ABC OF CLINICAL HAEMATOLOGY: Second Edition Edited by DREW PROVAN BMJ Books ABC OF CLINICAL HAEMATOLOGY Second Edition ABC OF CLINICAL HAEMATOLOGY Second Edition Edited by DREW PROVAN Senior Lecturer, Department of Haematology, Bart’s and the London, Queen Mary’s School of Medicine and Dentistry, London © BMJ Books 2003 BMJ Books is an imprint of the BMJ Publishing Group 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, electronic, mechanical, photocopying, recording and/or otherwise, without the prior written permission of the publishers. First published in 1998 Second edition 2003 by BMJ Books, BMA House, Tavistock Square, London WC1H 9JR www.bmjbooks.com British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0 7279 16769 Typeset by Newgen Imaging Systems (P) Ltd., Chennai, India Printed and bound in Spain by GraphyCems, Navarra Cover image: False colour SEM of blood with myeloid leukaemia. Robert Becker/Custom Medical Stock Photo/Science Photo Library. Contents Contributors vi Preface vii 1 Iron deficiency anaemia 1 Drew Provan 2 Macrocytic anaemias 5 Victor Hoffbrand, Drew Provan 3 The hereditary anaemias 9 David J Weatherall 4 Polycythaemia, essential thrombocythaemia, and myelofibrosis 14 George S Vassiliou, Anthony R Green 5 Chronic myeloid leukaemia 19 John Goldman 6 The acute leukaemias 23 T Everington, R JLiesner, A HGoldstone 7 Platelet disorders 28 R JLiesner, S JMachin 8 The myelodysplastic syndromes 33 David G Oscier 9 Multiple myeloma and related conditions 37 Charles R JSinger 10 Bleeding disorders, thrombosis, and anticoagulation 43 K KHampton, F EPreston 11 Malignant lymphomas and chronic lymphocytic leukaemia 47 G MMead 12 Blood and marrow stem cell transplantation 52 Andrew Duncombe 13 Haematological disorders at the extremes of life 57 Adrian C Newland, Tyrrell G J REvans 14 Haematological emergencies 61 Drew Provan 15 The future of haematology: the impact of molecular biology and gene therapy 65 Adele K Fielding, Stephen J Russell Index 71 v Contributors Andrew Duncombe S J Machin Consultant Haematologist, Southampton University Hospitals Professor of Haematology, Department of Haematology, NHS Trust, Southampton University College London Hospitals NHS Trust, London Tyrrell G J R Evans G M Mead Senior Lecturer, Department of General Practice and Consultant in Medical Oncology, Wessex Medical Oncology Primary Care, King’s College School of Medicine and Dentistry, Unit, Southampton University Hospitals NHS Trust, London Southampton T Everington Adrian C Newland Specialist Registrar, Department of Haematology, University Professor of Haematology, Department of Haematology, Bart’s College London Hospitals NHS Trust, London and the London, Queen Mary’s School of Medicine and Dentistry, London Adele K Fielding Senior Associate Consultant and Assistant Professor in David G Oscier Medicine, Molecular Medicine Program and Division of Consultant Haematologist, Department of Haematology and Hematology, Mayo Clinic, Rochester, MN, USA Oncology, Royal Bournemouth Hospital, Bournemouth, and Honorary Senior Lecturer, University of Southampton John Goldman Professor of Haematology, Imperial College School of F E Preston Medicine, Hammersmith Hospital, London Professor of Haematology, Royal Hallamshire Hospital, Sheffield A H Goldstone Consultant Haematologist, Department of Haematology, Drew Provan University College London Hospitals NHS Trust, London Senior Lecturer, Department of Haematology, Bart’s and the London, Queen Mary’s School of Medicine and Dentistry, Anthony R Green London Professor of Haemato-Oncology, Department of Haematology, Cambridge Institute for Medical Research, Cambridge Stephen J Russell Director, Molecular Medicine Program, Mayo Foundation, K K Hampton Rochester, MN, USA Senior Lecturer in Haematology, Royal Hallamshire Hospital, Sheffield Charles R J Singer Consultant Haematologist, Royal United Hospital, Bath Victor Hoffbrand Emeritus Professor of Haematology and Honorary Consultant George S Vassiliou Haematologist, Royal Free Hospital Hampstead NHS Trust and Leukaemia Research Fund Clinical Research Fellow/Honorary School of Medicine, London Specialist Registrar, Department of Haematology, Cambridge Institute for Medical Research, Cambridge R J Liesner Consultant Haematologist, Department of Haematology and Sir David J Weatherall Oncology, Great Ormond Street Hospital for Children NHS Regius Professor of Medicine Emeritus, Weatherall Institute of Trust, London, and Department of Haematology, Molecular Medicine, University of Oxford, University College London Hospitals NHS Trust, London John Radcliffe Hospital, Oxford vi Preface As with most medical specialties, haematology has seen major changes since this book was first published in 1998. We now have greater understanding of the molecular biology of many diseases, both malignant and non-malignant. This new knowledge has helped us to develop more sensitive assays for many conditions, and has been taken into the clinic, with the engineering of new drugs, such as STI571 used in the treatment of chronic myeloid leukaemia, amongst others. As with the first edition, the intention has been to encompass all aspects of haematology but with perhaps a greater emphasis on basic science than previously. Readers will note that the writing team is almost identical to that for the first edition, which provides continuity of style. I would like to express my gratitude to all my haematology colleagues for updating their sections and bringing the entire text up to date. Key reading lists are provided for all topics for those wishing to read about haematology in greater detail. Thanks must also go to the BMJ and in particular Mary Banks, Senior Commissioning Editor, and Sally Carter, Development Editor, who have been key players in the development of the second edition. I would welcome any comments concerning the book, and perhaps readers may have suggestions for the next edition. I can be contacted at [email protected]. vii 1 Iron deficiency anaemia Drew Provan Iron deficiency is the commonest cause of anaemia worldwide Table 1.1 Daily dietary iron requirements per 24 hours and is frequently seen in general practice. The anaemia of iron deficiency is caused by defective synthesis of haemoglobin, Male 1mg resulting in red cells that are smaller than normal (microcytic) Adolescence 2-3mg and contain reduced amounts of haemoglobin (hypochromic). Female (reproductive age) 2-3mg Pregnancy 3-4mg Infancy 1mg Iron metabolism Maximum bioavailability from normal diet about 4mg Iron has a pivotal role in many metabolic processes, and the Box 1.1 Risk factors in development of iron deficiency average adult contains 3-5g of iron, of which two thirds is in the oxygen-carrying molecule haemoglobin. • Age:infants (especially if history of prematurity); adolescents; postmenopausal women; old age A normal Western diet provides about 15mg of iron daily, • Sex:increased risk in women of which 5-10% is absorbed ((cid:1)1mg), principally in the • Reproduction:menorrhagia duodenum and upper jejunum, where the acidic conditions • Renal:haematuria (rarer cause) help the absorption of iron in the ferrous form. Absorption is • Gastrointestinal tract:appetite or weight changes; changes helped by the presence of other reducing substances, such as in bowel habit; bleeding from rectum/melaena; gastric or hydrochloric acid and ascorbic acid. The body has the capacity bowel surgery • Drug history:especially aspirin and non-steroidal to increase its iron absorption in the face of increased anti-inflammatories demand—for example, in pregnancy, lactation, growth spurts, • Social history:diet, especially vegetarians and iron deficiency. • Physiological:pregnancy; infancy; adolescence; breast Once absorbed from the bowel, iron is transported across feeding; age of weaning the mucosal cell to the blood, where it is carried by the protein transferrin to developing red cells in the bone marrow. Iron stores comprise ferritin, a labile and readily accessible source of iron, and haemosiderin, an insoluble form found predominantly in macrophages. About 1mg of iron a day is shed from the body in urine, faeces, sweat, and cells shed from the skin and gastrointestinal tract. Menstrual losses of an additional 20mg a month and the increased requirements of pregnancy (500-1000mg) contribute to the higher incidence of iron deficiency in women of reproductive age. Figure 1.1 Nail changes in iron deficiency anaemia (koilonychia) Clinical features of iron deficiency Box 1.2 Causes of iron deficiency anaemia The symptoms accompanying iron deficiency depend on how Reproductive system rapidly the anaemia develops. In cases of chronic, slow blood • Menorrhagia loss, the body adapts to the increasing anaemia, and patients Gastrointestinal tract can often tolerate extremely low concentrations of Bleeding haemoglobin—for example, (cid:1)70g/l—with remarkably few • Oesophagitis symptoms. Most patients complain of increasing lethargy and • Oesophageal varices dyspnoea. More unusual symptoms are headaches, tinnitus, and • Hiatus hernia (ulcerated) • Peptic ulcer taste disturbance. • Inflammatory bowel disease On examination, several skin, nail, and other epithelial • Haemorrhoids (rarely) changes may be seen in chronic iron deficiency. Atrophy of the • Carcinoma: stomach, colorectal skin occurs in about a third of patients, and (rarely nowadays) • Angiodysplasia nail changes such as koilonychia (spoon shaped nails) may • Hereditary haemorrhagic telangiectasia (rare) result in brittle, flattened nails. Patients may also complain of Malabsorption angular stomatitis, in which painful cracks appear at the angle • Coeliac disease of the mouth, sometimes accompanied by glossitis. Although • Atrophic gastritis (also may result fromiron deficiency) uncommon, oesophageal and pharyngeal webs can be a feature Physiological of iron deficiency anaemia (consider this in middle aged • Growth spurts (especially in premature infants) • Pregnancy women presenting with dysphagia). These changes are believed Dietary to be due to a reduction in the iron-containing enzymes in the • Vegans epithelium and gastrointestinal tract. • Elderly Tachycardia and cardiac failure may occur with severe Worldwide commonest cause of iron deficiency is hookworm anaemia irrespective of cause, and in such cases prompt infection remedial action should be taken. 1 ABC of Clinical Haematology When iron deficiency is confirmed a full clinical history including leading questions on possible gastrointestinal blood Anaemia Haemoglobin <135 g/l (male) loss or malabsorption (as in, for example, coeliac disease) <115 g/l (female) should be obtained. Menstrual losses should be assessed, and the importance of dietary factors and regular blood donation What is mean cell volume? should not be overlooked. Low (<76 fl) Diet alone is seldom the sole cause for iron deficiency microcytic red cells anaemia in Britain except when it prevents an adequate response to a physiological challenge—as in pregnancy, for Consider: Iron deficiency anaemia example. Thalassaemia Anaemia of chronic disorders Laboratory investigations History and physical examination Obvious source of blood loss? A full blood count and film should be taken. These will (eg menstrual or gastrointestinal (GI) tract) confirm the anaemia; recognising the indices of iron deficiency No Yes is usually straightforward (reduced haemoglobin concentration, reduced mean cell volume, reduced mean cell Investigation: Treat underlying cause or Full blood count and film examination consider specialist referral haemoglobin, reduced mean cell haemoglobin concentration). Serum ferritin estimation Urea, electrolytes, and liver function tests Some modern analysers will determine the percentage of Midstream urine GI tract visualisation (endoscopy or barium) hypochromic red cells, which may be high before the anaemia Consider specialist referral develops (it is worth noting that a reduction in haemoglobin concentration is a latefeature of iron deficiency). The blood Figure 1.2 Diagnosis and investigation of iron deficiency anaemia film shows microcytic hypochromic red cells. Hypochromic anaemia occurs in other disorders, such as anaemia of chronic disorders and sideroblastic anaemias and in globin synthesis Box 1.3 Investigations in iron deficiency anaemia disorders, such as thalassaemia. To help to differentiate the type, further haematinic assays may be necessary. Difficulties in • Full clinical history and physical examination • Full blood count and blood film examination diagnosis arise when more than one type of anaemia is • Haematinic assays (serum ferritin, vitamin B folate) present—for example, iron deficiency and folate deficiency in • % hypochromic red cells and soluble transfe1r2rin receptor malabsorption, in a population where thalassaemia is present, assay (if available) or in pregnancy, when the interpretation of red cell indices • Urea and electrolytes, liver function tests may be difficult. • Fibreoptic and/or barium studies of gastrointestinal tract Haematinic assays will demonstrate reduced serum ferritin • Pelvic ultrasound (females, if indicated) concentration in straightforward iron deficiency. As an acute phase protein, however, the serum ferritin concentration may be normal or even raised in inflammatory or malignant disease. A prime example of this is found in rheumatoid disease, in which active disease may result in a spuriously raised serum ferritin concentration masking an underlying iron deficiency caused by gastrointestinal bleeding after non-steroidal analgesic treatment. There may also be confusion in liver disease as the liver contains stores of ferritin that are released after hepatocellular damage, leading to raised serum ferritin concentrations. In cases where ferritin estimation is likely to be misleading, the soluble transferrin receptor (sTfR) assay may aid the diagnosis. Transferrin receptors are found on the surface of red cells in greater numbers in iron deficiency; a proportion of Figure 1.3 Blood film showing changes of iron deficiency anaemia receptors are shed into the plasma and can be measured using commercial kits. Unlike the serum ferritin, the sTfR does not rise in inflammatory disorders, and hence can help differentiate Table 1.2 Diagnosis of iron deficiency anaemia between anaemia due to inflammation from iron deficiency. Diagnostic bone marrow sampling is seldom performed in Reduced haemoglobin Men (cid:1)135g/l, women (cid:1)115g/l simple iron deficiency, but if the diagnosis is in doubt a marrow Reduced mean cell volume (cid:1)76fl aspirate may be carried out to demonstrate absent bone Reduced mean cell 29.5(cid:2)2.5pg marrow stores. haemoglobin When iron deficiency has been diagnosed, the underlying Reduced mean cell 325(cid:2)25g/l haemoglobin concentration cause should be investigated and treated. Often the history will Blood film Microcytic hypochromic red cells indicate the likely source of bleeding—for example, menstrual with pencil cells and target cells blood loss or gastrointestinal bleeding. If there is no obvious Reduced serum ferritin* Men (cid:1)10(cid:3)g/l, women cause, further investigation generally depends on the age and (postmenopausal) (cid:1)10(cid:3)g/l sex of the patient. In male patients and postmenopausal (premenopausal) (cid:1)5(cid:3)g/l women possible gastrointestinal blood loss is investigated by Elevated % hypochromic red cells ((cid:4)2%) visualisation of the gastrointestinal tract (endoscopic or barium Elevated soluble transferrin studies). Faecal occult bloods are of no value in the receptor level investigation of iron deficiency. *Check with local laboratory for reference ranges 2 Iron deficiency anaemia Management Table 1.3 Characteristics of anaemia associated with other disorders Effective management of iron deficiency relies on (a) the appropriate management of the underlying cause (for Iron Chronic Thalassaemia Sideroblastic example, gastrointestinal or menstrual blood loss) and (b) iron deficiency disorders trait ((cid:7)or (cid:8)) anaemia replacement therapy. Degree of Any Seldom Mild Any anaemia (cid:1)9.0g/dl Oral iron replacement therapy with gradual replenishment MCV b N orb bb N orbora of iron stores and restoration of haemoglobin is the preferred Serum b N ora N a treatment. Oral ferrous salts are the treatment of choice (ferric ferritin salts are less well absorbed) and usually take the form of Soluble a N a N ferrous sulphate 200mg three times daily (providing transferrin 65mg(cid:5)3(cid:6)195mg elemental iron/day). Alternative receptor assay preparations include ferrous gluconate and ferrous fumarate. Marrow iron Absent Present Present Present All three compounds, however, are associated with a high N(cid:6)norm incidence of side effects, including nausea, constipation, and diarrhoea. These side effects may be reduced by taking the tablets after meals, but even milder symptoms account for poor compliance with oral iron supplementation. Modified release preparations have been developed to reduce side effects but in practice prove expensive and often release the iron beyond the sites of optimal absorption. Effective iron replacement therapy should result in a rise in haemoglobin concentration of around 1g/l per day (about 20g/l every three weeks), but this varies from patient to patient. Once the haemoglobin concentration is within the normal range, iron replacement should continue for three months to replenish the iron stores. Failure to respond to oral iron Figure 1.4 Oral iron replacement therapy therapy The main reason for failure to respond to oral iron therapy is poor compliance. However, if the losses (for example, bleeding) exceed the amount of iron absorbed daily, the haemoglobin concentration will not rise as expected; this will also be the case in combined deficiency states. Table 1.4 Elemental iron content of various oral iron The presence of underlying inflammation or malignancy preparations may also lead to a poor response to therapy. Finally, an Preparation Amount (mg) Ferrous iron (mg) incorrect diagnosis of iron deficiency anaemia should be Ferrous fumarate 200 65 considered in patients who fail to respond adequately to iron Ferrous gluconate 300 35 replacement therapy. Ferrous succinate 100 35 Ferrous sulphate 300 60 Intravenous and intramuscular iron preparations Ferrous sulphate (dried) 200 65 Parenteral iron may be used when the patient cannot tolerate oral supplements—for example, when patients have severe gastrointestinal side effects or if the losses exceed the daily amount that can be absorbed orally. Iron sorbitol injection is a complex of iron, sorbitol and citric acid. Treatment consists of a course of deep intramuscular injections. The dosage varies from patient to patient and depends on (a) the initial haemoglobin Box 1.4 Intravenous iron preparations concentration and (b) body weight. Generally, 10-20 deep intramuscular injections are given over two to three weeks. • Iron dextran no longer available (severe reactions) • Iron-hydroxide sucrose is currently available in the UK Apart from being painful, the injections also lead to skin • Useful in selected cases staining at the site of injection and arthralgia, and are best • Must be given under close medical supervision and where avoided. An intravenous preparation is available (Venofer®) for full resuscitation facilities are available use in selected cases, and under strict medical supervision, for example, on haematology day unit (risk of anaphylaxis or other reactions). Alternative treatments Blood transfusion is not indicated unless the patient has decompensated due to a drop in haemoglobin concentration The rise in haemoglobin concentration is no faster with and needs a more rapid rise in haemoglobin—for example, in parenteral iron preparations than with oral iron therapy cases of worsening angina or severe coexisting pulmonary 3