Table of Contents
Title page
Copyright page
Preface to the fourth edition
Preface to the first edition
Glossary
Normal values
About the companion website
Part 1: Basic physiology and practice
1: Haemopoiesis: physiology and pathology
Definition and sites
Stem and progenitor cells
Growth factors
Assessment of haemopoiesis
2: Normal blood cells I: red cells
Peripheral blood cells
Red cells (erythrocytes)
3: Normal blood cells II: granulocytes, monocytes and the reticuloendothelial system
Function of white cells
Neutrophils
Eosinophils
Basophils
Monocytes
Reticuloendothelial system
4: Normal blood cells III: lymphocytes
Immune response
Natural killer cells
Immunoglobulins
Complement
5: Lymph nodes, the lymphatic system and the spleen
Lymph and the lymphatic system
Functions of the spleen
6: Clinical assessment
History
Examination
Special investigations
7: Laboratory assessment
Routine tests
Bone marrow aspiration
Specialized tests
Part 2: Red cell disorders
8: General aspects of anaemia
Anaemia
Anaemia of chronic disease
Malignancy
Connective tissue disorders
Renal disease
Endocrine disease
Liver disease
9: Iron I: physiology and deficiency
Distribution of body iron
Iron intake, absorption and loss
Iron deficiency
10: Iron II: overload and sideroblastic anaemia
Iron overload
Sideroblastic anaemia
11: Megaloblastic anaemia I: vitamin B12 (B12) and folate deficiency – biochemical basis, causes
Biochemical basis
Causes of B12 deficiency
Folate physiology
12: Megaloblastic anaemia II: clinical features, treatment and other macrocytic anaemias
B12 deficiency
Folate deficiency
Causes of macrocytosis
13: Haemolytic anaemias I: general
Haemolytic anaemias I: General
Physiology of red cell destruction
Clinical features
14: Haemolytic anaemias II: inherited membrane and enzyme defects
Membrane abnormalities
Enzyme abnormalities
15: Haemolytic anaemias III: acquired
Autoimmune haemolytic anaemia
Alloimmune haemolytic anaemia
Drug-induced immune haemolytic anaemia
Red cell fragmentation syndromes
Infections
Chemical and physical agents
Paroxysmal nocturnal haemoglobinuria
16: Haemolytic anaemias IV: genetic defects of haemoglobin – thalassaemia
Normal haemoglobins
Genetic disorders of haemoglobin
Thalassaemia
Prenatal diagnosis of haemoglobin defects
17: Haemolytic anaemias V: genetic defects of haemoglobin – sickle cell disease
Sickle cell disease
Sickle cell trait
Other sickling disorders
Other structural haemoglobin abnormalities
Part 3: Benign disorders of white cells
18: Benign disorders of white cells I: granulocytes, monocytes, macrophages
Granulocytes and monocytes
Lysosomal storage disease
Histiocyte disorders
Haemophagocytic syndromes
19: Benign disorders of white cells II: lymphocytes, lymph nodes, spleen, HIV
Immunodeficiency
Hyposplenism
Splenomegaly
Splenectomy
HIV infection and AIDS
Part 4: Haematological malignancies
20: Introduction to haematological malignancy: basic mechanisms
Neoplasia
Evidence of clonality
21: General aspects of treatment
Chemotherapy
Biological therapies
Apheresis
Infection
Radiotherapy
Counselling
22: Acute leukaemia I: classification and diagnosis
Classification
Aetiology and pathogenesis
Incidence
Clinical features
Laboratory features
23: Acute leukaemia II: treatment and prognosis
Treatment
Prognosis
24: Chronic myeloid leukaemia (BCR-ABL1 positive)
Aetiology and pathophysiology
Clinical features
Laboratory findings
Course and progress
Treatment
25: Myelodysplasia (myelodysplastic syndromes)
Aetiology and pathogenesis
Clinical features
Laboratory findings
Differential diagnosis
Course and prognosis
Treatment
Myelodysplastic/myeloproliferative diseases
26: Myeloproliferative disorders I: introduction
Differential diagnosis
27: Myeloproliferative disorders II: polycythaemia rubra vera
Polycythaemia rubra vera
28: Myeloproliferative disorders III: essential thrombocythaemia, primary myelofibrosis and systemic mastocytosis
Essential thrombocythaemia
Primary myelofibrosis
Systemic mastocytosis
29: Chronic lymphocytic leukaemia
Aetiology and pathophysiology
Clinical features
Laboratory findings
Course and prognosis
Treatment
Variants of CLL
30: Multiple myeloma and plasma cell disorders
Incidence
Aetiology and pathogenesis
Clinical features
Laboratory features
Treatment
Related disorders
Amyloid
31: Lymphoma I: introduction
32: Lymphoma II: Hodgkin lymphoma
Aetiology and epidemiology
Histological classification
Clinical features
Laboratory features
Staging
Treatment
Relapsed disease
Prognosis
33: Lymphoma III: non-Hodgkin lymphoma – aetiology and classification
Aetiology and epidemiology
Clinical features
Laboratory features
Radiographic features
Staging
Histological classification
34: Lymphoma IV: clinical and laboratory features of more common subtypes
Low-grade B-cell lymphoma
High-grade lymphomas
Mature T-cell diseases
35: Lymphoma V: treatment and prognosis
Treatment
Prognosis
Part 5: Treatment and procedures
36: Bone marrow failure
Bone marrow failure
Aplastic anaemia
Red cell aplasia
Congenital dyserythropoietic anaemias
37: Haematological effects of drugs
Idiosyncratic side effects of drugs
Drug-induced haematological abnormalities
38: Stem cell transplantation
Indications
Procedure
Complications
Part 6: Haemostasis
39: Normal haemostasis I: vessel wall and platelets
The vessel wall
Platelets
Thrombopoiesis (platelet production)
40: Normal haemostasis II: coagulation factors and fibrinolysis
Coagulation factors
Coagulation inhibitory factors
The fibrinolytic pathway
Laboratory tests of coagulation
Specialized tests
41: Disorders of haemostasis I: vessel wall and platelets
Vessel wall abnormalities
Inherited
Platelets
42: Disorders of haemostasis II: inherited disorders of coagulation
Factor VIII deficiency (haemophilia A)
Factor IX deficiency (haemophilia B, Christmas disease)
Von Willebrand disease
Other conditions
43: Disorders of haemostasis III: acquired disorders of coagulation
Liver disease
Disseminated intravascular coagulation
Other acquired disorders of coagulation
44: Thrombosis and antithrombotic therapy
Thrombosis
Thrombophilia
Lupus anticoagulant (antiphospholipid) syndrome
Antiplatelet therapy
Fibrinolytic therapy
45: Anticoagulation
Heparin
Warfarin
Other anticoagulant drugs
Other treatments
Part 7: Haematological aspects of tropical disease
46: Haematological aspects of tropical diseases
Malaria
Leishmaniasis
Filariasis
Trypanosomiasis
Splenomegaly in the Tropics
Anaemia of the tropics
47: Haematology of pregnancy and infancy
Anaemia
White cells
Platelets
Coagulation changes
Haemolytic disease of the fetus and newborn
Neonatal haematology
Part 8: Blood transfusion
48: Blood transfusion I
Blood grouping and compatibility testing
Red cell transfusion
Platelet transfusion
49: Blood transfusion II
Fresh frozen plasma
Other blood products
White cell transfusion
Complications of transfusion
Appendix: cluster of differentiation nomenclature system
Index
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Library of congress cataloging-in-publication data
Mehta, Atul B., author.
Haematology at a glance / Atul B. Mehta, A. Victor Hoffbrand. – Fourth edition.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-119-96922-8 (pbk. : alk. paper) – ISBN 978-1-118-26119-4 (Mobi) – ISBN 978-1-118-26120-0 (ePdf) – ISBN 978-1-118-26121-7 (ePub) – ISBN 978-1-118-73465-0 – ISBN 978-1-118-73467-4
I. Hoffbrand, A. V., author. II. Title.
[DNLM: 1. Hematologic Diseases. 2. Blood Cells–physiology. 3. Hematopoiesis–physiology. 4. Hemostasis–physiology. WH 120]
RB145
616.1′5–dc23
2013018140
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Cover image: © Steve Gschmeissner / Science Photo Library
Cover design by Meaden Creative
Preface to the fourth edition
Major advances in classification, diagnostic techniques and treatment have occurred over the 4 years since the third edition of this book was published. Much of this new knowledge has depended on the application of molecular techniques for diagnosis and determining treatment and prognosis, particularly for the malignant haematological diseases. New drugs are now available, not only for these diseases but also for treatment of red cell, platelet, thrombotic and bleeding disorders. In order to keep the book to the at a Glance size and format, we have included only the new information which represents major change in haematological practice and omitted more detailed knowledge, appropriate for a postgraduate text. The number of diagrams and tables has been increased to make the new information readily accessible to the undergraduate student but overall size of the book has not increased thanks to omission of all obsolete material.
Images have been reproduced, with permission, from Hoffbrand AV, Pettit JE & Vyas P (2010) Color Atlas of Clinical Hematology, 4e. Elsevier; Hoffbrand AV & Moss PAH (2011) Essential Haematology, 6e Blackwell Publishing Ltd; Hoffbrand AV, Catovsky D, Tuddenham EGD, Green AR Postgradaute Haematology, 6e, Blackwell Publishing Ltd, 2011.
We are grateful to June Elliott for her expertise in typing the manuscript, our publishers Wiley Blackwell, and particularly Karen Moore and Rebecca Huxley, for their encouragement and support, and Jane Fallows for the artwork.
Atul B. Mehta
A. Victor Hoffbrand
December 2013
Preface to the first edition
With the ever-increasing complexity of the medical undergraduate curriculum, we feel that there is a need for a concise introduction to clinical and laboratory haematology for medical students. The at a Glance format has allowed us to divide the subject into easily digestible slices or bytes of information.
We have tried to emphasize the importance of basic scientific and clinical mechanisms, and common diseases as opposed to rare syndromes. The clinical features and laboratory findings are summarized and illustrated; treatment is briefly outlined.
This book is intended for medical students, but will be useful to anyone who needs a concise and up-to-date introduction to haematology, for example nurses, medical laboratory scientists and those in professions supplementary to medicine.
We particularly thank June Elliott, who has patiently word-processed the manuscript through many revisions, and Jonathan Rowley and his colleagues at Blackwell Science.
Atul B. Mehta
A. Victor Hoffbrand
January 2000
Glossary
| Anaemia: | a haemoglobin concentration in peripheral blood below normal range for sex and age. |
| Anisocytosis: | variation in size of peripheral blood red cells. |
| Basophil: | a mature circulating white cell with dark purple-staining cytoplasmic granules which may obscure the nucleus. |
| Chromatin: | nuclear material containing DNA and protein. |
| Clone: | a group of cells all derived by mitotic division from a single somatic cell. |
| CT: | computerized scanning. |
| DIC: | disseminated intravascular coagulation. |
| Eosinophil: | mature circulating white cell with multiple orange-staining cytoplasmic granules and two or three nuclear lobes. |
| Fluorescent in situ hybridization (FISH): | the use of fluorescently labelled DNA probes which hybridize to chromosomes or sub-chromosomal sequences to detect chromosome deletions or translocations. |
| Haematocrit: | the proportion of a sample of blood taken up by red cells. |
| Haemoglobin: | the red protein in red cells which is composed of four globin chains each containing an iron-containing haem group. |
| Karyotype: | the chromosomal make-up of a cell. |
| Leucocytosis: | a rise in white cell levels in the peripheral blood to above the normal range. |
| Leucopenia: | a fall in white cell (leucocyte) levels in the peripheral blood to below the normal range. |
| Lymphocyte: | a white cell with a single, usually round, nucleus and scanty dark blue-staining cytoplasm. Lymphocytes divide into two main groups: B cells, which produce immunoglobulins; and T cells, which are involved in graft rejection and immunity against viruses. |
| Macrocytic: | red cells of average volume (MCV) above normal. |
| Mean cell volume (MCV): | the average volume of circulating red cells. |
| Mean corpuscular haemoglobin (MCH): | the average haemoglobin content of red blood cells. |
| Megaloblastic: | an abnormal appearance of nucleated red cells in which the nuclear chromatin remains open and fine despite maturation of the cytoplasm. |
| Microcytic: | red cells of average volume (MCV) below normal. |
| Monocyte: | mature circulating white cell with a few pink- or blue-staining cytoplasmic granules, pale blue cytoplasm and a single nucleus. There are usually cytoplasmic vacuoles. In the tissues, the monocyte becomes a macrophage. |
| MRI: | magnetic resonance imaging. |
| Myeloblast: | an early granulocyte precursor containing nucleoli and with a primitive nucleus; there may be some cytoplasmic granules. |
| Myelocyte: | a later granulocyte precursor containing granules, a single lobed nucleus and semi-condensed chromatin. |
| Neutrophil: | a mature white cell containing two to five nuclear lobes and many, fine, reddish or purple cytoplasmic granules. |
| Normoblast: | (erythroblast): nucleated red cell precursor normally found only in bone marrow. |
| Pancytopenia: | a fall in peripheral blood red cell, neutrophil and platelet levels to below normal. |
| Pappenheimer body: | an iron granule in red cells stained by standard (Romanovsky) stain. |
| Paraprotein: | a γ-globulin band on protein electrophoresis consisting of identical molecules derived from a clone of plasma cells. |
| PET scan: | positron emission tomography scan used to detect the sites of active disease, e.g. lymphoma. |
| Phagocyte: | a white blood cell that engulfs bacteria or dead tissue. It includes neutrophils and monocytes (macrophages). |
| Plasma cell: | usually an oval-shaped cell, derived from a B lymphocyte, which secretes immunoglobulin. Plasma cells are found in normal bone marrow but not in normal peripheral blood. |
| Platelet: | the smallest cell in peripheral blood, it is non-nucleated and involved in promoting haemostasis. |
| Poikilocytosis: | variation in shape of peripheral blood red cells. |
| Polycythaemia: | a haemoglobin concentration in peripheral blood above normal range for age and sex. |
| Red cell: | mature non-nucleated cell carrying haemoglobin. The most abundant cell in peripheral blood. |
| Reticulocyte: | a non-nucleated young red cell still containing RNA and found in peripheral blood. |
| Sideroblast: | a nucleated red cell precursor found in marrow and containing iron granules, which appear blue with Perls' stain. |
| Siderocyte: | a mature red cell containing iron granules and found in peripheral blood or marrow. |
| Stem cell: | resides in the bone marrow and by division and differentiation gives rise to all the blood cells. The stem cell also reproduces itself. Some stem cells circulate in the peripheral blood. |
| Thrombocytopenia: | a platelet level in peripheral blood below the normal range. |
| Thrombocytosis: | a platelet level in peripheral blood above the normal range. |
| Tissue factor: | a protein on the surface of cells which initiates blood coagulation. |
| White cell (leucocyte): | nucleated cell that circulates in peripheral blood and whose main function is combating infections. White cells include granulocytes (neutrophils, eosinophils, and basophils), monocytes and lymphocytes. |
| von Willebrand factor: | a plasma protein that carries factor VIII and mediates the adhesion of platelets to the vessel wall. |
Normal values
Normal peripheral blood count
| Cell | Normal concentration |
|---|---|
| Haemoglobin | 115–155 g/L (female) |
| 135–175 g/L (male) | |
| Red cell | 3.9–5.6 × 1012/L (female) |
| 4.5–6.5 × 1012/L (male) | |
| Reticulocyte | 0.5–3.5% |
| ∼25–95 × 109/L | |
| White cells | 4.0–11.0 × 109/L |
| Neutrophils | 1.8–7.5 × 103/L |
| (1.5–7.5 × 109/L in black people) | |
| Eosinophils | 0.04–0.4 × 109/L |
| Basophils | 0.01–0.1 × 109/L |
| Monocytes | 0.2–0.8 × 109/L |
| Lymphocytes | 1.5–3.0 × 109/L |
| Haematocrit | 0.38–0.54 |
| Mean cell volume | 80–100 (Fig. 8.2) |
| Mean cell haemoglobin | 27–33 (Fig. 8.2) |
| Haematinics | |
| Serum iron | 10–30 μmol/L |
| Total iron binding capacity | 40–75 μmol/L (2–4 g/L as transferrin) |
| Serum ferritin | 40–340 μg/L (males) |
| 15–150 μg/L (females) | |
| Serum folate | 3.0–15.0 μg/L (4–30 nmol/L) |
| Red cell folate | 160–640 μg/L (360–1460 nmol/L) |
| Serum vitamin B12 | 160–925 μg/L (120–682 pmol/L) |
About the companion website
1
Haemopoiesis: physiology and pathology
Haemopoiesis is the process whereby blood cells are made (Fig. 1.1). The yolk sac, and later the liver and spleen, are important in fetal life, but after birth normal haemopoiesis is restricted to the bone marrow.
Infants have haemopoietic marrow in all bones, but in adults it is in the central skeleton and proximal ends of long bones (normal fat to haemopoietic tissue ratio of about 50 : 50) (Fig. 1.2). Expansion of haemopoiesis down the long bones may occur in bone marrow malignancy, e.g. in leukaemias, or when there is increased demand, e.g. chronic haemolytic anaemias. The liver and spleen can resume extramedullary haemopoiesis when there is marrow replacement, e.g. in myelofibrosis, or excessive demand, e.g. in severe haemolytic anaemias such as thalassaemia major.
Haemopoiesis involves the complex physiological processes of proliferation, differentiation and apoptosis (programmed cell death). The bone marrow produces more than a million red cells per second in addition to similar numbers of white cells and platelets. This capacity can be increased in response to increased demand. A common primitive stem cell in the marrow has the capacity to self-replicate and to give rise to increasingly specialized or commited progenitor cells which, after many (13–16) cell divisions within the marrow, form the mature cells (red cells, granulocytes, monocytes, platelets and lymphocytes) of the peripheral blood (Fig. 1.1). The earliest recognizable red cell precursor is a pronormoblast and for granulocytes or monocytes, a myeloblast. An early lineage division is between lymphoid and myeloid cells. Stem and progenitor cells cannot be recognized morphologically; they resemble lymphocytes. Progenitor cells can be detected by in vitro assays in which they form colonies (e.g. colony-forming units for granulocytes and monocytes, CFU-GM, or for red cells, BFU-E and CFU-E). Stem and progenitor cells also circulate in the peripheral blood and can be harvested for use in stem cell transplantation.
The stromal cells of the marrow (fibroblasts, endothelial cells, macrophages, fat cells) have adhesion molecules that react with corresponding ligands on the stem cells to maintain their viability and to localize them correctly (Fig. 1.3). With osteoblasts these stromal cells form ‘niches’ in which stem cells reside. The marrow also contains mesenchymal stem cells that can form cartilage, fibrous tissue, bone and endothelial cells.
Haemopoiesis is regulated by growth factors (GFs) (Box 1.1) which usually act in synergy. These are glycoproteins produced by stromal cells, T lymphocytes, the liver and, for erythropoietin, the kidney (Fig. 2.6). While some GFs act mainly on primitive cells, others act on later cells already committed to a particular lineage. GFs also affect the function of mature cells. The signal is transmitted to the nucleus by a cascade of phosphorylation reactions (Fig. 1.4). GFs inhibit apoptosis (Fig. 1.5) of their target cells. GFs in clinical use include erythropoietin, granulocyte colony-stimulating factor (G-CSF), and analogues of thrombopoietin.
Act on stromal cells
Act on pluripotential cells
Act on early multipotential cells
Act on committed progenitor cells*
G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; M-CSF, monocyte colony-stimulating factor; TNF, tumour necrosis factor
*These growth factors (especially G-CSF and thrombopoietin) also act on earlier cells
These proteins regulate expression of genes e.g. GATA1/2 and NOTCH. They bind to specific DNA sequences and contribute to the assembly of a gene transcription complex at the gene promotor.
The binding of a GF with its surface receptor on the haemopoietic cell activates by phosphorylation, a complex series of biochemical reactions by which the message is transmitted to the nucleus. Figure 1.4 illustrates a typical pathway in which the signal is transmitted to transcription factors in the nucleus by phosphorylation of JAK2 and STAT molecules. The transcription factors in turn activate or inhibit gene transcription. The signal may activate pathways that cause the cell to enter cell cycle (replicate), differentiate, maintain viability (inhibition of apoptosis) or increase functional activity (e.g. enhancement of bacterial cell killing by neutrophils). Disturbances of these pathways due to acquired genetic changes, e.g. mutations, deletion or translocation, often involving transcription factors, underlie many of the malignant diseases of the bone marrow such as the acute or chronic leukaemias and lymphomas.
Apoptosis (programmed cell death) is the process by which most cells in the body die. The individual cell is activated so that intracellular proteins (caspases) kill the cell by an active process. Caspases may be activated by external stimuli as intracellular damage, e.g. to DNA (Fig. 1.5).
Haemopoiesis can be assessed clinically by performing a full blood count (see Normal values). Bone marrow aspiration also allows assessment of the later stages of maturation of haemopoietic cells (Fig. 7.3; see Chapter 7 for indications). Trephine biopsy (Fig. 1.2) provides a core of bone and bone marrow to show architecture. Reticulocytes (see Chapter 2) are young red cells. Assessment of their numbers can be performed by automated cell counters and will give an indication of the output of young red cells by the bone marrow. As a general rule, the action of GFs increases the number of young cells in response to demand.
2
Normal blood cells I: red cells
Normal peripheral blood contains mature cells that do not undergo further division. Their numbers are counted by automatic cell counters which also determine red cell size and haemoglobin content.
Red cells are the most numerous of the peripheral blood cells (1012/L) (Fig. 2.1). They are among the simplest of cells in vertebrates and are highly specialized for their function, which is to carry oxygen to all parts of the body and to return carbon dioxide to the lungs. Red cells exist only within the circulation – unlike many types of white blood cells they cannot traverse the endothelial membrane. They are larger than the diameter of the capillaries in the microcirculation. This requires them to have a flexible membrane.
Red cells contain haemoglobin which allows them to carry oxygen (O2) and carbon dioxide (CO2). Haemoglobin is composed of four polypeptide globin chains each with an iron containing haem molecule (Fig. 2.2). Three types of haemoglobin occur in normal adult blood: haemoglobin A, A2 and F (Table 2.1). The ability of haemoglobin to bind O2 is measured as the haemoglobin–O2 dissociation curve. Raised concentrations of 2,3-DPG, H+ ions or CO2 decrease O2 affinity, allowing more O2 delivery to tissues (Fig. 2.3). Some pathological variant haemoglobins are similar to Hb F in having a higher oxygen affinity than Hb A (Fig. 2.3); this leads, in adults, to a state of relative tissue hypoxia and the body compensates by increasing the number of red cells (secondary polycythaemia, see Chapter 26). In contrast, some pathological variant haemoglobins (e.g. Hb S, the major haemoglobin in sickle cell disease, see Chapter 17) have a lower oxygen affinity than Hb A (Fig. 2.3). This allows individuals to maintain a higher than normal tissue oxygenation for a given haemoglobin concentration.
Table 2.1 Normal haemoglobins
The earliest recognizable red cell precursor is a pronormoblast (Fig. 2.4). This arises from a progenitor cell CFU-E committed to red cell production. The pronormoblast has an open nucleus, a cytoplasm that stains dark blue (because of a high RNA content) with the usual (Romanowsky) stain for bone marrow blood cells. By a series of cell divisions and differentiation (with haemoglobin formation in the cytoplasm), the cells develop through different normoblast stages until they lose their nuclei. Ten to fifteen percent of developing erythroblasts die within the marrow without producing mature red cells. This ‘ineffective erythropoiesis’ is increased and becomes an important cause of reduced haemoglobin concentration (anaemia) in various pathological states, e.g. thalassaemia major, myelofibrosis, myelodysplasia and megaloblastic anaemia.
These are newly formed red cells that have lost a nucleus but retain some RNA. They can synthesise proteins. The RNA is lost after about 48 hours and the reticulocytes are then mature red cells. The RNA can be stained with supravital dyes before the cells have been ‘fixed’ on a blood film. Modern automatic counters are now used to measure reticulocytes in absolute numbers and as a percentage of the total red cells. Reticulocytes can also be counted on a specially stained blood film as a percentage of the red cells (Fig. 2.5). The normal range is 1–3% of red cells or 50 − 150 × 109/L. The reticulocyte count is a measure of new red cell production by the marrow. It is raised after haemorrhage or haemolysis when extra red cell production is needed. It is low if the marrow is incapable of normal red cell production, e.g. because of malignant infiltration or aplastic anaemia. More common causes include lack of iron, vitamin B12 or folate, or a chronic systemic disease or lack of erythropoietin in kidney disease.
This hormone controls the production of red cells. It is produced in the peritubular complex of the kidney (90%), liver and other organs (Fig. 2.6). Erythropoietin stimulates mixed lineage and red cell progenitors as well as pronormoblasts and early erythroblasts to proliferate, differentiate and synthesize haemoglobin (Table 2.1). Erythropoietin secretion is stimulated by reduced O2 supply to the kidney receptor. Thus, the principal stimuli to red cell production are tissue hypoxia and reduced haemoglobin concentration (anaemia) which act through the HIF pathway. Exogenous erythropoietin binds to the erythropoietin receptor on the surface of the red cell and initiates a signal transduction (see Fig. 1.4) by phosphorylation of the Janus kinase 2 (JAK2). This in turn induces gene transcription and red cell proliferation. Mutations in JAK2 underlie pathologically increased red cell production in polycythaemia rubra vera (PRV, see Chapter 27).
Mature red cells have no nucleus, ribosomes or mitochondria. They survive for about 120 days before being removed by macrophages of the reticuloendothelial system (see Chapter 3). Red cells are capable of only the simplest metabolic pathways.
The glycolytic pathway (Fig. 2.7) is the main source of energy (ATP) required to maintain red cell shape and deformability. The hexose monophosphate ‘shunt’ (pentose phosphate) pathway provides the main source of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which maintains reduced glutathione (GSH) and protects haemoglobin and the membrane proteins against oxidant damage (Fig. 2.7). Oxygen radicals are generated by the constant oxygenation and deoxygenation of haemoglobin.
Red cell membrane is a bipolar lipid layer that anchors surface antigens. It has a protein skeleton (spectrin, actin, protein 4.1 and ankyrin) which maintains the red cell's biconcave shape and deformability. These proteins contain several sulphydryl (-SH) groups which are essential for the maintenance of their tertiary structure and therefore the structural integrity of the red cell. These sulphydryl groups require NADPH generated by the pentose phosphate pathway to protect them from oxygen radicals.
Haematinics are naturally occurring substances, absorbed from the diet, that are essential for red cell production. They include minerals (e.g. iron) and vitamins (e.g. B12, B6 and folate).
3
Normal blood cells II: granulocytes, monocytes and the reticuloendothelial system
Normal white blood cells (leucocytes) in peripheral blood are of five types: three of them contain granules and are termed granulocytes (neutrophils or polymorphs, eosinophils and basophils) and the other two types are monocytes and lymphocytes (see Chapter 4). Granulocyte and monocyte production occurs in the bone marrow and is controlled by growth factors (see Table 1.1). External stimuli (e.g. infection, fever, inflammation, allergy and trauma) act on stromal and other cells to liberate cytokines, e.g. interleukin 1 (IL-1) and tumour necrosis factor (TNF), which then stimulate increased production of these growth factors. The earliest recognizable granulocyte precursors are myeloblasts. These undergo a final division followed by further maturation into promyelocytes, myelocytes, metamyelocytes and, finally, mature granulocytes (neutrophils, eosinophils and basophils).
The primary function of white cells is to protect the body against infection. They work closely with proteins of the immune response, immunoglobulins and complement. Neutrophils, eosinophils, basophils and monocytes are all phagocytes; they ingest and destroy pathogens and cell debris. Phagocytes are attracted to bacteria at the site of inflammation by chemotactic substances released from damaged tissues and by complement components. Opsonization is the coating of cells or foreign particles by immunoglobulin or complement; this aids phagocytosis (engulfment) because phagocytes have immunoglobulin Fc and complement C3b receptors (see below). Killing involves reduction of pH within the phagocytic vacuole, the release of granule contents and the production of antimicrobial oxidants and superoxides (the ‘respiratory burst’).