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This is defined as a reduction in the haemoglobin concentration of the blood below normal for age and sex (Table 2.4). Although normal values can vary between laboratories, typical values would be less than 135 g/L in adult males and less than 115 g/L in adult females (Fig. 2.13). From the age of 2 years to puberty, less than 110 g/L indicates anaemia. As newborn infants have a high haemoglobin level, 140 g/L is taken as the lower limit at birth (Fig. 2.13).

The lower limit of normal blood haemoglobin concentration in men, women and children of various ages.

Alterations in total circulating plasma volume as well as of total circulating haemoglobin mass determine the haemoglobin concentration. Reduction in plasma volume (as in dehydration) may mask anaemia or even cause (apparent, pseudo) polycythaemia (see p. 168); conversely, an increase in plasma volume (as with splenomegaly or pregnancy) may cause anaemia even with a normal total circulating red cell and haemoglobin mass.
After acute major blood loss, anaemia is not immediately apparent because the total blood volume is reduced. It takes up to a day for the plasma volume to be replaced and so for the degree of anaemia to become apparent (see p. 345). Regeneration of red cells and haemoglobin mass takes substantially longer. The initial clinical features of major blood loss are therefore a result of reduction in blood volume rather than of anaemia.

Global incidence
The WHO defines anaemia in adults as a haemoglobin less than 130 g/L in males and less than 120 g/L in females. On this basis, anaemia was estimated in 2010 to occur in about 33% of the global population. Prevalence was greater in females than males at all ages and most frequent in children less than 5 years old. Anaemia was most frequent in South Asia, and Central, West and East Sub‐Saharan Africa. The main causes are iron deficiency (hookworm, schistosomiasis), sickle cell diseases, thalassaemia, malaria and the anaemia of chronic disorders (see p. 37).

Clinical features of anaemia
The major adaptations to anaemia are in the cardiovascular system (with increased stroke volume and tachycardia) and in the haemoglobin O2 dissociation curve. In some patients with quite severe anaemia there may be no symptoms or signs, whereas others with mild anaemia may be severely incapacitated. The presence or absence of clinical features can be considered under four major headings.
1.   Speed of onset Rapidly progressive anaemia causes more symptoms than anaemia of slow onset because there is less time for adaptation in the cardiovascular system and in the O2 dissociation curve of haemoglobin.
2.   Severity Mild anaemia often produces no symptoms or signs but these are usually present when the haemoglobin is less than 90 g/L. Even severe anaemia (haemoglobin con- centration as low as 60 g/L) may produce remarkably few symptoms, when there is very gradual onset in a young subject who is otherwise healthy.
3.    Age The elderly tolerate anaemia less well than the young because normal cardiovascular compensation is impaired.
4.   Haemoglobin Odissociation curve Anaemia, in general, is associated with a rise in 2,3‐DPG in the red cells and a shift in the O2 dissociation curve to the right so that oxygen is given up more readily to tissues. This adaptation is particularly marked in some anaemias that either raise 2,3‐DPG directly (e.g. pyruvate kinase deficiency [p. 67]) or that are associated with a low‐affinity haemoglobin (e.g. Hb S) (see Fig. 2.10).

If the patient does have symptoms these are usually shortness of breath, particularly on exertion, weakness, lethargy, palpitation and headaches. In older subjects, symptoms of cardiac failure, angina pectoris or intermittent claudication or confusion may be present. Visual disturbances because of retinal haemorrhages may complicate very severe anaemia, particularly of rapid onset (Fig. 2.14).

These may be divided into general and specific. General signs include pallor of mucous membranes or nail beds, which occurs if the haemoglobin level is less than 90g/L (Fig. 2.15). Conversely, skin colour is not a reliable sign. A hyperdynamic circulation may be present with tachycardia, a bounding pulse, cardiomegaly and a systolic flow murmur especially at the apex. Particularl in the elderly, features of congestive heart failure may be present.

Specific signs are associated with particular types of anaemia, e.g. koilonychia (spoon nails) with iron deficiency, jaundice with haemolytic or megaloblastic anaemias, leg ulcers with sickle cell and other haemolytic anaemias, bone deformities with thalassaemia major.
The association of features of anaemia with excess infections or spontaneous bruising suggest that neutropenia or thrombocytopenia may be present, possibly as a result of bone marrow failure.

Retinal haemorrhages in a patient with severe anaemia (haemoglobin 25 g/L) caused by severe haemorrhage.

Classification and laboratory findings in anaemia
Red cell indices
The most useful classification is that based on red cell indices (Table 2.4) and divides the anaemia into microcytic, normocytic and macrocytic (Table 2.5). As well as suggesting the nature of the primary defect, this approach may also indicate an underlying abnormality before overt anaemia has developed.
In two common physiological situations, the mean corpuscular volume (MCV) may be outside the normal adult range. In the newborn for a few weeks the MCV is high but in infancy it is low (e.g. 70 fL at 1 year of age) and rises slowly throughout childhood to the normal adult range. In normal pregnancy there is a slight rise in MCV, even in the absence of other causes of macrocytosis (e.g. folate deficiency).

Other laboratory findings
Although the red cell indices will indicate the type of anaemia, further useful information can be obtained from the initial blood sample.

Leucocyte and platelet counts
Measurement of these helps to distinguish ‘pure’ anaemia from ‘pancytopenia’ (subnormal levels of red cells, neutrophils and platelets), which suggests a more general marrow defect or destruction of cells (e.g. hypersplenism). In anaemias caused by haemolysis or haemorrhage, the neutrophil and platelet counts are often raised; in infections and leukaemias, the leucocyte count is also often raised and there may be abnormal leucocytes or neutrophil precursors present.
Classification of anaemia.

Reticulocyte count
The normal percentage is 0.5–2.5%, and the absolute count 50–150 × 109/L (Table 2.4). This should rise in anaemia because of erythropoietin increase, and be higher the more severe the anaemia. This is particularly so when there has been time for erythroid hyperplasia to develop in the marrow as in chronic haemolysis. After an acute major haemorrhage there is an erythropoietin response in 6 hours, the reticulocyte count rises within 2–3 days, reaches a maximum in 6–10 days and remains raised until the haemoglobin returns to the normal level. If the reticulocyte count is not raised in an anaemic patient this suggests impaired marrow function or lack of erythropoietin stimulus (Table 2.6).
Blood film
It is essential to examine the blood film in all cases of anaemia. Abnormal red cell morphology (Fig. 2.16) or red cell inclusions (Fig. 2.17) may suggest a particular diagnosis. During the blood film examination, white cell abnormalities are sought, platelet number and morphology are assessed and the presence or absence of abnormal cells (e.g. normoblasts, granulocyte precursors or blast cells) is noted.

Some of the more frequent variations in size (anisocytosis) and shape (poikilocytosis) that may be found in different anaemias. DIC, disseminated intravascular coagulopathy; G6PD, glucose‐6‐phosphate dehydrogenase; HUS, haemolytic uraemic syndrome; TTP, thrombotic thrombocytopenic purpura.

Bone marrow examination
This is needed when the cause of anaemia or other abnormality of the blood cells cannot be diagnosed from the blood count, film and other blood tests alone. It may be performed by aspiration or trephine biopsy (Fig. 2.18). During bone marrow aspiration a needle is inserted into the marrow and a liquid sample of marrow is sucked into a syringe. This is then spread on a slide for microscopy and stained by the usual Romanowsky technique. The detail of the developing cells can be examined (e.g. normoblastic or megaloblastic), the proportion of the different cell lines assessed (myeloid: erythroid ratio, the proportion of granulocyte precursors to red cell precursors in the bone marrow, normally 2.5 : 1 to 12 : 1), and the presence of cells foreign to the marrow (e.g. secondary carcinoma) observed. The cellularity of the marrow can also be viewed provided fragments are obtained. An iron stain is performed routinely so that the amount of iron in reticuloendothelial stores (macrophages) and as fine granules (‘siderotic’ granules) in the developing erythroblasts can be assessed (see Fig. 3.10).
An aspirate sample may also be used for a number of other specialized investigations (Table 2.7).
A trephine biopsy provides a solid core of bone including marrow and is examined as a histological specimen after fixation in formalin, decalcification and sectioning. Usually immu- nohistology is performed depending on the diagnosis suspected (see Chapter 11). A trephine biopsy specimen is less valuable than aspiration when individual cell detail is to be examined but provides a panoramic view of the marrow from which overall marrow architecture, cellularity and presence of fibrosis or abnormal infiltrates can, with immunohistology, be reliably determined.

Red blood cell (RBC) inclusions which may be seen in the peripheral blood film in various conditions. The reticulocyte RNA and Heinz bodies are only demonstrated by supravital staining (e.g. with new methylene blue). Heinz bodies are oxidized denatured haemoglobin. Siderotic granules (Pappenheimer bodies) contain iron. They are purple on conventional staining but blue with Perls’ stain. The Howell–Jolly body is a DNA remnant. Basophilic stippling is denatured RNA.

Ineffective erythropoiesis
Erythropoiesis is not entirely efficient because approximately 10–15% of developing erythroblasts die within the marrow without producing mature cells. This is termed ineffective erythropoiesis and it is substantially increased in a number of chronic anaemias (Fig. 2.19). The serum unconjugated bilirubin (derived from breaking down haemoglobin) and lactate dehydrogenase (LDH, derived from breaking down cells) are usually raised when ineffective erythropoiesis is marked. The reticulocyte count is low in relation to the degree of anaemia and to the proportion of erythroblasts in the marrow.

Red blood cell (RBC) inclusions which may be seen in the peripheral blood film in various conditions. The reticulocyte RNA and Heinz bodies are only demonstrated by supravital staining (e.g. with new methylene blue). Heinz bodies are oxidized denatured haemoglobin. Siderotic granules (Pappenheimer bodies) contain iron. They are purple on conventional staining but blue with Perls’ stain. The Howell–Jolly body is a DNA remnant. Basophilic stippling is denatured RNA.

Assessment of erythropoiesis
Total erythropoiesis and the amount of erythropoiesis that is effective in producing circulating red cells can be assessed by examining the bone marrow, haemoglobin level and reticulocyte count.
Total erythropoiesis is assessed from the marrow cellularity and the myeloid : erythroid ratio. This ratio falls and may be reversed when total erythropoiesis is selectively increased.
Effective erythropoiesis is assessed by the reticulocyte count. This is raised in proportion to the degree of anaemia when erythropoiesis is effective, but is low when there is ineffective erythropoiesis or an abnormality preventing normal marrow response (Table 2.6).