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Home > 2 SYSTEM-BASED DISEASES > 19 Blood disorders > FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY AND HAEMATOPOIESIS
Blood which flows throughout the body in the vascular system is made up of plasma and three cellular components:
red cells, which transport oxygen from the lungs to the tissues
white cells, which protect against infection
platelets, which interact with blood vessels and clotting factors to maintain vascular integrity.

SITES OF HAEMATOPOIESIS
Haematopoiesis is the process relating to the formation of blood cells. In the embryo this occurs initially in the yolk sac, followed by the liver and spleen; by 5 months in utero haematopoiesis is established in the bone marrow. At birth haematopoietic (red) marrow is found in the medullary cavity of all bones, but with age this becomes progressively replaced by fat (yellow marrow) so that by adulthood haematopoiesis is restricted to the vertebrae, pelvis, sternum, ribs, clavicles, skull, upper humeri and proximal femora. Bone marrow usually accounts for 5% of an adult's weight but red marrow can expand in response to increased demands for blood cells.
Bone marrow occupies the intertrabecular spaces in trabecular bone and contains a range of immature haematopoietic precursor cells and a storage pool of mature cells for release at times of increased demand. Haematopoietic cells are set in, and interact closely with, a connective tissue stroma made of reticular cells, macrophages, fat cells, blood vessels and nerve fibres. This stroma provides the suitable microenvironment for blood cell growth and development. Normal marrow has a characteristic organisation (see Fig. 19.1). Nests of red cell precursors cluster around a central macrophage which provides iron and phagocytoses extruded nuclei. Megakaryocytes are large cells which produce and release platelets into vascular sinuses. White cell precursors are clustered next to the bone trabeculae; maturing cells migrate into the marrow spaces towards the vascular sinuses. Plasma cells normally represent 5% or less of the marrow population and are scattered throughout the intertrabecular spaces.
FORMATION OF BLOOD CELLS
Stem cells


Figure 19.1 Structural organisation of normal bone marrow.
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Haematopoiesis is an active process that must maintain normal numbers of circulating blood cells and be able to respond rapidly to increased demands such as bleeding or infection. All blood cells are derived from a pluripotent stem cell which has the ability to self-renew (make more stem cells) and to differentiate to form any of the blood elements. These comprise only 0.01% of the total marrow cells and produce a hierarchy of lineage-committed stem cells. As primitive progenitor cells cannot be distinguished morphologically, they are named according to the types of cells (or colonies) they form during cell culture experiments. CFU-GM (colony-forming unit-granulocyte, monocyte) is a stem cell that produces granulocytic and monocytic lines. CFU-E produces erythroid cells and CFU-Meg produces megakaryocytes and ultimately platelets (see Fig. 19.2). The proliferation and differentiation of stem cells and their progeny are under the control of a range of growth factors produced by several cells including stromal cells and lymphocytes. These growth factors bind to specific receptors on the cell surface and promote not only proliferation and differentiation but also survival and function of mature cells. Growth factors are often synergistic with other growth factors. Some, such as granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and stem cell factor (SCF), act on a wide number of cell types at both early and late time points. Others, such as erythropoietin (Epo), granulocyte colony stimulating factor (G-CSF) and thrombopoietin (Tpo), are lineage-specific. Many of these growth factors are now synthesised by recombinant DNA technology and are available for clinical use.
Red cells


Figure 19.2 Stem cells and growth factors in haematopoietic cell development. (BFU-E = blast-forming unit-erythroid; CFU-Meg = colony-forming unit-megakaryocyte; CFU-GM = colony-forming unit-granulocyte, monocyte; CFU-E = colony-forming unit-erythroid; IL = interleukin; SCF = stem cell factor; GM-CSF = granulocyte macrophage colony stimulating factor; Epo = erythropoietin; Tpo = thrombopoietin; G-CSF = granulocyte colony stimulating factor; M-CSF = macrophage colony stimulating factor)
Red cell precursors formed from the erythroid progenitor cells are called erythroblasts or normoblasts (see Fig. 19.3). These nucleated cells divide and acquire haemoglobin which turns the cytoplasm pink; the nucleus then condenses and is extruded from the cell. The first non-nucleated red cell is a reticulocyte which still contains ribosomal material in the cytoplasm. Under normal staining conditions reticulocytes are large cells with a faint blue tinge which is termed polychromasia. Reticulocytes lose their ribosomal material and mature over 3 days, during which time they are released into the circulation. Increased numbers of circulating reticulocytes (reticulocytosis) reflect increased erythropoiesis. Red cell production is controlled by erythropoietin, a polypeptide hormone produced by renal tubular cells in response to hypoxia. Erythropoietin stimulates committed erythroid stem cells to proliferate and decreases maturation time. Patients with renal failure (see p. 594) are anaemic due to failure of erythropoietin production, and exogenous recombinant hormone can be used to treat this anaemia.
White cells
Granulocytes (neutrophils, eosinophils, basophils) and monocytes are formed from the CFU-GM progenitor cell. The first recognisable granulocyte in the marrow is the myeloblast, a large cell with a small amount of basophilic cytoplasm and a primitive nucleus. As the cells divide and mature, the nucleus segments and the cytoplasm acquires specific neutrophilic, eosinophilic or basophilic granules (see Fig. 19.3). This takes about 14 days.
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Figure 19.3 Maturation pathway of red cells, granulocytes and platelets.
A large storage pool of mature neutrophils exists in the bone marrow. Every day some 1014 neutrophils enter the circulation, where cells may be freely circulating or attached to endothelium in the marginating pool. These two pools are equal in size and factors such as exercise or catecholamines increase the cells flowing in the blood, so increasing the white cell count. Neutrophils spend 6-10 hours in the circulation before being removed principally by the spleen. Alternatively, they pass into the tissues and either are consumed in the inflammatory process or undergo apoptotic cell death and phagocytosis by macrophages. Myelocytes or metamyelocytes are normally only found in the marrow but may appear in the circulation in infection or toxic states. The appearance of more primitive myeloid precursors in the blood is often associated with the presence of nucleated red cells and is termed a 'leucoerythroblastic' picture; this indicates a serious disturbance of marrow function. Monocytes are large cells derived from monoblasts. These cells circulate for a few hours and then migrate into the tissues where they can mature into macrophages which can proliferate for years. The cytokines G-CSF, GM-CSF and M-CSF are involved in the production of myeloid cells and can be used clinically, e.g. to hasten recovery of blood neutrophil counts after chemotherapy.
Lymphocytes are also derived from the pluripotent haematopoietic stem cell. There are two main types: T cells (80% of circulating lymphoid cells) and B cells. Lymphoid cells which migrate to the thymus develop into T cells, whereas B cells develop in the bone marrow.
Platelets
Platelets are derived from megakaryocytes. Megakaryocytic stem cells (CFU-Meg) divide to form a megakaryoblast; megakaryocytes are formed by endomitotic reduplication where the nucleus divides but not the cell. Thus mature megakaryocytes are large cells with several nuclei and cytoplasm containing platelet granules. Up to 3000 platelets then fragment off from each megakaryocyte into the circulation in the marrow sinusoids. The formation and maturation of megakaryocytes are under the influence of Tpo, a recombinant form of which is in clinical use. Platelets circulate for 8-14 days before they are destroyed in the reticulo-endothelial system. Some 30% of peripheral platelets are normally pooled in the spleen and not circulating.
MAJOR FUNCTIONS OF BLOOD CELLS
RED CELLS
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Figure 19.4 Normal structure of red cell membrane.
The mature red cell is an 8 µm biconcave disc which delivers oxygen to the tissues from the lungs, and carbon dioxide in the reverse direction. It has no nucleus and no mitochondria; the normal red cell lifespan is about 120 days and in this time it will travel approximately 300 miles around the circulation. Red cells have to pass through the smallest capillaries in the circulation and their membrane structure is adapted to be deformable. The membrane has a lipid bilayer to which a 'skeleton' of filamentous proteins is attached via special linkage proteins (see Fig. 19.4). Inherited abnormalities of any of these proteins result in loss of membrane as cells pass through the spleen, and the formation of abnormally shaped cells called spherocytes or elliptocytes (see p. 922). Red cells are exposed to osmotic stress in the pulmonary and renal circulation; to maintain normal homeostasis, the membrane contains ion pumps which control intracellular levels of sodium, potassium, chloride and bicarbonate. The energy for these functions is provided by the metabolic pathways of the cytosol; 90% of glucose metabolism occurs via anaerobic glycolysis which produces adenosine triphosphate (ATP), and 10% via the pentose phosphate pathway which produces nicotinamide adenine dinucleotide phosphate (NADPH). Membrane proteins inserted into the lipid bilayer also form the antigens recognised by blood grouping. The ABO and Rhesus systems are the most commonly recognised (see p. 912) but over 400 blood group antigens have been described.
Haemoglobin
Haemoglobin is a protein specially adapted for gas transport to and from the lungs. It is composed of four globin chains, each containing an iron-containing porphyrin pigment termed haem. Globin chains are a combination of two alpha and two non-alpha chains; haemoglobin A (aa/ßß) represents over 90% of adult haemoglobin, whereas haemoglobin F (aa/??) is the predominant type in the fetus. Each haem molecule contains a ferrous ion (Fe++) to which oxygen reversibly binds; the final oxygen to bind does so with 20 times the affinity of the first. When oxygen is bound, the beta chains 'swing' closer together; they move apart as oxygen is lost. In the 'open' deoxygenated state, 2,3 diphosphoglycerate (DPG), a product of red cell metabolism, binds to the haemoglobin molecule and lowers its oxygen affinity. These complex interactions produce the sigmoid shape of the oxygen dissociation curve (see Fig. 19.5). The position of this curve depends upon the concentrations of 2,3 DPG, H+ ions and CO2; increased levels shift the curve to the right and cause oxygen to be released more readily. Tissue hypoxia increases all three and favours increased availability of oxygen from the red cell. Haemoglobin F is unable to bind 2,3 DPG and has a left-shifted oxygen dissociation curve; this increased affinity, together with the low pH of fetal blood, ensures fetal oxygenation. Amino acid mutations affecting the haem-binding pockets of globin chains or the 'hinge' interactions between globin chains result in haemoglobinopathies or unstable haemoglobins. Alpha globin chains are produced by two genes on chromosome 16 and beta globin chains by a single gene on chromosome 11; imbalance in the production of globin chains produces the thalassaemias (see p. 928).
Destruction
Red cells at the end of their lifespan are phagocytosed by the reticulo-endothelial system. Amino acids from globin chains are recycled and iron is removed from haem for reuse in haemoglobin synthesis. The remnant haem structure is degraded to bilirubin and conjugated to glucuronic acid before being excreted into bile. In the small bowel, bilirubin is converted to stercobilin; most of this is excreted, but a small amount is reabsorbed and excreted by the kidney as urobilinogen. Increased red cell destruction due to haemolysis or ineffective haematopoiesis will result in jaundice and increased urinary urobilinogen. Free intravascular haemoglobin is toxic and haptoglobins are plasma proteins produced by the liver which normally bind free haemoglobin in the circulation.


Figure 19.5 Structure of the normal haemoglobin molecule and its relationship to the oxygen dissociation curve. (See text for details.)
WHITE CELLS
White cells or leucocytes in the blood consist of granulocytes (neutrophils, eosinophils and basophils), monocytes and lymphocytes (see Fig. 19.6).
Neutrophils
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Figure 19.6 Normal white blood cells.
Neutrophils, the most common white blood cells in the blood of adults, are 10-14 µm in diameter with a multilobular nucleus containing two to five segments and granules in their cytoplasm. Their main function is to recognise, ingest and destroy foreign particles and microorganisms. Two main types of granule are recognised: primary or azurophil granules, and the more numerous secondary or specific granules. Primary granules contain myeloperoxidase and other proteins which are important for killing ingested microbes. Secondary granules contain a number of membrane proteins such as adhesion molecules and components of the NADPH oxidase with which neutrophils produce superoxide anions for microbial killing. These fuse with the plasma membrane upon degranulation and the granule contents, such as lactoferrin, are released extracellularly. Granule staining becomes more intense in response to infection and is termed 'toxic granulation'.
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Eosinophils
Eosinophils represent 1-6% of the circulating white cells. They are a similar size to neutrophils but have a bilobed nucleus and prominent orange granules on Romanowsky staining. Eosinophils are phagocytic and their granules contain a peroxidase capable of generating reactive oxygen species and proteins involved in the intracellular killing of protozoa and helminths (see p. 69). They are also involved in allergic reactions (e.g. atopic asthma, p. 514).
Basophils
These cells are less common than eosinophils, representing less than 1% of circulating white cells. They contain dense black granules which obscure the nucleus. Mast cells resemble basophils but these are only found in the tissues. Basophils bind IgE antibody on their surface, and exposure to specific antigen results in degranulation with release of histamine, leukotrienes and heparin. These cells are involved in hypersensitivity reactions.
Monocytes
Monocytes are the largest of the white cells, with a diameter of 12-20 µm and an irregular nucleus in abundant pale blue cytoplasm containing occasional cytoplasmic vacuoles. These cells migrate into the tissue where they become macrophages, Kupffer cells or antigen-presenting dendritic cells. The former phagocytose debris, apoptotic cells and microorganisms. They produce a variety of cytokines when activated, such as interleukin-1, tumour necrosis factor-a and GM-CSF.
Lymphocytes
In children up to 7 years old lymphocytes are the most abundant white cell in the blood. They are heterogeneous, with the smallest cells the size of red cells and the largest cells the size of neutrophils. Small lymphocytes are circular with scanty cytoplasm but the larger cells are more irregular with abundant blue cytoplasm. The majority of lymphocytes in the circulation are T cells (80%), which can be recognised by their expression of the CD antigens CD1, 2, 3, 4, 5, 7 and 8. The T cells mediate cellular immunity and two major types are recognised: CD4 positive helper cells and CD8 positive suppressor cells. The B cells mediate humoral immunity and can be recognised by their expression of immunoglobulin light chains (kappa or lambda in a ratio of 2:1). Lymphocyte subpopulations can be defined with specific functions and their lifespan can vary from several days to many years.
HAEMOSTASIS
With the evolution of the circulation as a transport system, an efficient mechanism has developed not only to prevent blood loss from a damaged vessel to secure haemostasis but also to prevent the inappropriate cessation of flow. Haemostasis depends upon interactions between the vessel wall, platelets and clotting factors. Two phases of haemostasis can be recognised: primary and secondary. In the initial primary phase, the damaged vessel contracts and platelets aggregate at the site of damage to form a plug to arrest haemorrhage. This occurs over a number of minutes and is followed by the secondary deposition of a fibrin mesh to secure the platelet plug. These two processes are interlinked; damaged endothelium and the subendothelial matrix activate platelets, which then provide the optimal surface for the binding of the plasma clotting factors; their sequential activation results in the generation of insoluble fibrin.
PLATELETS


Figure 19.7 Normal platelet structure. (ATP = adenosine triphosphate; ADP = adenosine diphosphate)
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Under normal conditions platelets are discoid in shape, with a diameter of 2-4 µm (see Fig. 19.7). The surface membrane invaginates to form a tubular network, the canalicular system. This provides a large surface area of phospholipid on to which clotting factors bind. Three types of granule are present in the cytoplasm; alpha granules contain fibrinogen and von Willebrand factor, dense (delta) granules store adenosine diphosphate (ADP) and 5-hydroxytryptamine (5-HT, serotonin), and lysosomes contain acid hydrolases.
When platelets are activated by ADP, thrombin or collagen they contract to become spherical and extend pseudopodia which adhere to the subendothelium and other platelets. Upon activation, platelet granules discharge their contents, which encourages further platelet aggregation and fibrin formation. At the same time, arachidonic acid is released from the platelet membrane and converted by cyclo-oxygenase to endoperoxides and the powerful platelet aggregating agent, thromboxane A2. Aspirin and non-steroidal anti-inflammatory drugs irreversibly inhibit platelet cyclo-oxygenase and impair platelet function. Platelet-binding to the subendothelium is dependent on high molecular weight von Willebrand factor released from endothelial cells, which bridges the gap between platelet membrane glycoproteins and subendothelial collagen. Interplatelet aggregation is dependent upon fibrinogen binding to platelet glycoproteins.
CLOTTING FACTORS


Figure 19.8 Normal haemostatic mechanisms: clotting factors of the intrinsic and extrinsic pathways. Broken lines signify inhibitory activity. (TFPI = tissue factor pathway inhibition)
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The coagulation system consists of a series of soluble inactive zymogen proteins designated by roman numerals. When proteolytically cleaved and activated, each is capable of activating one or more components of the cascade. Activated factors are designated by the suffix 'a'. Some of these reactions require phospholipid and calcium. Two pathways of activation are recognised, named the 'extrinsic' and 'intrinsic' pathways. However, recent understanding has shown that the extrinsic pathway, where coagulation is initiated by factor VII interacting with tissue factor (TF), is the main physiological mechanism in vivo (see Fig. 19.8). TF is a transmembrane protein expressed widely in the body, including the epidermis, monocytes, organ capsules, gastrointestinal and respiratory tracts, the brain and renal glomeruli. Moreover, it is expressed during endothelial cell damage. Factor VII circulates in the plasma and can be activated to factor VIIa by TF, factors Xa, IXa, XIIa and VIIa, and thrombin. During coagulation, TF complexes with factor VIIa, which activates factor X. Factor Xa forms a complex with factor V on the surface of activated platelets which converts prothrombin to thrombin and this in turn converts fibrinogen to fibrin monomer, which polymerises and is cross-linked by factor XIII to form stable clot. Thrombin plays a crucial role in this 'final common pathway'; factors XI, VIII, V and platelets are activated by thrombin, which generates a positive feedback loop. Congenital deficiencies of any of these factors will result in a bleeding diathesis. Tests of coagulation are shown in Box 19.3, page 901.
Clotting factors are synthesised by the liver; factor V is also produced by platelets and endothelial cells. The vitamin K-dependent factors II, VII, IX and X are produced as inactive proteins. These factors are rich in glutamic acid (Gla) residues, which must be further carboxylated to permit calcium-binding and association with phospholipid to generate an active catalytic site. The carboxylase enzyme responsible for this in the liver uses vitamin K as a cofactor (see Fig. 19.9). Vitamin K is converted to an epoxide in this reaction and must be regenerated to its active form by a reductase enzyme. This reductase is inhibited by warfarin and this mechanism forms the basis of the anticoagulant effect of coumarins (see p. 955).


Figure 19.9 The role of vitamin K in clotting and the mechanism of action of warfarin.
To prevent inappropriate activity of the clotting cascade, natural inhibitors of the clotting systems are present (see Figs 19.8 and 19.10). The TF-VIIa complex, along with factor Xa, is rapidly inactivated by tissue factor pathway inhibitor (TFPI). Antithrombin is a protein produced by the liver which also has inhibitory activity, principally against thrombin and factor Xa. When antithrombin binds to heparin, however, this inhibitory activity is markedly accelerated and this forms the basis of the anticoagulant action of heparin. Protein C is a vitamin K-dependent factor produced by the liver; when activated by interaction with protein S, it degrades and inactivates factor Va. These natural inhibitors provide powerful mechanisms to prevent excessive coagulation in the circulation and hence abnormalities in their function result in a tendency to thrombosis (see p. 953).
FIBRINOLYSIS


Figure 19.10 Fibrinolysis. (tPA = tissue plasminogen activator; PAI = plasminogen activator inhibitor)
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The excessive deposition of fibrin within the circulation is prevented in health by the fibrinolytic system (see Fig. 19.10). This pathway is principally initiated by tissue plasminogen activator (tPA) which is released from endothelial cells. Some fibrinolysis is also promoted by the activator urokinase which is synthesised in the kidney and helps prevent obstruction to the urinary system by small clots of blood. These activators convert the circulating inactive zymogen plasminogen to the active enzyme plasmin which hydrolyses fibrin. Within intravascular thrombi both tPA and plasminogen bind to cross-linked fibrin, leading to the formation of plasmin which lyses the developing thrombus. The digested fibrin fragments, D-dimers, can be detected within the circulation and their concentration is usually raised in the presence of venous thrombosis.
Excessive tPA activity in the circulation is prevented by the presence of a further plasma component, plasminogen activator inhibitor (PAI), and plasmin is inactivated by a2 antiplasmin.
INVESTIGATION OF DISEASES OF THE BLOOD
THE FULL BLOOD COUNT
The measurement of the number of circulating red cells (RBC), white cells (WBC) and platelets, the concentration of haemoglobin (Hb) and the characteristics of the red cells is called the full blood count (FBC). Anticoagulated blood is processed through automatic blood analysers which use a variety of technologies (particle-sizing, radiofrequency and laser instrumentation) to measure the different haematological parameters. These include numbers of circulating cells, the proportion of red cells present in blood (the haematocrit, Hct), and the red cell indices which give information about the size of red cells (mean cell volume, MCV) and the amount of haemoglobin present in the red cells (mean cell haemoglobin concentration, MCH). Modern blood analysers can detect the different types of white blood cell and give automated white cell differential counts including neutrophils, lymphocytes, monocytes, eosinophils and basophils. It is important to appreciate, however, that a number of conditions can lead to spurious results (see Box 19.1). The reference values for a number of common haematological parameters in Caucasian adults are given in the Appendix.
19.1 SPURIOUS FBC RESULTS FROM AUTOANALYSERS
Result Explanation
Increased haemoglobin Lipaemia, jaundice, very high white cell count
Reduced haemoglobin Improper sample mixing, blood taken from vein into which an infusion is flowing
Increased red cell volume (MCV) Cold agglutinins, non-ketotic hyperosmolarity
Increased white cell count Nucleated red cells present
Reduced platelet count Clot in sample, platelet clumping

BLOOD FILM EXAMINATION
19.2 COMMON RED CELL APPEARANCES AND THEIR CAUSES
Microcytosis (reduced average cell size, MCV < 76 fl)
Iron deficiency
Thalassaemia
Sideroblastic anaemia
Macrocytosis (increased average cell size, MCV > 100 fl)
Vitamin B12/folate deficiency
Liver disease
Hypothyroidism
Target cells (central area of haemoglobinisation)
Liver disease
Thalassaemia
Post-splenectomy
HbC disease
Spherocytes (dense cells, no area of central pallor)
Autoimmune haemolysis
Disseminated intravascular coagulation (DIC)
Post-splenectomy
Hereditary spherocytosis
Red cell fragments (intravascular haemolysis)
DIC
Haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura
Nucleated red blood cells (normoblasts)
Marrow infiltration
Severe haemolysis
Myelofibrosis
Howell-Jolly bodies (small round nuclear remnants)
Hyposplenism
Post-splenectomy
Dyshaemopoiesis
Polychromasia (young red cells-reticulocytes present)
Haemolysis
Increased red cell turnover
Basophilic stippling (abnormal ribosomes appear as blue dots)
Dyshaemopoiesis
Lead poisoning


Although the technical advances of modern full blood count analysers have resulted in fewer blood films requiring examination, scrutiny of the blood film can often yield invaluable information (see Box 19.2). Analysers cannot identify abnormalities of red cell shape and content (e.g. Howell-Jolly bodies, basophilic stippling, malarial parasites) or fully define abnormal white cells such as blasts.
BONE MARROW EXAMINATION
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Figure 19.11 Bone marrow aspirate and trephine. A Trephine biopsy needle. B Macroscopic appearance of a trephine biopsy. C Microscopic appearance of stained section of trephine. D Bone marrow aspirate needle. E Stained macroscopic appearance of marrow aspirate: smear (left) and squash (right). F Microscopic appearance of stained marrow particles and trails of haematopoietic cells.
In adults bone marrow examination is usually performed from the posterior iliac crest. After a local anaesthetic, marrow may be sucked out from the medullary space, stained and examined under the microscope (bone marrow aspirate). In addition, a core of bone may be removed (trephine biopsy), fixed and decalcified before sections are cut for staining (see Fig. 19.11). A bone marrow aspirate is used to assess the composition and morphology of haematopoietic cells or abnormal infiltrates. Further investigations may be performed such as cell surface marker analysis (immunophenotyping), chromosome and molecular studies to assess malignant disease, or marrow culture for suspected tuberculosis. A trephine biopsy is superior for assessing marrow cellularity, marrow fibrosis, and infiltration by abnormal cells such as metastatic carcinoma.
INVESTIGATION OF THE COAGULATION SYSTEM
Bleeding disorders
The investigation of a patient with a possible bleeding disorder is directed by the clinical circumstances (see p. 947). The initial blood screening tests comprise a platelet count, blood film, and coagulation tests including the prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen (see Box 19.3). Coagulation tests usually measure the length of time a plasma sample takes to clot after the clotting process is initiated by activators and calcium. The result of the test sample is compared with normal controls. The clot used to be detected manually by observation but tests are now automated, and utilise mechanical, electrical and light methods of clot detection.
19.3 COAGULATION SCREENING TESTS
Investigation Normal range Situations in which tests may be abnormal
Platelet count 150-400 × 109/l Thrombocytopenia
Bleeding time < 8 minutes Thrombocytopenia
Abnormal platelet function
Deficiency of von Willebrand factor
Vascular abnormalities
Prothrombin time (PT) 12-15 seconds Deficiencies of factors II, V, VII or X
Activated partial thromboplastin time (APTT) 30-40 seconds Deficiencies of factors II, V, VIII, IX, X, XI, XII
Heparin
Antibodies against clotting factors
Lupus anticoagulant
Fibrinogen concentration 1.5-4.0 g/l Hypofibrinogenaemia


N.B. International normalised ratio (INR) is not a coagulation screening test.
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The PT assesses the extrinsic system (see Fig. 19.8, p. 898). The patient's plasma is incubated with tissue factor and calcium. The reaction proceeds with the activation of factor X by factor VIIa. The international normalised ratio (INR) is used only to control oral anticoagulant treatment. It is the ratio of the patient's prothrombin time to a normal control based on an international reference thromboplastin. The INR enables different laboratories to give similar results when assessing warfarin therapy and this ensures standardisation of anticoagulation between centres.
The intrinsic system may be assessed by the APTT or the partial thromboplastin time with kaolin (PTTK). The APTT is determined by adding an activator to plasma-for instance, a suspension of kaolin-along with an extract of phospholipid (to mimic the platelet membrane). The normal ranges and situations in which these tests may be abnormal are shown in Box 19.3. Special tests of coagulation including fibrinogen levels and individual factor assays can be performed as directed by the screening tests. Platelet function can be assessed by performing a standardised template bleeding time test. In this investigation a small incision is made on the forearm below a sphygmomanometer cuff inflated to 40 mmHg. The bleeding time is prolonged in those with platelet functional defects, thrombocytopenia or von Willebrand's disease. Platelet function can be further assessed by measuring aggregation in vitro in response to various agents, e.g. adrenaline (epinephrine) and collagen, or measuring the constituents of the intracellular granules, e.g. ATP/ADP.
Thrombotic disorders
The investigation of thrombosis depends upon the clinical situation (see Box 19.4). The available investigations to assess thrombophilia, i.e. the propensity to thrombosis, are set out in Box 19.5. Anticoagulants can alter either the concentration or the activity of several of the plasma factors and, if possible, blood samples should therefore be collected before, or after discontinuation of, anticoagulant therapy. On occasion this is not possible and the result has to be interpreted in the knowledge of the effect of the prevailing anticoagulant.
19.4 INDICATIONS FOR A THROMBOPHILIA SCREEN
Venous thrombosis < 45 years
Recurrent venous thrombosis
Family history of venous thrombosis
Venous thrombosis at an unusual site
Cerebral venous thrombosis
Hepatic vein (Budd-Chiari syndrome)
Portal vein
Arterial and venous thrombosis


19.5 LABORATORY INVESTIGATION OF THROMBOPHILIA
Antithrombin
Protein C
Protein S
Prothrombin G20210A
Factor V Leiden
Thrombin/reptilase time (for dysfibrinogenaemia)
Antiphospholipid antibody/lupus anticoagulant/anticardiolipin antibody
Homocysteine


ISSUES IN OLDER PEOPLE
HAEMATOLOGICAL FUNCTION
Blood cell counts and film components are not altered by ageing alone.
The ratio of bone marrow cells to marrow fat falls in old age.
Adequate neutrophil function is maintained overall throughout life, although some studies suggest that leucocytes may be less readily mobilised by bacterial invasion in old age.
Lymphocytes are functionally compromised by age due to a T cell-related defect in cell-mediated immunity.
There are no major changes in clotting factors with age, although mild congenital deficiencies of these may be first noticed only in old age.
The erythrocyte sedimentation rate (ESR) is raised above the normal range in old age, but this appears to be associated with chronic or subacute disease. When truly healthy older people are assessed, the ESR range is very similar to that in younger people.


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Home > 2 SYSTEM-BASED DISEASES > 19 Blood disorders > MAJOR MANIFESTATIONS OF BLOOD DISEASE
MAJOR MANIFESTATIONS OF BLOOD DISEASE
ANAEMIA
Anaemia refers to a state in which the level of haemoglobin in the blood is below the normal range appropriate for age and sex. Other factors including pregnancy and altitude also affect haemoglobin levels and must be taken into account when considering whether an individual is anaemic. The clinical features of anaemia reflect diminished oxygen supply to the tissue and depend upon the degree of anaemia, the rapidity of its development and the presence of cardiorespiratory disease. A rapid onset of anaemia (e.g. due to blood loss) will cause more profound symptoms than a gradually developing anaemia. Individuals with cardiorespiratory disease will have symptoms of anaemia at higher haemoglobin levels than those with normal cardiorespiratory function. The general symptoms and signs of anaemia are shown on page 891.
The diagnosis of anaemia must not only include the assessment of its clinical severity but also define the underlying cause. This rests on the clinical history and examination, assessment of the full blood count and blood film, and further appropriate investigations. Causes of anaemia are shown in Box 19.6.
History
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Iron deficiency anaemia (see p. 916) is the most common type of anaemia world-wide. A thorough gastrointestinal history is important, in particular looking for symptoms indicating blood loss. Menorrhagia is a common cause of anaemia in females still menstruating and hence women should always be asked about their periods.
A dietary history should assess the intake of iron and folate which may become deficient in comparison to needs (e.g. in pregnancy, during periods of rapid growth-see p. 916).
Past medical history may reveal a disease which is known to be associated with anaemia, such as rheumatoid arthritis (the anaemia of chronic disease) or previous surgery (e.g. resection of the stomach or small bowel which may lead to malabsorption of iron and/or vitamin B12).
Family history and ethnic background of the patient are important. Haemolytic anaemias such as the haemoglobinopathies and hereditary spherocytosis may be suspected from the family history. Pernicious anaemia may also be familial.
A drug history may reveal the ingestion of drugs which can be associated with blood loss (e.g. aspirin and anti-inflammatory drugs) or drugs that may cause haemolysis or aplasia.

19.6 CAUSES OF ANAEMIA
Decreased or ineffective marrow production
Lack of iron, vitamin B12 or folate
Hypoplasia
Invasion by malignant cells

Peripheral causes
Blood loss
Haemolysis
Hypersplenism


Examination


Figure 19.12 Investigation of anaemia: normal or low MCV.
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As well as the general physical findings of anaemia shown on page 891, there may be specific findings related to the aetiology of the anaemia; for example, a patient may be found to have a right iliac fossa mass due to an underlying caecal carcinoma. Haemolytic anaemias can cause jaundice. Vitamin B12 deficiency may be associated with neurological signs including peripheral neuropathy, dementia and signs of subacute combined degeneration of the cord (see p. 918). Sickle-cell anaemia (see p. 926) may result in leg ulcers. Anaemia may be multifactorial and the lack of specific symptoms and signs does not rule out silent pathology.
Schemes for the investigation of anaemias are often based on the size of the red cells, which is most accurately indicated by the mean cell volume (MCV) in the FBC. Commonly, in the presence of anaemia:
A normal MCV (normocytic anaemia) suggests either acute blood loss or the anaemia of chronic disease (ACD) (see Fig. 19.12).
A low MCV (microcytic anaemia) suggests iron deficiency or thalassaemia (see Fig. 19.12).
A high MCV (macrocytic anaemia) suggests vitamin B12 or folate deficiency (see Fig. 19.13).

Specific types of anaemia are dealt with separately later in this chapter (see pp. 914-929).


Figure 19.13 Investigation of anaemia: high MCV. (LDH = lactate dehydrogenase)
HIGH HAEMOGLOBIN
A haemoglobin level greater than the upper limit of normal (adult females 16.5 g/dl, adult males 18 g/dl) may be due to an increase in the number of red blood cells (true polycythaemia) or a reduction in the plasma volume (relative or apparent polycythaemia) (see Box 19.7). Circulating red cell mass is measured by radio-labelling an aliquot of the patient's red cells with 51Cr, reinjecting the cells and measuring the dilution of the isotope. The plasma volume is measured by a similar dilution technique using homologous albumin labelled with 125I.
True polycythaemia is caused by increased erythropoiesis in the bone marrow. This occurs due to a primary increase in marrow activity (the myeloproliferative disorder called primary proliferative polycythaemia or polycythaemia rubra vera, PRV) or in response to increased erythropoietin (Epo) production either as a consequence of chronic hypoxaemia or because of inappropriate erythropoietin secretion, e.g. lung or renal disorders (see Box 19.8).
19.7 CLASSIFICATION OF POLYCYTHAEMIA
Red cell mass Plasma volume
True polycythaemia Increased Normal
Relative polycythaemia Normal Decreased

19.8 CAUSES OF TRUE POLYCYTHAEMIA
Aetiology Examples
Primary Myeloproliferative disorder Polycythaemia rubra vera (primary proliferative polycythaemia)
Secondary Increased Epo due to tissue hypoxia High altitude
Lung disease
Cyanotic heart disease
High-affinity haemoglobins
Inappropriately increased Epo Renal disease
Hydronephrosis
Cysts
Carcinoma
Other tumours
Hepatoma
Bronchogenic carcinoma
Uterine fibroids
Phaeochromocytoma
Cerebellar haemangioblastoma


(Epo = erythropoietin)
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A clinical history and examination will provide clues as to the aetiology of the true polycythaemia. Those with PRV may have arterial thromboses, pruritus worse after a hot bath, gout due to high red cell turnover and hepatosplenomegaly. The cardiorespiratory systems should be assessed for evidence and causes of hypoxaemia, and further investigations to exclude inappropriate erythropoietin secretion should be performed.
Relative polycythaemia with a reduction in plasma volume is usually a consequence of dehydration, diuretic use or alcohol consumption.
LEUCOPENIA (LOW WHITE COUNT)
A reduction in the total numbers of circulating white cells is called leucopenia. This may be due to a reduction in all types of white cell or a reduction in individual cell types (usually neutrophils or lymphocytes). In turn, leucopenia may occur alone or as part of a reduction in all three haematological lineages (pancytopenia, see p. 909).
NEUTROPENIA
19.9 DRUG-INDUCED NEUTROPENIA
Group Examples
Analgesics/anti-inflammatory agents Phenylbutazone, gold, diflunisal, penicillamine, naproxen
Antithyroid drugs Carbimazole, propylthiouracil
Anti-arrhythmics Quinidine, procainamide
Antihypertensives Captopril, enalapril, nifedipine
Antidepressants/psychotropics Amitriptyline, dosulepin (dothiepin), mianserin
Antimalarials Pyrimethamine, dapsone, sulfadoxine, chloroquine
Anticonvulsants Phenytoin, sodium valproate, carbamazepine
Antibiotics Sulphonamides, penicillins, cephalosporins
Miscellaneous Cimetidine, ranitidine, chlorpropamide, zidovudine

A reduction in neutrophil count (usually less than 1.5 × 109/l, but dependent on age and race) is called neutropenia. The main causes are listed in Figure 19.6 (see p. 896). Drug-induced neutropenia is not uncommon and those drugs implicated in neutropenia are shown in Box 19.9. Clinical manifestations range from no symptoms to overwhelming sepsis. The risk of bacterial infection is related to the degree of neutropenia, with counts lower than 0.5 × 109/l conferring the highest risk. Fever is the first and the only manifestation of infection. A sore thoat, perianal pain or skin inflammation may be present. The lack of neutrophils allows the patient to become septicaemic and shocked within hours if immediate antibiotic therapy is not commenced. The management of such patients is discussed on page 933.
LYMPHOPENIA
This occurs when the absolute lymphocyte count is less than 1 × 109/l. The causes are shown in Figure 19.6 (see p. 896). Although minor deficiencies may be asymptomatic, deficiencies in cell-mediated immunity may cause infections with organisms such as fungi, viruses and mycobacteria (see Ch. 1).
LEUCOCYTOSIS (HIGH WHITE COUNT)
An increase in the total numbers of circulating white cells is called leucocytosis. This is usually due to an increase in a specific type of white blood cell (see Fig. 19.6, p. 896 for causes of a neutrophilia, eosinophilia, basophilia, monocytosis and lymphocytosis). It is important to realise that an increase in a single type of white cell (e.g. eosinophils or monocytes) may not increase the total WBC above the upper limit of normal and will only be apparent if the differential of the white count is examined.
NEUTROPHILIA
An increase in the number of circulating neutrophils is called a neutrophilia or a neutrophil leucocytosis. It can result from an increased production of cells from the bone marrow or redistribution from the marginated pool. The normal neutrophil count depends upon age, race and certain physiological parameters. In healthy neonates the neutrophil count is higher than at other times of life. During pregnancy not only is there an increase in neutrophils but also earlier forms such as promyelocytes can be found in the blood. The causes of a neutrophilia are shown in Figure 19.6 (see p. 896).
LYMPHOCYTOSIS
A lymphocytosis is an increase in circulating lymphocytes above that expected for the patient's age. In adults this is above 3.5 × 109/l. Infants and children have higher counts than adults; age-related normal ranges should be consulted. The causes are shown in Figure 19.6 (see p. 896); the most common cause is viral infection.
LYMPHADENOPATHY
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19.10 CAUSES OF LYMPHADENOPATHY
Infective
Neoplastic
Connective tissue disorders
Rheumatoid arthritis, systemic lupus erythematosus (SLE)

Sarcoidosis
Amyloidosis
Drugs
Phenytoin

Bacterial
Streptococcal, tuberculosis, brucellosis
Viral
Epstein-Barr, HIV
Protozoal
Toxoplasmosis
Fungal
Histoplasmosis, coccidioidomycosis
Primary
Leukaemias, lymphomas
Secondary
Lung, breast, thyroid, stomach


Enlarged lymph glands may be an important indicator of haematological disease but they are not uncommon in reaction to infection or inflammation (see Box 19.10). The sites of lymph node groups and symptoms and signs that may help elucidate the underlying cause are shown on page 891. Reactive nodes usually expand rapidly and are painful, whereas those due to haematological disease are more often painless. Localised nodes should elicit a search for a source of inflammation in the appropriate drainage area: the scalp, ear, mouth, face or teeth for the neck; the breast for the axilla; and the perineum or external genitalia for inguinal nodes. Generalised lymphadenopathy may be secondary to infection, connective tissue disease or extensive skin disease but is more likely to signify underlying haematological malignancy. Weight loss and drenching night sweats which may require a change of night clothes are associated with haematological malignancies, particularly lymphoma.
Initial investigations should include a full blood count (to detect neutrophilia in infection or evidence of haematological disease), an ESR and a chest radiograph (to detect mediastinal lymphadenopathy). If the findings are suspicious of malignancy, a formal cutting needle or excision biopsy of a representative node is indicated to confirm a histological diagnosis.
SPLENOMEGALY
19.11 CAUSES OF SPLENOMEGALY
Congestive
Infective
Inflammatory/granulomatous disorders
Felty's syndrome, SLE
Sarcoidosis

Haematological
Autoimmune haemolytic anaemias
Other malignancies
Metastatic cancer-rare

Storage diseases
Gaucher's disease
Niemann-Pick disease

Miscellaneous
Cysts, amyloid, hyperthyroidism

Intrahepatic portal hypertension
Cirrhosis
Hepatic vein occlusion
Extrahepatic portal hypertension
Thrombosis, stenosis or malformation of the portal or splenic vein
Cardiac
Chronic congestive cardiac failure
Constrictive pericarditis
Bacterial
Endocarditis
Septicaemia
Tuberculosis
Brucellosis
Salmonella
Viral
Hepatitis
Epstein-Barr
Cytomegalovirus
Protozoal
Malaria
Leishmaniasis
Trypanosomiasis
Fungal
Histoplasmosis
Red cell disorders
Megaloblastic anaemia
Haemoglobinopathies
Myeloproliferative disorders
Chronic myeloid leukaemia
Myelofibrosis
Polycythaemia rubra vera
Essential thrombocythaemia
Neoplastic
Leukaemias
Lymphomas


The spleen may be enlarged due to involvement by lymphoproliferative disease, the resumption of extramedullary haematopoiesis in myeloproliferative disease, or enhanced reticulo-endothelial activity in autoimmune haemolysis. A list of the causes of splenomegaly is given in Box 19.11. Massive splenomegaly occurs in chronic myeloid leukaemia, myelofibrosis, malaria or kala-azar. Hepatosplenomegaly is more suggestive of lympho- or myeloproliferative disease, liver disease or infiltration (e.g. with amyloid). The additional presence of lymphadenopathy makes a diagnosis of lymphoproliferative disease more likely. An enlarged spleen may cause abdominal discomfort, with back pain and abdominal bloating due to stomach compression. Splenic infarction may occur and produce severe abdominal pain radiating to the left shoulder tip, associated with a splenic rub on auscultation. Rarely, spontaneous or traumatic rupture may occur.
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Investigation will centre on the suspected cause. Imaging of the spleen by ultrasound or computed tomography (CT) will detect variations in density in the spleen which may be a feature of lymphoproliferative disease; it also allows imaging of the liver or abdominal lymph nodes. Biopsy of the latter or superficial nodes may provide the diagnosis. A chest radiograph is required to exclude mediastinal nodes. An FBC may show pancytopenia secondary to hypersplenism and, if other abnormalities are present, such as abnormal lymphocytes or a leucoerythroblastic blood film, a bone marrow examination is indicated. Screening for infectious or liver disease (see p. 835) may be appropriate. If all investigations are unhelpful, splenectomy may be diagnostic.
BLEEDING
History
Bleeding usually results either from a breach of the vessel wall due to a specific insult (e.g. peptic ulcer, trauma or from haemostatic failure). This may result from deficiency of one or more of the coagulation factors, thrombocytopenia or, occasionally, excessive fibrinolysis, which most commonly arises following therapeutic fibrinolytic therapy with tissue plasminogen activator (tPA) or streptokinase.
Prior to laboratory investigation it is important that a careful history is recorded of all bleeding episodes and a full clinical examination should be performed. A history of bleeding is often remarkably reproducible, particularly after dental extraction; if a socket oozes for 2 days after removal of a tooth on one occasion, this is likely to recur following each subsequent extraction.
It is important to consider the following points when taking a history:
Site of bleeds. Muscle and joint bleeds indicate a coagulation defect, whereas purpura, prolonged bleeding from superficial cuts, epistaxis, gastrointestinal haemorrhage or menorrhagia indicates a failure of primary haemostasis due to a platelet disorder, thrombocytopenia or von Willebrand's disease. Recurrent bleeds at a single site suggest a local structural abnormality.
Duration of history. It may be possible to assess whether the patient has a congenital or acquired disorder.
Precipitating causes. Bleeding arising spontaneously indicates a more severe defect than if haemorrhage arises only after trauma.
Surgery. Enquiry about all operations is useful, in particular regarding dental extractions, tonsillectomy and circumcision, as these are all stressful tests of the haemostatic system. Bleeding that starts immediately after surgery indicates defective platelet plug formation, whereas that which comes on after several hours is more indicative of failure of platelet plug stabilisation by fibrin due to a coagulation defect.
Family history. Absence of relatives with clinically significant bleeding does not exclude a hereditary bleeding diathesis; about one-third of cases of haemophilia, for example, arise in individuals without a family history.
Systemic illnesses. Many diseases, or their treatment, may be associated with bleeding but it is particularly important to consider the possibility of hepatic or renal failure, paraproteinaemia or a connective tissue disease.
Drugs. Almost any medicine can potentially produce bleeding, either by depressing marrow function with consequent thrombocytopenia or by interacting with warfarin. NSAIDs inhibit platelet function; the effect of aspirin may last for up to 10 days after a single tablet.

Examination
Superficial examination may reveal bruises and purpura or scars due to poor healing following prolonged superficial bleeding. Telangiectasia of lips and tongue points to hereditary haemorrhagic telangiectasia (see p. 947). Joints should be carefully scrutinised for evidence of haemarthroses. A full general medical examination is important because it may give clues as to systemic illness-for example, stigmata of liver disease; splenomegaly may cause thrombocytopenia due to hypersplenism.
Investigations
Screening investigations and their interpretation are described on page 901. If the patient has a history strongly suggestive of a bleeding disorder and all the preliminary screening tests give normal results, it is appropriate to perform further investigations. The clinical history may be a useful guide as to whether attention should be directed to platelet function (or von Willebrand's disease) or a defect in coagulation, e.g. haemophilia.
THROMBOCYTOPENIA (LOW PLATELETS)
A reduced platelet count may arise by one of three mechanisms:
failure of megakaryocyte maturation and hence platelet formation
excessive platelet consumption after their release into the circulation
platelet sequestration in an enlarged spleen.
The common causes of thrombocytopenia are listed in Box 19.12.
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19.12 CAUSES OF THROMBOCYTOPENIA
Marrow disorders
Vitamin B12/folate deficiency
Increased consumption of platelets
Disseminated intravascular coagulation (DIC)
Idiopathic thrombocytopenic purpura (ITP)
Viral infections-e.g. Epstein-Barr virus, HIV
Bacterial infections-e.g. Gram-negative septicaemia
Hypersplenism
Thrombotic thrombocytopenic purpura (TTP)/haemolytic uraemic syndrome (HUS)
Liver disease
Connective tissue diseases-e.g. SLE

Hypoplasia
Idiopathic
Drug-induced-cytotoxics, antimetabolites, thiazides
Infiltration
Leukaemia
Myeloma
Carcinoma
Myelofibrosis
Osteopetrosis


Spontaneous bleeding does not usually occur until the platelet count falls below about 30 × 109/l unless their function is also compromised-for example, following aspirin ingestion. Purpura and spontaneous bruising are characteristic but there may also be oral, nasal, gastrointestinal or genitourinary bleeding. Severe thrombocytopenia results in optic fundal haemorrhage (see Fig. 19.14), which may be a prelude to a rapidly fatal intracranial bleed.
Investigations to determine the possible cause of thrombocytopenia should be directed towards the conditions listed in Box 19.12. A blood film may give diagnostic information, e.g. acute leukaemia. Examination of the bone marrow will reveal whether there is an infiltrate such as carcinoma, a reduced number of megakaryocytes, e.g. hypoplastic anaemia, or an increased number of megakaryocytes indicating excessive peripheral destruction, e.g. idiopathic thrombocytopenic purpura (see p. 948).


Figure 19.14 Superficial fundal haemorrhage (arrow). The haemorrhage is in a patient with a platelet count of 5 × 109/l.
THROMBOCYTOSIS (HIGH PLATELETS)
The platelet count is most commonly raised as part of the secondary response to inflammation, as with infection, connective tissue disease, malignancy or gastrointestinal bleeding (see Box 19.13). In these circumstances the presenting clinical features are those of the underlying disorder. Thrombosis or bleeding secondary to a reactive increase in platelet count is rare.
19.13 CAUSES OF A RAISED PLATELET COUNT
Reactive thrombocytosis
Chronic inflammatory disorders
Malignant disease
Tissue damage
Haemolytic anaemias
Post-splenectomy
Post-haemorrhage
Malignant thrombocytosis
Essential thrombocythaemia
Polycythaemia rubra vera
Myelofibrosis
Chronic myeloid leukaemia


In essential thrombocythaemia, in which there is primary proliferation of megakaryocytes in the marrow, the patient may have haemorrhagic features secondary to platelet dysfunction, e.g. mucocutaneous or gastrointestinal haemorrhage. Alternatively, the patient may present with occlusion of a major artery, e.g. thrombotic stroke or venous thrombosis. Occlusion of smaller vessels may result in transient ischaemic attacks, amaurosis fugax, or distal ischaemia or gangrene (see Fig. 19.15). A high platelet count is also a feature of other myeloproliferative disorders such as primary proliferative polycythaemia or chronic myeloid leukaemia.


Figure 19.15 Thrombocytosis causing vessel occlusion and gangrene.
VENOUS THROMBOSIS
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Swelling of either one or both legs is a common presenting symptom. Deep venous thrombosis (DVT) in the leg characteristically causes pain, swelling, an increase in temperature and dilatation of the superficial veins. Often, however, there are only minimal symptoms and DVT cannot be excluded without appropriate objective investigations.
Unilateral leg-swelling may also result from a spontaneous or post-traumatic calf haematoma, cellulitis or a ruptured Baker's cyst (see Box 19.14). This latter condition usually arises in individuals with pre-existing rheumatoid disease of the knee. The leak of synovial fluid into the calf is accompanied by a decrease in the size of the cyst in the popliteal fossa and an intense pain in the calf due to the irritant synovial fluid (see p. 1004).
When both legs are swollen, apart from bilateral DVT, the likely cause is either impaired venous or lymphatic return due to obstruction in the pelvis or above, or impaired cardiac function resulting in right-sided heart failure. Hypoalbuminaemia often results in bilateral pitting leg oedema.
19.14 CAUSES OF A SWOLLEN LEG
Venous thrombosis
Calf haematoma
Skin inflammation, including cellulitis
Baker's cyst
Pelvic disease obstructing venous or lymphatic return
Congestive cardiac failure/cor pulmonale
Hypoalbuminaemia


Investigation of a swollen leg
For unilateral leg-swelling the initial assessment is usually to establish whether or not a DVT is present. DVTs are usually unilateral but may be bilateral when they are extensive and extend into the pelvic veins and inferior vena cava (IVC). For bilateral leg-swelling pelvic, retroperitoneal and cardiac pathology and hypoalbuminaemia should be excluded.
Venography remains the most accurate and reliable technique for assessing the presence of venous thrombosis. Radio-opaque dye is injected into a vein on the dorsum of the foot and the deep veins are visualised by dynamic X-ray imaging, with appropriate static films being taken to provide a permanent record of the findings. Venography for more proximal thrombosis can be performed by catheterisation of the femoral vein to image the pelvic veins and IVC.
Ultrasound is also a reliable, non-invasive method for detecting venous thrombosis. The technique depends upon demonstrating non-compressibility of the vein in the presence of thrombus. The technique can only detect thrombus in larger veins and is therefore only useful for assessing veins at or above the popliteal fossa and as far as the inguinal ligament. In some patients it can identify major thrombus in the IVC.
If a patient has a proven venous thrombosis, it is necessary to consider whether he or she may have a thrombophilic condition. Those individuals fulfilling the clinical criteria set out in Box 19.4 should be investigated, usually after anticoagulation has been discontinued, as in Box 19.5 (see p. 902).
ABNORMAL COAGULATION SCREEN
A coagulation screen should be undertaken when there is a history suggestive of a bleeding disorder (see p. 947), overt bleeding, or a clinical situation associated with a coagulation disorder, e.g. septicaemia, or the patient is taking an anticoagulant drug, e.g. warfarin. The prothrombin time is most sensitive to deficiencies of factors V, VII and X and may be prolonged in liver disease, in DIC or in patients on warfarin. The INR is a way of 'correcting' the reporting of the ratio of the patient's prothrombin time compared to that in normal plasma in patients on warfarin so that there is uniformity in ratios between different laboratories (see p. 902). The APTT is most sensitive to deficiencies in factors V, VIII, IX, X and XI and a prolongation is seen in haemophilia A and B, in those on standard or unfractionated heparin or in DIC. It is important to note that the APTT is not prolonged by low molecular weight heparins. The most common cause of a low fibrinogen is DIC although a reduced level in an otherwise well patient is seen in congenital hypofibrinogenaemia; this condition is uncommon, however. Fibrinogen is an acute phase reactant and is therefore increased in patients with inflammatory conditions, e.g. infection or malignancy.
PANCYTOPENIA
Pancytopenia refers to the combination of anaemia, leucopenia and thrombocytopenia.
19.15 CAUSES OF PANCYTOPENIA
Bone marrow failure
Hypoplastic/aplastic anaemia (see p. 945)
Inherited
Idiopathic
Viral
Drugs

Bone marrow infiltration
Acute leukaemia
Myeloma
Lymphoma
Carcinoma
Haemophagocytic syndrome
Myelodysplastic syndromes
Acquired immunodeficiency syndrome (AIDS)

Ineffective haematopoiesis
Megaloblastic anaemia

Peripheral pooling/destruction
Hypersplenism
Portal hypertension
Felty's syndrome
Malaria
Myelofibrosis

SLE

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It may be due to reduced production of blood cells as a consequence of bone marrow suppression or infiltration or there may be peripheral destruction or splenic pooling of mature cells. The causes of a pancytopenia are shown in Box 19.15.
A bone marrow aspirate and trephine are usually required to establish the diagnosis.
INFECTION
Infection is a major complication of haematological disorders. The cause relates to the immune deficit caused by the disease itself, to the treatment, e.g. chemotherapy, or commonly to a combination of both (see page 905).

pages 902 - 910


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Home > 2 SYSTEM-BASED DISEASES > 19 Blood disorders > BLOOD PRODUCTS AND TRANSFUSION
BLOOD PRODUCTS AND TRANSFUSION
Transfusion of a blood product may be needed when a patient has a deficiency of a blood constituent or constituents that causes symptoms or puts the patient at risk, and if a useful improvement is likely to result from temporary replacement of the deficiency. In some cases an alternative replacement product, not derived from human blood, may be used.
A safe blood supply depends on:
a well-organised supply system that ensures regular donation by healthy individuals who have no excess risk of infections transmissible by blood
testing of all donations to detect human immunodeficiency virus (HIV) 1 and 2, hepatitis B, hepatitis C, syphilis, and other infectious agents according to each country's regulations
effective control over the quality of safety testing, blood grouping, processing, storage and pre-transfusion testing of blood.

Safe and effective clinical use of blood depends on:
the correct storage and handling throughout the life of the product right to the point of administration
the use of clinical protocols or guidelines for the management of patients at risk of transfusion
informed assessment of the likely benefits and risks for each patient
the correct procedures for ordering and administration of blood when the decision is made to transfuse.

Figure 19.16 maps the main steps in blood collection, processing and storage. A basic knowledge of these underlies good practice in using blood products.
BLOOD PRODUCTS
Blood products are defined as any therapeutic substances made from human blood and are subdivided as described below.
Blood components
These are platelets, plasma or cryoprecipitate, prepared from single donations (see Box 19.16).
Plasma derivatives
Licensed pharmaceutical products are produced from pooled human plasma obtained from many individuals. Plasma derivatives are generally treated to remove or reduce virus contamination.
Coagulation factor concentrates factor VIII, IX
These are for the treatment of conditions such as haemophilia or von Willebrand's disease. Where it is possible to obtain coagulation factors made by recombinant DNA technology, they are preferred due to lack of infection risk (see p. 949).
Intravenous immunoglobulin (IVIgG)
This contains concentrated immunoglobulin and was developed to replace IgG and reduce infective complications in patients with hypogammaglobulinaemia. High-dose IVIgG can also modulate the immune response and is effective in some patients with immune thrombocytopenia and Guillain-Barré syndrome (see pp. 948 and 1180). There is at present no alternative to the plasma derivative. IVIgG infusions can cause acute renal failure, especially in the elderly. Specific immunoglobulins are made from donors with high titres of antibodies such as hepatitis B, tetanus and varicella zoster, and are generally used in an attempt to prevent the development of infection in exposed non-immune people.
Human albumin solution
This is available in two strengths:
5% albumin solution has been widely used for acute volume replacement. There is, however, uncertainty about the relative safety and effectiveness of albumin in comparison to other synthetic colloids (gelatin, dextran and starch solutions) and crystalloid solutions (see EBM panel). It is indicated for replacement in plasma exchange.
20% albumin solution is used in the management of hypoproteinaemic oedema with nephrotic syndrome and ascites in chronic liver disease. It is hyperoncotic and expands plasma volume by more than the amount infused.

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Figure 19.16 Blood donation, processing and storage.
EBM
FLUID RESUSCITATION IN CRITICALLY ILL PATIENTS-role of albumin and other colloid solutions vs crystalloid solutions
'Systematic review of 18 RCTs reporting a mortality endpoint shows worse survival in patients receiving albumin infusions. There was no evidence that resuscitation with colloids reduces the risk of death as compared to crystalloids in patients with trauma and burns or following surgery.'
Alderson P, Schierhout G, Roberts I, Bunn F. Colloids versus crystalloids for resuscitation in acutely ill patients. Cochrane Library, issue 1, 2001. Oxford: Update Software.
Further information: www.update-software.com/abstracts

EBM
CORRECTION OF A LOW HAEMOGLOBIN IN CRITICALLY ILL PATIENTS-role of red cell transfusion
'A single large RCT of red cell transfusion in patients in intensive care showed that patients who were maintained with an Hb in the range of 7-9 g/dl had a mortality and morbidity that were equivalent to, or better than, patients who were maintained with an Hb in the range of 10-12 g/dl. The former group received approximately half the number of red cell units.'
Herbert PC, Wells G, Bljachman MA, et al. with the Canadian Transfusion Requirements in Critical Care Group. A multicentre, randomised controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340:409-417.
Further information: www.transfusionguidelines.org.uk
www.sign.ac.uk

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19.16 BLOOD COMPONENTS
Properties Indications
Red cell components1 N.B. Red cell components must be compatible with the patient's ABO blood group To increase circulating red cell mass to relieve clinical features caused by insufficient oxygen delivery in patients with low Hb levels
Whole blood 450 ml donor blood collected into 63 ml anticoagulant/preservative solution
Stored at 2-6°C. Shelf life up to 5 weeks Contains fibrinogen, other coagulation factors, and plasma as a colloid volume expander. Whole blood is suitable for replacement of acute blood loss but red cell concentrates plus colloid or crystalloid are acceptable alternatives
Red cell concentrate Most of the plasma removed and replaced with a solution to optimise preservation of red cells Most usual product in many countries, e.g. UK, US Some restrictions on use in infants; otherwise suitable for any patient requiring red cell replacement
Platelet concentrate2 One adult dose is made from four or five donations of whole blood, or from a single platelet apheresis procedure
Stored at 20-24°C and must be agitated
Shelf life up to 5 days from collection
Platelets more effective if compatible with patient's
ABO type
Plasma in group O platelets can haemolyse red cells of group A patient Treatment of bleeding due to thrombocytopenia and some forms of platelet dysfunction
Prevention of bleeding due to thrombocytopenia in bone marrow failure
Plasma (Fresh frozen plasma, FFP) 150-300 ml plasma obtained from one donation of whole blood. Shelf life usually 1 year
Should be compatible with patient's ABO type
Group O plasma particularly is at risk of causing haemolysis in a group A patient Replacement of coagulation factor deficiency if a suitable licensed virus-inactivated product is not available, e.g. multiple coagulation deficiencies in major haemorrhage
Therapy of thrombotic thrombocytopenic purpura: by infusion or plasma exchange
Do not use to replace circulatory fluid volume, to raise plasma albumin level or as an alternative to total parenteral nutrition
Virus-inactivated plasma Plasma treated to remove or reduce infectivity of viruses from donor Obtained from a pool of donors' plasma treated with solvent and detergent, or from single donations treated with methylene blue and light Indications as for fresh frozen plasma
Cryoprecipitate High molecular weight proteins are modestly concentrated from plasma by precipitation near freezing point
Each 10-20 ml pack of precipitate contains fibrinogen, factor VIII and von Willebrand factor Replacement of fibrinogen if a suitable licensed virus-inactivated plasma derivative is not available
Use for von Willebrand's disease and haemophilia if virus-inactivated or recombinant products not available

1 Alternative oxygen-delivering fluids: perfluorocarbon and haemoglobin solutions will be licensed in the near future for clinical indications.
2 Platelet preparations treated to inactivate microbial pathogens are in clinical trial and may become available.
RED CELL COMPATIBILITY
ABO RED CELL GROUPS
Transfusing red cells that have an ABO blood type that is incompatible with the recipient is the main cause of fatal, acute transfusion reaction.
There are four different ABO groups, determined by whether or not an individual's red cells express the A or B antigens. Normal healthy individuals, from early in childhood, make antibodies against A or B antigens that are not expressed on their own cells (see Box 19.17). On transfusion of red cells, A or B antibodies in the recipient's plasma will bind to transfused red cells that express A or B antigen, as follows:
Anti-A reacts with red cells of group A or AB.
Anti-B reacts with red cells of group B or AB.

19.17 THE ABO SYSTEM
Blood group Red cell antigens Antibodies in plasma UK frequency (%)
O None Anti-A and anti-B 46
A A Anti-B 42
B B Anti-A 9
AB A and B None 3

ABO INCOMPATIBLE RED CELL TRANSFUSION
If red cells of the wrong group are transfused, the patient's IgM antibodies bind to the transfused cells as above, activating complement which damages the red cell membranes and causes lysis of the red cells. Fragments of ruptured cell membrane may initiate DIC. Released haemoglobin may cause renal failure.
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THE RHESUS D BLOOD GROUP
About 15% of Caucasians lack this red cell antigen (RhD negative). RhD positive red cells (acquired through transfusion or pregnancy) can stimulate the production of IgG antibodies to RhD. In subsequent pregnancies these antibodies cross the placenta and, if the fetus is RhD positive, can cause severe anaemia and hyperbilirubinaemia, potentially leading to the baby's death, or cause severe neurological damage (haemolytic disease of the newborn, HDN). Therefore an RhD negative woman who may in future become pregnant should not be transfused with RhD positive blood.
Anti-RhD immunoglobulin is the only effective product for preventing the development of Rhesus antibodies in RhD negative women who are at risk. Administration of anti-D is given after delivery and other potentially sensitising events during pregnancy. In some countries routine prophylactic anti-D is recommended for all Rh negative women. There is no alternative to the human plasma derivative, although monoclonal antibody products are in development.
There are several other red cell antigen groups that may stimulate the development of red cell antibodies with the potential to cause haemolytic transfusion reactions or to cross the placenta and cause HDN. Some examples of these are the other Rhesus antigens (RhC, [cmacr], E, [emacr ], Kell, Duffy and Kidd).
SAFE TRANSFUSION PROCEDURES
It is essential to ensure that no ABO-incompatible red cell transfusion is ever given. Such an accident is likely to kill or harm the patient and is avoidable. The patient's safety depends not only on correct pre-transfusion testing in the laboratory but also on the use of standard procedures for taking appropriately labelled blood samples from the patient and for infusing blood into the correct patient. The proposed transfusion and any alternatives should be discussed with the patient or, if that is not possible, a relative, and this should be documented in the case notes. Special issues may arise in some groups, e.g. Jehovah's Witness patients who usually refuse transfusion.
PRE-TRANSFUSION TESTING
The patient's blood sample is tested to determine the ABO and RhD type and to detect other red cell antibodies that could haemolyse transfused red cells. This is performed by testing the patient's serum against a panel of O positive red cells that express a known range of antigens. If the patient's serum contains an antibody, the red cells will agglutinate. The antibody must then be characterised and red cell units selected which lack that particular antigen.
The transfusion laboratory will usually perform one of the following procedures:
Type and screen (also called 'group and hold' or 'group and save'). Pre-transfusion testing is carried out and the patient's sample is held in the laboratory, usually for 7 days. If no antibodies are present on pre-transfusion testing, the hospital blood bank should subsequently be able to have blood available for collection within 15 minutes.
Cross-match (red cell compatibility testing). After pre-transfusion testing and confirmation of compatibility, red cell units are allocated to that patient for transfusion. Full cross-matching can take up to 45 minutes.

COMPATIBILITY PROBLEMS
If the patient has clinically significant red cell antibodies, further tests to identify the red cell units negative for the specific antigens detected must be performed. This additional matching will increase the time taken to provide red cells. Non-urgent transfusions should be delayed until suitable red cell units are available. If transfusion is urgently needed, the risk of a red cell unit that is not fully compatible may have to be balanced against the risk of delaying transfusion.
STANDARD PROCEDURES FOR PRE-TRANSFUSION SAMPLES AND ADMINISTERING TRANSFUSION
Most incompatible transfusions result from mistakes in taking or labelling the blood sample for pre-transfusion testing, or from failure to carry out standard checks before infusion to make certain the correct pack has been selected for the patient. Every hospital where blood is transfused should have a written transfusion policy that is used by all staff ordering and administering blood products. It should cover the following:
taking blood for pre-transfusion testing
administering blood
record-keeping and observations.

Taking blood for pre-transfusion testing
Positively identify the patient at the bedside.
Label the tubes and request form after identifying the patient.
Ensure that all the information requested by the transfusion laboratory is given on both the tube and the request form. This information must match!

Administering blood
Positively identify the patient at the bedside.
Ensure that the identification of each blood pack matches the patient's identification.
Check that the ABO and RhD groups of each pack are compatible with the patient's.
Check each pack for evidence of damage; if in doubt, do not use and return to the blood bank.
Complete the forms that document the transfusion of each pack.

Record-keeping and observations
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The reason for transfusion, what was given, any adverse effects and the clinical response should be recorded in the notes. Transfusions should only be given where the patient can be observed. Blood pressure, pulse and temperature should be monitored before and 15 minutes after starting each pack. If the patient is conscious, further observations are only needed if the patient becomes unwell or has symptoms or signs of a reaction. An unconscious patient should have pulse and temperature checked at intervals during the transfusion.
ADVERSE EFFECTS OF TRANSFUSION
ACUTE, LIFE-THREATENING COMPLICATIONS OF TRANSFUSION
The following reactions are rare but can be fatal:
acute haemolytic transfusion reaction
infusion of a bacterially contaminated unit
graft-versus-host disease
transfusion-associated lung injury
severe allergic reaction or anaphylaxis.

Fever and allergic symptoms or signs (itch, urticaria) during transfusion are relatively common and usually these reactions are not serious. However, new symptoms or signs that arise during a transfusion must be taken seriously as they may be the first warnings of a serious reaction. Since it may be impossible to identify the cause of a severe reaction immediately, the initial supportive management should generally cover all the possible causes. Figure 19.17 outlines the management and investigation of reactions to blood products.
EBM
RISKS OF FATAL TRANSFUSION REACTIONS-cases reported to national reporting systems
'In the UK between 1996 and 2000 there were 33 reports of death attributed to transfusion. During this period approximately 10 million units of blood components were supplied. The largest cause of major morbidity remains transfusion of the incorrect unit of blood leading to an incompatible red cell transfusion reaction.'
Love EM, Soldan K. Serious hazards of transfusion, Annual report 1999-2000. Manchester: SHOT; 2001.
Further information: www.shot.demon.co.uk
www.transfusionguidelines.org

INFECTIONS TRANSMITTED BY TRANSFUSION
Over the past 30 years, the viruses that cause hepatitis B, AIDS and hepatitis C have been identified and effective tests introduced to detect and exclude infected blood units. Where blood is from 'safe' donors and correctly tested, the current risk of a donation being infectious is very small. For example, in the UK the risk of HIV is less than 1/3 000 000, of hepatitis B about 1/100 000, and of hepatitis C less than 1/500 000 per unit of blood received.
However, some patients who received transfusions before these tests were available have suffered very serious consequences of these infections. This is a constant reminder to avoid non-essential transfusions. Licensed plasma derivatives that have been virus-inactivated do not transmit HIV, human T lymphotrophic virus (HTLV), HBV, HCV, cytomegalovirus or other lipid-enveloped viruses. There is a small risk due to non-enveloped viruses such as human parvovirus B19.
Several viruses have recently been described that are transmissible by transfusion, but they have not been shown to be pathogenic. These include GBV-C (so-called 'hepatitis G'), TT virus and SEN-V.
Presently in the UK there is great concern about variant Creutzfeldt-Jakob disease (vCJD), a human prion disease linked to bovine spongiform encephalitis (BSE; see p. 1202). There have been no reports of vCJD (or of sporadic CJD) associated with blood transfusion. Nevertheless, precautions such as leucodepletion have been introduced to reduce any possible risk.
Bacterial contamination of a blood component may rarely occur. This is a cause of very severe and often lethal transfusion reactions. In the UK 16 incidents with 9 fatalities were identified during the 5 years to 1999; about 80% of these episodes occurred with platelet transfusion.
Transfusion-transmitted malaria is extremely rare in the UK and US (about 1/4 000 000 units of blood or less) but may be more important where malaria is prevalent. Donor selection procedures are designed to exclude potentially infectious individuals from donating red cells for transfusion; blood testing has limitations. Chagas disease (see p. 60), caused by Trypanosoma cruzi, is transmissible by blood and is an important problem in parts of South America where the infection is endemic. Blood testing can reduce the risk of transmitting the trypanosome.

pages 910 - 914


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Home > 2 SYSTEM-BASED DISEASES > 19 Blood disorders > ANAEMIAS
ANAEMIAS
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Figure 19.17 Investigation and management of reactions to blood products.
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Figure 19.18 Factors which influence the size of red cells in anaemia.
Globally, 30% of the total world population are anaemic and half of these, some 600 million people, have iron deficiency. The classification of anaemia by the size of the red cells (MCV) is logical and indicates the likely cause. Red cells in the bone marrow must acquire a minimum level of haemoglobin before being released into the blood stream (see Fig. 19.18). Whilst in the marrow compartment red cell precursors undergo cell division driven by erythropoietin. If red cells cannot acquire haemoglobin at a normal rate in the marrow, they will undergo more divisions than normal and will have a low MCV when finally released into the blood. Thus in iron deficiency (iron), thalassaemia (globin chains), congenital sideroblastic anaemia (haem ring) and occasionally in the anaemia of chronic disease (poor iron utilisation) the MCV is low because component parts of the haemoglobin molecule are not fully available. In megaloblastic anaemia the biochemical consequence of vitamin B12 or folate deficiency is an inability to synthesise new bases to make DNA. A similar defect of cell division is seen in the presence of cytotoxic drugs or haematological disease in the marrow such as myelodysplasia. In these states cells haemoglobinise normally but undergo fewer cell divisions, resulting in circulating red cells with a raised MCV. The red cell membrane is composed of a lipid bilayer and contains lipid which will freely exchange with the plasma pool of lipid. Conditions such as liver disease, hypothyroidism, hyperlipidaemia and pregnancy are associated with raised lipids and may cause a raised MCV.
IRON DEFICIENCY ANAEMIA
This will occur when iron losses or physiological requirements exceed absorption.
Blood loss
The most common explanation in men and post-menopausal women is gastrointestinal blood loss (see p. 764). This may result from occult gastric or colorectal malignancy, gastritis, peptic ulceration, inflammatory bowel disease, diverticulitis, polyps and angiodysplastic lesions. On a world-wide basis hookworm and schistosomiasis are prevalent causes of gut blood loss (see pp. 70 and 76). Gastrointestinal blood loss may be exacerbated by the chronic use of aspirin or NSAIDs which cause intestinal erosions and impair platelet function. In women of childbearing age menstrual blood loss, pregnancy and breastfeeding contribute to iron deficiency by depleting iron stores; in developed countries one-third of women in this age bracket have low iron stores but only 3% display iron-deficient haematopoiesis.
Rarely, chronic haemoptysis or haematuria may cause iron deficiency.
Malabsorption
Gastric acid is required to release iron from food and helps to keep iron in the soluble ferrous state (see Fig. 19.19). Hypochlorhydria in the elderly or that due to drugs such as proton pump inhibitors may contribute to the lack of iron availability from the diet, as may previous gastric surgery. Iron is absorbed actively in the upper small intestine and hence can be affected by coeliac disease (see p. 792). Anyone with features of malabsorption or recurrent deficiency in the absence of other explanations, or young men with normal diet or young women with normal menstruation and diet in association with iron deficiency should be screened for coeliac disease. A dietary assessment should be made in all patients to assess their iron intake.
PHYSIOLOGICAL DEMANDS
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Figure 19.19 Iron absorption, uptake and distribution in the body.
At times of rapid growth such as infancy and puberty, iron demands increase and may outstrip absorption. This may be exacerbated by prematurity and breastfeeding in infants or menstruation in girls. In pregnancy, iron is diverted to the fetus, the placenta and the increased maternal red cell mass and is lost with bleeding at parturition. There is no consensus about the routine use of iron supplementation in pregnancy but if women with a poor dietary history or previous heavy menstrual losses become pregnant and the side-effects are acceptable, it is a justifiable practice.
Investigations
Confirmation of iron deficiency
Plasma ferritin is a measure of iron stores. It is a very specific test; a subnormal level is due to iron deficiency, hypothyroidism or vitamin C deficiency. There is little diurnal or day-to-day variation in the result of the test. Levels can be raised by liver disease and in an acute phase response; in these conditions a ferritin level of up to 100 µg/l may still be associated with absent bone marrow iron stores. Plasma iron and total iron binding capacity (TIBC) are measures of iron availability, hence are affected by many factors besides iron stores. Plasma iron becomes very low during an acute phase response but is raised in liver disease and haemolysis. Transferrin levels are lowered by malnutrition, liver disease, an acute phase response and nephrotic syndrome but raised by pregnancy or the oral contraceptive pill. A transferrin saturation of less than 16% is consistent with iron deficiency but less specific than a ferritin measurement. There is also a marked diurnal and day-to-day variation in plasma iron levels by 30-50%. For these reasons measurement of plasma ferritin is the best single test to confirm iron deficiency.
All proliferating cells express membrane transferrin receptors to acquire iron; a small amount of this receptor is shed into and found in a free soluble form in blood. At times of poor iron stores, cells up-regulate transferrin receptor expression; hence the levels of soluble plasma transferrin receptor increase. This can now be measured by immunoassay and used to distinguish storage iron depletion in the presence of an acute phase response or liver disease where a raised level indicates iron deficiency. In difficult cases it may still be necessary to examine a bone marrow aspirate for iron stores.
Investigation of the cause
This will depend upon the age and sex of the patient as well as the history and clinical findings. In men over the age of 40 years and in post-menopausal women with a normal diet, the upper and lower gastrointestinal tract should be investigated by endoscopy or barium studies. If coeliac disease is suspected, serum antigliadin and anti-endomysium antibodies and duodenal biopsy are indicated. In the tropics stool and urine should be examined for parasites (see p. 70).
Management
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Unless the patient has angina, heart failure or evidence of cerebral hypoxia, transfusion is not necessary and oral iron supplementation is appropriate. Ferrous sulphate 200 mg 8-hourly (120 mg of elemental iron per day) is more than adequate and should be continued for 3-6 months to replete iron stores. The occasional patient is intolerant of ferrous sulphate, with dyspepsia and altered bowel habit. In this case a reduction in dose to 200 mg 12-hourly or a switch to ferrous gluconate 300 mg 12-hourly (70 mg of elemental iron per day) should be made. Delayed-release preparations are not useful since they release iron beyond the upper small intestine where it cannot be absorbed.
The haemoglobin should rise by 1 g/dl every 7-10 days and a reticulocyte response will be evident by 1 week. A failure to respond adequately may be due to non-compliance, continued blood loss, malabsorption or an incorrect diagnosis. The occasional patient with malabsorption or chronic gut disease may need parenteral iron with deep intramuscular injection of iron sorbitol (1.5 mg of iron per kg body weight). This will produce a haematological response and rapidly replete iron stores. Patients should be warned that a brown skin discoloration like a tattoo is likely to develop at the sites of administration.
MEGALOBLASTIC ANAEMIA
This results from a deficiency of vitamin B12 or folic acid, or from disturbances in folic acid metabolism. Folate is an important substrate of, and vitamin B12 a cofactor for, the enzymatic generation of the essential amino acid methionine from homocysteine. This reaction produces tetrahydrofolate which is converted to thymidine monophosphate for incorporation into DNA. Deficiency of either vitamin B12 or folate will therefore produce high plasma levels of homocysteine and impaired DNA synthesis.
The end result of this is cells with arrested nuclear maturation but normal cytoplasmic development: so-called nucleo-cytoplasmic asynchrony. All proliferating cells will exhibit megaloblastosis; hence changes are evident in the buccal mucosa, tongue, small intestine, cervix, vagina and uterus. The high proliferation rate of bone marrow results in striking changes in the haematopoietic system in megaloblastic anaemia. Cells become arrested in development and die within the marrow; this ineffective erythropoiesis results in an expanded hypercellular marrow. The megaloblastic changes are most evident in the early nucleated red cell precursors, and intramedullary haemolysis results in a raised bilirubin and lactate dehydrogenase (LDH) but no reticulocytosis. Iron stores are usually raised. The mature red cells are large and oval, and sometimes contain nuclear remnants. Nuclear changes are seen in the immature granulocyte precursors and a characteristic appearance is that of 'giant' metamyelocytes with a large 'sausage-shaped' nucleus. The mature neutrophils show hypersegmentation of their nuclei with cells having six or more nuclear lobes. If severe, a pancytopenia may be present in the peripheral blood.
19.18 CLINICAL FEATURES OF MEGALOBLASTIC ANAEMIA
Symptoms
Malaise (90%)
Breathlessness (50%)
Paraesthesiae (80%)
Sore mouth (20%)
Weight loss
Altered skin pigmentation
Grey hair
Impotence
Poor memory
Depression
Personality change
Hallucinations
Visual disturbance
Signs
Smooth tongue
Angular cheilosis
Vitilig
Skin pigmentation
Heart failure
Pyrexia
Sensory disturbance
Dorsal column loss
Subacute combined degeneration
Optic atrophy
Altered colour vision


19.19 DIAGNOSTIC FEATURES OF MEGALOBLASTIC ANAEMIA
Investigation Result
Haemoglobin Often reduced, may be very low
Mean cell volume Usually raised, commonly > 120 fl
Erythrocyte count Low for degree of anaemia
Blood film Oval macrocytosis, poikilocytosis, red cell fragmentation, neutrophil hypersegmentation
Reticulocyte count Low for degree of anaemia
Leucocyte count Low or normal
Platelet count Low or normal
Bone marrow Increased cellularity, megaloblastic changes in erythroid series, giant metamyelocytes, dysplastic megakaryocytes, increased iron in stores, pathological non-ring sideroblasts
Serum iron Elevated
Iron-binding capacity Increased saturation
Serum ferritin Elevated
Plasma LDH Elevated, often markedly

The clinical features of megaloblastic anaemia are summarised in Boxes 19.18 and 19.19.
VITAMIN B12 ABSORPTION
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The average daily diet contains 5-30 µg of vitamin B12, mainly in meat, fish, eggs and milk; this is well in excess of the daily requirement for vitamin B12 of 1 µg. In the stomach, gastric enzymes release vitamin B12 from food and at gastric pH it binds to a carrier protein termed R protein. The gastric parietal cells produce acid and intrinsic factor; the latter is a vitamin B12-binding protein which optimally binds vitamin B12 at pH 8. As gastric emptying occurs, pancreatic secretion raises the pH and vitamin B12 released from the diet switches from the R protein to intrinsic factor. Bile also contains vitamin B12 which is available for reabsorption in the intestine, and a variety of cobalamin analogues with a similar chemical structure to vitamin B12 which are toxic. The freeing of R protein after gastric emptying ensures that the toxic cobalamin analogues are bound to R protein and excreted, whilst vitamin B12 is bound to intrinsic factor. The vitamin B12 intrinsic factor complex binds to specific receptors in the terminal ileum and vitamin B12 is actively transported by the enterocytes to plasma. In plasma, vitamin B12 binds to a transport protein produced by the liver termed transcobalamin II, which carries it to the tissues for utilisation. The liver stores enough vitamin B12 to supply the daily requirements for 3 years and this, together with the enterohepatic circulation, means that vitamin B12 deficiency takes years to become manifest even if all dietary intake is stopped.
Vitamin B12 deficiency
The causes of vitamin B12 deficiency are given below.
Dietary deficiency
This only occurs in strict vegans but the onset of clinical features can occur at any age between 10 and 80 years. The breastfed offspring of vegan mothers are at risk of developing nutritional vitamin B12 deficiency. Less strict vegetarians often have slightly low vitamin B12 levels but are not tissue vitamin B12-deficient.
Gastric factors
Normal gastric acid and enzyme secretion is required for the release of vitamin B12 from the food. Hypochlorhydria in elderly patients or following gastric surgery can impair the release of vitamin B12 from food. Total gastrectomy invariably results in vitamin B12 deficiency within 5 years, often combined with iron deficiency. These patients need life-long 3-monthly vitamin B12 injections. After partial gastrectomy vitamin B12 deficiency only develops in 10-20% of patients by 5 years. An annual injection of vitamin B12 should prevent deficiency in this group.
Pernicious anaemia
This is an autoimmune disorder in which the gastric mucosa is atrophic with loss of parietal cells causing intrinsic factor deficiency. In the absence of intrinsic factor less than 1% of dietary vitamin B12 is absorbed. Pernicious anaemia has an incidence of 25/100 000 population over the age of 40 years in developed countries but an average age of onset of 60 years. It is more common in individuals with a personal or family history of pernicious anaemia or autoimmune disease (Hashimoto's thyroiditis, Graves' disease, vitiligo, hypoparathyroidism or Addison's disease). Anti-parietal cell antibodies are present in over 90% of cases but are also present in 20% of normal females over the age of 60 years. A negative result makes pernicious anaemia less likely but a positive result is not diagnostic. Antibodies to intrinsic factor are found in the serum of 60% of patients with pernicious anaemia and, if present, are diagnostic.
Small bowel factors
One-third of all patients with pancreatic insufficiency fail to transfer dietary vitamin B12 from R protein to intrinsic factor. This usually results in slightly low vitamin B12 values but no tissue evidence of vitamin B12 deficiency.
Motility disorders or hypogammaglobulinaemia can result in bacterial overgrowth and the resulting competition for free vitamin B12 can result in deficiency. This will be corrected to some extent by a course of antibiotics.
A small number of people heavily infected with the fish tapeworm develop vitamin B12 deficiency.
Inflammatory disease of the terminal ileum such as Crohn's disease may impair the interaction of the vitamin B12-intrinsic factor complex with its receptor, as will surgery on this part of the bowel. Both may result in vitamin B12 malabsorption.
It is possible with a two-part Schilling test to distinguish pernicious anaemia from intestinal problems. The principles of the test are covered in Figure 19.20. The patient must be vitamin B12-replete, have normal renal function and be able to comply with a 24-hour urine collection. This latter criterion is important as up to 25% of tests are invalidated by an incomplete urine collection. It is important to realise that this is not a test of gut function but simply distinguishes pernicious anaemia from the other causes of vitamin B12 deficiency.
Levels of cobalamins fall in normal pregnancy. Each laboratory must validate its own normal range but levels below 150 ng/l are common and in the last trimester 5-10% of women have levels below 100 ng/l. Similarly, paraproteins can interfere with vitamin B12 assays and so myeloma may be associated with a spurious low vitamin B12.


Figure 19.20 The two-part Schilling test in the diagnosis of the cause of vitamin B12 deficiency.
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FOLATE ABSORPTION
Folates are produced by plants and bacteria; hence dietary leafy vegetables (spinach, broccoli, lettuce), fruits (bananas, melons) and animal protein (liver, kidney) are a rich source. An average Western diet contains more than the minimum daily intake of 50 µg but excess cooking for longer than 15 minutes destroys folates. Most dietary folate is present as polyglutamates; these are converted to monoglutamate in the upper small bowel and actively transported into plasma. Plasma folate is loosely bound to plasma proteins such as albumin and there is an enterohepatic circulation. Total body stores of folate are small and deficiency can occur in a matter of weeks.
Folate deficiency
19.20 CAUSES OF FOLATE DEFICIENCY
Diet
Poor intake of vegetables
Malabsorption
e.g. Coeliac disease
Increased demand
Pregnancy
Cell proliferation, e.g. haemolysis
Drugs
Certain anticonvulsants (e.g. phenytoin)
Contraceptive pill
Certain cytotoxic drugs (e.g. methotrexate)


19.21 DIAGNOSTIC FEATURES OF FOLIC ACID DEFICIENCY
Diagnostic findings
Low serum folate levels (fasting blood sample)
Red cell folate levels low (but may be normal if folate deficiency is of very recent onset)
Corroborative findings
Macrocytic dysplastic blood picture
Megaloblastic marrow


The causes and diagnostic features of folate deficiency are covered in Boxes 19.20 and 19.21. The edentulous elderly or psychiatric patient is particularly susceptible to dietary deficiency and this will be exacerbated in the presence of gut disease or malignancy. Pregnancy-induced folate deficiency is the most common cause of megaloblastosis world-wide and is more likely in the context of twin pregnancies, multiparity and hyperemesis gravidarum. Serum folate is very sensitive to dietary intake; a single meal can normalise it in a patient with true folate deficiency, and anorexia, alcohol and anticonvulsant therapy can reduce it in the absence of megaloblastosis. For this reason red cell folate levels are a more accurate indicator of folate stores and tissue folate deficiency.
Management
Where a patient with a severe megaloblastic anaemia is very ill and treatment must be started before vitamin B12 and red cell folate results are available, always treat with both folic acid and vitamin B12. The use of folic acid alone in the presence of vitamin B12 deficiency results in worsening of neurological defects.
Vitamin B12 deficiency
Vitamin B12 deficiency is treated with hydroxycobalamin 1000 µg i.m. in five doses 2 or 3 days apart followed by maintenance therapy of 1000 µg every 3 months for life. The reticulocyte count will peak by the 5th-10th day after therapy and may be as high as 50%. The haemoglobin will rise by 1 g/dl every week. The response of the marrow is associated with a fall in plasma potassium levels and rapid depletion of iron stores. If an initial response is not maintained and the blood film is dimorphic, the patient may need additional iron therapy. A sensory neuropathy may take 6-12 months to correct; long-standing neurological damage may not recover.
Folate deficiency
Oral folic acid 5 mg daily for 3 weeks will treat acute deficiency and 5 mg once weekly is adequate maintenance therapy. Prophylactic folic acid in pregnancy will prevent megaloblastosis in women at risk. Folic acid supplementation may reduce the risk of neural tube defects and in some countries all pregnant women receive routine folic acid supplementation. Prophylactic supplementation is also given in chronic haematological disease associated with reduced red cell lifespan (e.g. autoimmune haemolytic anaemia or haemoglobinopathies). There is also evidence that supraphysiological supplementation (400 µg/day) can reduce the risk of coronary and cerebrovascular disease by reducing plasma homocysteine levels. This has led the US Food and Drugs Administration to introduce fortification of bread, flour and rice with folic acid.
If severe angina or heart failure is present, transfusion can be used in megaloblastic anaemia. The cardiovascular system is adapted to the chronic anaemia present in megaloblastosis and the volume load imposed by transfusion may result in decompensation and severe cardiac failure. In such circumstances 1 unit of blood should be administered slowly each day with diuretic cover.
ANAEMIA OF CHRONIC DISEASE
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This is a common type of anaemia, particularly in hospital populations. Characteristic features are as follows:
The anaemia occurs in the setting of chronic infections, chronic inflammation or neoplasia.
The anaemia is not related to bleeding, haemolysis or marrow infiltration.
The anaemia is generally mild, in the range of 8.5-11.5 g/dl, and is usually associated with a normal MCV (normocytic, normochromic), but up to 25% may have a reduced MCV.
The serum iron is low but iron stores are normal or increased, as indicated by the ferritin or stainable marrow iron.

Pathogenesis
The pathogenesis of this type of anaemia is thought to involve abnormalities of iron metabolism and erythropoiesis. Recent interest has been centred on the role of erythropoietin and the inhibitory effect of various cytokines (e.g. IL-1 and TNF-a) on erythropoiesis. Erythropoietin levels appear to be lower than would be expected for the degree of anaemia. Administration of erythropoietin to patients with rheumatoid arthritis has a beneficial effect on the anaemia.
Management
A particular problem is to distinguish the anaemia of chronic disease (ACD) associated with a low MCV from iron deficiency. The ferritin level is elevated in inflammatory conditions and the serum iron is low in both ACD and iron deficiency. A ferritin in the low/normal range (up to 100 µg/l) in the setting of disorders associated with the ACD may indicate iron deficiency. A soluble transferrin receptor level may be elevated and would suggest iron deficiency. Examination of the marrow may be useful to assess iron stores directly. A trial of oral iron can be given in difficult situations. A positive response occurs in true iron deficiency but not in ACD. Measures which reduce the severity of the underlying disorder generally help to improve the ACD.
HAEMOLYSIS
The normal red cell lifespan of 120 days may be shortened by a variety of abnormalities. The bone marrow may increase its output of red cells six- to eightfold by increasing the proportion of red cells produced, expanding the volume of active marrow and releasing reticulocytes prematurely. If the rate of destruction exceeds this increased production rate, then anaemia will develop.
The basic laboratory diagnosis of haemolysis is covered in Figure 19.21. The red cell destruction will overload pathways for haemoglobin destruction, causing a modest rise in unconjugated bilirubin in the blood and mild jaundice. Increased reabsorption of urobilinogen from the gut results in an increase in urinary urobilinogen. Red cell destruction releases LDH and increases serum levels. The red cell compensation results in a reticulocytosis, and nucleated red cell precursors may also appear in the blood. The expansion of the active bone marrow may result in a neutrophilia and immature granulocytes appearing in the blood to cause a leucoerythroblastic blood film. The appearances of the red cells may give an indication of the likely cause of the haemolysis; spherocytes are small, dark-red cells and suggest autoimmune haemolysis or hereditary spherocytosis, sickle cells suggest haemoglobinopathy and red cell fragments indicate microangiopathic haemolysis.
Intravascular haemolysis


Figure 19.21 Laboratory features and classification of the causes of haemolysis. (LDH = lactate dehydrogenase; DCT = direct Coombs test)
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When rapid red cell destruction occurs free haemoglobin is released into the plasma. Free haemoglobin is toxic to cells and the body has evolved binding proteins to minimise this risk. Haptoglobin is an a2 globulin produced by the liver which binds free haemoglobin to form a complex too large to be excreted by the kidney but which is degraded by the liver. Levels of haptoglobin are reduced in intravascular haemolysis. Once haptoglobins are saturated, free haemoglobin is oxidised to form methaemoglobin which binds to albumin, in turn forming methaemalbumin which can be detected by the Schumm's test. Methaemoglobin is degraded and any free haem is bound to a second binding protein termed haemopexin. If all the protective mechanisms are overloaded, free haemoglobin may appear in the urine. When fulminant, this gives rise to black urine as in severe falciparum malaria infection (see p. 51). In smaller amounts renal tubular cells absorb the haemoglobin, degrade it and store the iron as haemosiderin. When the tubular cells are subsequently sloughed into the urine they give rise to haemosiderinuria which is always indicative of intravascular haemolysis.
Extravascular haemolysis
Physiological red cell destruction occurs in the fixed reticulo-endothelial cells in the liver or spleen, so avoiding free haemoglobin in the plasma. In most haemolytic states haemolysis is predominantly extravascular and little haptoglobin depletion occurs.
The erythroid hyperplasia may give rise to folate deficiency, when the blood findings will be complicated by the presence of megaloblastosis. Measurement of red cell folate is unreliable in the presence of haemolysis and serum folate will be elevated. Patients' red cells can be labelled with 51chromium; when reinjected, they can be used to determine red cell survival, or when combined with surface counting may indicate whether the liver or the spleen is the main source of red cell destruction. This is seldom performed in clinical practice.
CONGENITAL HAEMOLYSIS
Inherited red cell defects of structure or metabolism may result in a chronic haemolytic state. The principal pathologies are red cell membrane defects (hereditary spherocytosis or elliptocytosis), glucose-6-phosphate dehydrogenase (G6PD) deficiency and the haemoglobinopathies.
RED CELL MEMBRANE DEFECTS
The structure of the red cell membrane is shown in Figure 19.4 (see p. 895). The basic structure is a cytoskeleton 'stapled' on to the lipid bilayer by special protein complexes. This structure ensures great deformability and elasticity; the red cell diameter is 8 µm but the narrowest point in the circulation is 2 µm in the spleen. When this normal structure is disturbed, usually by a quantitative or functional deficiency of one or more proteins in the cytoskeleton, cells lose their normal elasticity. Each time such cells pass through the spleen they lose membrane relative to their cell volume. This results in an increase in mean cell haemoglobin concentration (MCHC), abnormal cell shape and reduced red cell survival due to extravascular haemolysis.
HEREDITARY SPHEROCYTOSIS
This is usually inherited as an autosomal dominant condition, although 25% of cases have no family history and represent new mutations. The incidence is approximately 1:5000 in developed countries but this may be an under-estimate since the disease may present de novo in patients over 65 years and is often discovered as a chance finding on a blood count. The pathogenesis varies between families; the most common abnormalities are deficiencies of beta spectrin or ankyrin (see Fig. 19.4, p. 895). The severity of spontaneous haemolysis varies. Most cases are associated with an asymptomatic compensated chronic haemolytic state with spherocytes present on the blood film and a reticulocytosis. Occasional cases are associated with more severe haemolysis; these may be due to coincidental polymorphisms in alpha spectrin or coinheritance of a second defect involving a different protein.
The clinical course may be complicated by crises:
A haemolytic crisis occurs when the severity of haemolysis increases; this is rarely seen in association with infection.
A megaloblastic crisis follows the development of folate deficiency; this may occur as a first presentation of the disease in association with pregnancy.
An aplastic crisis occurs in association with parvovirus infection. Parvovirus causes a common exanthem in children but if individuals with chronic erythroid hyperplasia become infected the virus directly invades red cell precursors and temporarily switches off red cell production. Patients present with severe anaemia and a low reticulocyte count.

Pigment gallstones are present in up to 50% of patients and may cause symptomatic cholecystitis.
Investigations
Tests will confirm the presence of haemolysis and the blood film will show spherocytes but the direct Coombs test (see p. 924) is negative excluding immune haemolysis. An osmotic fragility test will show increased sensitivity to lysis in hypotonic saline solutions. It is important to screen other family members for features of compensated haemolysis.
Management
Folic acid prophylaxis, 5 mg once weekly, should be given life-long. Consideration may be given to splenectomy which improves but does not normalise red cell survival. Potential indications include:
growth retardation in children, although splenectomy should be delayed until the child is over 5 years of age
recurrent severe crises
the death of other family members from the disease
symptomatic cholecystitis.

Guidelines for the management of patients after splenectomy are presented in Box 19.22.
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19.22 MANAGEMENT OF THE SPLENECTOMISED PATIENT
Vaccinate with multivalent pneumococcal and Haemophilus vaccines at least 2-3 weeks before elective splenectomy. Meningococcal C vaccination is only recommended for those living in areas with high endemic infection rates. Vaccinate after emergency surgery but protection may be less effective.
Life-long penicillin V 250 mg 12-hourly is recommended to protect against bacterial strains not covered by the vaccines. If penicillin-allergic, consider a macrolide.
Wherever possible, splenectomised patients should carry a card or bracelet indicating the date of their last vaccinations. In the event of overwhelming sepsis, this card may be life-saving in unconscious patients by guiding the rapid administration of appropriate antibiotics.
Splenectomised patients admitted with septicaemia should be resuscitated and given intravenous antibiotics to cover pneumococcus, Haemophilus and meningococcus.
Animal bites should be promptly treated with local disinfection and antibiotics to prevent serious soft tissue infection and septicaemia.


Acute, severe haemolytic crises require transfusion support but blood must be cross-matched carefully and transfused slowly as haemolytic transfusion reactions may occur. The typical blood film appearances are masked in the presence of iron deficiency or disorders which cause a raised MCV, such as jaundice; in these situations the red cell shape is normal but spherocytes will appear when the underlying abnormality is corrected.
HEREDITARY ELLIPTOCYTOSIS
This term refers to a heterogeneous group of disorders producing an increase in elliptocytic red cells on the blood film and a variable degree of haemolysis. It is due to a functional abnormality of one or more anchor proteins in the red cell membrane, e.g. alpha spectrin or protein 4.1. Inheritance may be autosomal dominant or recessive. It is less common than hereditary spherocytosis in the Western world, with an incidence of 1/10 000, but is more common in equatorial Africa and parts of South-east Asia. The clinical course is variable and depends upon the degree of membrane dysfunction caused by the inherited molecular defect(s); most cases present as an asymptomatic blood film abnormality but occasional cases result in neonatal haemolysis or a chronic compensated haemolytic state. Management of the latter is the same as for hereditary spherocytosis. A characteristic variant of hereditary elliptocytosis occurs in South-east Asia, particularly Malaysia and Papua New Guinea, with stomatocytes and ovalocytes in the blood. This has a prevalence of up to 30% in some communities because it offers relative protection from malaria which has sustained a high gene frequency. The differential diagnosis includes iron deficiency, thalassaemia, myelofibrosis, myelodysplasia and pyruvate kinase deficiency.
RED CELL ENZYMOPATHIES
The mature red cell must produce energy via ATP to maintain a normal internal environment and cell volume whilst protecting itself from the oxidative stress presented from oxygen carriage. Anaerobic glycolysis via the Embden-Meyerhof pathway generates ATP, and the hexose monophosphate shunt produces NADPH and glutathione to protect against oxidative stress. The impact of functional or quantitative defects in the enzymes in these pathways will depend upon the importance of the steps affected and the presence of alternative pathways. In general, defects in the hexose monophosphate shunt result in periodic haemolysis induced by oxidative stress, whilst those in the Embden-Meyerhof pathway result in shortened red cell survival and chronic haemolysis.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE
This enzyme is pivotal in the hexose monophosphate shunt and produces NADPH to protect the red cell against oxidative stress. Deficiencies of this enzyme are the most common human enzymopathy, affecting 10% of the world's population with a geographical distribution which parallels the malaria belt (see Fig. 1.46, p. 52) because heterozygotes are protected from malarial parasitisation. The enzyme is a heteromeric structure made of catalytic subunits which are produced from a gene on the X chromosome. The deficiency affects males but is carried by females who are usually only affected in the neonatal period or in the presence of extreme lyonisation or homozygosity. There are over 400 subtypes of G6PD described. The most common types associated with normal activity are the B+ enzyme present in most Caucasians and 70% of Afro-Caribbeans, and the A+ variant present in 20% of Afro-Caribbeans. The two common variants associated with reduced activity are the A- variety in approximately 10% of Afro-Caribbeans, and the Mediterranean or B- variety in Caucasians. In East and West Africa up to 20% of males and 4% of females (homozygotes) are affected and have enzyme levels of approximately 15%. The deficiency in Caucasian and Oriental populations is more severe, with enzyme levels as low as 1%.
Clinical features
Acute drug-induced haemolysis. This can occur with many drugs:
Analgesics: aspirin, phenacetin
Antimalarials: primaquine, quinine, chloroquine, pyrimethamine
Antibiotics: sulphonamides, nitrofurantoin, ciprofloxacin
Miscellaneous: quinidine, probenecid, vitamin K, dapsone.
Chronic compensated haemolysis.
Infection or acute illness.
Neonatal jaundice. This may be a feature of the B- enzyme.
Favism or acute haemolysis after ingestion of the broad bean Vicia faba.

Laboratory features
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During an attack there will be evidence of non-spherocytic intravascular haemolysis.
The blood film will show bite cells (red cells with a 'bite' of membrane missing), blister cells (red cells with surface blistering of the membrane) and irregular-shaped small cells. There will be polychromasia reflecting the reticulocytosis and, if stained with a supravital stain such as methyl violet, denatured haemoglobin is visible as Heinz bodies within the red cell cytoplasm.
The level of G6PD can be indirectly assessed by screening methods which usually depend upon the decreased ability to reduce dyes; direct assessment of G6PD is then made in those with low screening values. Care must be taken close to an acute haemolytic episode because reticulocytes may have normal enzyme levels and give rise to a false normal result.
The different isoenzyme types may be identifiable by altered electrophoretic mobility but this is not of clinical value.

Management
Stop any precipitant drugs or deal with underlying infection. Acute transfusion support may be life-saving.
PYRUVATE KINASE DEFICIENCY
This is the second most common red cell enzyme defect and affects thousands of people world-wide. It results in deficiency of ATP production and a chronic haemolytic anaemia. It is inherited as an autosomal recessive trait. The extent of anaemia is variable; the blood film shows characteristic 'prickle cells' which resemble holly leaves. Enzyme activity is only 5-20% of normal. Transfusion support may be necessary.
PYRIMIDINE 5' NUCLEOTIDASE DEFICIENCY
This enzyme catalyses the dephosphorylation of nucleoside monophosphates and is important during the degradation of RNA in reticulocytes. It is inherited as an autosomal recessive trait and is as common as pyruvate kinase deficiency in Mediterranean, African and Jewish populations. The accumulation of excess ribonucleoprotein in deficiency results in coarse basophilic stippling associated with a chronic haemolytic state. The enzyme is very sensitive to inhibition by lead and this is the reason why basophilic stippling is a feature of lead poisoning.
ACQUIRED HAEMOLYTIC ANAEMIA
AUTOIMMUNE HAEMOLYTIC ANAEMIA
This results from increased red cell destruction due to red cell autoantibodies. The antibodies may be IgG or M, or more rarely IgE or A. If an antibody avidly complement fixes, it will result in intravascular haemolysis, but if complement activation is weak, the haemolysis will be extravascular. Antibody-coated red cells lose membrane to macrophages in the spleen and hence spherocytes are present in the blood. The optimum temperature at which the antibody is active (thermal specificity) is used to classify immune haemolysis:
Warm antibodies bind best at 37°C and account for 80% of cases. The majority are IgG and usually react against Rhesus antigens.
Cold antibodies bind best at 4°C but can bind up to 37°C in some cases. They are usually IgM and bind complement. They account for the other 20% of cases.

Warm autoimmune haemolysis
The incidence of warm autoimmune haemolysis is approximately 1/100 000 population per annum; it occurs at all ages but is more common in middle age and there is a female excess. No underlying cause is identified in up to 50% of cases. The remainder are secondary to a wide variety of other conditions:
lymphoid neoplasms: lymphoma, chronic lymphocytic leukaemia, myeloma
solid tumours: lung, colon, kidney, ovary, thymoma
connective tissue disease: SLE, rheumatoid arthritis
drugs: methyldopa, mefenamic acid, penicillin, quinine
miscellaneous: ulcerative colitis, HIV.

Investigations
There is evidence of haemolysis and spherocytes on the blood film. The diagnosis is confirmed by the direct Coombs or antiglobulin test. In this, red cells are mixed with Coombs reagent which contains antibodies against human IgG/M/complement. If the red cells have been coated by antibody in vivo, the Coombs reagent will induce their agglutination which can be detected visually. The relevant antibody can be eluted from the red cell surface and tested against a panel of typed red cells to determine which red cell antigen it is directed against. The most common specificity is Rhesus and most often anti-e; this is helpful when choosing blood to cross-match. The direct Coombs test can be negative in the presence of brisk haemolysis; a positive test requires about 200 antibody molecules to attach to each red cell; with a very avid complement-fixing antibody, haemolysis may occur at lower levels of antibody-binding. The standard Coombs reagent will miss IgA or IgE antibodies.
Management
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If the haemolysis is secondary to an underlying cause, this must be dealt with; stop any offending drugs.
It is usual to treat initially with prednisolone 1 mg/kg orally. A response is seen in 70-80% of cases but this may take up to 3 weeks; a rise in haemoglobin will be matched by a fall in bilirubin and LDH levels. Once the haemoglobin has reached 10 g/dl, the steroid dose can be reduced by 5 mg per week down to 10 mg daily, then reduced slowly to stop over a further 10 weeks. Steroids work by decreasing macrophage destruction of antibody-coated red cells and reducing antibody production.
Transfusion support can be given for life-threatening problems; this will be the least incompatible blood but may still give rise to transfusion reactions or the development of further alloantibodies.
If the haemolysis fails to respond to steroids or can only be stabilised by large doses, then splenectomy should be considered. This removes a main site of red cell destruction and antibody production with a good response in 50-60% of cases. The operation can be performed laparoscopically with less morbidity for the patient.
For patients who fail to respond to steroids or for whom splenectomy is not appropriate, alternative immunosuppressive therapy may be considered. This is least suitable for young patients for whom long-term therapy may carry a risk of secondary neoplasms. The choice of drug is between azathioprine 1-2 mg/kg or cyclophosphamide 2 mg/kg, both orally; it usually takes 2-3 months for these drugs to induce a response.

Cold agglutinin disease
This is due to antibodies, usually IgM, which bind to the red cells at 4°C and cause them to agglutinate. It may cause intravascular haemolysis if complement fixation occurs. This can be chronic when the antibody is monoclonal, and acute or transient when the antibody is polyclonal.
Chronic cold agglutinin disease
This affects elderly patients and may be associated with an underlying low-grade B-cell lymphoma. It causes a low-grade intravascular haemolysis with cold, painful and often blue fingers, toes, ears or nose (so-called acrocyanosis). The latter is due to red cell agglutination in the small vessels in these exposed areas. The blood film shows red cell agglutination and the MCV may be spuriously raised because the automated analysers count aggregates as single cells. The monoclonal IgM usually has specificity against the I or, more rarely, i antigen and is present in a very high titre. Treatment is directed at any underlying lymphoma but if the disease is idiopathic, then patients must keep extremities warm, especially in winter. Some patients respond to steroid therapy and blood transfusion may be considered but the cross-match sample must be placed in a transport flask at a temperature of 37°C and blood administered via a blood-warmer.
Other causes of cold agglutination
Cold agglutination can occur in association with Mycoplasma pneumonia or with infectious mononucleosis. Paroxysmal cold haemoglobinuria is a very rare cause seen in children in association with congenital syphilis. An IgG antibody binds to red cells in the peripheral circulation but lysis occurs in the central circulation when complement fixation takes place. This antibody is termed the Donath-Landsteiner antibody and has specificity against the P antigen on the red cells.
NON-IMMUNE HAEMOLYTIC ANAEMIA
Mechanical trauma
Physical disruption of red cells may occur in a number of conditions and is characterised by the presence of red cell fragments on the blood film and markers of intravascular haemolysis:
Mechanical heart valves. High flow through incompetent valves or periprosthetic leaks through the suture ring holding a valve in place result in shear stress damage.
March haemoglobinuria. Vigorous exercise such as prolonged marching or marathon running can cause red cell damage in the capillaries in the feet.
Thermal injury. Severe burns cause thermal damage to red cells characterised by fragmentation and the presence of microspherocytes in the blood.
Microangiopathic haemolytic anaemia. Fibrin deposition in capillaries can cause severe red cell disruption. It may occur in a wide variety of conditions: disseminated carcinomatosis, malignant or pregnancy-induced hypertension, haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and DIC (see p. 952).

Infection
Falciparum malaria (see p. 51) may be associated with intravascular haemolysis; when severe this is termed blackwater fever due to the associated haemoglobinuria. Clostridium perfringens septicaemia (see p. 39), usually in the context of an ascending cholangitis, may cause severe intravascular haemolysis with marked spherocytosis due to bacterial production of a lecithinase which destroys the red cell's membrane.
Chemicals or drugs
These agents cause haemolysis by oxidant denaturation of haemoglobin. Dapsone and sulfasalazine can produce haemolysis associated with the presence of Heinz bodies in the red cells on supravital staining with brilliant cresyl blue. Heinz bodies contain denatured haemoglobin. Arsenic gas, copper, chlorates, nitrites and nitrobenzene derivatives may all cause haemolysis.
HAEMOGLOBINOPATHIES
Normal haemoglobin
The normal haemoglobin molecule is comprised of two alpha and two non-alpha globin chains (see p. 895). Alpha globin chains are produced from two genes present on each chromosome 16; these are active throughout embryonic, fetal, infant and adult life. Severe disorders of alpha globin chains may therefore cause intrauterine death and will be present at birth. The non-alpha chains are produced by genes present in single copy on each chromosome 11. Production varies with age; fetal haemoglobin (HbF-a2a2) has two gamma chains but after the first trimester small amounts of haemoglobin A (HbA-a2ß2>) with two beta chains are produced. At birth about 80% of haemoglobin is HbF and 20% HbA. Thereafter gamma chain production is suppressed such that by 6 months of age HbA is the predominant haemoglobin with less than 1% HbF. Disorders affecting the beta chain do not present until after 6 months of age. A constant small amount of haemoglobin A2 (HbA2-a2d2 usually < 2%) is made from birth.
Abnormal haemoglobins
The haemoglobinopathies can be classified into two subgroups.
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The first is where there is an alteration in the amino acid structure of the polypeptide chains of the globin fraction of haemoglobin, commonly called the abnormal haemoglobins; the best-known example is haemoglobin S, found in sickle-cell anaemia. These usually result from amino acid substitutions which change the function of the globin chain at critical sites. For example, mutations around the haem-binding pocket cause the haem ring to fall out of the structure and produce an unstable haemoglobin. These substitutions often change the charge of the globin chains, producing different electrophoretic mobility, and this forms the basis for the diagnostic use of electrophoresis to identify haemoglobinopathies. Several hundred such variants are known; they were originally designated by letters of the alphabet, e.g. S, C, D or E, but are now described by names usually taken from the town or district in which they were first described.
The second is where the amino acid sequence is normal but polypeptide chain production is impaired or absent for a variety of reasons; these are the thalassaemias. In these conditions the ratio of alpha to non-alpha chain production is disturbed. In alpha-thalassaemia excess beta chains are present, whilst in beta-thalassaemia excess alpha chains are present. The excess chains precipitate, causing red cell membrane damage and a reduced red cell survival.
SICKLE-CELL ANAEMIA
Sickle-cell disease results from a single glutamic acid to valine substitution at position 6 of the beta globin polypeptide chain. It is inherited as an autosomal recessive trait. Homozygotes only produce abnormal beta chains that make haemoglobin S (HbS, termed SS), and this results in the clinical syndrome of sickle-cell disease. Heterozygotes produce a mixture of normal and abnormal beta chains that make normal HbA and HbS (termed AS), and this results in the clinically asymptomatic sickle trait. The inheritance of sickle-cell disease is shown in Figure 19.22.
Epidemiology


Figure 19.22 Possible genotype of offspring of parents with sickle-cell trait.
Individuals with sickle-cell trait are relatively resistant to the lethal effects of falciparum malaria in early childhood. The high incidence of this deleterious gene in equatorial Africa can be explained by the selective survival advantage it confers in areas where falciparum malaria is endemic. Patients with sickle-cell anaemia do not have correspondingly greater resistance to falciparum malaria. The geographical distribution of sickle-cell anaemia and the other common haemoglobinopathies is shown in Figure 19.23. The greatest prevalence of haemoglobinopathies occurs in tropical Africa, where the heterozygote frequency is over 20%. In black American populations sickle-cell trait has a frequency of 8%.
Pathogenesis


Figure 19.23 The geographical distribution of the haemoglobinopathies.
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When haemoglobin S is deoxygenated, the molecules of haemoglobin polymerise to form pseudocrystalline structures known as 'tactoids'. These distort the red cell membrane and produce characteristic sickle-shaped cells. The polymerisation is reversible when reoxygenation occurs. The distortion of the red cell membrane, however, may become permanent and the red cell 'irreversibly sickled'. The greater the concentration of sickle-cell haemoglobin in the individual cell, the more easily tactoids are formed, but this process may be enhanced or retarded by the presence of other haemoglobins. Thus haemoglobin C participates in the polymerisation more readily than haemoglobin A, whereas haemoglobin F strongly inhibits polymerisation.




Integration link: Sickle cell disease - histology

Taken from Robbins & Cotran's Pathologic Basis of Disease 7e








Integration link: Sickle cell disease - pathophysiology

Taken from Robbins & Cotran's Pathologic Basis of Disease 7e








Integration link: Treatments for leukemia - GM-CSF

Taken from Pharmacology 5e




Clinical features
Sickling is precipitated by hypoxia, acidosis, dehydration and infection. Irreversibly sickled cells have a shortened survival and plug vessels in the microcirculation. This results in a number of acute syndromes termed 'crises' and chronic organ damage as shown in Figure 19.24:
Vaso-occlusive crisis. Plugging of small vessels in the bone produces acute severe bone pain. This affects areas of active marrow: the hands and feet in children (so-called dactylitis) or the femora, humeri, ribs, pelvis and vertebrae in adults. Patients usually have a systemic response with tachycardia, sweating and a fever. This is the most common crisis.
Sickle chest syndrome. This may follow on from a vaso-occlusive crisis and is the most common cause of death in adult sickle disease. Bone marrow infarction results in fat emboli to the lungs which cause sickling and infarction leading to ventilatory failure if not treated.
Sequestration crisis. Thrombosis of the venous outflow from an organ causes loss of function and acute painful enlargement. In children the spleen is the most common site. Massive splenic enlargement may result in severe anaemia and circulatory collapse with death. Recurrent sickling in the spleen in childhood results in infarction and adults may have no functional spleen. In adults the liver may undergo sequestration with severe pain due to capsular stretching.
Aplastic crisis. Infection of adult sicklers with parvovirus B19 results in a severe but self-limiting red cell aplasia. This produces a very low haemoglobin which may cause heart failure. Unlike all other sickle crises, the reticulocyte count is low.



Figure 19.24 Clinical manifestations of sickle-cell disease.
Investigations
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Patients with sickle-cell disease have a compensated anaemia, usually around 6-8 g/dl. The blood film shows sickle cells, target cells and features of hyposplenism. A reticulocytosis is present. The presence of HbS can be demonstrated by exposing red cells to a reducing agent such as sodium dithionite; HbA gives a clear solution, whereas HbS polymerises to produce a turbid solution. This forms the basis of emergency screening tests before surgery in appropriate ethnic groups but cannot distinguish between sickle trait and disease. The definitive diagnosis requires haemoglobin electrophoresis to demonstrate no HbA, 2-20% HbF and the predominance of HbS. Both parents of the affected individual will have sickle trait.
Management
All patients with sickle disease should receive prophylaxis with daily folic acid, and penicillin V to protect against pneumococcal infection which may be lethal in the presence of hyposplenism. These patients should be vaccinated against pneumococcus and, where available, Haemophilus and hepatitis B.
Vaso-occlusive crises are managed by aggressive rehydration, oxygen therapy, adequate analgesia (which often requires opiates) and antibiotics. Transfusion should be with fully genotyped blood wherever possible. Simple top-up transfusion may be used in a sequestration or aplastic crisis. A regular transfusion programme to suppress HbS production and maintain the HbS level below 30% may be indicated in recurrent severe complications such as cerebrovascular accidents in children or chest syndromes in adults. Exchange transfusion where a patient is simultaneously venesected and transfused to replace HbS with HbA may be used in life-threatening crises or to prepare patients for surgery.
A high HbF level inhibits polymerisation of HbS and reduces sickling. Patients with sickle-cell disease and high HbF levels have a mild clinical course with few crises. Some agents are able to induce increased synthesis of HbF and this has been used to reduce the frequency of severe crises. The oral cytotoxic agent hydroxycarbamide (hydroxyurea) has been shown to effect clinical benefit with acceptable side-effects in children and adults who have recurrent severe crises. Relatively few allogeneic transplants from HLA-matched siblings have been performed but this procedure appears to be potentially curative.
Prognosis
In Africa few children with sickle-cell anaemia survive to adult life without medical attention. Even with standard medical care approximately 15% die by the age of 20 years and 50% by the age of 40 years.
OTHER ABNORMAL HAEMOGLOBINS
Another beta chain haemoglobinopathy, haemoglobin C (HbC) disease, is clinically silent but associated with microcytosis and target cells on the blood film. Compound heterozygotes inheriting one HbS gene and one HbC gene from their parents have haemoglobin SC disease which behaves like a mild form of sickle-cell disease. It is associated with a reduced frequency of crises but is not uncommonly associated with complications in pregnancy and retinal vein thrombosis.
THE THALASSAEMIAS
Thalassaemia is an inherited impairment of haemoglobin production, in which there is partial or complete failure to synthesise a specific type of globin chain. In alpha-thalassaemia, the alpha genes are deleted; loss of one gene a-/a or both genes a-/a- from each chromosome 16 may occur, in association with the production of some or no alpha globin chains. In beta-thalassaemia defective production usually results from disabling point mutations causing no (ß0 or reduced (ß-) beta chain production.
BETA-THALASSAEMIA
Failure to synthesise beta chains (beta-thalassaemia) is the most common type of thalassaemia and is seen in highest frequency in the Mediterranean area. Heterozygotes have thalassaemia minor, a condition in which there is usually mild anaemia and little or no clinical disability. Homozygotes (thalassaemia major) either are unable to synthesise haemoglobin A or at best produce very little and, after the first 4 months of life, develop a profound hypochromic anaemia. The diagnostic features are listed in Box 19.23.
Beta-thalassaemia minor is often detected only when iron therapy for a mild microcytic anaemia fails. The diagnostic features are also summarised in Box 19.23. Symptoms are absent or mild. Intermediate grades of severity occur.
19.23 DIAGNOSTIC FEATURES OF BETA-THALASSAEMIA
Major
Profound hypochromic anaemia
Evidence of severe red cell dysplasia
Erythroblastosis
Absence or gross reduction of the amount of haemoglobin A
Raised levels of haemoglobin F
Evidence that both parents have thalassaemia minor

Minor
Mild anaemia
Microcytic hypochromic erythrocytes (not iron-deficient)
Some target cells
Punctate basophilia
Raised resistance of erythrocytes to osmotic lysis
Raised haemoglobin A2 fraction
Evidence that one parent has thalassaemia minor


Management
The treatment of beta-thalassaemia major is given in Box 19.24. Cure is now a possibility for selected children, with allogeneic bone marrow transplantation.
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19.24 TREATMENT OF BETA-THALASSAEMIA MAJOR
Phase Lymphoblastic Myeloid
Induction Vincristine (i.v.) Daunorubicin (i.v.)
Prednisolone (oral) Cytarabine (i.v.)
L-asparaginase (i.v.) Etoposide (i.v. and oral)
Daunorubicin (i.v.) Tioguanine (oral)
Methotrexate (intrathecal)
Consolidation Daunorubicin (i.v.) Cytarabine (i.v.)
Cytarabine (i.v.) Amsacrine (i.v.)
Etoposide (i.v.) Mitoxantrone (mitozantrone) (i.v.)
Methotrexate (i.v.)
Maintenance Prednisolone (oral)
Vincristine (i.v.)
Mercaptopurine (oral)
Methotrexate (oral)

Prevention
It is possible to identify a fetus with homozygous beta-thalassaemia by obtaining chorionic villous material for DNA analysis sufficiently early in pregnancy to allow termination. This examination is only appropriate if both parents are known to be carriers (beta-thalassaemia minor) and will accept a termination.
ALPHA-THALASSAEMIA
The reduction or absence of alpha chain synthesis is common in South-east Asia. There are two alpha gene loci on chromosome 16 and therefore four alpha genes. If one is deleted there is no clinical effect. If two are deleted there may be a mild hypochromic anaemia. If three are deleted the patient has haemoglobin H disease and if all four are deleted the baby is stillborn (hydrops fetalis). Haemoglobin H is a beta-chain tetramer formed from the excess of chains. It is functionally useless. Treatment of haemoglobin H disease is similar to that of beta-thalassaemia of intermediate severity. The combinations are shown in Box 19.25.
19.25 ALPHA-THALASSAEMIA
Cause
Failure of production of haemoglobin alpha chains due to gene deletion

Age and sex
Both sexes from birth onward

Genetics
Two alpha chain genes from each parent

Presentation
Hydrops fetalis if all genes deleted
Haemoglobin H if three genes deleted
Mild hypochromic microcytic anaemia if two genes deleted

Treatment
Hydrops fetalis: none available
Haemoglobin H: no specific therapy required; avoid iron therapy; folic acid if necessary


ISSUES IN OLDER PEOPLE
ANAEMIA
Although the mean haemoglobin falls with age in both sexes, it remains well within the normal range.
When a low haemoglobin does occur, it is generally due to disease. Anaemia can never be considered 'normal' in old age.
Symptoms may be subtle and of insidious onset, but cardiovascular features such as dyspnoea and oedema, and cerebral features such as dizziness and apathy, tend to predominate.
Ferritin of less than 45 µg/l in older people is highly predictive of iron deficiency; because of the prevalence of other disorders, serum iron and iron-binding capacity fall with age and are not reliable indicators of deficiency.
Iron deficiency results almost exclusively from gastrointestinal blood loss.
Vitamin B12 deficiency is most commonly due to pernicious anaemia as the prevalence of chronic atrophic gastritis rises in old age.
Neuropsychiatric symptoms are a well-established feature of vitamin B12 deficiency, but a causal relationship between vitamin B12 deficiency and fixed dementia has not been clearly shown. Descriptions of dementia associated with vitamin B12 deficiency in the absence of haematological abnormalities are rare.
Anaemia of chronic disease is frequent in old age because older people are prone to those diseases that reduce erythropoiesis.


pages 914 - 929


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Home > 2 SYSTEM-BASED DISEASES > 19 Blood disorders > HAEMATOLOGICAL MALIGNANCIES
HAEMATOLOGICAL MALIGNANCIES
Haematological malignancies arise when the processes of proliferation or apoptosis are corrupted in blood cells. If mature differentiated cells are involved, the cells will have a low growth fraction and produce indolent neoplasms such as the low-grade lymphomas or chronic leukaemias where patients have an expected survival of many years. In contrast, if more primitive stem cells are involved, the cells can have the highest growth fractions of all human neoplasms, producing rapidly progressive life-threatening illnesses such as the acute leukaemias or high-grade lymphomas. Involvement of the pluripotent stem cells produces the most aggressive acute leukaemias. In general, haematological neoplasms are diseases of elderly patients, the exceptions being acute lymphoblastic leukaemia which predominantly affects children, and Hodgkin's disease which affects young people in the 20-40-year age range (see Fig. 19.25).
LEUKAEMIAS
Leukaemias are a group of malignant disorders of the haematopoietic tissues characteristically associated with increased numbers of white cells in the bone marrow and/or peripheral blood. The course of leukaemia may vary from a few days or weeks to many years, depending on the type.
Epidemiology
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Figure 19.25 Variation in the incidence of different haematological malignancies in the UK by age.
The incidence of leukaemia of all types in the population is approximately 10/100 000 per annum, of which just under half are acute leukaemia. Males are affected more frequently than females, the ratio being about 3:2 in acute leukaemia, 2:1 in chronic lymphocytic leukaemia and 1.3:1 in chronic myeloid leukaemia. Geographical variation in incidence does occur, the most striking being the rarity of chronic lymphocytic leukaemia in the Chinese and related races. Acute leukaemia occurs at all ages. Acute lymphoblastic leukaemia shows a peak of incidence in the 1-5 age group. All forms of acute myeloid leukaemia have their lowest incidence in young adult life and there is a striking rise over the age of 50. Chronic leukaemias occur mainly in middle and old age.
Aetiology
The cause of the leukaemia is unknown in the majority of patients. Several factors, however, are associated with the development of leukaemia and these are listed in Box 19.26.
Terminology and classification
The terms 'acute' and 'chronic', when applied to leukaemia, refer to the clinical behaviour of the disease. In acute leukaemia the history is usually brief and life expectancy, without treatment, short. In chronic leukaemias the patient may have been unwell for months and survival is usually measured in years. A significant number of chronic leukaemias are discovered incidentally.
Not all leukaemias are associated with an increased peripheral blood leucocyte count or even the appearance of abnormal cells in the blood. The diagnosis is made from an examination of the bone marrow.
19.26 FACTORS ASSOCIATED WITH THE DEVELOPMENT OF LEUKAEMIA
Exposure to benzene in industry
Ionising radiation
A significant increase in myeloid leukaemia followed the atomic bombing of Japanese cities
An increase in leukaemia was observed after the use of radiotherapy for ankylosing spondylitis and diagnostic radiographs of the fetus in pregnancy
Cytotoxic drugs
These, particularly alkylating agents, may induce myeloid leukaemia, usually after a latent period of several years
Retroviruses
One rare form of T-cell leukaemia/lymphoma appears to be associated with a retrovirus similar to the viruses causing leukaemia in cats and cattle
Genetic
There is a greatly increased incidence of leukaemia in the identical twin of patients with leukaemia
Increased incidence occurs in Down's syndrome and certain other genetic disorders
Immunological
Immune deficiency states (e.g. hypogammaglobulinaemia) are associated with an increase in haematological malignancy


19.27 SUBCLASSIFICATIONS OF LEUKAEMIA
Acute myeloid

Acute lymphoblastic
Common type (pre-B)
T-cell
B-cell
Undifferentiated
FAB classification
M0 undifferentiated
M1 minimal differentiation
M2 differentiated
M3 promyelocytic
M4 myelomonocytic
M5 monocytic
M6 erythrocytic
M7 megakaryocytic
Chronic lymphocytic
B-cell-common
T-cell-rare
Chronic myeloid
Ph positive
Ph negative, BCR-abl positive
Ph negative, BCR-abl negative
Eosinophilic leukaemia


Leukaemias are traditionally classified into four main groups:
acute lymphoblastic
acute myeloid
chronic lymphocytic
chronic myeloid.
A more detailed subclassification is provided in Box 19.27.
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Although leukaemias are divided into lymphoid and myeloid varieties, recent advances have shown that this division may be artificial because in acute leukaemias the two types may coexist in the same patient. Nevertheless, there is a value in maintaining the distinction, as the drug therapy of the two main types is substantially different.
The subclassification of the lymphoblastic varieties is possibly of greater value, for the subtype dictates greater variation in treatment. The 'common' type, which constitutes 70% of all patients, responds well to treatment and carries the best chance of long-term remission. The classification of acute myeloid leukaemia into eight varieties reflects the variable degree of maturation of the granulocyte series, the common involvement of the monocyte series with the granulocyte series, and also the involvement of erythrocytic and megakaryocytic elements.




Integration link: Treatments for leukemia - tretinoin

Taken from Pharmacology 5e




ACUTE LEUKAEMIA
There is a failure of cell maturation in acute leukaemia. Proliferation of cells which do not mature leads to an increasing accumulation of useless cells which take up more and more marrow space at the expense of the normal haematopoietic elements. Eventually, this proliferation spills into the blood. The evolution of acute leukaemia is illustrated schematically in Figure 19.26. Acute myeloid leukaemia is about four times more common than acute lymphoblastic leukaemia in adults. In children the proportions are reversed, with the lymphoblastic variety more common. The clinical features are usually those of bone marrow failure (anaemia, bleeding or infection-see pp. 902, 907 and 910).


Figure 19.26 The development of leukaemia.
Investigations
Blood examination usually shows anaemia with a normal or raised MCV. The leucocyte count may vary from as low as 1 × 109/l to as high as 500 × 109/l or more. In the majority of patients the count is below 100 × 109/l. The blood film appearance of blast cells and other primitive cells is usually diagnostic. Sometimes the blast cell count may be very low in the peripheral blood and a bone marrow examination is necessary to establish the diagnosis. Severe thrombocytopenia is usual but not invariable.


Figure 19.27 Acute myeloid leukaemia. Bone marrow aspirate showing infiltration with large blast cells which display nuclear folding and prominent nucleoli.
19.28 INVESTIGATIONS FOR THE ASSESSMENT OF ACUTE LEUKAEMIA
Haemostatic function
Coagulation screen
Fibrinogen
D-dimers (see pp. 898 and 900)
Renal function
Plasma urea and creatinine
Hepatic function
Total protein
Albumin
Bilirubin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Cellular proliferation
Plasma LDH
Plasma urate


The bone marrow is the most valuable diagnostic investigation and will provide material for cytology (see Fig. 19.27), cytogenetics and immunological phenotyping. A trephine biopsy should be taken if no marrow is obtained (dry tap). The marrow is usually hypercellular, with replacement of normal elements by leukaemic blast cells in varying degrees (but more than 20% of the cells). The presence of Auer rods in the cytoplasm of blast cells indicates a myeloblastic type of leukaemia.
Other basic investigations required at diagnosis are given in Box 19.28.
Management
The general strategy for acute leukaemia is given in Figure 19.28. The first decision must be whether or not to give specific treatment. However, specific treatment is generally aggressive and has a number of side-effects. It may not be appropriate for the very elderly or patients with other serious disorders. In these patients supportive treatment only should be offered; this can effect considerable improvement in well-being.
Specific therapy
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Figure 19.28 Treatment strategy in acute leukaemia.
19.29 MANAGEMENT OF ACUTE LEUKAEMIA: SPECIFIC THERAPY
Existing infections identified and treated (e.g. urinary tract infection, oral candidiasis, dental, gingival and skin infections)
Anaemia corrected with red cell concentrate infusion
Thrombocytopenic bleeding controlled with platelet transfusion
If possible, central venous catheter (e.g. Hickman line) inserted to facilitate access to the circulation for delivery of chemotherapy
Therapeutic regimen carefully explained to the patient


If a decision to embark on specific therapy has been taken, the patient should be prepared in the ways listed in Box 19.29. It is unwise to attempt aggressive management of acute leukaemia unless adequate services are available for the provision of supportive therapy.
19.30 DRUGS COMMONLY USED IN THE TREATMENT OF ACUTE LEUKAEMIA
Problem Management
Erythropoietic failure Allogeneic bone marrow transplantation from human leucocyte antigen (HLA)-compatible sibling
Transfusion to maintain Hb > 10 g/dl
Folic acid 5 mg daily
Iron overload Iron therapy forbidden
Desferrioxamine therapy
Splenomegaly causing mechanical problems, excessive transfusion required Splenectomy

The aim of treatment is to destroy the leukaemic clone of cells without destroying the residual normal stem cell compartment from which repopulation of the haematopoietic tissues will occur. There are three phases:
Remission induction. In this phase the bulk of the tumour is destroyed by combination chemotherapy. The patient goes through a period of severe bone marrow hypoplasia, requiring intensive support and inpatient care from specially trained medical and nursing staff.
Remission consolidation. If remission has been achieved by induction therapy, residual disease is attacked by therapy during the consolidation phase. This consists of a number of courses of chemotherapy, again resulting in periods of marrow hypoplasia.
Remission maintenance. If the patient is still in remission after the consolidation phase for acute lymphoblastic leukaemia, a period of maintenance therapy is given, consisting of a repeating cycle of drug administration. This may extend for up to 2 years if relapse does not occur and is usually given on an outpatient basis. Thereafter, specific therapy is discontinued and the patient observed. (This phase is not thought to be of benefit in most patients with acute myeloblastic leukaemia who have been brought into complete remission by induction and consolidation therapy.)
In patients with acute lymphoblastic leukaemia it is necessary to give therapy to the central nervous system. This usually consists of a combination of cranial irradiation and intrathecal methotrexate.
The detail of the schedules for these treatments will be found in specialist texts. The drugs most commonly employed for the two main varieties of acute leukaemia are given in Box 19.30. If a patient fails to go into remission with induction treatment, alternative drug combinations may be tried but generally the outlook is poor unless a remission can be achieved and the patient has a donor for an allogeneic stem cell transplant. Alternatively, a decision may be taken not to give any further specific therapy and to provide supportive treatment only. Disease which relapses during treatment or soon after the end of treatment carries a poor prognosis and is difficult to treat. The longer after the end of treatment that relapse occurs, the more likely it is that further treatment will be effective.
Supportive therapy
Aggressive and potentially curative therapy which involves periods of severe bone marrow failure would not be possible without adequate and skilled supportive care. The following problems commonly arise.
Anaemia. Anaemia is treated with red cell concentrate infusions to maintain a haemoglobin above 10 g/dl.
Bleeding. Thrombocytopenic bleeding requires platelet transfusions unless the bleeding is trivial. Prophylactic platelet transfusion should be given to maintain the platelet count above 10 × 109/l. Coagulation abnormalities occur and need accurate diagnosis and treatment as appropriate, usually with fresh frozen plasma.
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Figure 19.29 Skin necrosis due to extravasation of anthracycline chemotherapy (e.g. doxorubicin, daunorubicin).
Infection. Fever (> 38°C) lasting over 1 hour in a neutropenic patient (absolute neutrophil count < 1.0 × 109/l) indicates possible septicaemia. Parenteral broad-spectrum antibiotic therapy is essential. Empirical therapy with a combination of an aminoglycoside (e.g. gentamicin) is given with a broad-spectrum penicillin (e.g. piperacillin/tazobactam). This combination is synergistic and bactericidal and should be continued for at least 5 days after the fever has resolved. The organisms most commonly associated with severe neutropenia are Gram-positive bacteria such as Staphylococcus aureus and Staph. epidermidis. The Gram-negative infections with organisms such as Escherichia coli, Pseudomonas and Klebsiella are more likely to cause rapid clinical deterioration and these organisms must be covered with the initial empirical therapy. Gram-positive infection, particularly when the patient has an in-dwelling intravenous catheter, may require vancomycin. Patients with lymphoblastic leukaemia are susceptible to infection with Pneumocystis carinii (see p. 120), which causes a severe pneumonia. Prophylaxis with co-trimoxazole is given during therapy. Diagnosis may be difficult and may require either bronchoalveolar lavage or open lung biopsy. Treatment is with high-dose co-trimoxazole, initially intravenously, with change to oral treatment as soon as possible.
Oral and pharyngeal monilial infection is common. Prophylaxis with fluconazole is often considered; this drug is effective for the treatment of established local infection.
For systemic fungal infection with Candida or pulmonary aspergillosis, intravenous amphotericin is required: 0.5-1 mg/kg per day for at least 3 weeks. Amphotericin is nephrotoxic and hepatotoxic. Renal and hepatic function should therefore be monitored closely, particularly if the patient is receiving antibiotics which are also nephrotoxic. Potassium supplementation is usually required. For patients who experience nephrotoxicity with standard amphotericin, newer lipid formulations of amphotericin can be administered without further deterioration of renal function (see p. 143).
Herpes simplex infection (see p. 30) occurs frequently round the lips and nose during ablative therapy for acute leukaemia. Aciclovir (200 mg 5 times per day) may be prescribed prophylactically to patients with a history of cold sores or elevated titres to herpes simplex. The intravenous dose is 5 mg/kg over 1 hour, repeated 8-hourly. Herpes zoster (see p. 32) can also be treated in the early stage with aciclovir at a dose of 10 mg/kg 8-hourly i.v. for 5 days.
The value of isolation facilities, such as laminar flow rooms, is debatable but may contribute to staff awareness of careful barrier nursing practice. The isolation is often psychologically stressful for the patient.
Metabolic problems. Continuous monitoring of renal, hepatic and haemostatic function is necessary, together with fluid balance measurements. Patients are often severely anorexic and may find drinking difficult and hence require intravenous fluids and electrolytes. Renal toxicity occurs with some antibiotics (e.g. aminoglycosides) and antifungal agents (amphotericin).
Psychological support. This is a key aspect of care. Patients should be kept informed, and their questions answered and fears allayed as far as possible. An optimistic attitude from the staff is vital. Delusions, hallucinations and paranoia are not uncommon during periods of severe bone marrow failure and septicaemic episodes, and should be met with patience and understanding.
Alternative chemotherapy. Gentle chemotherapy not designed to achieve remission may be used to curb excessive leucocyte proliferation. Drugs used for this purpose include hydroxycarbamide (hydroxyurea) up to 4 g daily and mercaptopurine up to 150 mg daily. The effect is to reduce the leucocyte count without inducing bone marrow failure.
Prognosis
Without treatment the median survival of patients with acute leukaemia is about 5 weeks. This may be extended to a number of months with supportive treatment. Patients who achieve remission with specific therapy have a better outlook. Around 80% of adult patients under 60 years of age with acute lymphoblastic leukaemia or acute myeloblastic leukaemia achieve remission. Remission rates are lower for older patients. However, the relapse rate continues to be high. Median survival for acute lymphoblastic leukaemia patients is about 30 months; patients with acute myeloblastic leukaemia under 55 have a 40% 5-year survival with the best modern chemotherapy. Poor prognostic factors are given in Box 19.31. Genetic analysis by conventional cytogenetics, fluorescent in situ hybridisation or polymerase chain reaction is very important. The presence of a Philadelphia chromosome in acute lymphoblastic leukaemia carries a poor prognosis, as does the presence of chromosome 7 abnormalities in acute myeloid leukaemia. Conversely, the presence of the t(15,17) or t(8,21) translocations confers a good prognosis in acute myeloid leukaemia.
19.31 POOR PROGNOSTIC FEATURES IN ACUTE LEUKAEMIA
Increasing age
Male sex
High leucocyte levels at diagnosis
Cytogenetic abnormalities
CNS involvement at diagnosis
Antecedent haematological disorder


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Allogeneic bone marrow transplantation
Until recently, bone marrow transplantation (BMT) has been the only therapeutic measure which held out the hope of 'cure' for persons with a variety of haematological disorders, particularly those listed in Box 19.32.
19.32 GENERAL INDICATIONS FOR ALLOGENEIC BONE MARROW TRANSPLANTATION
Neoplastic disorders affecting the totipotent or pluripotent stem cell compartment (e.g. leukaemias)
Those with a failure of haematopoiesis (e.g. aplastic anaemia)
A major inherited defect in blood cell production (e.g. thalassaemia, immunodeficiency diseases)
Inborn errors of metabolism with missing enzymes or cell lines


Healthy marrow or stem cells collected from the peripheral blood of a normal donor may be injected intravenously into a recipient who has been suitably 'conditioned'. The conditioning therapy used most frequently is high-dose cyclophosphamide and total body irradiation. Conditioning destroys malignant cells but as a side-effect ablates the recipient's haematopoietic and immunological tissues. The injected donor cells 'home' to the marrow, engraft and produce enough erythrocytes, granulocytes and platelets for the patient's needs after about 3-4 weeks. It may take several years to regain normal immunological function. During this period, particularly in the first year, the patient is at great risk from opportunistic infections. The use of peripheral blood stem cells is associated with more rapid engraftment and immunological reconstitution, making the procedure safer. The donor's immunological system can recognise residual malignant recipient cells and destroy them. This immunological 'graft versus disease' effect is a powerful tool against many haematological tumours and can be boosted in post-transplantation relapse by the infusion of T cells taken from the donor, so-called donor leucocyte infusion (DLI).
19.33 HAEMATOLOGICAL INDICATIONS FOR ALLOGENEIC BONE MARROW TRANSPLANTATION
Acute myeloblastic leukaemia in first remission
Chronic myeloid leukaemia in chronic phase
T- and B-cell lymphoblastic leukaemia in first remission
Acute lymphoblastic leukaemia (common pre-B type) in second remission
Severe aplastic anaemia
Acute myelofibrosis
Severe immunodeficiency syndromes
Lymphoma
Myeloma


19.34 COMPLICATIONS OF ALLOGENEIC BONE MARROW TRANSPLANTATION
Mucositis
Infection
Acute graft-versus-host disease
Pneumonitis
Chronic graft-versus-host disease
Infertility
Cataract formation
Secondary malignant disease


The preferred donors are histocompatible siblings and the best results are obtained in patients aged under 20. Older patients can be transplanted, but results become progressively worse with age and an upper age limit of 55 years is usually applied. The patient should be free of other disorders which might seriously limit lifespan. BMT requires specialised supervision and supportive facilities with fully trained staff. Disorders for which allogeneic transplantation is currently considered are shown in Box 19.33. Transplantation is also a possibility for resistant acute leukaemia and in selected patients with lymphoma. The role of allogeneic BMT in patients with haemoglobinopathies such as sickle-cell disease is controversial.
The main complications of allogeneic BMT are outlined in Box 19.34.
The long-term survival for patients undergoing allogeneic BMT in acute leukaemia is around 50%. Up to 30% succumb to procedure-related morbidity (e.g. graft-versus-host disease, pneumonitis) and in 20% the disease relapses.
Graft-versus-host disease (GVHD)
Problems of GVHD and interstitial pneumonitis may cause serious morbidity and death. Even low-grade GVHD, which is probably advantageous in terms of survival, can reduce the quality of life. GVHD is due to the cytotoxic activity of donor T lymphocytes which become sensitised to their new host, regarding it as foreign. This may cause either an acute or a chronic form of GVHD.
Acute GVHD. This usually appears 14-21 days after the graft, although it may appear earlier or up to 70 days later. It can affect the skin, liver and gut, and may vary from mild to lethal. It appears to be associated with infection, although the relationship is not fully understood. Methotrexate, ciclosporin, antithymocyte globulin, high-dose corticosteroids and T-cell depletion of the donor marrow have all been used to try to prevent the disorder. The more severe forms prove very difficult to control; high-dose corticosteroids may be helpful.
Chronic GVHD. This may follow acute GVHD or arise independently; it occurs later than acute GVHD. It often resembles a connective tissue disorder, although in mild cases a rash may be the only manifestation. Chronic GVHD is usually treated with corticosteroids. Ciclosporin can be used in cases associated with thrombocytopenia. Associated with chronic GVHD is a graft-versus-leukaemia effect, which results in a lower relapse rate.
Infection
Infection is the other major problem encountered during recovery from BMT. Details are given in Box 19.35.
Low-intensity allografting
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19.35 INFECTION DURING RECOVERY FROM BONE MARROW TRANSPLANTATION (BMT)
Infection Time after BMT Treatment
Herpes simplex (see p. 143) 0-4 weeks Aciclovir
Bacterial, fungal 0-4 weeks As for acute leukaemia (see p. 933)
Cytomegalovirus (see p. 17) 7-21 weeks If patient is CMV-negative, use
CMV-negative blood products
Hyperimmune immunoglobulin and ganciclovir for documented infections
Varicella zoster (see p. 31) After 13 weeks Aciclovir 10 mg/kg per day for 1-2 weeks i.v.
Pneumocystis carinii (see p. 120) 8-26 weeks Co-trimoxazole
Interstitial pneumonitis (non-infective) 6-18 weeks No specific therapy
Prednisolone, 60 mg daily orally, may be tried

This concept has been developed in an attempt to reduce the mortality of allografting. Rather than use very intensive conditioning which causes morbidity from end-organ damage, relatively low doses of drugs such as fludarabine and cyclophosphamide are used simply to immunosuppress the recipient and allow donor stem cells to engraft. The emerging donor immune system then eliminates the malignant cells via the 'graft versus disease' effect which may be boosted by the elective use of donor T-cell infusions post-transplant. This type of transplant is less toxic but long-term results are still awaited.
Autologous bone marrow transplantation-peripheral blood stem cell transplantation
In this procedure the patient's own marrow is harvested and frozen to be given back again after intensive therapy to rescue the patient from the marrow damage and aplasia caused by the chemotherapy. It may be used for disorders which do not primarily involve the haematopoietic tissues or in patients in whom very good remissions have been achieved in conditions such as acute leukaemias and high-grade lymphomas. In acute leukaemias the procedure carries a lower procedure-related mortality rate than with allogeneic bone marrow transplantation but there is a high relapse rate (50%). However, there are some data to suggest that in certain patients with acute leukaemia autologous transplantation might confer a modest advantage over chemotherapy, although results from further trials are required to substantiate this. The issue of whether the stem cells should be treated (purged) in an attempt to remove any residual leukaemia cells is controversial.
Stem cells were originally obtained by harvesting them from the marrow. More recently, they have been collected from the peripheral blood during the recovery phase following a period of chemotherapy-induced marrow hypoplasia. The dose of stem cells collected from the peripheral blood is much greater than that harvested from marrow, resulting in significantly faster engraftment and a reduction in transplant-related mortality to less than 1% in patients under 55 years of age.
CHRONIC MYELOID LEUKAEMIA
Chronic myeloid leukaemia is a disorder of proliferation which is unrestrained and excessive. Maturation proceeds fairly normally. The disease occurs chiefly between the ages of 30 and 80 years, with a peak incidence at 55 years. It is rare, with an annual incidence in the UK of 1/100 000, and accounts for 20% of all leukaemias. The disease is found in all races. The aetiology is unknown.
Cytogenetic and molecular aspects
Approximately 90% of patients with chronic myeloid leukaemia have a chromosome abnormality known as the Philadelphia (Ph) chromosome. This is a shortened chromosome 22 and is the result of a reciprocal translocation of material with chromosome 9. The break on chromosome 22 occurs in the breakpoint cluster region (BCR). The fragment from chromosome 9 that joins the BCR carries the Abelson (abl) oncogene, which forms a chimeric gene with the remains of the BCR. This chimeric gene codes for a 210 kDa protein with tyrosine kinase activity, which plays a causative role in the disease. Some Ph-negative patients also have evidence of the same molecular abnormality.




Integration link: Chromosomal translocation in CML

Taken from Textbook of Medical Genetics




Natural history
The disease has three phases: a chronic phase, in which the disease is responsive to treatment, is easily controlled and is essentially a benign neoplasm; an accelerated phase (not always seen), in which disease control becomes more difficult; and a blast crisis phase, in which the disease transforms into an acute leukaemia, either myeloid (70%) or lymphoblastic (30%), which is relatively refractory to treatment. Blast crises occur randomly and are the cause of death in the majority of patients. Patient survival is therefore dictated by the timing of blast crises, which cannot be predicted.
Clinical features
The frequency of the more common symptoms at presentation is given in Box 19.36. About 25% of patients are asymptomatic at diagnosis. On examination the principal clinical finding is splenomegaly, which is present in 90% of patients. In about 10% the enlargement is massive, extending to over 15 cm below the costal margin. A friction rub may be heard in cases of splenic infarction. Hepatomegaly occurs in about 50% of patients. Lymphadenopathy is unusual.
Investigations
19.36 SYMPTOMS AT PRESENTATION OF CHRONIC MYELOID LEUKAEMIA
Symptom Present (%)
Tiredness 37
Weight loss 26
Breathlessness 21
Abdominal pain and discomfort 21
Lethargy 13
Anorexia 12
Sweating 11
Abdominal fullness 10
Bruising 7
Vague ill health 7

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Examination of the blood usually shows a normocytic, normochromic anaemia. The mean haemoglobin is 10.5 g/dl with a range of 7-15 g/dl. The mean leucocyte count is 220 × 109/l with a range of 9.5-600. The mean platelet count is 445 × 109/l with a range of 162-2000. In the blood film the full range of granulocyte precursors from myeloblasts to mature neutrophils is seen, with peaks at the myelocyte and mature granulocyte stage of maturation. Myeloblasts are usually less than 10%. There is often an absolute increase in eosinophils and basophils, and nucleated red cells are common. If the disease progresses through an accelerated phase, the percentage of the more primitive cells increases. There is a dramatic increase in the number of circulating myeloblasts as the disease enters blast transformation. In about one-third of patients very high platelet counts are seen during treatment, both in chronic and accelerated phases, but these usually drop dramatically at blast transformation. Basophilia tends to increase as the disease progresses.
The peripheral blood is the most useful diagnostically but bone marrow material should be obtained for chromosome analysis to demonstrate the presence of the Philadelphia chromosome. Increasingly, RNA analysis is being undertaken to demonstrate the presence of the chimeric BCR-abl gene. Other characteristic findings on investigation include a very low neutrophil alkaline phosphatase score and very high vitamin B12 levels in the plasma. LDH levels are also substantially elevated.
Management
No specific therapy is required if the patient is asymptomatic and the leucocyte count not greatly elevated. In the majority of patients, however, treatment is necessary.
Chemotherapy
Hydroxycarbamide (hydroxyurea) is currently the most widely used oral agent to provide initial control of the disease. A daily dose of around 2-4 g is used initially, then tailored to maintain the white count in the normal range. Treatment with hydroxycarbamide (hydroxyurea) alone, however, does not diminish the frequency of the Ph chromosome or affect the onset of blast cell transformation. Three types of treatment given in chronic phase can affect survival and result in the loss of the Ph chromosome.
Alpha interferon
EBM
CHRONIC PHASE CHRONIC MYELOID LEUKAEMIA (CML)-role of a-interferon
'In a meta-analysis of over 1500 patients treated in RCTs around the world to compare standard chemotherapy with a-interferon in the initial treatment of chronic myeloid leukaemia, the 5-year survival rate with interferon (57%) was significantly better than that seen with hydroxycarbamide (hydroxyurea) or busulfan (42%, p < 0.001). This confirmed the role of a-interferon in the initial management of chronic phase disease.'
Chronic Myeloid Leukaemia Trialists' Collaborative Group. Interferon alpha versus chemotherapy for chronic myeloid leukaemia: a meta-analysis of 7 randomised controlled trials. N Engl J Med 1997; 89:1616-1620.


This is given intramuscularly or subcutaneously at 3-9 mega units daily. It can induce and maintain control of this disease in chronic phase in about 70% of patients. In addition, however, reduction in the percentage of Ph-positive cells is seen in about 20% and apparent elimination of the Ph chromosome in about 5%. There is evidence that interferon prolongs survival in those who achieve a significant reduction in Ph-positive cells. Only prolonged follow-up will determine whether such patients are cured. Interferon therapy causes 'flu-like' symptoms initially: tiredness, somnolence, weight loss, dizziness, nausea, vomiting, loss of taste, diarrhoea and headache. Some of these side-effects may be controlled with paracetamol; others such as severe bone pain and severe weight loss are reasons for discontinuation. The majority of patients tolerate the therapy well, particularly if the dose can be reduced to 3 mega units 3 times per week. It is unwise to use interferon therapy in patients over 75 years of age because of neurotoxicity. During treatment the aim should be to maintain the leucocyte count at low levels between 2 and 5 × 109/l.
Allogeneic or syngeneic bone marrow transplant from a matched sibling donor
This provides the only means of obtaining long-term remission in this disease. It is available in the UK to those under the age of 55 years who have a suitable donor. The best results are obtained in patients in early chronic phase when about 80% can expect probable cure. Monitoring for relapse by detecting the presence of the BCR-abl protein and the use of donor T-cell infusion in such cases has proven very effective at returning patients to durable complete remission. The results of transplantation in accelerated and blast transformation phases are significantly worse. As only a few patients have matched family donors available, there is increasing interest in transplantation using matched unrelated volunteer donors obtained from donor panels. Such a transplant carries higher morbidity and mortality but may offer the prospect of long-term survival in up to 40%. Various autografting approaches are also under evaluation.
Treatment of the accelerated phase and blast crisis of the disease is more difficult. In accelerated phase, hydroxycarbamide (hydroxyurea) can be an effective single agent; low-dose cytarabine can also be tried. When blast transformation occurs, the type of blast cell should be ascertained by cytochemical and immunological techniques. If lymphoblastic, the response to appropriate treatment (see p. 932) is better than if myeloblastic. Response to treatment for the latter is very poor. There is a strong case for supportive therapy only, particularly in older patients.
Initab mesylate (STI 571)
This agent is an inhibitor of the BCR-abl tyrosine kinase. Early trials have demonstrated excellent activity in chronic phase disease, with over 50% achieving Ph-chromosome negativity. It is also very active in interferon-resistant cases, in accelerated phase and blast crisis. This is a very promising new agent and trials are in progress to define its use in chronic phase disease and as an adjunct to transplantation.
Prognosis
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Patients treated conventionally have a 15% risk of death in the first 12 months, and thereafter an annual risk of 20-25%. Median survival is about 45 months with chemotherapy, but 65 months with interferon; patients who have a significant reduction in the Ph chromosome with interferon do best. Patients receiving an allograft from a sibling early in chronic phase have an 80% chance of prolonged survival.
Philadelphia chromosome-negative chronic myeloid leukaemia
About half of these patients have the classical molecular abnormality (BCR-positive) without a demonstrable Ph chromosome. They behave as Ph chromosome-positive patients and they should be managed in the same way. The remainder (BCR-negative) tend to be older, mostly males, with lower platelet counts and higher absolute monocyte counts, and respond poorly to treatment. Median survival is less than 1 year.
CHRONIC LYMPHOCYTIC LEUKAEMIA
This is the most common variety of leukaemia, accounting for 30% of cases. The male to female ratio is 2:1 and the majority of patients are over the age of 45, with a peak at 65. In this disease B lymphocytes, which would normally respond to antigens by transformation and antibody formation, fail to do so. An ever-increasing mass of immunoincompetent cells accumulate, to the detriment of immune function and normal bone marrow haematopoiesis. The receptor profile of the lymphocytes demonstrates a B-cell type of disease. The light chains of immunoglobulins produced by these B cells tend to be either kappa or lambda in type, indicating in the majority of cases a monoclonal expansion of cells. The B cells of chronic lymphocytic leukaemia characteristically express a T-cell antigen, CD5.
Clinical features
The onset is very insidious. Indeed, in around 25% of patients the diagnosis is made incidentally. Presenting problems may be anaemia, painless lymphadenopathy or splenomegaly; infections may be present at the time of diagnosis but often occur later in the progress of the disease. Herpes zoster (shingles) is more common.
Investigations
Peripheral blood examination usually shows a mild but gradually increasing anaemia. Haemolytic anaemia may occur and is usually warm autoimmune in type (see p. 924). In the majority of patients the leucocyte count is between 50 and 200 × 109/l, although it may occasionally be greatly increased, up to 1000 × 109/l. About 95% or more of these cells are mature lymphocytes. Bone marrow examination by aspirate and trephine may be helpful not only in the diagnosis of cases with a low white count but also for prognosis. Patients with diffuse marrow involvement tend to do worse. Chromosome analysis can be helpful; cases with trisomy 12, the most common abnormality, or 13q abnormalities are associated with a poorer prognosis. The platelet count may be low due to marrow failure or an immune destruction. Estimations of total proteins and immunoglobulin levels should be undertaken to establish the degree of immunosuppression which is common and progressive. In some patients there may be a monoclonal band. Urate levels are seldom raised because cell turnover is low.
19.37 STAGING OF CHRONIC LYMPHOCYTIC LEUKAEMIA
Clinical stage A
No anaemia or thrombocytopenia and less than three areas of lymphoid enlargement

Clinical stage B
No anaemia or thrombocytopenia, with three or more involved areas of lymphoid enlargement

Clinical stage C
Anaemia and/or thrombocytopenia, regardless of the number of areas of lymphoid enlargement


Staging
The disease may be staged according to the criteria given in Box 19.37.
Management
Treatment depends upon the stage of the disease:
Clinical stage A. No specific treatment is required. Life expectancy is normal in older patients. The patient should be reassured.
Clinical stage B. Chemotherapy with chlorambucil may be initiated in symptomatic patients (see below). Local radiotherapy to lymph nodes may be given if causing discomfort.
Clinical stage C. Anaemia may require transfusion with red cell concentrate. Bone marrow failure, if present, is treated initially with prednisolone, 40 mg daily for 2-4 weeks. A degree of bone marrow recovery is usually achieved.

Cytotoxic therapy
Chlorambucil, 5 mg orally daily, over long periods with dose adjustment according to blood counts, will reduce the abnormal lymphocyte mass and produce symptomatic improvement in most patients. Alternatively, chlorambucil may be given as intermittent high-dose therapy, 0.4 mg/kg every 2 weeks, incrementing by 0.1 mg/kg until the maximum tolerated dose is reached. This is continued until the desired therapeutic effect is obtained. In stage C disease there is some evidence that more aggressive combination chemotherapy might be beneficial in terms of disease-free but not overall survival. Fludarabine, a synthetic nucleoside, appears to be the most active drug and is now available orally.
Radiotherapy
Total body irradiation using very small doses spread over 5 weeks in 10 fractions is effective and well tolerated, especially by the elderly. Local radiotherapy may be used to reduce spleen size or treat local problems due to the disease.
Infections
These must be vigorously treated. Recurrent viral or non-specific infections (often respiratory) sometimes respond to immunoglobulin replacement therapy.
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Splenectomy
This may be required to treat autoimmune haemolytic anaemia or gross splenic enlargement.
Prognosis
The overall median survival for patients with chronic lymphocytic leukaemia is about 6 years. Clinical stage A patients have a normal life expectancy but stage C patients have a median survival of between 2 and 3 years. Approximately 50% of patients die of infection and 30% of causes unrelated to chronic lymphocytic leukaemia. Unlike chronic myeloid leukaemia, chronic lymphocytic leukaemia rarely transforms to an aggressive high-grade lymphoma, so-called Richter's transformation.
PROLYMPHOCYTIC LEUKAEMIA
This is a variant of chronic lymphatic leukaemia found mainly in males over the age of 60; 25% of cases are of the T-cell variety. There is massive splenomegaly with little lymphadenopathy and a very high leucocyte count, often in excess of 400 × 109/l; the characteristic cell is a large lymphocyte with a prominent nucleolus. Treatment is generally unsuccessful and the prognosis very poor. Leucopheresis, splenectomy and chemotherapy may be tried.
HAIRY CELL LEUKAEMIA
This is a rare chronic lymphoproliferative B-cell disorder. The male to female ratio is 6:1 and the median age at diagnosis is 50. Presenting symptoms are generally those of ill health and recurrent infections. Splenomegaly occurs in 90% but lymph node enlargement is unusual.
Severe neutropenia, monocytopenia and the characteristic hairy cells in the blood and bone marrow are typical. These cells usually type as B lymphocytes but characteristically express CD25 and CD103. A characteristic test is the demonstration that the acid phosphatase staining reaction in the cells is resistant to the action of tartrate. The neutrophil alkaline phosphatase score is almost always very high.
Over recent years a number of treatments have been shown to produce long-lasting remissions. Cladribine and deoxycoformycin are effective in producing long periods of disease control.
MYELODYSPLASTIC SYNDROME (MDS)
This syndrome consists of a group of clonal disorders which represent steps in the progression to the development of leukaemia. It is characterised by macrocytosis, variable cytopenia, hypogranular neutrophils with nuclear hyper- or hyposegmentation, and a hypercellular marrow with dysplastic changes in all three cell lines. The syndrome is being recognised more frequently; its exact incidence is uncertain but it is thought to be more common than acute leukaemia. Usually the disease presents as a primary problem in elderly patients, although it may occur as a secondary complication of treatment for malignant disease in younger patients. The syndrome comprises the following conditions:
refractory anaemia
refractory anaemia with ring sideroblasts (sideroblastic anaemia)
chronic myelomonocytic leukaemia
refractory anaemia with excess of blasts (RAEB)
refractory anaemia with excess of blasts in transformation (RAEB-t).

Diagnosis
The diagnosis should be considered in any patient with a cytopenia and the dysplastic features indicated above. A marrow aspiration should be performed, which is usually hypercellular with evidence of dysplasia. Blast cells may be increased but do not reach the 30% level which indicates acute leukaemia. Chromosome analysis frequently reveals abnormalities, particularly of chromosomes 5 or 7.
Management
Treatment is unsatisfactory. Transfusion of blood and platelets and treatment of infection are required for all. Aggressive antileukaemic therapy is used in young patients with excess blasts in the marrow. Low-dose cytarabine (20 mg subcutaneously, 12-hourly) produces occasional remission but this is short-lived. Allogeneic transplantation should be considered in younger patients who have a donor, with the best results seen in patients with refractory anaemias without excess blasts.
Prognosis
The first two conditions listed above are relatively chronic disorders, while the latter three show a more aggressive course with a tendency to terminate as acute myeloid leukaemia. Thus patients with refractory and sideroblastic anaemia may survive for years but prognosis in the other three conditions is measured usually in months.
LYMPHOMAS
These neoplasms are divided clinically and histologically into Hodgkin's and non-Hodgkin's lymphoma. The majority are of B-cell origin. Non-Hodgkin's lymphomas are divided into low-grade and high-grade tumours on the basis of their proliferation rate. High-grade tumours are dividing rapidly, have only been present for a matter of weeks before diagnosis and may be life-threatening. Low-grade tumours are dividing slowly, may have been present for many months before diagnosis and behave in an indolent fashion.




Integration link: Normal lymph nodes

Taken from Robbins & Cotran's Pathologic Basis of Disease 7e




HODGKIN'S DISEASE (see Box 19.38)
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19.38 EPIDEMIOLOGY AND AETIOLOGY OF HODGKIN'S DISEASE
Incidence
Approximately 4 new cases/100 000 population/year
Sex ratio
Slight male excess (1.5:1)
Age
Median age 31 years; first peak in 20-35 and second peak in 50-70 age group
Aetiology
Unknown. More common in patients from well-educated backgrounds and small families. Three times more likely with a past history of glandular fever but no causal link to Epstein-Barr virus infection proven




Figure 19.30 Hodgkin's disease showing typical Reed-Sternberg cell.
19.39 PATHOLOGICAL CLASSIFICATION OF HODGKIN'S LYMPHOMA
Lymphocyte-predominant
Nodular sclerosing
Mixed cellularity
Lymphocyte-depleted


The histological hallmark of Hodgkin's disease is the presence of Reed-Sternberg cells, which are large malignant lymphoid cells of B-cell origin (see Fig. 19.30). They are often present in only small numbers but surrounded by large numbers of reactive normal T cells, plasma cells and eosinophils. Four types of Hodgkin's disease are recognised from the appearance of the Reed-Sternberg cells and surrounding reactive cells (see Box 19.39). The nodular sclerosing type accounts for the initial peak in young patients and is more common in women. Mixed cellularity is more common in the elderly peak. Lymphocyte-predominant Hodgkin's disease is now recognised as a low-grade B-cell non-Hodgkin's lymphoma. Lymphocyte-depleted Hodgkin's disease is rare and probably represents a T-cell non-Hodgkin's lymphoma.




Integration link: Hodgkin's Lymphoma

Taken from General & Systematic Pathology 4e




Clinical features
There is painless rubbery lymphadenopathy, usually in the neck or supraclavicular fossae; the lymph nodes may fluctuate in size. Young patients with nodular sclerosing disease may have large mediastinal masses which are surprisingly asymptomatic but may cause dry cough and some breathlessness. Isolated subdiaphragmatic nodes occur in less than 10% at diagnosis. Hepatosplenomegaly may be present but does not always indicate disease. Spread is contiguous from one node to the next and extranodal disease, such as bone, brain or skin involvement, is rare.
Investigations
Full blood count. This may be completely normal. A normochromic, normocytic anaemia may be present and, together with lymphopenia, is a bad prognostic factor. An eosinophilia or a neutrophilia may be present.
ESR. This may be raised.
Renal function. Ensure this is normal prior to treatment.
Liver function. This may be abnormal in the absence of disease or reflect hepatic infiltration. An obstructive pattern may be caused by nodes at the porta hepatis.
LDH. Raised levels are an adverse prognostic factor.
Chest radiograph. This may show a mediastinal mass.
CT. Scan chest and abdomen to permit staging (see Box 19.40). This investigation has replaced laparotomy. Bulky disease greater than 10 cm in a single node mass is an adverse prognostic feature.
Lymph node biopsy. This may be undertaken surgically or by percutaneous needle biopsy under radiological guidance (see Fig. 19.31).

19.40 CLINICAL STAGES OF HODGKIN'S DISEASE (ANN ARBOR CLASSIFICATION)
Stage Definition
I Involvement of a single lymph node region (I) or extralymphatic site (IAE)
II Involvement of two or more lymph node regions (II) or an extralymphatic site and lymph node regions on the same side of (above or below) the diaphragm (IIE)
III Involvement of lymph node regions on both sides of the diaphragm with (IIIE) or without (III) localised extralymphatic involvement or involvement of the spleen (IIIS) or both (IIISE)
IV Diffuse involvement of one or more extralymphatic tissues, e.g. liver or bone marrow
A No systemic symptoms
B Weight loss, drenching sweats


The lymphatic structures are defined as the lymph nodes, spleen, thymus, Waldeyer's ring, appendix and Peyer's patches
Management
Treatment options include radiotherapy, chemotherapy or a combination of the two (see Box 19.41).
Radiotherapy
Good results are obtained in localised stage IA or stage IIA disease with no adverse prognostic features. Fertility is usually preserved after radiotherapy. Careful planning is required to limit the doses delivered to normal tissues. Women receiving breast irradiation during the treatment of chest disease have an increased risk of breast cancer and should be placed on a screening programme. Patients continuing to smoke after lung irradiation are at particular risk of lung cancer.
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Figure 19.31 CT-guided percutaneous needle biopsy of retroperitoneal nodes involved by lymphoma.
19.41 THERAPEUTIC GUIDELINES FOR HODGKIN'S LYMPHOMA
Indications for radiotherapy
Stage I disease
Stage IIA disease with three or fewer areas involved
After chemotherapy to sites where there was originally bulk disease
To lesions causing serious pressure problems

Indications for chemotherapy
All patients with B symptoms
Stage II disease with more than three areas involved
Stage III and stage IV disease


Chemotherapy
All other patients are treated initially with chemotherapy. The regimen in Box 19.42 is widely used in the UK. This regimen was developed from the original MOPP regimen (nitrogen mustard, vincristine, prednisolone and procarbazine) with drugs substituted to reduce vomiting, alopecia and long-term toxicity. Over 80% of patients will respond to this combination therapy, with drugs delivered on an outpatient basis every 3-4 weeks for a total of 6-8 cycles. Routine support with growth factors such as G-CSF is not required. Treatment response is assessed clinically and by repeat CT.
19.42 THE ChIVPP REGIMEN FOR HODGKIN'S LYMPHOMA
Drug Dose
Chlorambucil 6 mg/m2 (up to 10 mg total) days 1-14 orally
Vinblastine 6 mg/m2 (up to 10 mg total) days 1 and 8 i.v.
Procarbazine 100 mg/m2 days 1-14 orally
Prednisolone 40 mg/m2 days 1-14 orally

This type of chemotherapy carries a high risk of inducing permanent infertility in men; adequate counselling and sperm storage must be offered at diagnosis. The risk of infertility is lower for women but advice about obtaining ovarian tissue before starting treatment should be discussed as appropriate. Premature menopause may result from the treatment and hormone replacement therapy should be discussed with the patient. Steroids can cause avascular necrosis of bone, particularly the femoral head. Myelodysplasia and acute leukaemia can occur 5-10 years after alkylating therapy but the incidence is less than 5%.
Combined modality therapy
Radiotherapy may be given to the original sites of bulky disease after treatment by chemotherapy to reduce the risk of relapse. This form of treatment carries the greatest risk of long-term complications.
Prognosis
Over 90% of patients with stage IA disease are cured by radiotherapy alone. Patients with stage IIA disease have a reduced cure rate from radiotherapy. Approximately 70% of patients treated with chemotherapy are cured. The 15% of patients who fail to respond to initial chemotherapy have a poor prognosis but some may achieve long-term survival after high-dose therapy and autologous stem cell rescue. Patients relapsing after local radiotherapy have a good cure rate after subsequent chemotherapy but with an increased risk of long-term toxicity. Patients relapsing within a year of initial chemotherapy have a good salvage rate with high-dose therapy and autologous stem cell rescue. Patients relapsing after 1 year may obtain long-term survival with further chemotherapy.
NON-HODGKIN'S LYMPHOMA (see Box 19.43)
Non-Hodgkin's lymphoma (NHL) represents a monoclonal proliferation of lymphoid cells and may be of B-cell (70%) or T-cell (30%) origin. The incidence of these tumours has increased by 50% in the last 10-20 years in the Western world. At the same time treatment outcomes have not improved and hence mortality rates from NHL have increased.
The difficulties of establishing a reproducible and clinically useful histological classification of NHL are reflected in the large number of classification systems to date. A recently developed system, the REAL classification, has introduced phenotypic, molecular and cytogenetic information which, together with morphology, has allowed reproducible definition of clinical disease entities. Clinically, the most important factor is grade, which is a reflection of proliferation rate. High-grade NHL has high proliferation rates, rapidly produces symptoms, is fatal if untreated, but is potentially curable. Low-grade NHL has low proliferation rates, may be asymptomatic for many months before presentation, runs an indolent course, but is not curable by conventional therapy. Overall, about one-third of cases are high-grade diffuse large-cell NHL and a further third are low-grade follicular NHL (see Fig. 19.32).




Integration link: Non-Hodgkin's lymphoma

Taken from General & Systematic Pathology 4e




Clinical features
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Figure 19.32 Non-Hodgkin's lymphoma. A (Low-grade) follicular or nodular pattern. B (High-grade) diffuse pattern of histology.
19.43 EPIDEMIOLOGY AND AETIOLOGY OF NON-HODGKIN'S LYMPHOMA
Aetiology
No single causative abnormality described
Viruses
Lymphoma is a late manifestation of HIV infection (see p. 127)
Specific lymphoma types are associated with EBV, human herpes virus 8 (HHV8) and HTLV infection
Bacteria
The development of gastric lymphoma can be associated with Helicobacter pylori infection
Genetics
Some lymphomas are associated with specific chromosome lesions; the t(14:18) translocation in follicular lymphoma results in the dysregulated expression of the bcl-2 gene product which inhibits apoptotic cell death
Immunology
Lymphoma occurs in congenital immunodeficiency states and in immunosuppressed patients post-organ transplantation

Incidence
12 new cases/100 000 people/year
Sex ratio
Slight male excess
Age
Median age 65-70 years


Compared to Hodgkin's disease, NHL is often widely disseminated at presentation. Patients present with lymph node enlargement which may be associated with systemic upset: weight loss, sweats, fever and itching. Hepatosplenomegaly may be present. Extranodal disease is more common in NHL, with involvement of the bone marrow, gut, thyroid, lung, skin, testis, brain and, more rarely, bone. Extranodal disease is more common in T-cell disease, whilst bone marrow involvement is more common in low-grade (50-60%) than high-grade (10%) disease. The same staging system is used for both Hodgkin's disease and NHL but NHL is more likely to be stage III or IV at presentation. Compression syndromes may occur; gut obstruction, ascites, superior vena caval obstruction and spinal cord compression may all be presenting features.
Investigations
These are as for Hodgkin's disease but in addition the following should be performed:
Routine bone marrow aspirate and trephine.
Immunophenotyping of surface antigens to distinguish T- and B-cell tumours. This may be done on blood, marrow or nodal material.
Immunoglobulin determination. Some lymphomas are associated with IgG or IgM paraproteins which serve as markers for treatment response.
Measurement of uric acid levels. Some very aggressive high-grade NHL is associated with very high urate levels, which can precipitate renal failure when treatment is started.
HIV testing. This may be appropriate if risk factors are present (see p. 109).

Management
The factors listed in Box 19.44 will influence the choice of therapy in NHL.
Low-grade NHL
19.44 FACTORS DETERMINING MANAGEMENT STRATEGY IN NON-HODGKIN'S LYMPHOMA
Age of the patient
Degree of concomitant disease
Histological grade
Staging of the disease
HIV status
Patient's wishes


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Asymptomatic patients may not require therapy. Indications for treatment include marked systemic symptoms, lymphadenopathy causing discomfort or disfigurement, bone marrow failure or compression syndromes. The options are:
Radiotherapy. This can be used for localised stage I disease, which is rare.
Chemotherapy. This is the mainstay of therapy. Most patients will respond to oral therapy with chlorambucil, which is well tolerated. More intensive intravenous chemotherapy in younger patients produces better quality of life but no survival benefit. Neither therapy will cure patients.
Monoclonal antibody therapy. Humanised monoclonal antibodies can be used to target surface antigens on tumour cells and deliver cytotoxic drugs or radiotherapy, or induce tumour cell apoptosis directly. Such antibodies targeted to low-grade lymphoma cells have been shown to induce durable clinical responses in up to 60% of patients. Synergistic effects are seen when treatment is combined with standard chemotherapy, and trials are under way to define their optimal usage.
Transplantation. Studies of autologous stem cell transplantation are in progress. Such high-dose therapy improves disease-free survival but longer follow-up is awaited before conclusions can be made about cure.

High-grade NHL
Patients with high-grade NHL need treatment at initial presentation:
Chemotherapy. The majority (> 90%) will need intravenous combination chemotherapy. The CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) remains the mainstay of therapy.
Radiotherapy. A few stage I patients without bulky disease may be suitable for radiotherapy. Radiotherapy is indicated to a residual localised site of bulk disease after chemotherapy, and for spinal cord and other compression syndromes.
Transplantation. Autologous stem cell transplantation appears to benefit some patients at first relapse, with cure rates of 50% compared to < 10% with chemotherapy alone. Lymphoblastic lymphoma is a very aggressive lymphoma which predominantly affects young adults, who should be considered candidates for allogeneic or autologous transplantation after response to initial chemotherapy.
Monoclonal antibody therapy. Humanised monoclonal antibodies can be used as described above. In preliminary studies in elderly patients such antibodies, when combined with CHOP chemotherapy, have dramatically improved overall survival. Mature data are awaited but are expected to confirm this benefit.

EBM
RELAPSED HIGH-GRADE NON-HODGKIN'S LYMPHOMA-role of autologous bone marrow transplantation
'With a median follow-up of 63 months, a phase III RCT comparing conventional salvage chemotherapy with the same consolidated by an autologous bone marrow transplant in 215 patients with relapsed high-grade lymphoma demonstrated a very significant benefit for event-free (46% vs 12%) and overall survival (54% vs 42%) in favour of bone marrow transplantation. This study established the role of transplantation in relapsed, chemosensitive high-grade lymphoma.'
Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplant as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995; 333:1540-1545.
Further information: www.lymphoma.org.uk

Prognosis
Low-grade NHL
These tumours run an indolent remitting and relapsing course, with an overall median survival of 10 years. Transformation to a higher-grade NHL is associated with poor survival.
High-grade NHL
Some 80% of patients respond initially to therapy but only 35% will have disease-free survival at 5 years. Relapse is associated with a poor response to further chemotherapy (< 10% 5-year survival), but in patients under 65 years stem cell transplantation improves survival.
Increasing age, advanced stage, concomitant disease, a raised LDH and T-cell phenotype predict poor outcome.
PARAPROTEINAEMIAS
A gammopathy refers to over-production of one or more classes of immunoglobulin. This may be polyclonal in association with inflammation such as infection, sarcoidosis or Sjögren's syndrome. Alternatively, a monoclonal increase in a single immunoglobulin class may occur in association with normal or reduced levels of the other immunoglobulins. Monoclonal proteins occur as a feature of myeloma, lymphoma and amyloidosis, in connective tissue disease such as rheumatoid arthritis or polymyalgia rheumatica, in infection such as HIV and in solid tumours. In addition, they may be present with no underlying disease. Paraproteins of the IgA, IgM and IgG3 subclasses can polymerise and may be associated with clinical hyperviscosity.
MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (MGUS)
A paraprotein is present in the blood but with no other features of myeloma or disease.
Clinical features
Patients are usually asymptomatic. MGUS is present in 3% of the population over the age of 65 years and 10% of hospital inpatients of a similar age.
Investigations
Routine blood count and biochemistry are normal.
The paraprotein is usually present in a small amount with no associated immune paresis.
There are no lytic lesions on the bones.
The bone marrow may have increased plasma cells but these are usually less than 10%.

Prognosis
Long-term follow-up is required to monitor clinical symptoms and paraprotein levels since approximately 20% of patients develop myeloma and 10% solid tumours.
WALDENSTRÖM'S MACROGLOBULINAEMIA
This is a low-grade lymphoplasmacytoid lymphoma associated with an IgM paraprotein causing clinical features of hyperviscosity syndrome. It is a rare tumour occurring in the elderly and affects a slight excess of males.
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Patients classically present with features of hyperviscosity such as nosebleeds, bruising, confusion and visual disturbance. However, presentation may be with anaemia, systemic symptoms, splenomegaly or lymphadenopathy. Patients are found on investigation to have an IgM paraprotein associated with a raised plasma viscosity. The bone marrow has a characteristic appearance, with infiltration of lymphoid cells and prominent mast cells.
Management
Severe hyperviscosity and anaemia may necessitate plasmapheresis to remove IgM and make blood transfusion possible. Treatment with oral agents such as chlorambucil is effective but rather slow and fludarabine may be more active in this disease. The median survival is 5 years.
MULTIPLE MYELOMA
This is a malignant proliferation of plasma cells. Normal plasma cells are derived from B cells and produce immunoglobulins which contain heavy and light chains. Normal immunoglobulins are polyclonal, which means that a variety of heavy chains are produced and each may be of kappa or lambda light chain type. In myeloma plasma cells produce immunoglobulin of a single heavy and light chain, a monoclonal protein commonly referred to as a paraprotein. In some cases only light chain is produced and this appears in the urine as Bence Jones proteinuria. The frequency of different paraprotein types in myeloma is shown in Box 19.45.
Pathology
19.45 CLASSIFICATION OF MULTIPLE MYELOMA
Type of paraprotein Relative frequency (%)
IgG 55
IgA 21
Light chain only 22
Others (D, E, non-secretory) 2

19.46 MULTIPLE MYELOMA: THE RELATIONSHIP BETWEEN PATHOLOGY, THE EFFECT OF THE DISEASE PROCESS AND SYMPTOMS
Pathology Effect Symptoms
Marrow involvement with malignant plasma cells Bone erosion due to stimulation of osteoclasts Pain
Pathological fracture Severe local pain
Hypercalcaemia Lethargy, thirst
Bone marrow failure: anaemia Tiredness
Excess production of paraprotein and light chains Renal damage None until uraemic
Increased blood viscosity None until severe, then blurred vision, headache, vertigo, stupor, coma
Amyloidosis Nephrotic syndrome
Reduction in number of normal plasma cells Impaired immune function Susceptibility to infection, particularly respiratory

Although a small number of malignant plasma cells are present in the circulation, the majority are present in the bone marrow. The malignant plasma cells produce cytokines, which stimulate osteoclasts and result in net bone absorption. The resulting lytic lesions cause bone pain, fractures and hypercalcaemia. Marrow involvement can result in anaemia or pancytopenia (see Box 19.46). The aetiology of this condition is unknown.
Clinical features
The incidence of myeloma is 4/100 000 new cases per annum, with a male:female ratio of 2:1. The median age of diagnosis is 60-70 years and the disease is more common in Afro-Caribbeans. The clinical features are demonstrated in Figure 19.33.
Investigations (see Box 19.47)
19.47 POINTS TO NOTE IN THE DIAGNOSIS OF MYELOMA
In the absence of fractures or bone repair the plasma alkaline phosphatase and the bone scan are normal
Serum ß2-microglobulin estimations may provide a useful assessment of prognosis
The absence of immune paresis (reduction of normal immunoglobulin levels) should cast doubt on the diagnosis
Only about 5% of patients with an ESR persistently above 100 mm/hr have myeloma


The diagnosis of myeloma requires two of the following criteria:
marrow plasmacytosis
serum and/or urinary paraprotein
skeletal lesions.
Investigations are listed in Box 19.48.
Management
If patients are asymptomatic, treatment may not be required. Otherwise, treatment consists of the following:
Immediate support
High fluid intake to treat renal impairment and hypercalcaemia.
Analgesia for bone pain.
Bisphosphonates for hypercalcaemia (see p. 223).
Allopurinol to prevent urate nephropathy.
Plasmapheresis, which may be necessary for hyperviscosity.

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Figure 19.33 Clinical manifestations of multiple myeloma.
19.48 RATIONALE FOR INVESTIGATIONS IN MULTIPLE MYELOMA
Problem Investigations
Renal function Urea and electrolytes, creatinine, urate
Presence of hypercalcaemia Blood calcium
Albumin
Presence of bone fractures Radiographs
Blood alkaline phosphatase
Isotope bone scan
Degree of immune paresis Plasma immunoglobulins
Degree of bone marrow failure Blood counts
Reticulocyte count
Degree of haemostasis Bleeding time
Coagulation screen
Blood viscosity Plasma viscosity
Disease activity Serum
ß2-microglobulin

Chemotherapy
In older patients, melphalan is an effective oral therapy, whilst in younger patients treatment with intravenous agents may improve response. Higher doses of intravenous melphalan appear to be well tolerated even in patients over 65 years and may produce better clinical responses.
EBM
MYELOMA-role of oral melphalan
'RCTs suggest that melphalan with or without prednisolone is the initial treatment of choice for most patients with myeloma in whom high-dose therapy is not planned. Treatment should continue until the paraprotein level is stable for 3 months. Cyclophosphamide is suitable for those patients not eligible for melphalan. There is no convincing evidence for a survival benefit of combination chemotherapy.'
Myeloma Trialists' Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomised trials. J Clin Oncol 1998; 16:3832-3842.
Medical Research Council's Working Party on Leukaemia in Adults. Report on the second myelomatosis trial after five years of follow-up. Br J Cancer 1980; 42:813-822.
Further information: www.ukmf.org.uk

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Treatment is administered until paraprotein levels have stopped falling. This is termed 'plateau phase' and may last for weeks or years. Successive relapses respond less well to treatment.
Radiotherapy
This is effective for localised bone pain not responding to simple analgesia and for pathological fractures. It is also useful for the emergency treatment of spinal cord compression complicating extradural plasmacytomas.
Transplantation
Standard treatment does not cure myeloma. Stem cell autotransplants improve quality of life and prolong survival. All patients under 65 years should be offered intravenous chemotherapy to maximum response and then an autologous stem cell transplant. Allogeneic bone marrow transplantation may cure some patients and should be considered in those under the age of 55 years with a sibling donor. Reduced-intensity allografting may improve outcomes by reducing transplant-related mortality and extending the upper age limit.
EBM
MULTIPLE MYELOMA-role of autologous bone marrow transplantation
'An RCT in 200 previously untreated myeloma patients compared conventional intravenous chemotherapy with the same consolidated by an autologous bone marrow transplant. The study demonstrated a highly significant benefit for disease-free survival (28% vs 10%) and overall survival (52% vs 12%) at 5 years in favour of the transplanted group. This study established the role of autologous transplantation for myeloma patients under the age of 65 years.'
Attal M, Harrousseau JL, Stoppa AM, et al. A prospective randomised trial of autologous bone marrow transplant and chemotherapy in myeloma. N Engl J Med 1996; 335:91-97.
Further information: www.ukmf.org

Bisphosphonates
Chronic bisphosphonate therapy reduces bone pain and skeletal events. These drugs protect bone and may cause apoptosis of malignant plasma cells.
Thalidomide
This drug has anti-angiogenic effects against the blood vessels supplying tumours and also has immunomodulatory effects. At low doses it has been shown to be effective against refractory myeloma and, when combined with dexamethasone, response rates over 50% are described. Trials are currently planned to investigate the use of thalidomide as an adjunct to other treatments earlier in the natural history of the disease. It can cause somnolence, constipation and a peripheral neuropathy; it is vital that females of childbearing age use adequate contraception.
Prognosis (see Box 19.49)
The median survival of patients receiving standard treatment is approximately 40 months. Autotransplantation improves survival and quality of life by slowing the rate of progression of bone disease. Less than 5% of patients survive longer than 10 years with standard treatment.
19.49 POOR PROGNOSTIC FEATURES AT DIAGNOSIS IN MULTIPLE MYELOMA
A haemoglobin concentration of less than 7 g/dl
Severe hypoalbuminaemia
Intractable renal failure
Thrombocytopenia
High ß2-microglobulin levels
Plasma cell leukaemia


APLASTIC ANAEMIA
PRIMARY IDIOPATHIC ACQUIRED APLASTIC ANAEMIA
This is a rare disorder in developed countries, with 3-6 new cases per million population per annum; the disease is much more common in certain other parts of the world-for example, China. The basic problem is failure of the pluripotent stem cells, producing hypoplasia of the marrow elements. An autoimmune mechanism may be responsible in a proportion of cases and it may occur in association with pregnancy. Careful enquiry should be made with regard to exposure to drugs, chemicals and radiation. A history of viral illness, particularly hepatitis, may be important.
Clinical features
A full blood count demonstrates pancytopenia, reticulocytopenia and often macrocytosis. The bone marrow should be examined by aspiration and trephine.
Management
All patients will require blood product support and aggressive management of infection. The curative treatment for young (< 20 years old) patients with severe idiopathic aplastic anaemia is allogeneic bone marrow transplantation if there is an available donor. Those with a compatible sibling donor should proceed to transplantation as soon as possible. Successful pre-transplant conditioning can be achieved with cyclophosphamide alone. In older patients immunosuppressive therapy with ciclosporin and antithymocyte globulin gives equivalent results. The prognosis of severe aplastic anaemia managed with supportive therapy only is poor and more than 50% of patients die, usually in the first year. However, a survival of over 60% has been reported after bone marrow transplantation in young patients and similar results can be achieved with immunosuppressive regimens involving antithymocyte globulin.
SECONDARY APLASIA
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19.50 CAUSES OF ACQUIRED APLASTIC ANAEMIA
Radiation
Viral hepatitis
Pregnancy
Paroxysmal nocturnal haemoglobinuria
Drugs
Cytotoxic drugs, idiosyncratic
Antibiotics-chloramphenicol, sulphonamides
Antirheumatic agents-penicillamine, gold, phenylbutazone, indometacin
Antithyroid drugs
Anticonvulsants
Immunosuppressives-azathioprine
Chemicals
Benzene toluene solvent misuse-glue-sniffing
Insecticides-chlorinated hydrocarbons (DDT), organophosphates and carbamates


Causes of this condition are listed in Box 19.50. It is not practical to list all the drugs which have been suspected of causing aplasia but it is important to investigate the reported side-effects of all drugs taken over the preceding months. In some instances the cytopenia is more selective and affects only one cell line, most often the neutrophils. Frequently, this is an incidental finding unassociated with ill health. It probably has an immune basis but this is difficult to prove. The clinical features and methods of diagnosis are the same as for primary idiopathic aplastic anaemia. An underlying cause should be treated or removed but otherwise management is as for the idiopathic form.
ISSUES IN OLDER PEOPLE
HAEMATOLOGICAL MALIGNANCY
The median age of most haematological malignancies is approximately 70 years.
Haematological malignancy in elderly patients is more likely to be associated with poor-risk biological features such as adverse cytogenetics or the presence of a multidrug resistance phenotype.
Age is an independent prognostic variable in myeloma, acute leukaemia and aggressive lymphoma.
Elderly patients tolerate chemotherapy less well, are more likely to have antecedent cardiac, pulmonary or metabolic problems, tolerate systemic infection less well and metabolise cytotoxic drugs differently.
For those patients who tolerate treatment well, however, cure rates similar to those in younger patients can be achieved.
The decision to treat should not be based on chronology but on the individual's biological status, the level of social support available, the patient's wishes and those of the immediate family.


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Home > 2 SYSTEM-BASED DISEASES > 19 Blood disorders > MYELOPROLIFERATIVE DISORDERS
MYELOPROLIFERATIVE DISORDERS
These make up a group of chronic conditions characterised by clonal proliferation of marrow erythroid precursors (polycythaemia rubra vera, PRV), megakaryocytes (essential thrombocythaemia and myelofibrosis) or myeloid cells (chronic myeloid leukaemia). Although the majority of patients are classifiable as having one of these disorders, some have overlapping features. Furthermore, there is often progression from one to another, e.g. PRV to myelofibrosis.
Chronic myeloid leukaemia is considered in detail elsewhere (see p. 935).
MYELOFIBROSIS
Myelofibrosis is characterised by bone marrow fibrosis, extramedullary haematopoiesis (blood cell formation outside the bone marrow) and a leucoerythroblastic blood picture. The marrow is initially hypercellular, with an excess of abnormal megakaryocytes, which release growth factors, e.g. platelet-derived growth factor, to the marrow microenvironment, resulting in a reactive proliferation of fibroblasts. As the disease progresses, the marrow becomes fibrosed.
Most patients with myelofibrosis present over the age of 50 years with lassitude, weight loss and night sweats. The spleen can be massively enlarged due to extramedullary haematopoiesis and splenic infarcts may occur.
The characteristic blood picture is a leucoerythroblastic anaemia, with circulating immature red blood cells (reticulocytes and nucleated red blood cells) and granulocyte precursors. The red cells are shaped like teardrops (teardrop poikilocytes) and giant platelets may be seen in the blood. The white count varies from low to moderately high and the platelet count may be high, normal or low. Urate levels may be high due to increased cell breakdown and folate deficiency is common. The marrow is often difficult to aspirate and a trephine biopsy shows an excess of megakaryocytes, increased reticulin and fibrous tissue replacement.
Median survival is 4 years from diagnosis but ranges from 1 year to over 20 years. Treatment is directed at control of symptoms, e.g. red cell transfusions. Folic acid should be given to prevent deficiency. Cytotoxic therapy with hydroxycarbamide (hydroxyurea) may help control spleen size, the white cell count or systemic symptoms. Splenectomy may be required if the grossly enlarged spleen is causing distress or significant hypersplenism. Bone marrow transplantation may be considered for younger patients.
ESSENTIAL THROMBOCYTHAEMIA
The malignant proliferation of megakaryocytes results in a raised level of circulating platelets that are often dysfunctional. Prior to making a diagnosis of essential thrombocythaemia it is essential to exclude reactive causes of increased platelets (see p. 908). Patients present at a median age of 60 years with vascular occlusive or bleeding events or with an isolated raised platelet count. In most individuals the condition is chronic, with the platelet count gradually increasing. The risks are of microvascular and major vessel occlusion and haemorrhage. A very small percentage may transform to acute leukaemia and others to myelofibrosis.
Low-risk patients (age less than 40 years, platelet count less than 1000 × 109/l and asymptomatic, i.e. no bleeding or thrombosis) may require no treatment to reduce the platelet count. Aspirin therapy is often recommended. For those with a platelet count over 1000 × 109/l or those with symptoms, treatment to control platelets should be given. Agents include oral hydroxycarbamide (hydroxyurea) or anagrelide, an inhibitor of megakaryocyte maturation. Intravenous radioactive phosphorus (32P) may be useful in the elderly. Aspirin is particularly useful therapy for those with digital ischaemia.
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POLYCYTHAEMIA RUBRA VERA (PRV)
PRV occurs mainly in patients over the age of 40 years and presents either as an incidental finding of a high haemoglobin or with symptoms such as lassitude, loss of concentration, headaches, dizziness, blackouts, pruritus and epistaxis. Some present with manifestations of arterial peripheral vascular disease or a cerebrovascular accident. Patients are often plethoric and the majority have a palpable spleen at diagnosis. Thrombotic complications may occur and peptic ulceration is common, sometimes complicated by bleeding.
The diagnosis of polycythaemia is discussed on page 904. It requires a raised red cell mass, the absence of causes of secondary erythrocytosis, and palpable splenomegaly. The neutrophil and platelet counts are frequently raised, an abnormal karyotype may be found in the marrow, and in vitro culture of the marrow demonstrates autonomous growth in the absence of added growth factors.
Venesection gives prompt symptomatic relief. Between 400 and 500 ml of blood (less if the patient is elderly) are removed and the venesection is repeated every 5-7 days until the haematocrit is reduced to below 45%. Less frequent but regular venesection will maintain this until the haemoglobin remains reduced because of iron deficiency. The underlying myeloproliferation can be suppressed by hydroxycarbamide (hydroxyurea), interferon or radioactive phosphorus (5 mCi of 32P i.v.) for older patients. Treatment of proliferation may reduce vascular occlusion, control spleen size and reduce transformation to myelofibrosis. Radioactive phosphorus does increase the risk of transformation to acute leukaemia by six- to tenfold.
Median survival after diagnosis in treated patients exceeds 10 years. Some patients survive more than 20 years; however, cerebral or coronary events occur in up to 60% of patients. The disease may convert to another myeloproliferative disorder; for example, about 15% develop myelofibrosis. Acute leukaemia develops principally in those patients who have been treated with radioactive phosphorus.

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Home > 2 SYSTEM-BASED DISEASES > 19 Blood disorders > BLEEDING DISORDERS
BLEEDING DISORDERS
DISORDERS OF PRIMARY HAEMOSTASIS
Platelet functional disorders, thrombocytopenia and von Willebrand's disease, along with diseases affecting the vessel wall, may all result in failure of the initial platelet plug formation in primary haemostasis.
VESSEL WALL ABNORMALITIES
19.51 CAUSES OF NON-THROMBOCYTOPENIC PURPURA
Senile purpura
Factitious purpura
Henoch-Schönlein purpura (see p. 616)
Vasculitis (see p. 1040)
Paraproteinaemias
Purpura fulminans


Abnormalities of the vessel walls, both congenital and acquired-for example, vasculitis-may result in a propensity to purpuric lesions which are often slightly raised. Causes of non-thrombocytopenic purpura are listed in Box 19.51.
HEREDITARY HAEMORRHAGIC TELANGIECTASIA
Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited condition in which telangiectasia and small aneurysms are found on the fingertips, on the face, in the nasal passages, on the tongue, in the lung and in the gastrointestinal tract. A significant proportion of these patients develop larger pulmonary arteriovenous malformations (PAVMs) that cause arterial hypoxaemia due to a right-to-left shunt. These predispose the individual to paradoxical embolism that can result in stroke or cerebral abscess. All patients with HHT should be screened for PAVMs which, if found, should be ablated by percutaneous embolisation.
Patients present either with recurrent bleeds, particularly epistaxis, or with iron deficiency due to occult gastrointestinal bleeding. Treatment can be difficult because of the multiple bleeding points but regular iron therapy often allows the marrow to compensate for blood loss. Local cautery or laser therapy may prevent single lesions from bleeding. A variety of medical therapies have been tried-for example, oestrogens-but none has been found to be universally effective.
EHLERS-DANLOS DISEASE
Ehlers-Danlos disease is a congenital disorder of collagen synthesis in which the capillaries are poorly supported by subcutaneous collagen and ecchymoses are commonly seen.
PLATELET FUNCTIONAL DISORDERS
Even in the presence of a normal platelet count an individual may bleed if the function of the platelets is reduced. Congenital abnormalities include rare disorders of the membrane glycoproteins, e.g. thrombasthenia and Bernard-Soulier syndrome, or the presence of defective platelet granules, e.g. a deficiency of dense (delta) granules giving rise to storage pool disorders. Such patients exhibit bleeding of 'platelet type' (see p. 891) which varies in severity between patients, some presenting with frequent recurrent bleeds whilst others are only diagnosed because of excessive post-operative haemorrhage. Mild functional disorders, which only cause excessive bleeding after trauma or surgery, are often not diagnosed and are probably relatively common.
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19.52 DRUGS INHIBITING PLATELET FUNCTION
Dextran
Heparin
ß-blockers
NSAIDs
Aspirin
Indometacin
Phenylbutazone
Sulfinpyrazone
Antibiotics
Penicillins
Cephalosporins


Many drugs inhibit platelets. Aspirin and other NSAIDs inhibit platelet cyclo-oxygenase, preventing the conversion of arachidonic acid to the potent platelet aggregator thromboxane B2. Drugs which inhibit platelet function are listed in Box 19.52.
THROMBOCYTOPENIA
Thrombocytopenia causing bleeding constitutes a haematological emergency which should be promptly investigated and treated. Treatment should be directed at the underlying condition as well as including specific measures to raise the platelet count. In general, platelet transfusions should be given only if the platelet count is less than 10 × 109/l, to treat troublesome bleeding such as persistent epistaxis, or to treat potentially life-threatening bleeding, e.g. gastrointestinal haemorrhage. Such transfusions provide only temporary relief because the survival of the platelets in the circulation is only a few days at most, and in many instances may be only a matter of minutes or hours if the thrombocytopenia is due to increased platelet consumption, as in idiopathic thrombocytopenic purpura or disseminated intravascular coagulation (DIC).
IDIOPATHIC THROMBOCYTOPENIC PURPURA
The presence of autoantibodies, often directed against platelet membrane glycoprotein IIb-IIIa, causes the premature removal of platelets by the monocyte-macrophage system. Occasionally, antigen-antibody immune complexes adhere to platelets at their Fc receptor, resulting in their premature removal from the circulation.
Clinical features
In children idiopathic thrombocytopenic purpura (ITP) often presents 2-3 weeks after a viral illness, with the sudden onset of purpura and sometimes oral and nasal bleeding. The peripheral blood film is normal, apart from a greatly reduced platelet number, whilst the bone marrow reveals an obvious increase in megakaryocytes. It is important to ascertain that the child does not have any other systemic illness and in particular DIC.
In adults ITP more commonly affects females and has an insidious onset. It is unusual for there to be a history of a preceding viral infection. At presentation some cases may be associated with symptoms or signs of a connective tissue disease, whilst in others these disorders may become apparent several years later. The condition is likely to become chronic, with remissions and relapses.
Management
Children
If the child has only mild bleeding symptoms, it is usual to withhold any specific treatment, as the condition in the majority of instances is self-limiting within a few weeks. The presence of moderate to severe purpura, bruising or epistaxis and a platelet count less than 10 × 109/l are indications for oral prednisolone 2 mg/kg daily. The platelet count usually rises promptly within 1-3 days. Persistent epistaxis, gastrointestinal bleeding, retinal haemorrhages or any suggestion of intracranial bleeding should be treated immediately by a platelet transfusion. If fresh bleeding persists for more than a few days following the introduction of steroids, intravenous immunoglobulin should be given.
Adults
Treatment with prednisolone 1 mg/kg daily is often less rewarding than in children; the platelet count rises in response to therapy but falls again when the dose is reduced or stopped. As with children, persistent or potentially life-threatening bleeding should be treated with platelet transfusion. Intravenous immunoglobulin (IVIgG) (1 g/kg) should be given if the patient is very haemorrhagic or the bleeding is immediately life-threatening. The mechanism by which IVIgG raises the platelet count remains uncertain, although increasing evidence indicates that it may be due to blocking of monocyte-macrophage Fc receptors.
Relapses should be treated by increasing the dose of prednisolone. If a patient has two relapses, it is customary to consider splenectomy. This should be preceded by pneumococcal, meningococcal and Haemophilus influenzae vaccination. As so many adults with ITP eventually require splenectomy, it is prudent to vaccinate all patients at presentation before they become immunosuppressed with a prolonged course of steroids; this should be performed by subcutaneous injection since if vaccination is given by the customary intramuscular route it may result in a haematoma. Splenectomy is curative in about 70% of patients and in the remainder the aim should be to keep the patient free of symptoms rather than treat the platelet count alone. Often such patients have platelet counts of 20-30 × 109/l without symptoms; some require long-term maintenance with prednisolone at 5 mg/day. If significant bleeding persists despite splenectomy and low-dose steroid therapy, vincristine, immunosuppressive therapy-e.g. cyclophosphamide-or repeated infusions of intravenous immunoglobulin should be considered.
COAGULATION DISORDERS
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Coagulation factor disorders can arise either from deficiency, usually congenital, of a single factor-e.g. factor VIII, resulting in haemophilia A-or from multiple factor deficiencies which are often acquired-e.g. secondary to liver disease or warfarin therapy. Of the single congenital deficiencies, haemophilia A and B are the most common although, rarely, any of the coagulation factors may be reduced. The congenital disorders almost exclusively arise as a result of an abnormality in the gene coding for the coagulation factor.




Integration link: Clotting cascade and factors

Taken from Pharmacology 5e




CONGENITAL BLEEDING DISORDERS
HAEMOPHILIA A
Of the various congenital disorders of coagulation, a reduction of factor VIII resulting in haemophilia A, which affects 1/10 000 individuals, is the most common. Factor VIII is primarily synthesised by the liver but other organs such as the spleen, kidney and placenta may also contribute. Plasma factor VIII has a half-life of about 12 hours and is carried non-covalently bound to the von Willebrand factor (vWF). The factor VIII gene is located on the X chromosome and consists of 26 exons; many different defects in the gene have been identified, ranging from single-base changes to deletions and inversions.
Genetics
The factor VIII gene is localised on the X chromosome, making haemophilia A a sex-linked disorder. Thus on pedigree grounds all daughters of haemophiliacs are obligate carriers and sisters have a 50% chance of being a carrier. If a carrier has a son, he has a 50% chance of having haemophilia, and a daughter has a 50% chance of being a carrier. Haemophilia 'breeds true' within a family. All members will have the same abnormality of the factor VIII gene; thus if one individual has severe haemophilia, all others affected will also have a severe form of the disorder. Female carriers of haemophilia may have reduced factor VIII levels because of random inactivation of the X chromosome in the developing fetus (lyonisation). A reduced factor VIII level in a carrier will result in a mild bleeding disorder; thus all known or suspected carriers of haemophilia should have their factor VIII level measured.
The use of molecular genetic techniques has revolutionised the ability to identify carriers and the antenatal diagnosis of haemophilia. Antenatal diagnosis can be undertaken in a female who has a high probability of being a carrier. This is accomplished by chorionic villous sampling, usually around 11 weeks' gestation, sexing the fetus and using informative factor VIII probes. Alternatively, the fetus can be sexed at 16 weeks' gestation by amniocentesis and, if male, a fetal blood sample obtained at about 19-20 weeks.
Clinical features
Although haemophilia A is a congenital disorder, it is unusual for excessive bleeding to be noticed until babies are about 6 months old, when superficial bruising or a haemarthrosis may occur. This apparent delay in presentation is due to the relative inactivity of babies in the first few months of life and it is only when they begin to move about that more trauma results in bleeding. It is not uncommon for children to be initially classified as having non-accidental injury.
19.53 SEVERITY OF HAEMOPHILIA (UK CRITERIA)
Degree of severity Factor VIII or IX level Clinical presentation
Severe < 2% Spontaneous haemarthroses and muscle haematomas
Moderate 2-10% Mild trauma or surgery causes haematomas
Mild 10-50% Major injury or surgery results in excess bleeding

The normal factor VIII level is 50-150% and is usually measured by a clotting assay. In haemophilia the propensity to bleeding is related to the plasma factor VIII level. The classification of severity of haemophilia is set out in Box 19.53.
Individuals with severe haemophilia experience recurrent haemarthroses in large joints (see Fig. 19.34). These usually begin spontaneously without apparent trauma and most commonly affect the knees, elbows, ankles and hips. A typical severe haemophiliac may have one or two bleeds each week. Patients are aware that bleeding has started because they experience an abnormal sensation in the joint. If treatment is not given at this stage, bleeding continues, resulting in a hot, swollen and very painful joint. Without treatment these symptoms may last for days before gradually subsiding. Recurrent bleeds into joints lead to synovial hypertrophy, destruction of the cartilage and secondary osteoarthrosis (see Fig. 19.35). The resultant limitation of movement may greatly reduce the function of joints, making walking difficult.
Muscle haematomas are also characteristic of haemophilia. These occur most commonly in the calf and psoas muscles but they can arise in almost any muscle. Although less common than haemarthroses, a single episode can leave severe lasting damage if not effectively treated. A large psoas bleed, for example, may extend to press on the femoral nerve. Calf haematomas are also serious because of the inflexible fascial sheath surrounding the soleus and gastrocnemius muscles. Untreated haemorrhage causes a rise in pressure with eventual ischaemia, necrosis, fibrosis, and subsequent contraction and shortening of the Achilles tendon (see Fig. 19.36).


Figure 19.34 Large haemarthrosis in the right knee of a boy with haemophilia A.
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Figure 19.35 Chronic haemophilic arthropathy of the left knee. A Repeated bleeds have led to broadening of the femoral epicondyles. Unilateral atrophy of the quadriceps (A) is easily seen. B Radiograph confirms broadening of femoral epicondyles. There is no cartilage present, as evidenced by the close proximity of the femur and tibia (B); sclerosis (C), osteophyte (D) and bony cysts (E) are present. C A haemophiliac's stiff joint with minimal flexion has been replaced by a prosthesis. This enabled the joint to have a greatly extended range of motion which very markedly improved the patient's mobility.
Although joint and muscle bleeds are the most common sites for haemorrhage, bleeding can occur at almost any site. It is particularly serious if it takes place in a confined anatomical space associated with vital structures. The intracranial area is one such site and, unless it is treated very promptly, haemorrhage here is often fatal (see Fig. 19.37).
Individuals with moderate haemophilia usually only experience haemorrhage after minor trauma, and those with the mild form of the disorder, following more major trauma or surgery. Whereas severe haemophilia is usually diagnosed within the first 2 years of life, individuals with moderate and mild forms may escape diagnosis until adulthood.
Management
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Figure 19.36 Atrophy of the calf in an adult following an inadequately treated gastrocnemius haematoma as a child. The increased pressure of the haematoma caused ischaemia of the muscle, this being followed by necrosis, fibrosis and subsequent contraction to give the equinus deformity.


Figure 19.37 CT revealing a major intracerebral haematoma. This apparently arose spontaneously in a severe haemophiliac.
Bleeding episodes should be treated early by raising the factor VIII level. In the UK this is most commonly accomplished by intravenous infusion of factor VIII concentrate. Factor VIII concentrates are freeze-dried and stable at 4°C and can therefore be stored in domestic refrigerators. This facility, which allows many patients to treat themselves at home, has revolutionised haemophilia care. In countries where factor VIII is not available, cryoprecipitate should be used. All plasma-derived factor VIII concentrates are prepared from donors who are perceived as having a low risk of viral carriage, e.g. of HIV. The plasma is screened for the presence of antibodies to hepatitis B and C viruses and HIV, and the final product is treated either by heat or by chemicals in an attempt to inactivate any residual viruses. Concentrates prepared with these precautions have a good safety record. However, factor VIII prepared by recombinant DNA technology is now available, is perceived as being safer than that derived from human plasma and is therefore likely to replace plasma-derived concentrates.
In addition to factor VIII concentrate therapy, resting of the bleeding site by either bed rest or a splint reduces continuing haemorrhage. Once bleeding has settled, the patient should be mobilised and given physiotherapy to restore strength to the surrounding muscles.
19.54 LONG-TERM SEQUELAE OF HAEMOPHILIA
Complications due to repeated haemorrhages
Arthropathy of large joints, e.g. knees, elbows
Atrophy of muscles secondary to haematomas
Mononeuropathy resulting from pressure by haematomas

Complications due to therapy
Anti-factor VIII antibody development
Virus transmission
Hepatitis A virus-acute self-limiting illness
Hepatitis B virus-5-10% become chronic HBsAg carriers
Hepatitis C virus-chronic progressive liver disease
Hepatitis D virus-only arises in those with HBsAg
HIV-AIDS
Parvovirus-acute systemic self-limiting illness


Complications of therapy
Although factor VIII concentrates have transformed the lives of haemophiliacs by allowing many to lead near-normal lives, this freedom has been bought at a cost (see Box 19.54). Many patients treated before 1985, when concentrates were first virally inactivated with heat or chemicals to destroy viruses, became infected by HIV and the hepatitis viruses. As a result most adult severe haemophiliacs have been exposed to hepatitis B virus and have developed immunity, as evidenced by the development of anti-HBs. A small number become chronic HBsAg carriers and may infect sexual partners, who should therefore be offered hepatitis B immunisation (see p. 864). They are also at risk of delta virus infection. All potential recipients of pooled blood products should be offered hepatitis A and B immunisation because it will protect against hepatitis A, B and D infection. Hepatitis C virus was ubiquitously transmitted by concentrates prior to 1985, resulting in virtually all recipients becoming infected. It is clear that many of these patients have hepatitis, and a significant proportion progress to cirrhosis and hepatocellular carcinoma. Interferon and ribavirin therapy appear to cure a proportion of patients. Patients with clinically severe liver disease or liver cancer should be considered for hepatic transplantation.
Prior to 1985 HIV was transmitted to haemophiliacs by concentrates, resulting in at least 60% of severe haemophiliacs becoming infected (see p. 109). The clinical consequences are very similar to those for other individuals who have become infected with HIV, although their clinical course is perhaps more like that of those who become infected intravenously-e.g. drug users-than those who become infected sexually. Kaposi's sarcoma is rare in haemophiliacs compared with homosexuals.
There is now concern about the possibility that the infectious agent which causes variant CJD in humans (see p. 1202) might be transmissible by blood and blood products. Hence pooled plasma products, including factor VIII concentrate, are now manufactured from plasma collected in countries with a low incidence of BSE.
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The other serious consequence of factor VIII infusion is the development of anti-factor VIII antibodies, which arises in about 20-30% of severe haemophiliacs. Such antibodies rapidly neutralise therapeutic infusions, making treatment relatively ineffective. Individuals may be treated with porcine factor VIII because the antibody may have lower activity against animal factor VIII than against the human type. Alternatively, infusions of activated clotting factors, e.g. VIIa or Feiba (factor eight inhibitor bypassing activity-an activated concentrate of factors II, IX and X), may stop bleeding.
In individuals with a basal factor VIII level of 10% or greater it may be possible to raise the level approximately three- to fivefold with desmopressin; this is usually best given intravenously but can be administered intranasally. This is often sufficient to treat a mild bleed or cover minor surgery such as dental extraction.
Surgery in haemophiliacs can be safely performed provided the patient does not have an inhibitor to factor VIII and receives appropriate doses of concentrate. A single infusion of factor VIII is usually adequate for simple dental extractions in an individual with severe haemophilia, along with a 10-day course of tranexamic acid (a fibrinolytic inhibitor) and an antibiotic. Major surgery, such as orthopaedic surgery, requires twice-daily therapy for 14 days or longer.
HAEMOPHILIA B (CHRISTMAS DISEASE)
Aberrations of the factor IX gene, which is also present on the X chromosome, result in a reduction of the plasma factor IX level, giving rise to haemophilia B. This disorder is clinically indistinguishable from haemophilia A but is less common. The frequency of bleeding episodes is related to the severity of the deficiency of the plasma factor IX level.
Treatment is with a factor IX concentrate; it is used in much the same way as factor VIII for haemophilia A. Carrier identification and antenatal diagnosis can be accomplished if the specific mutation is known.
VON WILLEBRAND'S DISEASE
Von Willebrand's disease is a common but usually mild bleeding disorder. The gene for von Willebrand factor (vWF) is located on chromosome 12 and therefore the disorder is inherited in an autosomal fashion. In most families it has the appearance of being inherited in a dominant manner; rarely, it appears in a clinically severe form with almost undetectable levels of vWF. In these circumstances the patient usually inherits a different abnormal vWF gene from each parent and is thus a compound heterozygote. Gene probes are available to trace the gene in a family and can be used to identify carriers and for antenatal diagnosis.
The vWF is a protein, synthesised by endothelial cells and megakaryocytes, that performs two principal functions. It acts as a carrier protein for factor VIII, to which it is non-covalently bound. A deficiency of vWF therefore results in a secondary reduction in the plasma factor VIII level. Its other function is to form bridges between platelets and subendothelial components (e.g. collagen), allowing platelets to adhere to damaged vessel walls (see Fig. 19.7, p. 897). A deficiency of vWF therefore also leads to prolonged primary haemorrhage after trauma.
Clinical features
As vWF participates, along with platelets, in primary haemostasis, patients present with haemorrhagic manifestations which are similar to those in individuals with reduced platelet function. Superficial bruising, epistaxis, and menorrhagic and gastrointestinal haemorrhage are common. Bleeding episodes are usually much less common than in severe haemophilia and excessive haemorrhage may only be observed after trauma or surgery. Within a single family the disease can be of very variable expression so that some members may have quite severe and frequent bleeds, whereas others are relatively little troubled.
Investigations
The disorder is characterised by finding a reduced level of vWF, which is often accompanied by a secondary reduction in factor VIII and a prolongation of the bleeding time.
Management
Many episodes of mild haemorrhage can be successfully treated with desmopressin, which raises the vWF level, resulting in a secondary increase in factor VIII. For more serious or persistent bleeds haemostasis can be achieved with selected factor VIII concentrates which contain considerable quantities of vWF in addition to factor VIII.
ACQUIRED BLEEDING DISORDERS
DISSEMINATED INTRAVASCULAR COAGULATION
Clinical features
19.55 CAUSES OF DISSEMINATED INTRAVASCULAR COAGULATION
Infections
E. coli
Neisseria meningitidis
Streptococcus pneumoniae
Malaria
Cancers
Lung
Pancreas
Prostate
Obstetric
Abruptio placentae
Retained dead fetus
Pre-eclampsia
Amniotic fluid embolism


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Disseminated intravascular coagulation (DIC) can be initiated by a variety of different mechanisms in a number of diverse but distinct clinical situations, as set out in Box 19.55. Endothelial damage, due to many causes-e.g. endotoxaemia due to Gram-negative septicaemia-may activate endothelial cells to produce tissue factor, which leads to activation of the coagulation cascade through the extrinsic pathway (see Fig. 19.8, p. 898). The presence of thromboplastin from damaged tissues, placenta or fat embolus, or following brain injury may also activate coagulation. Intravascular coagulation takes place with consumption of platelets, factors V and VIII, and fibrinogen. This results in a potential haemorrhagic state, due to the depletion of haemostatic components, which may be exacerbated by activation of the fibrinolytic system secondary to the deposition of fibrin.
Investigations
DIC should be suspected when any of the conditions in Box 19.55 are encountered. Definitive diagnosis depends on the finding of thrombocytopenia, prolongation of the prothrombin time (due to factor V and fibrinogen deficiency) and activated partial thromboplastin time (due to factors V, VIII and fibrinogen deficiency), a low fibrinogen concentration and increased levels of D-dimer (which is cleaved from fibrin by plasmin, establishing evidence of fibrin lysis).
Management
Therapy should be aimed at treating the underlying condition causing the DIC, e.g. intravenous antibiotics for suspected septicaemia. Exacerbating factors such as acidosis, dehydration, renal failure and hypoxia should be corrected. If the patient is bleeding, blood products such as platelets and/or cryoprecipitate (which is enriched in factor VIII and fibrinogen) should be given to correct identified abnormalities. It may also be reasonable to treat severe coagulation abnormalities in the absence of frank bleeding to prevent sudden catastrophic haemorrhage such as intracranial bleed or massive gastrointestinal haemorrhage.
LIVER DISEASE
In severe parenchymal liver disease bleeding may arise from many different causes. Local anatomical abnormalities are often the site of major bleeding (such as oesophageal varices or peptic ulcer), and this may be difficult to arrest because of deficiencies in components of the haemostatic system. These may arise because of reduced hepatic synthesis, e.g. factors II, VII, IX, X and fibrinogen, DIC, reduced clearance of plasminogen activator, or thrombocytopenia secondary to hypersplenism. Treatment should be reserved for acute bleeds or to cover interventional procedures such as liver biopsy.
Cholestatic jaundice reduces vitamin K absorption and leads to a deficiency of function of factors II, VII, IX and X due to reduced gamma glutamate carboxylation. This deficiency can be readily and effectively treated with vitamin K1 10 mg daily parenterally for several days.
RENAL FAILURE
The severity of the haemorrhagic state in renal failure is proportional to the plasma urea concentration. Bleeding manifestations are of platelet type, with gastrointestinal haemorrhage being particularly common. The causes are multifactorial, including anaemia, mild thrombocytopenia and the accumulation of low molecular waste products, normally excreted by the kidney, that inhibit platelet function. Treatment is by dialysis to reduce the urea concentration, and platelet concentrate infusions; red cell transfusions raise the haemoglobin and decrease the propensity to bleed. Increasing the concentration of vWF, either by cryoprecipitate or by desmopressin, may promote haemostasis.

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Home > 2 SYSTEM-BASED DISEASES > 19 Blood disorders > VENOUS THROMBOSIS
VENOUS THROMBOSIS
Venous thrombosis may arise either because of damage to, or pressure on, veins (e.g. varicose veins or pelvic tumour), or as a result of changes in the plasma or cellular elements of the blood. Predisposing conditions for venous thromboembolism are listed in Box 19.56.
19.56 FACTORS PREDISPOSING TO VENOUS THROMBOSIS
Patient factors
Age > 40 years
Obesity
Varicose veins
Previous deep venous thrombosis
Oral contraceptive
Pregnancy/puerperium
Dehydration
Immobility

Surgical conditions
Surgery, especially if > 30 minutes' duration
Abdominal or pelvic
Orthopaedic to lower limb

Medical conditions
Myocardial infarction/heart failure
Inflammatory bowel disease
Malignancy
Nephrotic syndrome
Behçet's syndrome
Homocystinaemia

Haematological disorders
Primary proliferative polycythaemia
Essential thrombocythaemia
Myelofibrosis
Paroxysmal nocturnal haemoglobinuria

Deficiency of anticoagulants
Antithrombin
Protein C
Prothrombin G20210A
Protein S
Factor V Leiden

Antiphospholipid antibody
Lupus anticoagulant
Anticardiolipin antibody


HAEMATOLOGICAL DISORDERS PREDISPOSING TO VENOUS THROMBOEMBOLISM
When a thrombotic event arises in an individual under the age of 40 years, particularly if there is a family history of thrombosis, investigations should be undertaken to assess whether there is a predisposing plasma abnormality (see Box 19.56). Often several risk factors are present when an acute deep venous thrombosis (DVT) occurs. Thus an obese patient over the age of 40 years, with factor V Leiden, may undergo abdominal surgery and develop a post-operative DVT.
ANTITHROMBIN DEFICIENCY
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Antithrombin is a protease inhibitor which inactivates factors IIa, IXa, Xa and XIa, especially in the presence of heparin (which greatly potentiates its activity). Familial deficiency of antithrombin is a dominantly inherited disorder and is associated with a marked predisposition to venous thromboembolism.
PROTEIN C AND S DEFICIENCIES
Protein C is a vitamin K-dependent protein. When thrombin binds to thrombomodulin, on the endothelial cell surface, it becomes an anticoagulant by activating protein C. In the presence of protein S, this inactivates factors Va and VIIIa. Thus a deficiency of either protein C or S results in a prothrombotic state due to reduced inhibition of activated factor V and VIII. A deficiency of either factor is usually inherited in an autosomal fashion.
FACTOR V LEIDEN
This common disorder is associated with venous thrombosis. It was originally characterised as an inability of the patient's plasma clotting time to lengthen in the presence of activated protein C (APC), giving rise to its original description as activated protein C resistance (APCR). Further investigation revealed that the abnormality resided in a substrate for APC, namely factor Va; a substitution of arginine by glutamine at position 506 prevents its cleavage and hence inactivation. Factor Va will therefore persist, resulting in a tendency to venous thrombosis.
The mutation has been identified in about 3-5% of healthy individuals in Western Europe and North America and about 20-40% of those with a history of venous thrombosis at a young age. The risk of venous thrombosis in individuals with this mutation is substantially increased if the patient has a second plasma abnormality, e.g. a lupus anticoagulant (see below).
PROTHROMBIN G20210A
This genetic polymorphism at the non-coding 3' end of the prothrombin gene is associated with an increased plasma level of prothrombin and venous thromboembolism. It is present in about 2% of the normal population and about 6% of those with venous thrombus.
ANTIPHOSPHOLIPID ANTIBODY SYNDROME
In the antiphospholipid antibody syndrome an antibody in the patient's plasma has activity against enzymic reactions in the coagulation cascade that are dependent on platelet membranes (or in vitro by phospholipid). The antibody, in vitro, has the effect of prolonging the APTT because it interacts with phospholipid in the reaction tube and inhibits the binding or enzymic interactions of the coagulation components. It is most sensitively diagnosed by prolongation of the dilute Russell viper venom time (DRVVT) of plasma, an effect that can be neutralised by adding platelet membranes. When the antibody inhibits coagulation in these ways it is known as the lupus anticoagulant. In some individuals the plasma protein ß2-glycoprotein-1 undergoes a conformational change after it has bound to anionic phospholipids, and is then recognised by the antibody. In vitro this is usually detected by its ability to bind to the ß2-glycoprotein-1 in an assay with cardiolipin when it is known as an anticardiolipin antibody. The term antiphospholipid antibody encompasses both a lupus anticoagulant and an anticardiolipin antibody; some individuals are only positive for one of these activities, whereas in others both are present.
Clinical features
The antiphospholipid antibody is associated with a constellation of clinical conditions (see Box 19.57) found in association with a history of thromboembolism. The antibody has now been found in some individuals with a history of arterial or venous thromboembolism, often at a young age but without features of SLE; in this case it is known as the primary antiphospholipid antibody syndrome. The antibody is also associated with recurrent spontaneous abortions as well as with intrauterine fetal growth retardation. The mechanism by which the antibody predisposes to thrombosis is unclear but it may be related to either maintaining platelets in an activated state within the circulation or, possibly, to inhibiting the fibrinolytic activity of endothelial cells.
19.57 ANTIPHOSPHOLIPID SYNDROME
The clinical features are mainly related to arterial or venous occlusion which may affect one or several organs
Haematological
Thrombocytopenia
Autoimmune haemolytic anaemia

Cardiac
Myocardial infarction
Pulmonary hypertension
Valvular disease

Neurological
Cerebral ischaemia
Single lesions
Multi-infarct dementia
Migraine
Epilepsy
Chorea
Transverse myelopathy

Renal
Renal vein thrombosis
Glomerular thrombosis

Endocrine
Adrenal thrombosis-Addison's disease

Gastrointestinal tract
Bowel ischaemia
Budd-Chiari syndrome

Skin
Livedo reticularis
Recurrent skin ulcers

Obstetric
Recurrent spontaneous abortions
Intrauterine growth retardation


MANAGEMENT OF VENOUS THROMBOEMBOLISM
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The treatment of a thrombosis depends on its site and extent and on the age of the thrombus. Prior to any antithrombotic therapy it is essential to consider whether the patient has a significant contraindication to anticoagulant therapy. On occasion antithrombotic therapy may have to be given to a patient who has a contraindication and in this instance the potential benefits have to be weighed against the risk of serious haemorrhage. Indications for and contraindications to anticoagulation are given in Boxes 19.58 and 19.59.
Anticoagulant therapy
Heparin
Standard (unfractionated) heparin (SH) produces its anticoagulant effect by potentiating the activity of antithrombin which inhibits the procoagulant enzymic activity of factors IIa, VIIa, IXa, Xa and XIa (see Fig. 19.8, p. 898).
The more recently developed low molecular weight heparins (LMWHs) augment antithrombin activity preferentially against factor Xa. LMWH does not prolong the APTT, unlike SH, and if its plasma level needs to be measured this is accomplished using a specific anti-Xa-based assay. LMWH, because of its high bioavailability after subcutaneous injection, is given as either a standard or a weight-related dose. Normally, therefore, the plasma LMWH level does not need to be measured.
The therapeutic indications for heparin are listed in Box 19.58.
19.58 INDICATIONS FOR ANTICOAGULATION
Heparin
Treatment and prevention of deep venous thrombosis
Pulmonary embolism
Myocardial infarction, to prevent:
Coronary reocclusion after thrombolysis
Mural thrombosis
Unstable angina pectoris
Acute peripheral arterial occlusion




Warfarin
Prophylaxis against deep venous thrombosis
Treatment of deep venous thrombosis and pulmonary embolism
Arterial embolism
Mitral stenosis with atrial fibrillation
Transient ischaemic attacks


Therapeutic corrected prothrombin ratio (INR) 2.5 Recurrent deep venous thrombosis
Mechanical prosthetic cardiac valves


INR 3.5
(INR = international normalised ratio)
19.59 CONTRAINDICATIONS TO ANTICOAGULATION
Recent surgery, especially to eye or CNS
Pre-existing haemorrhagic state
e.g. Liver disease
Renal failure
Haemophilia
Thrombocytopenia
Pre-existing structural lesions
e.g. Peptic ulcer
Recent cerebral haemorrhage
Uncontrolled hypertension


LMWHs are now licensed for the treatment of both DVT and pulmonary embolism and are now replacing standard heparin as the initial treatment of choice for many patients. As injections of LMWH need only be given once daily subcutaneously, many patients can be treated at home.
Standard heparin is often reserved for treating patients with very severe, life-threatening thromboembolism, e.g. major pulmonary embolism giving rise to significant hypoxaemia or hypotension. It should be started with a loading dose of 5000 U i.v., followed by a continuous infusion of 20 U/kg/hr initially. The level of anticoagulation should be assessed after 6 hours and then, if satisfactory, daily by use of a coagulation test which is appropriately sensitive to heparin, e.g. APTT. It is usual to aim for a patient time which is 1.5-2.5 times the control time of the test. The half-life of intravenous heparin is about 1 hour and if a patient bleeds it is usually sufficient just to discontinue the infusion as the anticoagulant effect diminishes relatively rapidly; however, if bleeding is severe, the excess can be neutralised with intravenous protamine. The short half-life of SH makes it useful for those with a predisposition to bleeding, e.g. who have peptic ulcer, or those who may require surgery. Treatment with either LMWH or SH should continue for 6-8 days, depending upon the extent of the thrombus. In most patients it is appropriate to start warfarin therapy at the same time as heparin, as it takes several days to decrease the concentration of the vitamin K-dependent clotting factors. Heparin should be continued until the INR is > 2.0 for 2 consecutive days.
Warfarin
Warfarin inhibits the vitamin K-dependent carboxylation of factors II, VII, IX and X in the liver (see Fig. 19.9, p. 899). Carboxylation of glutamyl residues of these coagulation factors increases their negative charge and allows them to maintain their active three-dimensional structure. The recognised indications for warfarin therapy are listed in Box 19.58.
Therapy with warfarin must be initiated with a loading dose-e.g. 10 mg orally-on the first day, and subsequent daily doses depending on the INR. The degree of anticoagulation depends on the clinical circumstances, and the appropriate target INRs are given in Box 19.58. Following a single episode of venous thromboembolism it is usual to continue oral anticoagulation for 3-6 months. If a patient has had two episodes of venous thromboembolism, life-long warfarin is often considered appropriate. It is important to remember that nearly all drugs can potentially modify the degree of warfarin therapy, and therefore the INR should be checked 3-6 days after stopping or starting any other medicine.
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Bleeding is the most common serious side-effect of warfarin and occurs in about 0.5-1.0% of patients each year. The anticoagulant benefit of warfarin must therefore be demonstrably greater than the risk of serious bleeding. If the patient bleeds, the anticoagulant effect of warfarin may be reversed by vitamin K1 1-5 mg slowly i.v.; the effect becomes apparent within about 6 hours, although it may not fully reverse anticoagulation for 1 or 2 days. The INR should be repeated after 6 hours and a further dose of vitamin K1 given if appropriate. If the patient has a serious haemorrhage, reversal can be effected quickly by giving coagulation concentrate containing factors II, VII, IX and X (50 U/kg) or, if this is unavailable, fresh frozen plasma.
EBM
TREATMENT OF DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM-heparin before warfarin
'In the treatments of DVT and pulmonary embolism, RCTs have shown that initial treatment with heparin before the introduction of warfarin results in fewer recurrences and that treating DVT with an INR in the range of 2.0-3.0 results in the same incidence of recurrences but fewer bleeds compared to treatment with an INR of 3.0-4.0.'
Brandjes DP, Heijboer H, Buller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992; 327:1485-1489.
Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982; 307:1676-1681.
Further information: www.clinicalevidence.org

Prevention of venous thrombosis
All patients admitted to hospital should be assessed for their risk of developing venous thromboembolism. A summary of the risk categories is given in Box 19.56, page 952 and Box 19.60. Early mobilisation of all patients is important to prevent DVTs. Patients at medium or high risk may require additional antithrombotic measures. Knee-length graduated compression stockings are effective in medium-risk individuals. In medium-risk patients SH or LMWH can also be used; it should be started pre-operatively and continued until the patient is fully mobile. High-risk individuals should receive anti-embolism stockings and LMWH at a higher prophylactic dose. Routine monitoring of SH or LMWH for prophylaxis is not necessary. Particular care should be taken with the use of heparin prophylaxis in any patient in whom intra- or post-operative bleeding could have serious consequences, e.g. those with spinal anaesthesia, and it is usually contraindicated with neurosurgery. Any individual who has any of the additional risk factors is also at increased likelihood of thrombosis and every care should be taken to ensure that, as far as possible, the risk can be lessened prior to surgery-for instance, the haemoglobin reduced in polycythaemia.
19.60 ANTITHROMBOTIC PROPHYLAXIS
Patients in the following categories should be considered for specific antithrombotic prophylaxis:
Moderate risk of DVT
Major surgery in patients > 40 years or with other risk factor
Major medical illness
e.g. Heart failure
Chest infection
Malignancy
Inflammatory bowel disease
High risk of DVT
Hip or knee surgery
Major abdominal or pelvic surgery for malignancy or with history of DVT or known thrombophilia (see Box 19.4, p. 902)


ISSUES IN OLDER PEOPLE
HAEMOSTASIS AND THROMBOSIS
Thrombocytopenia is not uncommon because of the rising prevalence of disorders in which it may be a secondary feature, and also because of the greater use of drugs which can cause it.
'Senile' purpura is presumed to be due to an age-associated loss of subcutaneous fat and the collagenous support of small blood vessels, making them more prone to damage from minor trauma.
Thrombosis-related events become more frequent in old age. These may be due to stasis to which older people are prone; some studies show increased platelet aggregation with age, and others age-associated hyperactivity of the haemostatic system which could create a prothrombotic state.


FURTHER INFORMATION
www.bcshguidelines.com British Committee for Standards in Haematology guidelines.
www.ibmtr.org
BLOOD PRODUCTS AND TRANSFUSION
Emmanuel JC, McClelland DBL, Page R. The clinical use of blood (WHO/BTS/99.2). Geneva: WHO; 2001.
McClelland DBL, ed. Handbook of transfusion medicine. 3rd edn. London: HMSO; 2001.
Murphy MF, Pamphilon DH. Transfusion medicine. Oxford: Blackwell Science; 2001.
www.transfusionguidelines.org.uk Contains the UK Transfusion Services' Handbook of transfusion medicine and links to other relevant sites.
ANAEMIAS
Castro O. Management of sickle cell anaemia: recent advances and controversies. Br J Haematol 1999; 107(1):2 Medline Similar articles Full article
Chanarin I, Metz J. Diagnosis of cobalamin deficiency. Br J Haematol 1997; 97(4):695. Medline Similar articles Full article
Oliviero NF. The beta thalassemias. N Engl J Med 1999; 341:99.
Tse WT, Lux SE. Red blood cell membrane disorders. Br J Haematol 1999; 104(1):2. Medline Similar articles
HAEMATOLOGICAL MALIGNANCIES
Aisenberg A. Problems of management in Hodgkin's disease. Blood 1999; 93:761. Medline Similar articles
Bataille R, Harousseau JL. Multiple myeloma. N Engl J Med 1997; 336:1657. Medline Similar articles Full article
Goldman J. Chronic myeloid leukemia: current treatment options. Blood 2001; 98:2039. Medline Similar articles Full article
Heany ML, Gold DW. Myelodysplasia. N Engl J Med 1999; 340:1649.
Linch DC, Goldstone AH. High dose therapy for Hodgkin's disease. Br J Haematol 1999; 111:287-291.
Lokhorst HM, Sonneveld P, Verdonck L. Intensive treatment for myeloma. Br J Haematol 1999; 106:18. Medline Similar articles Full article
Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med 1999; 341:1057.
Marsh J. Modern management of severe aplastic anaemia. Br J Haematol 1999; 110:41.
BLEEDING DISORDERS AND VENOUS THROMBOSIS
Guidelines for the investigation and management of antiphospholipid syndrome. Br J Haematol 2000; 109:704-715 (http://www.bcshguidelines.com).
Investigation and management of heritable thrombophilia. Br J Haematol 2001; 114(3):512-528 (http://www.bcshguidelines.com).
Lee AY, Hirsh J. Diagnosis and treatment of venous thromboembolism. Annu Rev Med 2002; 53:15-33. Medline Similar articles Full article
Mannucci PM, Tuddenham EG. The haemophilias-from royal genes to gene therapy. N Engl J Med 2001; 344:1773-1779. Medline Similar articles Full article
Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344:1222-1231.
http://www.show.scot.nhs.uk/sign/clinical.htm 1999 SIGN guideline for antithrombotic therapy. Full article

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