Cover
Title Page
Contributors
CHAPTER 1: Iron‐Deficiency Anaemia
1. Iron metabolism
2. Clinical features of iron deficiency
3. Laboratory investigations
4. Management
5. Failure to respond to oral iron therapy
6. Acknowledgements
7. Further reading
CHAPTER 2: Macrocytic Anaemias
1. Deficiency of vitamin B12 (cobalamin) or folate
2. Diagnosis
3. Treatment
4. Further reading
CHAPTER 3: The Hereditary Anaemias
1. The sickling disorders
2. The thalassaemias
3. Red cell enzyme defects
4. Red cell membrane defects
5. Other hereditary anaemias
6. Further reading
CHAPTER 4: Polycythaemia Vera, Essential Thrombocythaemia and Myelofibrosis
1. Molecular pathogenesis of myeloproliferative neoplasms
2. Erythrocytosis and polycythaemia vera
3. Thrombocytosis
4. Primary myelofibrosis
5. Further reading
CHAPTER 5: Chronic Myeloid Leukaemia
1. Clinical features
2. Pathophysiology
3. Diagnosis
4. Treatment of chronic‐phase disease
5. Imatinib mesylate
6. Monitoring of patients on tyrosine kinase inhibitors
7. Second‐ and third‐generation tyrosine kinase inhibitors
8. Resistance to tyrosine kinase inhibitors
9. Treatment duration and treatment‐free remission
10. Advanced‐phase disease
11. Further reading
CHAPTER 6 The Acute Leukaemias
1. Introduction
2. Classification
3. Epidemiology
4. Clinical features of acute (myeloid and lymphoblastic) leukaemia
5. Diagnosis of acute (myeloid and lymphoblastic) leukaemia
6. Principles of treatment
7. Specific management of acute myeloid leukaemia
8. Specific management of acute lymphoblastic leukaemia
9. Novel therapies
10. Further reading
CHAPTER 7: Platelet Disorders
1. Normal haemostasis
2. Congenital abnormalities
3. Acquired abnormalities
4. History and examination of patients
5. Investigations
6. Management
7. Further reading
CHAPTER 8: Myelodysplastic Syndromes
1. Introduction
2. Pathogenesis
3. Presentation
4. Investigation
5. Classification
6. Prognosis
7. Management
8. Further reading
CHAPTER 9: Multiple Myeloma
1. Epidemiology
2. Pathogenesis
3. Clinical features
4. Diagnosis
5. Investigations and staging
6. Management
7. Future therapies
8. Monoclonal gammopathy of undetermined significance
9. Other plasma cell disorders
10. Further reading
CHAPTER 10: Bleeding Disorders, Thrombosis and Anticoagulation
1. Bleeding disorders
2. Congenital bleeding disorders
3. Acquired bleeding disorders
4. Venous thromboembolism
5. The inherited thrombophilias
6. Treatment of venous thromboembolism
7. Further reading
CHAPTER 11: Lymphoproliferative Disorders
1. Introduction
2. Aetiology
3. Presenting features
4. Diagnosis
5. Staging and prognosis
6. Treatment
7. Lymphoma subtypes
CHAPTER 12: Stem Cell Transplantation
1. Introduction
2. Stem cells
3. Stem cell collection
4. Autologous stem cell transplantation
5. Allogeneic stem cell transplantation
6. Donor selection
7. Complications of allogeneic stem cell transplantation
8. Conclusions
9. Further reading
CHAPTER 13: Haematological Problems in Older Adults
1. Introduction
2. Anaemia
3. Haematological malignancies
4. Chronic lymphocytic leukaemia
5. Further reading
CHAPTER 14: Haematological Emergencies
1. Hyperviscosity syndrome
2. Sickle cell crisis
3. Spinal cord compression
4. Bleeding
5. Thrombotic thrombocytopenic purpura
6. Infection in patients with impaired immunity
7. Further reading
CHAPTER 15: The Future of Haematology
1. Introduction
2. Gene therapy
3. Genomics
4. Genome editing
5. Immunological modulation without bone marrow transplant
6. Rational drug design
7. Conclusion
8. Glossary
9. Further reading
Index
End User License Agreement

List of Tables

Chapter 01
1. Table 1.1 Daily dietary iron requirements.
2. Table 1.2 Diagnosis of iron‐deficiency anaemia (normal values in parentheses).
3. Table 1.3 Characteristics of anaemia associated with other disorders.
4. Table 1.4 Elemental iron content of various oral iron preparations.
Chapter 05
1. Table 5.1 Response evaluation to TKIs used as first‐line therapy (European LeukaemiaNet data, 2013).
Chapter 06
1. Table 6.1 Risk factors for the development of acute leukaemia.
2. Table 6.2 Differential diagnosis of acute leukaemia.
3. Table 6.3 Principles of management of acute leukaemia.
4. Table 6.4 Supportive care.
5. Table 6.5 Side‐effects of chemotherapy.
Chapter 08
1. Table 8.1 Examples of mutations seen in MDSs.
2. Table 8.2 Dysplastic features.
3. Table 8.3 Other causes of dysplasia.
4. Table 8.4 WHO classification of MDSs.
5. Table 8.5 R‐IPSS for MDSs.
6. Table 8.6 Risk stratification for R‐IPSS.
7. Table 8.7 WHO classification‐based prognostic scoring system (WPSS).
8. Table 8.8 Risk category and prognosis.
Chapter 09
1. Table 9.1 Clinical features of multiple myeloma.
2. Table 9.2 Diagnostic criteria for multiple myeloma and MGUS.
3. Table 9.3 International Staging Score (ISS).
4. Table 9.4 Supportive treatment in myeloma.
Chapter 10
1. Table 10.1 Interpretation of coagulation screening tests.
2. Table 10.2 The heritable thrombophilias.
Chapter 11
1. Table 11.1 WHO classification (major categories) of lymphoma.
2. Table 11.2 Flow cytometry expression patterns in common LPDs: B‐cell neoplasms.
3. Table 11.3 Flow cytometry expression patterns in common LPDs: T‐cell neoplasms.
4. Table 11.4 Common genetic aberrations in lymphoproliferative conditions.
5. Table 11.5 Ann Arbor staging for lymphoma.
6. Table 11.6 Rai staging of CLL.
7. Table 11.7 Binet staging for CLL.
8. Table 11.8 Lymphoma prognostic scoring systems.
9. Table 11.9 European Organization for Research and Treatment of Cancer prognostic criteria for early stage Hodgkin’s disease.
Chapter 12
1. Table 12.1 Use of stem cell transplantation in adult practice (in order of frequency)
2. Table 12.2 Use of stem cell transplantation in paediatric practice (in order of frequency).
3. Table 12.3 Types of stem cell transplant.
4. Table 12.4 Complications post‐transplant.
5. Table 12.5 Definitions of aGvHD and cGvHD.
6. Table 12.6 Clinical characteristics of cGvHD.
Chapter 13
1. Table 13.1 Prevalence of paraproteinaemia in different age groups.
Chapter 14
1. Table 14.1 Symptoms and signs of hyperviscosity.
2. Table 14.2 Sickle cell crises.
3. Table 14.3 Causes of bleeding according to phase of haemostasis.
4. Table 14.4 Clinical features of DIC.
5. Table 14.5 Essential diagnostic investigations for DIC.
6. Table 14.6 Causes of acute DIC.
7. Table 14.7 Clinical subtypes of TTP.
8. Table 14.8 Risks of infection in patients with no spleen or hypofunctioning spleen.
Chapter 15
1. Table 15.1 Scientific techniques and approaches that will continue to make major contributions to modern haematology
2. Table 15.2 Gene therapy strategies

List of Illustrations

Chapter 01
1. Figure 1.1 Nail changes in iron‐deficiency anaemia (koilonychia).
2. Figure 1.2 Diagnosis and investigation of iron‐deficiency anaemia.
3. Figure 1.3 Blood film showing changes of iron‐deficiency anaemia.
4. Figure 1.4 Oral iron replacement therapy.
Chapter 02
1. Figure 2.1 Patient with vitiligo on neck and back.
2. Figure 2.2 Patient with gluten‐induced enteropathy (coeliac disease): underweight and low stature.
3. Figure 2.3 Blood film in vitamin B₁₂ deficiency showing macrocytic red cells and a hypersegmented neutrophil.
4. Figure 2.4 Glossitis due to vitamin B₁₂ deficiency.
5. Figure 2.5 Bone marrow appearances in megaloblastic anaemia: developing red cells are larger than normal, with nuclei that are immature relative to their cytoplasm (nuclear : cytoplasmic asynchrony).
6. Figure 2.6 Bone marrow aspirate in myelodysplasia showing characteristic dysplastic neutrophils with bilobed nuclei.
Chapter 03
1. Figure 3.1 Simplified representation of the genetic control of human Hb. Because α chains are shared by both fetal and adult Hb, mutations of the α globin genes affect Hb production in both fetal and adult life; diseases that are due to defective β globin production are only manifest after birth when Hb A replaces Hb F.
2. Figure 3.2 Hb electrophoresis showing (1) normal, (2) newborn, (3) Hb C trait (A–C), (4) Hb SC disease (SC), (5) sickle cell disease (SS), (6) sickle cell trait (A–S), (7) newborn, (8) normal.
3. Figure 3.3 Peripheral blood film from patient with sickle cell anaemia showing sickled erythrocytes.
4. Figure 3.4 Distribution of the thalassaemias (red area).
5. Figure 3.5 Inheritance of Hb disease (open boxes represent normal α globin genes and red boxes deleted α globin genes).
6. Figure 3.6 Pathophysiology of α thalassaemia.
7. Figure 3.7 Peripheral blood film in homozygous β thalassaemia showing pronounced hypochromia and anisocytosis with nucleated red blood cells.
8. Figure 3.8 Liver biopsy from patient with β thalassaemia showing pronounced iron accumulation.
Chapter 04
1. Figure 4.1 Raised PCV in a patient with PV (left) compared with a blood sample from a person with a normal PCV (right).
2. Figure 4.2 Algorithm for investigation of a patient presenting with a raised haematocrit. Note that red cell mass estimation is unnecessary if the haematocrit is >0.6 in men or >0.56 in women.
3. Figure 4.3 Toe ischaemia in a patient with ET.
4. Figure 4.4 Algorithm for investigation of a patient presenting with a raised platelet count.
5. Figure 4.5 Bone marrow trephine biopsy from a patient with ET showing clustering of large megakaryocytes (arrows).
6. Figure 4.6 Bone marrow trephine biopsy from a patient with advanced PMF. Note the marked linear reticulin staining (e.g. arrow).
7. Figure 4.7 Leucoerythroblastic blood film in a patient with PMF. Note the nucleated red blood cell (lower arrow) and the myelocyte (upper arrow).
Chapter 05
1. Figure 5.1 Typical blood film in chronic phase (CP) CML showing many mature granulocytes, myelocytes, basophils (arrow) and a blast cell (double arrow).
2. Figure 5.2 Massive splenomegaly in CP CML.
3. Figure 5.3 Phases of CML.
4. Figure 5.4 G‐banded karyotype showing classical Philadelphia pattern 46,XY,t(9;22)(q34;q11).
5. Figure 5.5 Formation of the Philadelphia chromosome resulting in a BCR–ABL fusion gene that generates a fusion protein (p210) responsible for the CML phenotype.
6. Figure 5.6 Fluorescent in‐situ hybridisation showing reciprocal translocation showing BCR–ABL dual fusion using dual‐colour probes.
7. Figure 5.7 Mechanism of action of TKIs.
8. Figure 5.8 Peripheral blood appearance of a patient in lymphoid blast crisis.
Chapter 06
1. Figure 6.1 Photomicrograph showing myeloid blasts and pathognomonic Auer rod in patient with AML.
2. Figure 6.2 Photomicrograph showing lymphoid blasts in patient with ALL.
3. Figure 6.3 Karyotypic analysis in patient with AML associated with t(8;21).
4. Figure 6.4 Fluorescence in‐situ hybridisation examination in patient with APML demonstrating t(15;17).
Chapter 07
1. Figure 7.1 Normal platelet function.
2. Figure 7.2 Amegakaryocytic thrombocytopenia with absent radii syndrome.
3. Figure 7.3 Giant granular platelets in peripheral blood film as seen in Bernard–Soulier syndrome or May–Hegglin anomaly.
4. Figure 7.4 Site of abnormality in congenital platelet disorders (SPD: storage pool deficiency).
5. Figure 7.5 Spontaneous skin purpura in severe immune thrombocytopenia.
6. Figure 7.6 Bone marrow aspirate showing increased megakaryocytes in immune thrombocytopenia.
7. Figure 7.7 Red cell fragmentation in patient who presented with confusion and lethargy in whom thrombotic thrombocytopenic purpura was diagnosed. She responded well to large‐volume plasma exchange for 1 week.
8. Figure 7.8 Investigation of suspected platelet disorder.
Chapter 08
1. Figure 8.1
2. Figure 8.2
3. Figure 8.3
4. Figure 8.4
5. Figure 8.5
Chapter 09
1. Figure 9.1 Plasma cells adhere to bone marrow stromal cells, resulting in cytokine and growth factor secretion. This results in increased osteoclastic activity and osteoblast inhibition, leading to bone resorption.
2. Figure 9.2 Radiograph showing pathological fracture of the humerus.
3. Figure 9.3 Magnetic resonance image showing compressive myelomatous infiltration at T4, T5 and T7.
4. Figure 9.4 Radiograph showing large lytic lesion of the femur.
5. Figure 9.5 Protein electrophoresis strip showing IgG kappa serum paraprotein. The first and largest peak is albumin, which lies closest to the positive electrode. The next five peaks are alpha‐1, alpha‐2, beta‐1, beta‐2, and gamma. Within the gamma peak (shaded), a monoclonal IgG protein is characterised by the presence of a sharp, well‐defined band.
6. Figure 9.6 Bone marrow aspirate showing plasma cell infiltrate.
Chapter 10
1. Figure 10.1 A simplified version of the coagulation cascade (TF: tissue factor).
2. Figure 10.2 Knee arthropathy in haemophilia.
3. Figure 10.3 DVT.
4. Figure 10.4 A possible diagnostic algorithm for diagnosis of DVT.
5. Figure 10.5 The natural anticoagulants. APC, activated protein C; AT, antithrombin; PC, protein C; PS, protein S.
6. Figure 10.6 The G → A point mutation results in the arginine at the protein C cleavage site being replaced by glutamine.
Chapter 11
1. Figure 11.1 Peripheral blood smear of chronic lymphocytic leukaemia. Arrows = CLL cells.
2. Figure 11.2 Lymph node microscopy (a) DLBCL‐high power and (b) FL‐low power note visible follicles.
3. Figure 11.3 Interval CT/positron emission tomography scan showing residual metabolically active disease (arrows).
4. Figure 11.4 B‐cell signalling pathways and targeted drug therapies. mTOR: mammalian target of rapamycin; NFκB: nuclear factor kappa‐light‐chain‐enhancer of activated B cells; LYN: Lck/Yes novel tyrosine kinase (or tyrosine protein kinase LYN); PI3K: phosphatidylinositol 3‐kinase; AKt: protein kinase B; PKC: protein kinase C; BCl‐2: B‐cell lymphoma 2; BTK: Bruton tyrosine kinase; SYK: spleen tyrosine kinase; SIg: surface immunoglobulin.
5. Figure 11.5 HL high‐power view showing multiple large mononuclear Reed–Sternberg cells (arrows).
Chapter 12
1. Figure 12.1 Skin involvement in GvHD.
Chapter 13
1. Figure 13.1 Causes of anaemia in older patients, as found in NHANES III study.
2. Figure 13.2 The incidence of the four most common haematological malignancies in adults (National Cancer Registration and Analysis Service statistics).
3. Figure 13.3 Abnormal, multinucleated plasma cells in plasma cell myeloma.
4. Figure 13.4 Blood film in a patient with an MDS. Shown are giant platelets, a dysplastic neutrophil and a myeloblast.
Chapter 14
1. Figure 14.1 Blood film in acute myeloid leukaemia. Note the extremely high number of circulating white blood cells (hyperleucocytosis), leading to hyperviscosity.
2. Figure 14.2 Fundal changes in a patient with hyperviscosity (newly diagnosed myeloma) with immunoglogulin (Ig)A concentration 50 g/dL showing retinal venous engorgement, papilloedema and haemorrhages (left) compared with normal (right).
3. Figure 14.3 The viscosity of blood increases exponentially as the haematocrit rises beyond 45%.
4. Figure 14.4 Sickle cell disease. Anteroposterior chest radiographs: (a) at presentation showing generalised air space change/consolidation in the lower zone of the right lung; (b) showing progressive air space changes in the right lower zone a day following presentation.
5. Figure 14.5 Sickled red cells (crescent shaped) in homozygous sickle cell disease.
6. Figure 14.6 Magnetic resonance scan of a patient with multiple myeloma showing loss of height of T7 vertebra with associated spinal cord compression.
7. Figure 14.7 Red cell fragments (irregularly shaped cells amongst the normal round red cells) seen on the blood film of a patient with thrombotic thrombocytopenic purpura. Note also the marked thrombocytopenia seen in this blood film.
8. Figure 14.8 Temperature chart showing marked swinging pyrexia in a patient with chronic lymphocytic leukaemia (CLL). Fevers of this type are also seen in other immunocompromised patients, such as those with neutropenia.
Chapter 15
1. Figure 15.1 Haemophilic patient with inhibitors and severe spontaneous bleeding. Gene therapy approaches can make this a thing of the past.
2. Figure 15.2 Microarray technology allows the analysis of thousands of different genes simultaneously.

Edition History
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Library of Congress Cataloging‐in‐Publication Data

Names: Provan, Drew, 1955– editor.
Title: ABC of clinical haematology / edited by Drew Provan.
Description: Fourth edition. | Hoboken, NJ : John Wiley & Sons, Inc., 2018. | Includes bibliographical references and index. |
Identifiers: LCCN 2017055360 (print) | LCCN 2017056756 (ebook) | ISBN 9781118892473 (pdf) | ISBN 9781118892480 (epub) | ISBN 9781118892343 (pbk.)
Subjects: | MESH: Hematologic Diseases–diagnosis | Hematologic Diseases–therapy | Hematologic Diseases–physiopathology
Classification: LCC RC633 (ebook) | LCC RC633 (print) | NLM WH 120 | DDC 616.1/5–dc23
LC record available at https://lccn.loc.gov/2017055360

Cover Design: Wiley
Cover Image: © Science Photo Library ‐ STEVE GSCHMEISSNER./Gettyimages

Contributors

Katharine Bailey
Haematology, Cancer Institute, UCL, Royal Free Campus, London, UK

Catherine Booth
Specialist Registrar in Haematology, Barts and the London NHS Trust, London, UK

Richard Burt
Haematology, Cancer Institute, UCL, Royal Free Campus, London, UK

Tom Butler
Department of Clinical Haematology, Barts Health NHS Trust, Pathology & Pharmacy Building, Royal London Hospital, London, UK

Jenny L. Byrne
Nottingham University Hospitals NHS Trust, Nottingham, UK

Jamie Cavenagh
Consultant Haematologist, Department of Haemato‐Oncology, St Bartholomew’s Hospital, West Smithfield, London, UK

John de Vos
Consultant Haematologist, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK

Robin Dowse
Senior Specialist Registrar, Haematological Medicine, King’s College Hospital NHS Foundation Trust, Hambleden Wing, London, UK

Adele K. Fielding
Haematology, Cancer Institute, UCL, Royal Free Campus, London, UK

Anna L. Godfrey
Consultant Haematologist, Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Anthony R. Green
Director, Wellcome Trust/MRC Cambridge Stem Cell Institute, University of Cambridge;
Department of Haematology, University of Cambridge, Cambridge, UK

Sandra Hassan
Consultant Haematologist, Queen’s Hospital, BHR NHS Trust, Romford, UK

Catherine Hockings
Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK

Victor Hoffbrand
Emeritus Professor of Haematology, University College London, London, UK

David M. Keeling
Consultant Haematologist, Oxford University Hospitals, Oxford Haemophilia & Thrombosis Centre, Churchill Hospital, Oxford, UK

R. J. Liesner
Director Haemophilia CCC, Great Ormond Street Hospital, London, UK

Christopher McNamara
Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK

Ghulam J. Mufti
Professor of Haemato‐oncology & Head of Department, Haematological Medicine, King’s College Hospital NHS Foundation Trust, Hambleden Wing, London, UK

Jim Murray
Haematology – University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, UK

Adrian C. Newland
Barts and the London Medical School, Queen Mary University of London; Department of Clinical Haematology, Barts Health NHS Trust, Pathology & Pharmacy Building, Royal London Hospital, London, UK

Igor Novitzky‐Basso
Stem Cell Laboratory Medical Director, Queen Elizabeth University Hospital Glasgow, NHS Greater Glasgow and Clyde, Glasgow, UK

Drew Provan
Emeritus Reader in Autoimmune Haematology, Department of Haematology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Marie A. Scully
Department of Haematology, University College London Hospitals NHS Trust, Cardiometabolic Programme‐NIHR UCLH/UCL BRC, London, UK

Julia Sikorska
Specialist Registrar in Haematology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK

George S. Vassiliou
Group Leader and Consultant Haematologist, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton;Wellcome Trust/MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

David J. Weatherall
Regius Professor of Medicine Emeritus, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, UK

Fourth Edition