Anaemia
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).
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 O2 dissociation 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).
Symptoms
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).
Signs
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.
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.
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.
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.
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.
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).
