ANAEMIA
Investigation and
management of anaemia
Alison Thomas
Abstract
The average lifespan of an erythrocyte is 120 days, and maintenance
of a normal haemoglobin requires the rate of production of erythroid
cells to match the rate of loss from the circulation. Where this is insuf-
cient, anaemia ensues. Deciency of haematinics (iron, vitamin B12,
folate), bone marrow inltration or chronic inammation and organ
dysfunction can all result in impaired erythropoiesis. Abnormalities of
the erythroid membrane, globin chains or intracellular enzymes
shorten red cell lifespan, resulting in a congenital haemolytic anaemia.
Acquired haemolysis is commonly immune or microangiopathic in
aetiology. A detailed history including dietary, drug and family history,
followed by interpretation of the full blood count, examination of the
blood lm and appropriate interpretation of simple tests (e.g. vitamin
B12, folate, ferritin), often identies the cause of the anaemia. Older pa-
tients and those with complex co-morbidities can have multiple factors
contributing to their anaemia. Management of anaemia is primarily
focused on treating the underlying cause. Blood transfusion is
reserved for cases of acute-onset symptomatic anaemia and cases
of anaemia with no remedial cause.
Keywords Anaemia; folate; haematinic; haemolysis; iron deciency;
megaloblastic; microangiopathic; thalassaemia; vitamin B12
Dening anaemia
Anaemia, in which the haemoglobin (and hence oxygen-carrying
capacity of the blood) is insufficient to meet the bodys physio-
logical needs, is the most common blood abnormality. The
normal haemoglobin range varies with age and sex, and for
adults is defined by the World Health Organization as a hae-
moglobin less than 130 g/litre in men and less than 120 g/litre in
women. Anaemia arises from either inadequate production of
erythrocytes or loss of red cells from the circulation because of
either destruction or blood loss. Iron deficiency anaemia is the
most common cause of anaemia worldwide. Anaemia itself is a
descriptor not a diagnosis, and the underlying cause(s) should
always be sought.
Clinical manifestations of anaemia
Beyond the presence of pallor, anaemia is often asymptomatic
when of slow onset in otherwise healthy individuals. Decreased
oxygen-carrying capacity of the blood can result in shortness of
breath on exertion, exertional angina and fatigue, while a
compensatory increase in cardiac output can result in tachy-
cardia, an ejection systolic murmur (flow murmur) and even
Alison Thomas MRCP FRCPath is Consultant Haematologist, St
Georges University Hospitals NHS Foundation Trust, London, UK.
Competing interests: none declared.
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Key points
C Anaemia arises from inadequate red cell production or
decreased red cell survival
C Anaemias can be microcytic, normocytic or macrocytic
C Microcytic anaemias are most commonly caused by iron defi-
ciency anaemia or thalassaemia trait
C Causes of macrocytic anaemia include vitamin B12 or folate
deficiency, haemolysis, myelodysplasia and alcohol excess
C Haemolysis can be congenital (e.g. hereditary spherocytosis)
or acquired (e.g. autoimmune haemolytic anaemia)
C Anaemia in the elderly is commonly multifactorial
cardiac failure in elderly individuals. Acute-onset anaemia (e.g.
haemorrhage, haemolysis) is usually symptomatic.
Pathophysiology of anaemia
The average lifespan of an erythrocyte is approximately 120 days,
and senescent erythrocytes are removed by cells of the reticulo-
endothelial system, predominately in the spleen. The loss of
erythrocytes from the circulation is balanced by the production of
new erythrocytes in bone marrow. When the rate of production
falls below the rate of loss of red cells from the circulation, anaemia
ensues (Table 1). Production of erythrocytes within the bone
marrow depends on an adequate supply of nutrients, hormonal
and cytokine stimulation and a functioning bone marrow micro-
environment. Particularly in elderly patients1 or those with multi-
ple co-morbidities, multiple factors can contribute to anaemia.
Classifying and investigating anaemia
Although the kinetic approach to anaemia is useful for under-
standing the pathophysiology, a morphological approach based
on red blood cell volume is more commonly used in clinical
practice. Anaemias are divided into three groups: microcytic
(reduced cell volume), normocytic (normal cell volume) and
macrocytic (increased cell volume).
Beyond establishing symptoms of anaemia, a comprehensive
history should be taken to help identify the cause. This should
include dietary intake, evidence of blood loss, medications, travel,
ethnic origin and family history, as well as co-morbidities. Initial
laboratory investigations should include a full blood count, retic-
ulocyte count, blood film, renal function, bilirubin and measure-
ment of ferritin, vitamin B12 and folate. In cases of inadequate red
cell production unexplained by haematinic or hormonal deficiency,
a bone marrow biopsy is usually required to establish the cause.
Microcytic, hypochromic anaemia
Microcytic, hypochromic anaemias are characterized by a low
mean corpuscular volume (MCV) and mean cell haemoglobin
(MCH). The differential diagnosis includes:
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 ANAEMIA

Kinetic approach to the causes of anaemia

Decreased release of red blood cells into Increased loss of red blood cells from circulation
circulation
Decreased red cell production Red cell destruction (haemolysis) Haemorrhage Splenic pooling

Nutritional: iron/B12/folate deficiency Congenital: membranopathy, Acute: e.g. ruptured vessel Secondary to
Organ dysfunction: renal, liver, enzymopathy, haemoglobinopathy Chronic: e.g. menorrhagia, splenomegaly
endocrine Acquired: immune, fragmentation, gastrointestinal tract loss
Aplasia: drugs, viruses, immune infectious
Infiltration: carcinoma, leukaemia,
fibrosis
Multifactorial: including inflammation

Table 1

 iron deficiency be present, but pencil cells are not seen. The diagnosis of b-
 thalassaemia syndromes (reduced synthesis of a- or b- thalassaemia trait can be made by demonstrating a raised hae-
globin chains) moglobin A2 on a haemoglobinopathy screen.3 A putative diag-
 some cases of anaemia of chronic disease (reduced iron nosis of a-thalassaemia trait is usually made from the red cell
availability) indices and the presence of a normal haemoglobin A2. DNA
 congenital sideroblastic anaemias (defective haem analysis can be performed to confirm the diagnosis where this
synthesis). would influence clinical decision-making (e.g. for confirmation
of an a0 mutation e deletion of both a genes on the same
Iron deciency anaemia chromosome e in partners to ascertain the risk of having a baby
Red blood cells are reduced in size and number, and there is with Barts hydrops fetalis).
increased variation in red blood cell size and shape as the defi-
ciency becomes more severe, reflected in an increased red cell Anaemia of chronic disease
distribution width. The reticulocyte count is reduced as red blood This arises in the context of chronic inflammation including
cell production is impaired. Blood film features include the chronic infection, connective tissue disease, heart failure, ma-
presence of hypochromia (increased central pallor), pencil- lignancy and renal disease. It is most commonly normocytic and
shaped cells and a few target cells. The white cells are normal. normochromic but can be microcytic when an abnormal cytokine
The platelet count can be normal or increased. A low serum profile results in a reduced release of iron from macrophages and
ferritin confirms the diagnosis of iron deficiency. Ferritin is an a functional iron deficiency affecting developing erythroid cells
acute-phase reactant and can be elevated to within the normal within the bone marrow. Other factors (e.g. folate deficiency,
range when iron deficiency occurs in the presence of inflamma- reduced red cell survival) often contribute to the anaemia. The C-
tion. In these circumstances, iron-binding studies demonstrating reactive protein concentration and erythrocyte sedimentation
an increased total iron-binding capacity and low transferrin rate are usually raised. Treatment is directed toward the under-
saturation support the diagnosis of iron deficiency. lying cause(s).
Causes of iron deficiency are listed in Table 2, and the cause
should always be sought. Further investigations can include a Causes of iron deficiency anaemia
coeliac screen, urine dipstick for haematuria, and investigation of
the upper and lower gastrointestinal tract.2 Cause Examples
Management is twofold: replacement of iron and correction of
Inadequate intake Vegetarian/vegan
the underlying cause. Oral iron replacement is the treatment of
Malnutrition
choice and should be continued for a least 3 months after correction
Increased physiological Prematurity and toddlerhood
of the anaemia to replenish the bodys iron stores. With impaired
demands Adolescent growth spurt
absorption or intolerance of oral iron preparations, parenteral iron
Pregnancy
replacement is indicated. Red cell transfusion is reserved for
Impaired absorption Coeliac disease
correction of uncompensated or symptomatic anaemia.
Previous gastrointestinal surgery
Gastrointestinal tract tuberculosis
Thalassaemia trait
Blood loss Menorrhagia
This is suspected where there is a microcytic anaemia with a
Gastrointestinal tract
normal or increased ferritin concentration. The MCH and MCV
Urological tract
are disproportionately low for the haemoglobin compared with
Haemoglobin loss Chronic intravascular haemolysis with
iron deficiency anaemia, and the red cell count is usually high
haemoglobinuria
normal or increased. The blood film shows small blood cells with
little variation in size. Target cells and basophilic stippling may Table 2

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 ANAEMIA

Macrocytic anaemia
Causes of folate deficiency
Macrocytosis can occur in both abnormal red cell production and
haemolysis. Deficiency of vitamin B12 or folate results in impaired Cause Examples
DNA synthesis and abnormal erythrocyte development called
Inadequate intake Poor diet, elderly, alcoholics
megaloblastic anaemia. Similar features can be seen as a result
Malabsorption Coeliac disease
of medications that affect folate metabolism (e.g. methotrexate).
Tropical sprue
Increased red cell destruction results in increased red cell produc-
Increased use or loss Pregnancy, lactation
tion and increased numbers of reticulocytes, which are macrocytic,
Haemolytic anaemias
in the circulation. Other causes of macrocytosis include:
Exfoliative dermatitis
 hypothyroidism
Renal dialysis (loss through membrane)
 excess alcohol intake
Antifolate drugs Methotrexate, trimethoprim, antiepileptics
 liver impairment
 pregnancy (physiological) Table 4
 myelodysplasia
 myeloma. In patients with confirmed vitamin B12 deficiency, anti-
Initial investigation should include a full blood count, retic- intrinsic factor and gastric parietal cell antibodies should be
ulocyte count, vitamin B12 and folate.4 If vitamin B12 and/or requested to investigate for pernicious anaemia. If these are
folate deficiency is identified, it should be treated and the patient negative, gastroscopy should be considered to look for the un-
reassessed before proceeding to further investigations. derlying cause. If there is no obvious cause (e.g. diet, haemolysis)
for folate deficiency, a coeliac screen (anti-endomysial immuno-
Vitamin B12 and folate deciency
globulin A (IgA), anti-tissue transglutaminase IgA) should be
In addition to a macrocytic anaemia, megaloblastic anaemias can
requested. If this is negative, an endoscopy and jejunal biopsy
result in result in a neutropenia or thrombocytopenia; severe
should be considered.
cases are often pancytopenic. The blood film shows evidence of
Vitamin B12 deficiency is treated with intramuscular hydrox-
abnormal red cell production including oval macrocytes and
ycobalamin, given as an initial loading course and then 3-
small numbers of teardrop poikilocytes and fragments. Neutro-
monthly maintenance.4 In folate deficiency, vitamin B12 defi-
phils are hypersegmented.
ciency must be excluded before treatment as folate replacement
Neurological manifestations of vitamin B12 deficiency include:
in the presence of untreated vitamin B12 deficiency can worsen
 peripheral neuropathy in a glove and stocking distribution
the neurological manifestations of vitamin B12 deficiency.
 subacute combined degeneration of the cord from demy-
Treatment of folic acid deficiency is with oral folic acid (1e5 mg).
elination of the posterior and lateral tracts
 memory impairment.
Haemolytic anaemias
Folate deficiency has been associated with neural tube defects
in the developing fetus. Haemolysis occurs where there is increased destruction of red
Causes of B12 and folate deficiency are listed in Tables 3 and 4. blood cells resulting in reduced red cell survival. The initial
The most common cause of B12 deficiency is pernicious anaemia, response of the bone marrow is to increase red cell production,
an autoimmune disorder affecting the gastric parietal cells that resulting in the release of an increased number of reticulocytes
results in reduced intrinsic factor and inability to absorb vitamin and nucleated red blood cells into the circulation (compensated
B12. Folate deficiency is commonly the result of inadequate haemolysis). When the rate of increased production does not
intake. keep up with the rate of destruction, the patient becomes
anaemic (uncompensated anaemia).
Increased red cell breakdown results in release of haemoglo-
Causes of vitamin B12 deficiency bin, which is degraded, producing an unconjugated hyper-
Cause Examples bilirubinaemia. Excess haemoglobin may be excreted in the
urine, resulting in haemoglobinuria, and in chronic haemolysis
Inadequate intake Veganism increased iron may be seen in the epithelial cells shed in the
Intrinsic factor deficiency Autoimmune (pernicious urine (urinary haemosiderin). Splenomegaly is common in hae-
anaemia) molytic anaemias, and chronic haemolysis can result in the for-
Gastric resection mation of pigment gallstones.
Hypochlorhydria Atrophic gastritis The red cells are usually destroyed by macrophages in the
Inadequate binding of vitamin Bacterial overgrowth liver and spleen (extravascular haemolysis). In intravascular
B12 to intrinsic factor (blind-loop syndrome) haemolysis, red cell destruction occurs primarily within the
Fish tapeworm blood vessels. Haemolytic anaemias can be congenital or
Decreased ileal absorption of Ileal resection acquired.
vitamin B12eintrinsic factor Ileal dysfunction (e.g. Crohns
complex disease, tropical sprue) Congenital haemolytic anaemias
Medications (e.g. metformin) Congenital haemolytic anaemias are usually the result of an
inherited abnormality of the red cell membrane, red cell enzymes
Table 3 or globin chain synthesis (Table 5). The history and blood film

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 ANAEMIA

Autoimmune haemolysis can be primary or secondary to an

Classification of haemolytic anaemias autoimmune disorder (e.g. systemic lupus erythematosus) or
Congenital Acquired lymphoproliferative disorders. First-line treatment is with high-
dose corticosteroids (e.g. prednisolone 1 mg/kg) to suppress
Membrane: Immune: the immune response and folic acid supplementation.5 A bone
C Hereditary spherocytosis C Alloimmune: transfusion reac- marrow biopsy can be performed to exclude an underlying
C Hereditary elliptocytosis tion, haemolytic disease of the lymphoproliferative disorder.
Haemoglobin: newborn
C Thalassaemias C Autoimmune: primary, second- Microangiopathic haemolysis
C Sickle cell anaemia ary, drug-induced Abnormalities within small blood vessels can result in a red cell
Enzyme: Non-immune: fragmentation syndrome, usually with concomitant thrombocy-
C G6PD deficiency C Microangiopathic haemolysis topenia, termed microangiopathic haemolysis (MAHA). Causes
C Pyruvate kinase C Other red cell fragmentation include:
deficiency C Infection  disseminated intravascular coagulation
C Paroxysmal nocturnal  malignant hypertension
haemoglobinuria  sclerodermic renal crisis
 viral infection (e.g. cytomegalovirus)
Table 5  disseminated carcinoma
 thrombotic thrombocytopenic purpura
features usually suggest the diagnosis. Glucose-6-phosphate de-  obstetric: pre-eclampsia, HELLP (haemolysis, elevated
hydrogenase (G6PD) deficiency usually manifests as acute hae- liver enzymes, low platelets) syndrome.
molysis following oxidant challenge (e.g. certain drugs, infection, A careful history, blood pressure, coagulation and renal
fava beans) and can be confirmed by measuring reduced enzyme analysis are useful initial investigations to help delineate a cause.
activity. MAHA often arises in the context of an acutely sick patient, and
In addition to disease-specific manifestations, chronic haemo- prompt identification and treatment of the underlying cause is
lytic anaemias are associated with increased risk of gallstone vital. Red cell fragmentation without microangiopathy often has
formation and the risk of an acute aplastic anaemia secondary to a mechanical cause, for example a leaky mechanical heart
parvovirus B19 infection. Routine folic acid supplementation is valve. A
often given because of increased folic acid requirements for red
cell production. In membrane disorders with marked anaemia and KEY REFERENCES
splenomegaly, splenectomy usually ameliorates the anaemia. 1 Price EA, Schrier SL. Anemia in the elderly: introduction. Semin
Hematol 2008; 45: 207e9.
Immune haemolytic anaemias
2 Goddard AF, James MW, McIntyre AS, Scott BB. Guidelines for the
In immune haemolysis, the presence of an antibody against the
management of iron deciency anaemia. Gut 2011; 60: 1309e16.
patients red blood cells in their plasma result in a positive direct
3 Ryan K, Bain BJ, Worthington D, et al. Signicant haemoglobino-
antiglobulin test. Patients usually present with acute symptom-
pathies: guidelines for screening and diagnosis. Br J Haematol
atic anaemia with jaundice, reticulocytosis and a positive direct
2010; 149: 35e49.
antiglobulin test.
4 Devalia V, Hamilton MS, Molloy AM. Guidelines for the diagnosis
In immune transfusion reactions, the transfusion of red blood
and treatment of cobalamin and folate disorders. Br J Haematol
cells with antigens different from those on the recipient results in
2014; 166: 496e513.
the formation of an antibody against the donor blood cells and
5 Lechner K, Jager U. How I treat autoimmune hemolytic anemias in
haemolysis of the transfused cells. Haemolytic anaemia of the
adults. Blood 2010; 116: 1831e8.
newborn is the result of transplacental passage of maternal an-
tibodies against the babys red blood cells.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 Investigations
 Haemoglobin 71 g/litre (115e165)
A 35-year-old woman presented with a 3-month history of fatigue
 Mean corpuscular volume 69 fl (80e96)
and a 2-week history of dizziness on climbing the stairs.
 White cell count 8.6  109/litre (4.0e11.0)
Clinical examination was non-contributory.
 Platelets 512  109/litre (150e400)

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 ANAEMIA

What is likely to be the best treatment for her? C Delayed haemolytic transfusion reaction
A Folic acid replacement D Autoimmune haemolytic anaemia
B Vitamin B12 replacement E Folate deficiency
C Iron replacement
D Red cell transfusion
Question 3
E Gluten-free diet
A 51-year-old woman presented feeling non-specifically unwell
with a sore mouth. There was no history of dysphagia or weight
Question 2
loss. She had a past medical history of essential hypertension and
A 63-year-old man presented with a 5-day history of lethargy and hypothyroidism. She had a normal diet. Medications were ram-
jaundice. He had a history of ulcerative colitis and had had a ipril 2.5 mg once daily and thyroxine 75 micrograms once daily.
right hemi-colectomy 6 months previously, when he required a On clinical examination, she had some areas of skin hypo-
blood transfusion. pigmentation but no other abnormalities.
Clinical examination showed him to be jaundiced, with a pulse of
80 beats/minute and blood pressure 135/88 mmHg. A urine Investigations
sample was negative for bilirubin and positive for urobilinogen.  Haemoglobin 71 g/litre (115e165)
 Mean corpuscular volume 126 fl (80e96)
Investigations  Neutrophils 1.2  109/litre
 Haemoglobin 61 g/litre (130e180)  Platelets 69  109/litre (150e140)
 Mean corpuscular volume 109 fl (80e96)  Reticulocytes 20  109/litre (25e85)
 Reticulocytes 368  109/litre (25e85)
 Blood film showing spherocytes, polychromasia and
What is the most likely diagnosis?
nucleated red blood cells.
A Gastric carcinoma
B Fanconi syndrome
What is the most likely diagnosis? C Pernicious anaemia
A Hepatitis B infection D Autoimmune haemolytic anaemia
B Hereditary spherocytosis E Folate deficiency

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