Anaemia

Anaemia
■ Anaemia
■ Clinical features of anaemia
■ Classification and laboratory findings
■ Assessment of erythropoiesis
Anaemia 1
This is defined as a reduction in the haemoglobin concentration of the
blood below normal for age and sex.
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.
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.
Anaemia 2
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; 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.
Anaemia 3
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.
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.
Normal values for blood cells and haematinics.
The lower limit of normal blood haemoglobin concentration in men, women
and children of various ages
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.
Clinical features of anaemia 1
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.
Clinical features of anaemia 2
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 concentration 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.
Clinical features of anaemia 3
3. Age The elderly tolerate anaemia less well than the young because
normal cardiovascular compensation is impaired.
4. Haemoglobin O2dissociation 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) or that are
associated with a low‐affinity haemoglobin (e.g. Hb S).
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.
Signs 1
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 90 g/L. 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.
Particularly in the elderly, features of congestive heart failure may be
present.
Pallor of the conjunctival mucosa (a) and of the nail bed (b) in two patients with
severe anaemia (haemoglobin 60 g/L).
Signs 2
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
Red cell indices 1
The most useful classification is that based on red cell indices and
divides the anaemia into microcytic, normocytic and macrocytic.
As well as suggesting the nature of the primary defect, this approach
may also indicate an underlying abnormality before overt anaemia has
developed.
Classification and laboratory findings
Red cell indices 2
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).
Classification of anaemia
Classification and laboratory findings
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 and laboratory findings
Reticulocyte count
The normal percentage is 0.5–2.5%, and the absolute count 50–150 ×
109/L. 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.
Factors impairing the normal reticulocyte response to anaemia
Classification and laboratory findings
Blood film
It is essential to examine the blood film in all cases of anaemia.
Abnormal red cell morphology or red cell inclusions 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.
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.
Classification and laboratory findings
Bone marrow examination 1
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.
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.
Classification and laboratory findings
Bone marrow examination 2
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.
Classification and laboratory findings
Bone marrow examination 3
An aspirate sample may also be used for a number of other specialized
investigations.
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 immunohistology is performed
depending on the diagnosis suspected. 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.
(a) The bone marrow aspiration needle and a smear made
from a bone marrow aspirate. (b) The bone marrow
trephine (biopsy) needle and normal trephine section.
Classification and laboratory findings
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. 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.
Indications for bone marrow aspiration and trephine biopsy
The relative proportions of marrow erythroblastic
activity, circulating red cell mass and red cell
lifespan in normal subjects and in three types of
anaemia
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.