hematology Transplant Coordinator, Southampton; Professor Sally Davies, Consultant Hematologist, Impe rial College School of Medicine, Central Middlesex Hospital, London; Dr Denise O \200\231Sh aughnessy, Consultant Hematologist, Southampton University Hospitals NHS Trust; Dr Kornelia Cinkotai, Consultant Hematologist, Barts and The London NHS Trust; Dr Mansel Haeney, Consu ltant Immunologist, Hope Hospital, Salford; Dr Simon Rule, Derriford Hospital, Plymouth; Dr Adam Mead, Specialist Registrar Barts and The London; Dr Chris Knechtli, Consultant Hemato logist, Royal United Hospital, Bath. And finally, we would like to thank Alastair Smith, Mo rag Chisholm and Andrew Duncombe for their contributions to the first edition of the handbo ok. in Hematology; Dr Tanay Sheth, SHO Warm thanks are also extended to Oxford University Press, and in partic- ular Catherine Bar nes, commissioning editor for medicine. She has been a calming influence throughout the rew orking of the handbook. Kate Martin, production manager, has helped immensely with artwork and matters of book design. Our thanks also go to Georgia Pinteau, PA to Catherine, who has facilitated throughout, chasing up electronic artwork and other materials required for the book. Typographical notes \200\224the entire book was typeset using Quark Express \204 4.11 on a Mac G4 minitower. Body text is a modified Gill Sans (designed and very kindly supplied by Jonathan Coleclough) with headings/subhead- ings in Frutiger and Gill Sans. Symbols compris e Universal Greek w. Math Pi, Zapf Dingbats, Universal News w. Commercial Pi, and a modifie d version of Murray Longmore \200\231s OUP font (modified by Jonathan Coleclough). 00-Prelims ix-xxii 10.12.2003 03.52 PM Page ix Symbols and abbreviations (cid:9) (cid:2) cross-reference important very important decreased increased normal male: female ratio prim ary secondary 2,3 diphosphoglycerate 2-chlorodeoxyadenosine alpha2 microglobulin 6-mercapto purine 99mTc methoxyisobutyl-isonitride or 99mTc-MIBI scintigraphy aplastic anemia or react ive amyloidosis antibody adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine acid -citrate-dextrose or anemia of chronic disease angiotensin converting enzyme anticardiolipi n antibody atypical chronic myeloid leukemia adenosine deaminase cytosine arabinoside (Ara- C) daunorubicin etoposide adenosine 5-diphosphate acid fast bacilli antigen acquired immuno deficiency syndrome autoimmune haemolytic anemia autoimmune neutropenia (primary) amyloidos is serum albumin anti-lymphocyte globulin abnormal localization of immature myeloid precurs ors acute lymphoblastic leukemia advanced life support alanine aminotransferase (cid:2)(cid:2) 5 4 6 9:3 1 2 2,3 DPG 2-CDA 2-M 6-MP 99mTc-MIBI AA Ab ABVD ACD ACE ACL ACML ADA ADE ADP AFB Ag AIDS AIHA AIN AL ALB ALG ALIPs ALL ALS ALT 00-Prelims ix-xxii 10.12.2003 03.52 PM Page x AML AMP ANA ANCA ANAE APC APCR APL APML APS APTR APTT APTT ratio ARDS ARF ARMS AST ASCT AT (ATIII) ATCML ATG ATLL ATP ATRA A-V BAL B-CLL bd BEAC BEAM b2-M BFU-E BJP BL BM BMJ BMT BNF BP BPL BSS acute myeloid leukemia adenosine monophosphate antinuclear antibodies anti-neutrophilic cyt oplasmic antibody alpha naphthyl acetate esterase activated protein C activated protein C r esistance antiphospholipid antibody acute promyelocytic leukemia antiphospholipid syndrome activated partial thromboplastin ratio activated partial thromboplastin time activated part ial thromboplastin time ratio adult respiratory distress syndrome acute renal failure ampli fication refractory mutation system aspartate aminotranferase autologous stem cell transpla ntation antithrombin III Adult-type chronic myeloid (granulocytic) leukemia anti-thymocyte globulin adult T-cell leukemia/lymphoma adenosine triphosphate all-trans retinoic acid arte riovenous broncho-alveolar lavage B-cell chronic lymphocytic leukemia bis die (twice daily) BCNU, etoposide, cytosine & cyclophosphamide BCNU, etoposide, cytarabine (ara-C), melphala n b2-microglobulin burst-forming unit-erythroid Bence Jones protein Burkitt lymphoma bone m arrow British Medical Journal bone marrow transplant(ation) British National Formulary bloo d pressure BioProducts Laboratory Bernard \200\223Soulier syndrome 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xi Symbols and abbreviations BU Ca Ca2+ CABG cALL CBA CBV Bethesda Units carcinoma calcium coronary artery by pass graft common acute lymphoblastic l eukemia collagen binding activity cyclophosphamide, carmustine (BCNU), etoposide (VP16) con gestive cardiac failure complete cytogenetic response cluster designation congenital dysery thropoietic anemia complementary DNA chronic eosinophilic leukemia chronic granulocytic leu kemia cold haemagglutinin disease cyclophosphamide, adriamycin, vincristine, prednisolone c onsolidation/intensification Creutzfeldt \200\223Jakob disease (v = variant) chloride chron ic liver disease chronic lymphocytic ( \200\230lymphatic \200\231) leukemia chronic mucocut aneous candidiasis chronic myeloid leukemia chronic myelomonocytic leukemia cytomegalovirus central nervous system chronic obstructive airways disease combined oral contraceptive cyc lophosphamide, vincristine, methotrexate, prednisolone complete remission chronic renal fai lure C-reactive protein central retinal renous thrombosis cerebrospinal fluid computed tomo graphy chemoreceptor trigger zone CCF CCR CD CDA cDNA CEL CGL CHAD CHOP C/I CJD Cl \200\223 CLD CLL CMC CML CMML CMV CNS COAD COC COMP CR CRF CRP CRVT CSF CT CTZ 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xii CVA CVP cerebrovascular accident cyclophosphamide, vincristine, prednisolone; central venous pressu re cardiovascular system chest x-ray cyclosporin A cytarabine, bleomycin, vincristine, meth otrexate day direct antiglobulin test direct antiglobulin test; daunorubicin, cytosine (Ara -C), thioguanine deoxy ATP Diamond \200\223Blackfan anemia dyskeratosis congenita dendritic cell system direct Coombs \200\231 test desamino D-arginyl vasopressin detection of early antigen fluorescent foci diepoxy butane disease-free survival dexamethasone, cytarabine, ci splatin delayed intensification disseminated intravascular coagulation decilitre diffuse la rge B-cell lymphoma donor leucocyte/lymphocyte infusion dimethyl sulphoxide deoxyribonuclei c acid date of birth diphosphoglycerate dilute Russell \200\231s viper venom test dilute th romboplastin 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 event-free survival epidermal gro wth factor CVS CXR CyA CytaBOM d DAGT DAT dATP DBA DC DCS DCT DDAVP DEAFF DEB DFS DHAP DI DIC dL DLBCL DLI DMSO DNA DOB DPG DRVVT DTT DVT DXT EACA EBV EBVP ECG ECOG EDTA EFS EGF 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xiii Symbols and abbreviations ELISA EMU Epo EPOCH enzyme-linked immunosorbent assay early morning urine erythropoietin doxorubicin/epirubicin , vincristine, etoposide over 96h IVI with bolus cyclophosphamide and oral prednisolone ele ctrophoresis etoposide, methylprednisolone, cytarabine, platinum erythrocyte sedimentation rate essential thrombocythaemia or exchange transfusion French \200\223American \200\223Bri tish fluorescence-activated cell sorter full blood count (complete blood count, CBC) fludar abine, cyclophosphamide, melphalan fibrin degradation products 218 fluoro \200\223D \200 \2232 \200\223deoxyglucose positron emission tomography iron factor eight inhibitor bypassi ng activity familial erythrophagocytic lymphohistiocytosis ferrous sulfate fresh frozen pla sma failure-free survival family history fluorescence in situ hybridisation fluorescein iso thiocyanate factor IX femtolitre follicular lymphoma fine needle aspirate fecal occult bloo d alpha-fetoprotein factor VIII factor V Leiden gram glucose-6-phosphate dehydrogenase gene ral anesthetic granulocyte colony stimulating factor gastrointestinal tract EPS ESHAP ESR ET FAB FACS FBC FCM FDP FDG-PET Fe FEIBA FEL FeSO4 FFP FFS FH FISH FITC FIX fL FL FNA FOB -FP FVIII FVL g G6PD GA G-CSF G IT 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xiv GM-CSF GP GPI G&S GvHD GvL h HAV Hb HbA HbA2 HbF HbH HBsAg HBV HCII HCD HCG HCL \200\223 H CO3 Hct HCV HDM HDN HDT HE HELLP HES HHT HIT(T) HIV HL HLA HLH H/LMW HMP HMWK HPA HPFH HPLC HPP granulocyte macrophage colony stimulating factor glycoprotein glycosylphosphatidylinositol group, screen and save graft versus host disease graft versus leukemia hour hepatitis A vir us hemoglobin hemoglobin A hemoglobin A2 hemoglobin F (fetal Hb) hemoglobin H hepatitis B s urface antigen hepatitis B virus heparin cofactor II heavy chain disease human chorionic go nadotrophin hairy cell leukemia bicarbonate haematocrit hepatitis C virus high dose melphal an haemolytic disease of the newborn high dose therapy hereditary elliptocytosis haemolysis , elevated liver enzymes and low platelets hypereosinophilic syndrome hereditary haemorrhag ic telangiectasia heparin-induced thrombocytopenia (with thrombosis) human immunodeficiency virus Hodgkin \200\231s lymphoma (Hodgkin \200\231s disease) human leucocyte antigen haemo phagocytic lymphohistiocytosis high/low molecular weight hexose monophosphate shunt high mo lecular weight kininogen human platelet antigen hereditary persistence of fetal hemoglobin high performance liquid chromatography hereditary pyropoikilocytosis 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xv Symbols and abbreviations HRT HS HTLV-1 HUS IAGT IAHS ICE ICH IDA IF IFA IFN-(cid:2) Ig IgA IgD IgE IgG IgM IL-1 IM I MF INR inv IPI IPSS IT ITP ITU iu/IU IUT IV IVI IVIg JCMML JML JVP kg L hormone replacement therapy hereditary spherocytosis human T-lymphotropic virus type 1 haem olytic uraemic syndrome indirect antiglobulin test Infection-associated haemophagocytic syn drome ifosfamide, carboplatin, etoposide intracranial hemorrhage iron deficiency anemia inv olved field [radiotherapy] intrinsic factor antibody interferon alpha immunoglobulin immuno globulin A immunoglobulin D immunoglobulin E immunoglobulin G immunoglobulin M interleukin- 1 intramuscular idiopathic myelofibrosis International normalized ratio chromosomal inversi on International Prognostic Index International Prognostic Scoring System intrathecal idiop athic thrombocytopenic purpura Intensive Therapy Unit international units intrauterine tran sfusion intravenous intravenous infusion intravenous immunoglobulin juvenile chronic myelom onocytic leukemia juvenile myelomonocytic leukemia jugular venous pressure kilogram liter 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xvi LA LAP LC LCH LDH LFTs LFS LGL LLN LMWH LN LP LPD LSCS M&P MACOP-B lupus anticoagulant leucocyte alkaline phosphatase (score) light chain Langerhans cell hist iocytosis lactate dehydrogenase liver function tests leukemia free survival large granular lymphocyte lower limit of normal low molecular weight heparin lymph node(s) lumbar puncture lymphoproliferative disorder lower segment Caesarian section melphalan and prednisolone me thotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisolone microangiop athic haemolytic anemia mucosa-associated lymphoid tissue methotrexate, bleomycin, adriamyc in (doxorubicin), cyclophosphamide, vincristine, dexamethasone mast cell(s) mean cell hemog lobin mean corpuscular hemoglobin concentration mantle cell lymphoma mitoxantrone, chloramb ucil, prednisolone major cytogenetic response macrophage colony stimulating factor mean cel l volume myelodysplastic syndrome methaemoglobin myelofibrosis milligram monoclonal gammopa thy of undetermined significance major histocompatibility complex myocardial infarction min ute(s) multiple myeloma mitomycin C mononuclear cell(s) month(s) monoclonal antibody MAHA MALT m-BACOD MC MCH MCHC MCL MCP MCR M-CSF MCV MDS MetHb MF mg MGUS MHC MI min(s) MM MMC MNC MO MoAb 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xvii Symbols and abbreviations MPD MPO MPS MPV MRD MRI mRNA MRSA MSBOS Mst II MSU MT MTX MUD Na+ NADP NADPH NAIT NAP NBT N EJM NHL NRBC NS NSAIDs NSE OCP od OPG OR OS PA PAI PaO2 PAS PB PBSC PC PCC myeloproliferative disease myeloperoxidase mononuclear phagocytic system mean platelet volu me minimal residual disease magnetic resonance imaging messenger ribonucleic acid methicill in-resistant Staphylococcus aureus maximum surgical blood ordering schedule a restriction e nzyme midstream urine mass: thoracic methotrexate matched unrelated donor (transplant) sodi um nicotinamide adenine diphosphate nicotinamide adenine diphosphate (reduced) neonatal all oimmune thrombocytopenia neutrophil alkaline phosphatase nitro blue tetrazolium New England Journal of Medicine non-Hodgkin \200\231s lymphoma nucleated red blood cells non-secretory [myeloma] non-steroidal antiinflammatory drugs non-specific esterase oral contraceptive pi ll omni die (once daily) orthopantomogram overall response overall survival pernicious anem ia plasminogen activator inhibitor partial pressure of O2 in arterial blood periodic acid \200\223Schiff peripheral blood peripheral blood stem cell protein C prothrombin complex co ncentrate 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xviii PCH PCL PCP PCR PCV PDGF PDW PE PEP PET PF PFA PFK PFS PGD2 PGE1 PGK Ph PIG PIVKA PK PLL PM L PNET PNH PO PPH PPI PPP PRCA PRN ProMACE PRV PS PSA PT PTP PUVA PVO PV QoL paroxysmal cold haemoglobinuria plasma cell leukemia Pneumocystis carinii pneumonia polymer ase chain reaction packed cell volume platelet-derived growth factor platelet distribution width pulmonary embolism post-expoure prophylaxis pre-eclamptic toxemia or position emissio n tomography platelet factor platelet function analysis phosphofructokinase progression-fre e survival prostaglandin D2 prostaglandin E1 phosphoglycerate kinase Philadelphia chromosom e phosphatidylinositol glycoproteins protein induced by vitamin K absence pyruvate kinase p rolymphocytic leukemia promyelocytic leukemia primitive neuroectodermal tumor paroxysmal no cturnal haemoglobinuria per os (by mouth) post-partum haomorrhage proton pump inhibitor pri mary proliferative polycythaemia pure red cell aplasia as required prednisolone, doxorubici n, cyclophosphamide, etoposide polycythaemia rubra vera protein S prostate-specific antigen prothrombin time post-transfusion purpura phototherapy with psoralen plus UV-A pyrexia of unknown origin polycythaemia vera quality of life 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xiv GM-CSF GP GPI G&S GvHD GvL h HAV Hb HbA HbA2 HbF HbH HBsAg HBV HCII HCD HCG HCL \200\223 H CO3 Hct HCV HDM HDN HDT HE HELLP HES HHT HIT(T) HIV HL HLA HLH H/LMW HMP HMWK HPA HPFH HPLC HPP granulocyte macrophage colony stimulating factor glycoprotein glycosylphosphatidylinositol group, screen and save graft versus host disease graft versus leukemia hour hepatitis A vir us hemoglobin hemoglobin A hemoglobin A2 hemoglobin F (fetal Hb) hemoglobin H hepatitis B s urface antigen hepatitis B virus heparin cofactor II heavy chain disease human chorionic go nadotrophin hairy cell leukemia bicarbonate haematocrit hepatitis C virus high dose melphal an haemolytic disease of the newborn high dose therapy hereditary elliptocytosis haemolysis , elevated liver enzymes and low platelets hypereosinophilic syndrome hereditary haemorrhag ic telangiectasia heparin-induced thrombocytopenia (with thrombosis) human immunodeficiency virus Hodgkin \200\231s lymphoma (Hodgkin \200\231s disease) human leucocyte antigen haemo phagocytic lymphohistiocytosis high/low molecular weight hexose monophosphate shunt high mo lecular weight kininogen human platelet antigen hereditary persistence of fetal hemoglobin high performance liquid chromatography hereditary pyropoikilocytosis 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xx SD SE SEP SLE SLL SLVL SM SmIg SOB SPB SPD stat sTfR SVC SVCO T (4T ) t1/2 T4 TAM TAR TB TBI TCR tds TdT TEC TENS TF TFT TGF-b TIAs TIBC tiw TNF topo II TORCH TPA TPI TPN TPO TPR standard deviation secondary erythrocytosis extramedullary plasmacytoma systemic lupus eryt hematosus small lymphocytic lymphoma splenic lymphoma with villous lymphocytes systemic mas tocytosis surface membrane immunoglobulin short of breath solitary plasmacytoma of bone sto rage pool deficiency statim (immediate; as initial dose) soluble transferrin receptor super ior vena cava superior vena caval obstruction temperature (fever) half-life thyroxine trans ient abnormal myelopoiesis thrombocytopenia with absent radius tuberculosis total body irra diation T-cell receptor ter die sumendum (to be taken 3 times a day) terminal deoxynucleoti dyl transferase transient erythroblastopenia of childhood transcutaneous nerve stimulation tissue factor thyroid function test(s) transforming growth factor-b transient ischaemic att acks total iron binding capacity three times in a week tumor necrosis factor topoisomerase II toxoplasmosis, rubella, cytomegalovirus, herpes simplex tissue plasminogen activator tri phosphate isomerase total parenteral nutrition thrombopoietin temperature, pulse, respirati on 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xxi Symbols and abbreviations TRAP TRM TSH TT TTP TXA TXA2 U&E u/U UC UFH URTI USS UTI VAD VBAP tartrate-resistant acid phosphatase treatment related mortality thyroid-stimulating hormone thrombin time thrombotic thrombocytopenic purpura tranexamic acid thromboxane A2 urea and electrolytes units ulcerative colitis unfractionated heparin upper respiratory tract infect ion ultrasound scan urinary tract infection vincristine adriamycin dexamethasone regimen vi ncristine, carmustine (BCNU), doxorubicin (adriamycin), prednisolone vincristine, carmustin e, melphalan, cyclophosphamide, prednisolone Factor VIII clotting activity screening test f or syphilis (Venereal Disease Research Laboratory) ventricular fibrillation vitamin K vincr istine, melphalan, cyclophosphamide, prednisolone veno-occlusive disease venous thromboembo lism von Willebrand \200\231s disease von Willebrand factor von Willebrand factor antigen w hite blood count or white blood cell White cell count Waldenstr m \200\231s macroglobulina emia cross-linked fibrin degradation products cross-match microgram VBMCP VIII:C VDRL VF Vit K VMCP VOD VTE vWD vWF vWFAg WBC WCC WM XDPs X match g 00-Prelims ix-xxii 10.12.2003 03.52 PM Page xxii Foreword to the first edition by David Weatherall v Preface to the second edition vii Preface to the first edition vii Acknowledgements viii Symbols and abbreviations ix 1 Clinical approach 1 2 Red cell disorders 43 3 White blood cell abnormalities 133 4 Leukemia 149 5 Lymphoma 193 6 Myelodysplasia 217 7 Myeloproliferative disorders 237 8 Paraproteinaemias 265 9 Transplantation 293 10 Haemostasis and thrombosis 343 11 Immunodeficiency 407 12 Pediatric hematology 421 13 Hematological emergencies 499 14 Supportive care 535 15 Protocols and procedures 543 16 Hematological investigations 631 17 Blood transfusion 643 18 Phone numbers and addresses 663 19 Hematology on-line 671 20 Charts and nomograms 677 21 Normal ranges 687 Index 693 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 1 Clinical approach 1 History taking in patients with hematological disease 2 Physical examination 4 Splenomegaly 6 Lymphadenopathy 8 Unexplained a nemia 10 Patient with elevated hemoglobin 12 Elevated WBC 14 Reduced WBC 16 Elevated platel et count 20 Reduced platelet count 22 Easy bruising 24 Recurrent thromboembolism 26 Pathologica l fracture 28 Raised ESR 30 Serum or urine paraprotein 32 Anemia in pregnancy 34 Thro mbocytopenia in pregnancy 36 Prolonged bleeding after surgery 38 Positive sickle test (HbS solubility test) 40 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 2 History taking in patients with hematological disease 2 Approach to patient with suspected hematological disease An accurate history combined with a careful physical examination are fun- damental parts of clinical assessment. Although the likely hematological diagnosis may be apparent from tests carried out before the patient h as been referred, it is nevertheless essential to assess the clinical background fully \200 \224this 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 fea r 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: 2 Non-specific symptoms such as fatigue, fevers, weight loss. 2 Symptoms relating to anemia e.g. reduced exercise capacity, recent onset of breathlessness and nature of its onset, or worsening of angina, presence of ankle oedema. 2 Symptoms relating to neutropenia e.g. recurrent oral ulceration, skin infections, oral sepsis. 2 Evidence of compromised immunity e.g. recurrent oropharyngeal infec- tion. 2 Details of potential haemostatic problems e.g. easy bruising, bleeding episodes, rashes. 2 Anatomical symptoms, e.g. abdominal discomfort (splenic enlargement or pressure from enla rged lymph nodes), CNS symptoms (from spinal compression). 2 Past medical history, i.e. detail on past illnesses, information on pre- vious surgical procedures which may suggest previous hematological problems (e.g. may sugge st an underlying bleeding diathesis) or be associated with hematological or other sequelae e.g. splenectomy. 2 Drug history: ask about prescribed and non-prescribed medications. 2 Al lergies: since some hematological disorders may relate to chemicals or other environmental hazards specific questions should be asked about occupational factors and hobbies. 2 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 deficiency anem ia. History of previous transfusion(s) and their timing is also critical in some cases e.g. post-transfusion purpura. 2 Tobacco and alcohol consumption is essential; both may produce sig- nificant hematological morbidity. 2 Travel: clearly important in the case of suspected malaria but also rele- vant in considering other causes of hematological abnormality, including HIV infection. 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 3 Clinical approach 3 2 Family history 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 assess- ment of the patient \200\231s social situation. A well taken history also provides a basis for good communication which will often prove very imp ortant once it comes to discussion of the diagnosis. 01-Clinical approach.qxd 10.12.2003 03.52 PM Page 4 Physical examination This forms part of the clinical assessment of the hematology patient. Pay specific attentio n to: 4 General examination \200\224e.g. evidence of weight loss, pyrexia, pallor (not a reliable clinical measure of anemia), jaundice, cyanosis or abnormal pigmentation or skin rashes. The mouth \200\224ulceration, purpura, gum bleeding or infiltration, and the state of the patient \200\231s teeth. Hands and nails may show features associated with hematological ab normalities e.g. koilonychia in chronic iron deficiency (rarely seen today). Record \200\224weight, height, T , pulse and blood pressure; height and weight give impor tant baseline data against which sequential measurements can subsequently be compared. In m yelofibrosis, for example, evidence of significant weight loss in the absence of symptoms m ay be an indication of clinical progression. Examination \200\224of chest and abdomen should focus on detecting the presence of lymphad enopathy, hepatic and/or splenic enlargement. Node sizes and the extent of organ enlargemen t should be carefully recorded. Lymph node enlargement \200\224often recorded in centimete rs e.g. 3cm 3cm 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 distanc e palpable from the lower costal margin. Erythematous margins of infected skin lesions \200\224mark these to monitor treatment effe cts. Bones and joints \200\224recording of joint swelling and ranges of movement are standard a spects of hemophilia care. In myeloma, areas of bony tenderness and deformity are commonly present. Optic in the hematology patient. May yield the only objective evidence of ((cid:9)Emergenci es p510) or hyperviscosity hyperleucocytosis ((cid:9)Emergencies p510) such as in e.g. CML. Regular examination form part of routine observations in the severely myelosuppressed pati ent; rarely changes of opportunistic infection such as candidiasis can be seen in the optic fundi. fundi \200\224examination is a key clinical assessment