Assessment of anaemia

The right clinical information, right where it's needed

Last updated: Apr 19, 2018

 Table of Contents
Summary 3

Overview 5
Aetiology 5

Emergencies 14
Urgent considerations 14
Red flags 16

Diagnosis 18
Step-by-step diagnostic approach 18
Differential diagnosis overview 27
Differential diagnosis 30
Diagnostic guidelines 52

References 54

Images 59

Disclaimer 65
 Summary

◊ Anaemia is defined as a haemoglobin (Hb) level <120 g/L (<12 g/dL) in females and <140 g/
L (<14 g/dL) in males, or as a Hb level <125g/L (<12.5 g/dL) in adults.[1] [2] [3] It is the most
common haematological disorder seen in general medical practice. Risk factors include extremes
of age, female gender, lactation, and pregnancy. The most common cause internationally is iron
deficiency.[4] Anaemia can cause significant morbidity if left untreated, and is often the presenting
sign of a more serious underlying condition.[5] The rate at which anaemia develops is often as
important as the severity, as a rapid decline can overwhelm the compensatory mechanisms of the
body.

◊ Pathophysiology :
Erythropoiesis takes place within the bone marrow and is controlled by the stromal network,
cytokines, and the hormone erythropoietin. A series of differentiation steps results in the generation
of reticulocytes (RBCs with an intact ribosomal network). Reticulocytes remain in the bone marrow
for 3 days before being released into the circulation. After one further day in the circulation,
reticulocytes lose their ribosomal network and become mature RBCs, which circulate for 110 to 120
days before being removed from the circulation by macrophages. At steady state, the rate of RBC
production equals the rate of RBC loss.
Haemolytic anaemias are a group of anaemias produced by increased destruction of RBCs with a
resultant increase in circulating indirect bilirubin.[6] [7] Clinical jaundice appears once bilirubin levels
rise above 34.2 to 68.4 mmol/L (2-4 mg/dL). Additional disease-specific symptoms may also be
present. The resulting anaemia can be microcytic or hyperproliferative normocytic, depending on the
cause.
Microangiopathic haemolytic anaemias are often considered as a group. They produce a
hyperproliferative normocytic anaemia. The underlying disease process produces endothelial
damage and activates the coagulation cascade, leading to fibrin deposition on the damaged
endothelial surfaces. In small vessels, the endothelial fibrin causes mechanical fragmentation and
shearing of RBCs, leading to haemolysis. The irregular-shaped RBC fragments produced by this
process are called schistocytes and can be seen on a peripheral blood smear.

◊ Morphological classification of anaemia :

The most clinically useful classification system is based on the mean corpuscular volume (MCV).[8]
[9] [10]
• Microcytic (MCV <80 femtolitres [fL]).
[Fig-1]
• Normocytic (MCV 80-100 femtolitres [fL]); further subclassified according to the reticulocyte
count as:
• Hyperproliferative (reticulocyte count >2%): the proportion of circulating reticulocytes
increases as part of a compensatory response to increased destruction or loss of RBCs.
The cause is usually acute blood loss or haemolysis.

• Hypoproliferative (reticulocyte count <2%): these are primarily disorders of decreased

RBC production, and the proportion of circulating reticulocytes remains unchanged.
• Macrocytic (MCV >100 femtolitres [fL]); further subclassified as:
• Megaloblastic: a deficiency of DNA production or maturation resulting in the appearance
of large immature RBCs (megaloblasts) and hypersegmented neutrophils in the
circulation.

[Fig-2]
• Non-megaloblastic: encompasses all other causes of macrocytic anaemia in which DNA
synthesis is normal. Megaloblasts and hypersegmented neutrophils are absent.

Classification of anaemia: MCV, mean corpuscular volume; fL, femtolitres

Created by the BMJ Knowledge Centre

Assessment of anaemia Overview

Aetiology
Anaemia occurs when the production of RBCs is decreased, the destruction of RBCs is accelerated, or there
is a loss of RBCs due to bleeding. In many cases, a combination of these mechanisms is present. Anaemia

OVERVIEW
is the most common haematological disorder seen in general medical practice. Risk factors include extremes
of age, female gender, lactation, and pregnancy.

Blood loss
Acute haemorrhage

• Any acute haemorrhage can cause a normocytic anaemia. A reticulocytosis is seen within 6 hours of
the onset of bleeding. By contrast, chronic slow bleeding leads to ongoing iron loss and produces a
microcytic anaemia due to iron deficiency.
• The most common causes are trauma (including gunshot wounds, major fractures, or crush injuries),
acute GI bleeding, rupture of a vascular aneurysm (especially abdominal aortic aneurysm), and recent
surgery.
• Patients are at increased risk of haemorrhage if they are taking anticoagulant therapy, have an
underlying defect in haemostasis, or have a consumptive or dilutional coagulopathy following repeated
blood transfusions.
Gradual, prolonged bleeding

• Bleeding due to any cause produces iron depletion, because two-thirds of the total body iron is
contained in circulating haemoglobin (Hb).
• Excessive menstrual losses are a common cause in females.
• The GI tract is a common site of bleeding. Common causes include haemorrhoids, salicylate ingestion,
peptic ulcer disease, hiatal hernia, diverticulosis, neoplastic disease, and ulcerative colitis.
• Rare causes include hookworm, milk allergy in infants, Meckel's diverticulum, schistosomiasis,
trichuriasis, and hereditary haemorrhagic telangiectasia. Rare sources of blood loss from other
sites include pulmonary bleeding (seen in idiopathic pulmonary haemosiderosis and Goodpasture's
syndrome), blood donation, and self-harm. In addition, any underlying disorder that impairs
haemostasis increases the risk of bleeding and iron deficiency anaemia.

Nutrient deficiency or depletion

Iron deficiency anaemia[8] [11] [12] [13]

• The most common cause of anaemia worldwide. It includes a range of underlying causes.
Approximately 4% of women in the US aged between 20 and 49 years have been estimated to be
iron deficient.[14] The formation of the haem moiety in Hb, myoglobin, and cytochrome requires iron;
inadequate intake or absorption of iron, or excessive iron loss, leads to a microcytic anaemia.
• Meat provides the main source of haem iron, and iron deficiency is common in geographical regions
where meat is sparse and there is poor dietary iron intake. There is a strong relationship between
pica (a medical disorder in which children develop an appetite for non-nutritive substances) and iron
deficiency.
• Gradual prolonged bleeding due to any cause produces iron depletion, because two-thirds of the total
body iron is contained in circulating Hb.

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 Assessment of anaemia Overview
• Iron malabsorption occurs due to achlorhydria, gastric surgery, destruction of small bowel absorptive
area in chronic diseases such as coeliac disease, or following extensive resection of the proximal
small bowel.
• Runner's anaemia is caused by volume expansion accompanied by increased destruction of RBCs
OVERVIEW

due to repetitive impact of the foot on the ground.

• Haemoglobinuria (iron loss in the urine) is rare. The usual cause is paroxysmal nocturnal
haemoglobinuria, but haemoglobinuria can occur following rapid intravascular haemolysis of any
cause.
Vitamin B12 deficiency[10]

• Vitamin B12 is an essential co-factor in DNA synthesis, being obtained only from the diet or by
supplementation. Dietary sources include animal and dairy products such as meat, poultry, milk, and
eggs. Deficiency produces neurological disorders and a megaloblastic anaemia.
• Causes include decreased dietary intake (e.g., chronic malnutrition, alcohol abuse, strict vegan diets),
diminished breakdown of dietary vitamin B12 (due to pernicious anaemia, previous gastric or intestinal
surgery, atrophic gastritis), or malabsorption (gastric malabsorption, Crohn's disease, coeliac disease,
bacterial overgrowth). A systematic review of the literature concluded that there is no clear evidence
linking anaemia to subnormal B12 levels in the geriatric population.[15]
Folate deficiency[10] [16]

• Folate is an essential co-factor in DNA synthesis, being obtained only from the diet or by
supplementation. Dietary sources include green leafy vegetables, citrus fruits, and animal products.
Deficiency produces a range of signs, including a swollen, red, painful tongue; angular stomatitis;
patchy hyperpigmentation of the skin and mucous membranes; a persistent mild pyrexia (in the
absence of infection); and a megaloblastic anaemia.
• Common causes include decreased dietary intake (e.g., chronic malnutrition, alcohol abuse, dietary
restriction of protein intake), impaired absorption (achlorhydria, coeliac disease, tropical sprue, zinc
deficiency, bacterial overgrowth), and increased folate requirement (infancy, pregnancy, lactation,
malignancy).
• Patients with vitamin B12 deficiency can have excessive renal folate excretion. Similarly, chronic
alcohol abuse can lead to excessive biliary folate excretion.
• Rarely, hypothyroidism and congenital enzyme deficiencies may impair folate metabolism.

Generalised malnutrition

• Often causes iron deficiency. Patients often have associated vitamin B12 and/or folate deficiency, in
which case the resulting anaemia is normocytic. Associated copper deficiency is rare, but should be
considered in patients on prolonged total parenteral nutrition (TPN).

Acquired bone marrow disease

Myelodysplastic syndrome[17]

• A heterogeneous group of clonal stem cell disorders. Uncontrolled proliferation and clonal expansion
of neoplastic multipotential haematopoietic stem cells compromise the production of normal cells,
producing a range of cytopenias.
• Usually due to acquired chromosomal abnormalities, but can be caused by chemotherapy or
radiotherapy.

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Assessment of anaemia Overview
• The anaemia is a non-megaloblastic macrocytic anaemia, but the peripheral blood smear may show
hypersegmented neutrophils similar to those seen in megaloblastic macrocytic anaemias. A normal
random distribution of red cell width (RDW) in the setting of macrocytic anaemia in an older adult
should raise this suspicion.

OVERVIEW
Leukaemias

• Acute lymphocytic leukaemia, acute myelogenous leukaemia, and chronic myelogenous leukaemia
are caused by the uncontrolled proliferation and clonal expansion of abnormal progenitor cells. These
diseases affect progenitor cells at different stages of the differentiation process, but all cause anaemia
by compromising the production of normal RBCs.
Infiltration of the bone marrow by secondary malignancy

• Metastasis of solid tumours to the bone marrow can cause anaemia by infiltration of the marrow
space. Any tumour can metastasise to the bone marrow, but the most commonly seen are
neuroblastoma in children, and breast, prostate, and lung cancer in adults. Metastasis to the bone
marrow is a poor prognostic sign.
Aplastic anaemia (AA)[18] [19]

• A disorder of stem cell failure, leading to pancytopenia in the absence of splenomegaly.

• Can be due to an inherited bone marrow failure syndrome or acquired (induced by a variety of
disorders, e.g., autoimmune or toxic) where immune mechanisms with local activation of interferon
gamma may be a common aetiological pathway.

• Affected patients typically present with recurrent infections due to neutropenia, bleeding episodes due
to thrombocytopenia, and, less often, fatigue due to anaemia.

• Toxic causes include benzene, dipyrone, chloramphenicol, penicillamine, and gold.

• Patients with paroxysmal nocturnal haemoglobinuria can develop aplastic anaemia, although the
mechanism is not known.

• Definitive diagnosis is established following bone marrow aspiration and biopsy. In AA, characteristic
findings include the following:[18]

• Profoundly hypocellular marrow with a decrease in all elements; marrow space is composed of
fat and marrow stroma

• Residual haematopoietic cells that are morphologically normal

• The absence of malignant infiltrates or fibrosis

• Haematopoiesis is non-megaloblastic.

Pure red cell aplasia

• Caused by congenital or acquired impairment of erythroid progenitor cells. Acquired forms can be self-
limiting or chronic.
• Self-limiting acquired disease can be caused by infections or medications. The most common
infectious cause is parvovirus B19. Other infectious causes include infectious mononucleosis, viral
hepatitis, malaria, respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps.

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 Assessment of anaemia Overview
• Medications exert a toxic effect on erythroid progenitor cells that is reversible once the medication
is discontinued. Examples include anti-epileptic medications (phenytoin, carbamazepine, valproate
sodium), azathioprine, chloramphenicol (which can also cause aplastic anaemia), sulphonamides,
isoniazid, and procainamide.
OVERVIEW

• Chronic acquired disease is caused by autoimmune diseases (e.g., SLE, rheumatoid arthritis,
dermatomyositis, polyarteritis nodosa, scleroderma), persistent infection (persistent parvovirus B19
infection in immunosuppressed patients, chronic active hepatitis), and thymomas.
• Congenital forms are produced by in-utero damage of erythroid progenitor cells. The cause is
unknown.
• Autoimmune diseases can also cause autoimmune haemolytic anaemia.

Toxin exposure
Drugs

• Certain drugs may produce immune-mediated or direct RBC haemolysis; interfere directly with DNA
synthesis; impair the absorption, metabolism, or action of important DNA synthesis co-factors; or have
a toxic effect on progenitor cells in the bone marrow.
• A wide range of drugs are known to cause haemolytic anaemia. Common examples include penicillin,
methyldopa, levodopa, quinidines, cephalosporins, and some non-steroidal anti-inflammatory drugs
(NSAIDs).
• Drugs that directly interfere with DNA synthesis include purine analogues (6-mercaptopurine,
tioguanine, aciclovir), pyrimidine analogues (5-fluorouracil, azacitidine, zidovudine), and ribonucleotide
reductase inhibitors (hydroxycarbamide, cytarabine arabinoside).
• Antifolates act by impairing folic acid function, and include methotrexate and trimethoprim.
Anticonvulsants (phenytoin, phenobarbital, primidone) interfere with folate absorption. Other drugs that
can decrease folate levels include oral contraceptives and cycloserine.
• Drugs that interfere with vitamin B12 metabolism include p-aminosalicylic acid, metformin, colchicine,
neomycin, and biguanides.
• Drugs and chemicals that produce a toxic effect on a range of progenitor cells, producing aplastic
anaemia, include benzene, chloramphenicol, penicillamine, and gold.
• Drugs that produce a toxic effect on erythroid progenitor cells, producing pure red cell aplasia,
include anti-epileptic medications (phenytoin, carbamazepine, sodium valproate), azathioprine,
chloramphenicol (which can also cause aplastic anaemia), sulfonamides, isoniazid, and procainamide.
• Drugs that inhibit erythroid stimulation and suppress erythropoetin production include ACE inhibitors
and angiotensin-II receptor blockers.[20]
Radiation exposure

• Radiation exposure can produce a pancytopenia.

Lead toxicity

• Occurs after occupational or home exposure to lead. Anaemia can occur because lead competes with
zinc, an important co-factor in haem synthesis. Some patients also have a concurrent iron deficiency
anaemia.
Alcohol abuse

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Assessment of anaemia Overview

• Long-term alcohol intake directly suppresses the bone marrow, independent of any concurrent liver
disease or vitamin deficiency. The effect resolves only after months of abstinence, and may persist
even after normalisation of vitamin B12 and folate levels.

OVERVIEW
Chronic systemic disease
Anaemia of chronic disease[8] [21]

• Can be a mild hypoproliferative normocytic anaemia or a microcytic anaemia, depending on the

severity. It is caused by chronic inflammation. Proinflammatory cytokines, especially interleukin-6
(IL-6), trigger a cascade of events, mediated via upregulation of hepcidin, that decrease RBC
production (by lowering serum iron and erythropoietin levels) and increase RBC destruction (by
stimulating erythrophagocytosis and oxygen free radical formation).[22]
• Common underlying processes include infection, neoplasms, autoimmune reactions, and injury to
tissue from trauma or major surgery.
Chronic kidney disease[23]

• Produces a normocytic or microcytic anaemia. The aetiology is complex and multifactorial. The
main cause is decreased erythropoietin production, leading to decreased RBC production and a
hypoproliferative normocytic anaemia. Inhibitors of erythropoiesis accumulate, further exacerbating
the effects of decreased erythropoietin. Serum ferritin may be elevated in chronic kidney disease,
but patients should still receive concurrent iron supplementation with erythropoietin-stimulating agent
(ESA) therapy as long as serum ferritin is <500 micrograms/L.[24]
• Other causes of anaemia may also be present. Secondary hyperparathyroidism exacerbates anaemia
in patients with renal failure, but the mechanism is unclear. Concurrent hyperparathyroidism should
also be addressed, as treatment improves the management of anaemia in this setting.[24] Chronic
blood loss, inflammation, and nutritional deficiency cause an iron deficiency anaemia (which would be
microcytic rather than normocytic). Patients often need to reduce their protein intake, which leads to
decreased meat in the diet and poor iron intake. Poor iron absorption may also occur. Erythropoietin
therapy and chronic inflammation can cause functional iron deficiency, produced by an inability to
mobilise iron stores effectively.
Chronic liver disease

• A mild to moderate non-megaloblastic macrocytic anaemia is a common feature of a range of

liver diseases, and is produced by a combination of intravascular dilution due to volume overload,
increased RBC destruction, and impaired bone marrow compensatory responses.
Hypothyroidism

• Causes a mild hypoproliferative normocytic anaemia due to the loss of the stimulatory effect of thyroid
hormones on erythropoiesis.

Immune reactions
Autoimmune haemolytic anaemia[25]

• RBCs are attacked by autoantibodies and targeted for extravascular destruction. This usually occurs
either as part of other autoimmune conditions (e.g., SLE, rheumatoid arthritis, or scleroderma) or in

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 Assessment of anaemia Overview
relation to a lymphoproliferative disorder (usually non-Hodgkin's lymphoma or chronic lymphocytic
leukaemia).
• Autoimmune diseases can also cause pure red cell aplasia.

Alloimmune haemolytic anaemia

OVERVIEW

• Can be caused by transfusion reactions, usually due to ABO incompatibility.

Infections
A range of infections can produce a haemolytic anaemia, including cytomegalovirus (CMV), infectious
mononucleosis, and toxoplasmosis. Leishmaniasis produces combined RBC haemolysis, bone marrow
suppression, and blood loss.

Causes of pure red cell aplasia include parvovirus B19, infectious mononucleosis, viral hepatitis, malaria,[26]
respiratory infections, gastroenteritis, primary atypical pneumonia, and mumps.

Genetic disorders
Thalassaemias[27] [28]

• Haemolytic anaemias. A group of autosomal-recessive genetic conditions that result in decreased or

absent production of the alpha-globin (alpha-thalassaemia) or beta-globin (beta-thalassaemia) chains
in the Hb molecule. The decreased or absent globin production results in impairment of erythropoiesis.
Increased RBC destruction occurs, producing haemolytic anaemia.
• Alpha-thalassaemia has at least 4 distinct forms: silent carrier (1 affected alpha-globin gene), which
does not cause anaemia; alpha-thalassaemia trait (2 affected alpha-globin genes); Hb H disease
(typically 3 affected alpha-globin genes); and Hb Bart hydrops fetalis syndrome (typically deletion of
all 4 alpha-globin genes), which is incompatible with life. PCR DNA testing and Southern blot analysis
may be used to determine the specific defect in alpha-thalassaemia trait.[29]
• Beta-thalassaemia is classified as silent carrier, beta-thalassaemia minor, beta-thalassaemia
intermedia, or beta-thalassaemia major, depending on the clinical and haematological features.
Disease severity depends on the underlying mutation, and ranges from asymptomatic (in silent carriers
and beta-thalassaemia minor) to a severe transfusion-dependent anaemia with skeletal changes (beta-
thalassaemia major). Note that in the presence of iron deficiency, a normal HbA2 does not exclude
beta-thalassaemia trait. Genetic testing is not typically performed as increases in haemoglobin F are
readily seen on electrophoresis.
Sickle cell anaemia[27]

• A haemolytic anaemia caused by an autosomal-recessive single gene defect in the beta chain of Hb
(HbA), which results in sickle cell Hb. RBCs containing sickle cell Hb become rigid and are distorted
into a crescent shape.
• Patients are prone to episodes of vaso-occlusion due to the rigid, deformed RBCs, and to a
prothrombotic state created by the accompanying leukocytosis, which increases cytokine release.
Persistent pain in the abdomen, chest, or skeleton and dactylitis are the key presenting symptoms.
Hereditary spherocytosis

• A haemolytic anaemia caused by an autosomal-dominant inherited abnormality of RBCs that produces

defects in the skeletal proteins of the red cell membrane. As a result, RBCs lose their biconcave

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Assessment of anaemia Overview
structure and become spherical (spherocytes). Spherocytes are fragile, and are selectively removed
and destroyed by the spleen. Increased RBC destruction leads to anaemia with hyperbilirubinaemia
and splenomegaly.
• Disease severity ranges from asymptomatic to a transfusion-dependent anaemia with jaundice,

OVERVIEW
depending on the severity of the underlying membrane defect.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency[30]

• An inherited (X-linked) haemolytic anaemia due to an enzyme deficiency that is common among
populations originating from parts of the world where malaria is or was common, such as sub-Saharan
Africa, Asia, the Mediterranean region, and the Middle East.
• G6PD catalyses a reaction that is linked to the generation of reduced glutathione, a key antioxidant
defence of the cell. Deficiency of the enzyme renders cells vulnerable to oxidant damage towards the
end of their lifespan. RBCs rely solely on reduced glutathione as an antioxidant defence, so deficiency
of G6PD increases RBC destruction.
• The severity of the disease varies, depending on the severity of the underlying mutation. Most patients
are asymptomatic. Symptomatic disease produces episodes of acute haemolysis, with pallor and
jaundice, following exposure to oxidant stress. Triggers include fava beans (favism), sulfa drugs,
aspirin, nitrofurantoin, naphthalene, and febrile illness. The resulting haemolysis is usually self-limiting.
Life-threatening symptoms are more common with the Mediterranean variant.
Congenital bone marrow failure syndromes

• Fanconi anaemia is the most common. It is usually autosomal recessive, but can also be X-linked.
Mutations in 13 genes have been identified. The genes code for proteins that form a nuclear complex
involved in the DNA damage response. However, the precise mechanisms by which the mutations
produce bone marrow failure are not known.
• Dyskeratosis congenita is characterised by the triad of abnormal nails, reticulated skin rash, and
leukoplakia. X-linked, autosomal-dominant, and autosomal-recessive inheritance patterns have been
observed. The genetic defects all decrease telomerase function. Telomeres maintain chromosomal
stability, and the bone marrow is heavily dependent on telomere preservation to support its high rate of
cell proliferation. Loss of telomerase produces bone marrow failure.
• Shwachman-Diamond syndrome is a rare autosomal-recessive disease that produces exocrine
pancreatic dysfunction, anaemia, neutropenia (which can be intermittent), and skeletal abnormalities.
About 90% of patients harbour mutations in a gene known as the SBDS gene, but the relationship of
the mutations to bone marrow failure is not understood.

Microvascular disease
Haemolytic uraemic syndrome (HUS)[31]

• Damage to the endothelium of the glomerular bed produces haemolytic anaemia (due to fragmentation
and shearing of RBCs), thrombocytopenia (due to platelet consumption), and nephropathy.
• Causes include verotoxins, produced by Escherichia coli ; neuraminidase, produced by streptococcal
species; inherited defects in proteins that control complement; and drugs (cyclosporine and some
chemotherapy agents).
Disseminated intravascular coagulation (DIC)[31] [32]

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 Assessment of anaemia Overview

• An acquired syndrome produced by activation of coagulation pathways, resulting in the formation of

intravascular thrombi and the depletion of platelets and coagulation factors.
• DIC can be triggered by major trauma; burns; organ failure (pancreatitis, acute liver failure); sepsis[33]
or severe infection; severe obstetric disorders (amniotic fluid embolism, eclampsia, abruptio placentae,
OVERVIEW

retained dead fetus syndrome); malignancies (acute myelocytic leukaemia or metastatic mucin-
secreting adenocarcinoma); major vascular disorders (haemangiomas, large aortic aneurysms); and
severe toxic or immunological reactions.
• A haemolytic anaemia is produced by fragmentation and shearing of RBCs against clots in the small
vessels.
Thrombotic thrombocytopenic purpura (TTP)[31] [34]

• A clinical syndrome of microangiopathic haemolytic anaemia and thrombocytopenic purpura.

• Believed to be due to the production of abnormally large von Willebrand factor (vWF) multimers. The
abnormal vWF triggers aggregation of circulating platelets at sites of high intravascular shear stress,
which in turn results in thrombi in the microvasculature system.
• A haemolytic anaemia is produced by fragmentation and shearing of RBCs against clots in the small
vessels. Thrombocytopenia is produced by excessive consumption of platelets; purpura and other
signs of bleeding appear in a small proportion of patients. Thrombus formation in the microvasculature
also produces severe CNS symptoms and renal disease.
Haemangiomas[31]

• Vascular tumours that occur as a result of abnormal angiogenesis and overproliferation of blood
vessels. They occur in a wide range of locations, ranging from obvious superficial lesions to internal
organs.
• A local consumptive coagulopathy (Kasabach-Merritt syndrome) can occur as a complication, leading
to thrombus formation and thrombocytopenia. Shearing and fragmentation of RBCs against the clots in
the small vessels of the haemangiomas can lead to a haemolytic anaemia.
• Kasabach-Merritt syndrome can also produce DIC in severe cases.

Malignant hypertension

• A hypertensive emergency with systolic BP >210 mmHg and diastolic BP >130 mmHg, associated with
rapid deterioration of vital organ function. Common causes include untreated essential hypertension,
renal disease, eclampsia, use of sympathomimetic drugs, and use of monoamine oxidase inhibitors.
The disease is more common in older people, males, and those of black ethnicity.
• Causes endothelial injury and endothelial fibrin deposition. Mechanical RBC shearing and
fragmentation, resulting from high pressures and fibrin in the small vessels, produces haemolytic
anaemia.
Prosthetic valves and surfaces[35]

• The shear stresses and turbulence created by the foreign surface cause shearing and fragmentation
of RBCs. Improved prosthetics have reduced the incidence of this complication, and the anaemia, if it
occurs, is usually mild.

Other causes
Pregnancy[36]

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Assessment of anaemia Overview

• Anaemia in pregnancy may be due to a dilutional effect, as the plasma volume expands out of
proportion to the RBC mass. To account for this effect, anaemia in pregnancy is defined as an Hb <10
g/dL. Iron deficiency is the cause in 95% of cases, due to an increase in demand for iron, and one
third of women will have either iron deficiency or folate deficiency by the third trimester.[37]

OVERVIEW
• Despite being an important problem in pregnancy with effective treatment available, there is a lack of
high-quality evidence on the benefits of a national screening programme for anaemia in pregnancy in
terms of improved maternal and infant morbidity.[38]
Thermal burns

• Patients with burns affecting more than 10% of the body's surface area can develop a haemolytic
anaemia due to intravascular haemolysis of RBCs (at the site of the burn and systemically), loss of red
cell mass due to thrombus formation, and damage to RBCs from systemically released proteases and
oxygen free radicals.[39]
Hospital-acquired anaemia

• New-onset anaemia in hospitalised patients with previously normal haemoglobin. Hospital-acquired

anaemia (HAA) is typically related to increased phlebotomy and iatrogenic blood loss from invasive
procedures or haemodilution. Acute inflammatory response to illness decreases compensatory
erythropoesis. HAA is associated with increased morbidity and length of hospital stay.[40]

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 Assessment of anaemia Emergencies

Urgent considerations
(See Differential diagnosis for more details)
Anaemia is life threatening if there is more than 40% loss of total body volume. These patients should
receive packed RBC transfusions for stabilisation as soon as possible, especially if there are underlying
cardiac or pulmonary comorbidities. A reticulocyte count, ferritin, and peripheral smear should be obtained
before transfusion, if possible, as this makes subsequent work-up more accurate. Dilutional, or consumptive,
coagulopathy from tissue injury may result from the decrease of platelets and coagulation factors (factor V,
factor VIII, and fibrinogen) in massive transfusions and must be corrected by the addition of these factors.

Generally, healthy individuals tolerate extreme anaemia well, with cardiovascular status being the major
limiting factor. The landmark TRICC study showed that, in haemodynamically stable patients without active
bleeding, Hb levels between 70 g/L (7 g/dL) and 90 g/L (9 g/dL) were well tolerated with equivalent or
lower mortality/morbidity outcomes compared with a liberal transfusion trigger of <100 g/L (<10 g/dL).[41]
It is generally recommended that determination of transfusion requirements be based upon severity of
illness parameters rather than arbitrary Hb levels. Clinical guidelines from the AABB (formerly known as
EMERGENCIES

the American Association of Blood Banks) suggest a restrictive transfusion threshold of 70 g/L (7 g/dL) in
hospitalised haemodynamically stable patients, and 80 g/L (8 g/dL) in those undergoing orthopaedic or
cardiac surgeries, or with pre-existing cardiovascular disease, unless there is an underlying acute coronary
syndrome, severe thrombocytopenia, or chronic transfusion dependence.[42] Transfusion thresholds in
ischaemic CAD and resuscitation of septic shock remain controversial.

Acute haemorrhage
Causes of acute haemorrhage include trauma (such as gunshot wounds, major fractures, and crush injuries),
acute GI bleeding, rupture of a vascular aneurysm (especially abdominal aortic aneurysm), and recent
surgery. Rapid evaluation, identification, and control of bleeding are essential before any further work-up.
Dilution does not occur acutely, so haemoglobin (Hb) and haematocrit levels do not provide an accurate
reflection of the degree of blood loss and anaemia. Perfusion to critical organs must be maintained through
early goal-directed therapy, including crystalloid volume resuscitation (using 2-4 times the estimated volume
of blood loss), blood pressure support, and tissue perfusion.

A meta-analysis concluded that the use of hydroxyethyl starch solutions to decrease volume overload in large
volume resuscitations was associated with increased risk of acute kidney injury and death. [43] Hydroxyethyl
starch solutions are not available in some countries, or their use is restricted. In January 2018, the European
Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) recommended suspending
marketing authorisations for hydroxyethyl starch solutions for infusion across the European Union.

Cross-matched blood (or O negative, if cross-match is unavailable) should be given as soon as possible.

In addition, bleeding following major trauma requires coagulation support and monitoring, and the
appropriate use of local haemostatic measures, tourniquets, calcium, desmopressin, and consideration for
tranexamic acid.[44] [45]

Tranexamic acid has been shown to reduce mortality in trauma patients with haemorrhage when given within
3 hours of injury, so should be administered as soon as possible in people with acute severe haemorhage
due to trauma.[44] [46] A meta-analysis of data from over 40,000 patients with traumatic bleeding or post-
partum haemorrhage found that delays in administration of tranexamic acid were associated with reduced

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Assessment of anaemia Emergencies
survival (survival benefit decreasing by about 10% for every 15 minutes of treatment delay until 3 hours, after
which there was no benefit).[47]

Definitive management of acute haemorrhage depends on the underlying cause, but usually requires
surgery.

Microangiopathic haemolytic anaemias

Haemolytic uraemic syndrome, disseminated intravascular coagulation (DIC), and thrombotic
thrombocytopenic purpura (TTP) produce life-threatening rapid haemolysis.[48] The underlying cause must
be quickly assessed and treatment tailored accordingly to minimise end-organ damage and the likelihood of
death. Treatment of DIC is aimed at the underlying cause. Corticosteroids and immunosuppression should
be commenced if haemolytic uraemic syndrome or TTP are suspected. Intravenous immunoglobulins (IVIG)
or urgent plasmapheresis may be necessary for rapid clearance of autoantibodies. Antibody screening
should be done prior to blood transfusion. Antibody-free blood products should be used to prevent additional
alloimmune haemolysis.

EMERGENCIES
Malignant hypertension
This condition is characterised by very high blood pressure in association with bilateral retinal changes,
including exudates and haemorrhages, with or without papilloedema. The most common symptoms include
headaches (often occipital), visual disturbances, chest pain, dyspnoea, and neurological deficits. Results
include cerebral infarction or haemorrhage, transient blindness or paralyses, seizures, stupor, or coma.
The initial goal of therapy in hypertensive emergencies is to reduce mean arterial BP by no more than 25%
(within minutes to 1 hour), then, if stable, to 160/100 to 110 mmHg within the next 2 to 6 hours. Labetalol is
the agent of choice.

Sickle cell vaso-occlusive crisis

This is a common complication of sickle cell anaemia, which presents with severe pain precipitated by
cold, dehydration, infection, or ischaemia (often due to strenuous exercise). The crisis may give rise
to skeletal pain due to bone infarction or avascular necrosis, especially of the hip or shoulder. Other
presentations include acute abdominal pain and acute chest syndrome, which is clinically indistinguishable
from pneumonia. Treatment involves adequate analgesia, hydration with oral or intravenous fluids, oxygen,
and treatment of the underlying cause.

Combined vitamin B12 and folate deficiency

If a patient has folate deficiency, it is essential to check for and correct any co-existing vitamin B12 deficiency
before giving folate. Folate is believed to exacerbate inhibition of vitamin B12-containing enzymes, thereby
worsening vitamin B12-associated neuropathy and subacute combined degeneration of the cord.[49] If
vitamin B12 levels are normal, methylmalonic acid levels should be checked to definitively exclude vitamin
B12 deficiency, as this is a more sensitive test. An elevated serum methylmalonic acid indicates vitamin B12
deficiency, unless there is a history of renal insufficiency, where levels may be artificially elevated due to
inadequate renal clearance.

Leukaemias or aplastic anaemia

Usually present with a normocytic anaemia and co-existing neutropenia and thrombocytopenia. Circulating
blasts may be reported on peripheral smear. If these conditions are suspected, an immediate haematology
consultation is required for bone marrow biopsy and flow cytometry studies. If the anaemia requires

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 Assessment of anaemia Emergencies
transfusion, only leuko-reduced, irradiated blood products should be used, as these patients may be
transplant candidates.[50] [51]

Decreased physiological reserve

It is important to identify patients with decreased physiological reserve, such as those with co-existing
cardiovascular or pulmonary disease, as these patients are less able to tolerate anaemia and have more
severe symptoms.

Red flags
• Trauma

• Acute GI bleeding

• Rupture of a vascular aneurysm

EMERGENCIES

• Surgery

• Generalised malnutrition

• Myelodysplastic syndrome

• Acute lymphocytic leukaemia

• Acute myelogenous leukaemia

• Chronic myelogenous leukaemia

• Hairy cell leukaemia

• Acquired aplastic anaemia

• Infiltration by secondary malignancy

• Cytotoxic chemotherapy

• Radiotherapy

• Lead toxicity

• Anaemia of chronic disease

• Transfusion reaction

• Malaria

• Viral hepatitis

• Toxoplasmosis

• Leishmaniasis

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Assessment of anaemia Emergencies
• Bone marrow failure syndromes

• Haemolytic uraemic syndrome

• Disseminated intravascular coagulation (DIC)

• Thrombotic thrombocytopenic purpura

• Malignant hypertension

• Cutaneous burns

EMERGENCIES

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 Assessment of anaemia Diagnosis

Step-by-step diagnostic approach

Patients may present in several ways. The urgency with which anaemia is evaluated depends on the severity
at presentation. Patients with an acute severe haemorrhage present with hypovolaemia and symptoms and
signs of the underlying cause.[6]

Initial assessment
Evaluation should include identification of any source of active or acute bleeding.

• The initial goal in a patient with acute bleeding is rapid haemodynamic stabilisation. Up to 30% of
total blood volume (TBV) may be lost before clinical manifestations are appreciated at rest. Key signs
include hypotension, pallor, cold clammy skin, a thready pulse, tachycardia, dyspnoea or air hunger,
altered mental status, confusion, and coma. Flat neck veins when supine indicate at least 30% to 40%
total body volume loss. All orifices should be examined for bleeding. The mechanism and site of any
trauma should also be determined.
• History of prior episodes of GI bleeding, gastritis, non-steroidal anti-inflammatory drug (NSAID) or
corticosteroid use, alcohol use, or cirrhosis should prompt suspicion of GI bleeding. NSAIDs and
corticosteroids are associated with peptic ulcer disease. Alcohol use and cirrhosis are associated
with coagulation disorders and oesophageal varices. A lower GI bleed presents with fresh red rectal
bleeding (haematochezia). Melaena and/or haematemesis with or without abdominal pain indicate
an upper GI bleed. Sudden tearing pain should prompt suspicion of a ruptured vascular aneurysm;
the pain may be spontaneous, or precipitated by trauma or by cocaine or amphetamine use. Loss of
consciousness may occur if a major vessel is involved. A history of hypertension or collagen disorders
may also be present. A wide pulse pressure suggests a ruptured aneurysm. A pulsatile abdominal
mass may indicate an abdominal aortic aneurysm. Flank or abdominal ecchymosis suggests intra-
abdominal bleeding.
• If there is a history of recent surgery, ongoing blood loss at the surgical site must be considered.
A detailed history of the pre-, intra-, and postoperative course should be obtained, including any
complications noted during the operation. A history of bleeding disorders or excessive bruising may
DIAGNOSIS

indicate an underlying coagulation disorder. Any antibiotics administered should be noted, as some
can produce a decrease in platelet levels.
• Tests are guided by the history and examination and the suspected aetiology of active bleeding. These
may include the following procedures.

• FBC, which shows a normocytic anaemia with a high reticulocyte count (>2%) and a normal or
decreased haematocrit (Hct). Dilution does not occur initially, so haemoglobin (Hb) and Hct do
not accurately reflect the true severity of the anaemia.
• Prothrombin time/activated partial prothrombin time, which is usually normal, but tested to
identify patients with decreased coagulation due to anticoagulants, underlying defects in
haemostasis, or consumptive coagulopathy. In patients with upper GI bleeding, elevated urea
may be seen, even in absence of renal issues, due to digestion of blood, which is a source of
urea.
• Abdominal ultrasound scan: allows rapid identification of intra-abdominal bleeding and indicated
if abdominal trauma or a ruptured abdominal aortic aneurysm are suspected.
• Joint x-rays, indicated in patients with trauma to identify fractures. Long-bone fractures can be a
significant source of bleeding.

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Assessment of anaemia Diagnosis
• Upper GI endoscopy, required to identify sources of upper GI bleeding. Nasogastric lavage with
saline is no longer routinely recommended in initial management unless it is done to facilitate
subsequent direct visualisation for endoscopic procedures.[52] [53] [54]
• Colonoscopy, required to identify sources of lower GI bleeding. A retrospective review of the
medical records of a sample of patients with colorectal cancer found that anaemia was one
of the commonest symptoms/signs in those considered to have had a missed diagnostic
opportunity (a clinical encounter where, even in the presence of presumptive symptoms of
colorectal cancer, the colorectal cancer diagnostic process was not started).[55]
• Exploratory laparotomy, which may be required in patients with abdominal bleeding to identify
the source, especially if there is a history of abdominal trauma or previous abdominal surgery.
• CT scanning of the body region affected by trauma or aneurysm rupture, which will identify
internal injuries or the extent and nature of the aneurysm, and identify sources of bleeding.

Many anaemic patients with no acute or active bleeding are asymptomatic, and the anaemia is only noted
on an FBC taken as part of the assessment of an unrelated condition. Symptoms of anaemia may include
pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise. FBC should
be ordered if these symptoms are present. Jaundice is an additional sign seen in patients with haemolytic
anaemias.

The first step in diagnosis is to identify the type of anaemia that is present, using the results of the FBC. Due
to their relative reproducibility, mean corpuscular volume (MCV) and red cell width (RDW) are the most useful
components in the inital classification of most anaemias.

The anaemia may be:

• Microcytic (MCV <80 femtolitres [fL]): serum iron studies should be performed.[56]
• Normocytic (MCV 80-100 femtolitres [fL]): the reticulocyte count should be examined to determine
whether the anaemia is hypoproliferative (<2%) or hyperproliferative (>2%).
• Macrocytic (MCV >100 femtolitres [fL]): the peripheral smear should be examined for megaloblasts
and hypersegmented neutrophils. If these cells are present, the anaemia is megaloblastic. If they are
absent, the anaemia is non-megaloblastic.

DIAGNOSIS

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 Assessment of anaemia Diagnosis
Algorithm for the assessment of anaemia
Created by the BMJ Knowledge Centre

Microcytic anaemia: abnormal serum iron studies

A low serum iron, a high total iron-binding capacity (TIBC), and a low ferritin indicate iron deficiency anaemia.

• Iron deficiency produces an associated reactive thrombocytosis that provides an additional clue. Iron
deficiency is not a diagnosis and requires further investigation to elucidate the cause.[11] [12] [13]
• Diets low in meat produce iron deficiency. Generalised malnutrition often produces combined vitamin
B12 and/or folate deficiency, in which case the resulting anaemia is normocytic. Children may have
pica.
• There may be a history of bleeding. Females may have a history of excessive menstrual losses.
Coffee-ground vomiting, haematemesis, or melaena indicate upper GI bleeding. NSAIDs and
corticosteroids are associated with peptic ulcer disease. Alcohol use and cirrhosis are associated
with coagulation disorders and oesophageal varices. Fresh red rectal bleeding indicates a lower GI
bleed. Rectal pain may indicate haemorrhoids, which will be seen on rectal examination. Haemoptysis
may indicate Goodpasture's syndrome or idiopathic pulmonary haemosiderosis. Rarely, a history
of excessive blood donation or self-harm may be elicited. Patients who are avid runners may have
runner's anaemia from repetitive mechanical trauma (also known as march haematuria). A history
of gastric surgery, coeliac disease, or extensive small bowel resection suggests malabsorption as
the cause. Pregnancy is a common cause. A history of dark-coloured urine may indicate paroxysmal
nocturnal haemoglobinuria.
• Signs of iron deficiency include koilonychia, angular cheilosis, glossitis, and thinning hair.
• Investigations are guided by the history and examination, and include the following.

• Faecal occult blood testing, which should be done in all patients and is positive if GI bleeding is
present.
• Upper GI endoscopy, which should be performed if there is a history of upper GI bleeding or
a positive faecal occult blood test. It may identify sources of an upper GI bleed (peptic ulcer
DIAGNOSIS

disease, gastritis, oesophageal varices), hiatus hernia, Meckel's diverticulum, or increased

gastric pH in achlorhydria.
• In the setting of persistent iron deficiency anaemia, after negative endoscopy, testing for
Helicobacter pylori may be considered after malignancies, B12 deficiency, and idiopathic
thrombocytopenic purpura have been excluded.[57]
• Immunoglobulin A-tissue transglutaminase (IgA-tTG) test should be performed in all patients
and is positive in coeliac disease.
• Colonoscopy, which should be performed if there is a history of lower GI bleeding or a positive
faecal occult blood test. It may reveal malignancy, diverticulosis, ulcerative colitis, or rare causes
such as hereditary haemorrhagic telangiectasia; malignancy should be considered in all patients
aged over 40 years with symptoms of rectal bleeding or a positive faecal occult blood test.
• Flow cytometry should be considered if there is a history of passing red urine, or RBC results
consistent with a haemolytic anaemia. It detects decreased expression of RBC surface proteins
(CD55 and CD59) and is diagnostic of paroxysmal nocturnal haemoglobinuria.
• Transvaginal ultrasound, which may reveal causes of menorrhagia including hyperplasia,
dysplasia, fibroids, or polyps; malignancy should be considered in patients with menorrhagia
who are over 40 years old.

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Assessment of anaemia Diagnosis
• Stool microscopy, which may identify hookworm, whipworm, or Schistosoma eggs. This should
be performed if clinical features suggest the diagnosis or there is a history of travel to endemic
areas.

A low serum iron, a low total iron-binding capacity, and a low ferritin suggest anaemia of chronic disease.

• A history of an underlying inflammatory process (infection, neoplasms, autoimmune reactions, and

injury to tissue from trauma or major surgery) is usually present. A serum erythropoietin level should
be considered; the result is usually normal or mildly elevated. Hypothyroidism and vitamin C deficiency
may produce a falsely low ferritin level.[58]

Microcytic anaemia: normal serum iron studies

The most important cause to exclude is thalassaemia. A family history is usually present. The disease is
more common in individuals of Mediterranean, Middle Eastern, or Southeast Asian descent. The severity
ranges from asymptomatic to severe transfusion-dependent symptoms.[27] [28]

The examination findings may be normal, or reveal splenomegaly, jaundice, abdominal distension, and
icterus. Morphological changes including skeletal abnormalities, a large head, chipmunk facies, and
misaligned teeth are seen in beta-thalassaemia intermedia and major.

Distinct features on the FBC that suggest the diagnosis include a marked decrease in MCV (usually close
to 70 femtolitres [fL]) with a low mean corpuscular Hb, target cells on the peripheral smear, and an elevated
reticulocyte count (>2%). A Mentzer's index (MCV/RBC) <13 is suggestive of thalassaemia, and an index
>14 suggests iron deficiency.[59] In a meta-analysis of various mathematical indices used to distinguish
between iron deficiency anaemia and thalassaemias, the microcytic to hypochromic RBC ratio (M/H) showed
the best performance, although the authors concluded that none were high enough to make definitive
diagnoses.[60] Thalassaemia is diagnosed using Hb electrophoresis. The presence of Hb H, Hb Bart, and
concomitant haemoglobinopathies (Hb E, Hb S, Hb C, Hb D) is diagnostic of alpha-thalassaemia. A high HbF
with minimal or absent HbA and an elevated HbA2 is diagnostic of beta-thalassaemia.

Normocytic anaemia: hypoproliferative

DIAGNOSIS
Potential diagnoses

• These include disorders that decrease RBC production.

• Haematological malignancies and aplastic anaemia[18] are the most important diagnoses to exclude,
and are usually associated with multiple cytopenias.
• An isolated anaemia is usually due to pure red cell aplasia, which may be self-limiting or persistent.
Chronic kidney disease[23] or hypothyroidism can also cause an isolated anaemia.
• Secondary hyperparathyroidism exacerbates the anaemia of chronic kidney disease.

History

• Symptoms of bleeding, easy bruising, night sweats, or weight loss suggest haematological malignancy
or aplastic anaemia. Parvovirus infection, infectious mononucleosis, viral hepatitis, malaria, respiratory
infections, gastroenteritis, primary atypical pneumonia, and mumps can result in a self-limiting pure
red cell aplasia, and these should be excluded.
• Antiepileptic medications (phenytoin, carbamazepine, valproate sodium), azathioprine, sulfonamides,
isoniazid, and procainamide cause pure red cell aplasia. Benzene, penicillamine, and gold can

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 Assessment of anaemia Diagnosis
cause aplastic anaemia. Chloramphenicol can cause either aplastic anaemia or pure red cell aplasia.
Chemotherapy causes pancytopenia.[61] Discontinuation of causative medications leads to resolution
of the anaemia.
• Radiotherapy, especially to pelvic or sternal areas, can cause pancytopenia.
• A history of immunosuppression or chronic hepatitis suggests persistent pure red cell aplasia. There
may be a history or features of chronic kidney disease or hypothyroidism.
Examination

• Ecchymoses or petechiae due to thrombocytopenia suggest haematological malignancy,

myelodysplastic syndrome, or aplastic anaemia. Lymphadenopathy or fever suggest malignancy
or infections (e.g., infectious mononucleosis). Splenomegaly may be seen in haematological
malignancies.
• Clinical features of SLE, rheumatoid arthritis, dermatomyositis, polyarteritis nodosa, or scleroderma
resulting in persistent pure red cell aplasia may be present. Abnormal lung examination (if lung cancer
is the primary cancer) or a breast mass (if breast cancer is the primary) may be present.
• A positive Trousseau's sign or Chvostek's sign in patients with chronic kidney disease indicates
hypocalcaemia, probably due to associated secondary hyperparathyroidism.
Initial investigations

• Should be guided by the history and examination findings.

• FBC may show an associated cytopenia and characteristic changes specific to a haematological
malignancy. A pancytopenia suggests aplastic anaemia, or may be due to chemotherapy or
radiotherapy. An isolated anaemia suggests pure red cell aplasia or anaemia due to chronic kidney
disease.
• Bone marrow aspiration provides a definitive diagnosis of aplastic anaemia.
• Bone marrow biopsy is required for the definitive diagnosis of acute leukaemia (acute lymphocytic
leukaemia, acute myelogenous leukaemia), chronic myelogenous leukaemia (CML), aplastic anaemia,
or bone marrow metastases.
• Antiparvovirus antibodies are positive in parvovirus infection, the most common infectious cause of
DIAGNOSIS

pure red cell aplasia.

Other tests to consider

• Hepatitis serology, to exclude acute or chronic active hepatitis

• Monospot test or Epstein-Barr virus (EBV) IgM, to exclude infectious mononucleosis
• Thick and thin peripheral smear, to exclude malaria if history and clinical findings suggest the
diagnosis
• Thyroid function tests; TSH is elevated and free T4 reduced in hypothyroidism
• Antinuclear antibodies, which are positive in SLE or scleroderma
• Rheumatoid factor, which is positive in rheumatoid arthritis
• Serum CK, which is elevated in dermatomyositis
• Chest x-ray, which may show infiltrates in atypical pneumonia or a smooth mass in thymoma
• Erythropoietin levels, which may be decreased in patients with chronic renal failure. Serum calcium
and parathyroid hormone levels should be considered if associated secondary hyperparathyroidism is
suspected.

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Assessment of anaemia Diagnosis

Normocytic anaemia: hyperproliferative

Potential diagnoses

• Include haemolytic anaemias.

• These conditions can be caused by microangiopathic haemolytic anaemias, autoimmune haemolytic
anaemia, drugs, infections, inherited conditions, transfusion reactions, or burns.
History

• Drugs that can cause haemolysis include penicillin, methyldopa, levodopa, quinidines, cephalosporins,
and some NSAIDs. Cyclosporine, tacrolimus, clopidogrel, oral contraceptive pills, and some
chemotherapy drugs may cause haemolytic uraemic syndrome. Discontinuation of causative
medications produces resolution of the anaemia.
• There may be a history suggestive of microangiopathic disease. Known triggers of disseminated
intravascular coagulation (DIC) include ongoing severe infection, sepsis, malignancy, obstetric
emergency, trauma, burns, envenomation, drug overdose, or any cause of endothelial damage. The
presence of acute-onset neurological symptoms, including headache, confusion, focal weakness,
seizures, or coma, should prompt suspicion of thrombotic thrombocytopenic purpura (TTP). Female
patients may have associated menorrhagia. Sudden-onset dizziness, headache, mental status
changes, loss of sensation or motor strength, chest pain or pressure, dyspnoea, or oedema in a
patient with known hypertension should prompt suspicion of malignant hypertension; a history of renal
failure or eclampsia may also be present. An expanding vascular skin lesion in a young infant or child
should prompt suspicion of a haemangioma. A history of prosthetic valve replacement may indicate
haemolysis induced by the prosthesis.
• Cutaneous burns affecting more than 10% of the body surface area can cause a haemolytic anaemia,
or trigger DIC.
• Infective causes include cytomegalovirus (CMV), infectious mononucleosis, toxoplasmosis, and
leishmaniasis. Bloody diarrhoea should prompt suspicion of Escherichia coli infection and haemolytic
uraemic syndrome.
• Patients with inherited haemolytic anaemias such as sickle cell anaemia, hereditary spherocytosis, or

DIAGNOSIS
glucose-6-phosphate dehydrogenase (G6PD) deficiency may have a positive family history. Persistent
pain in the skeleton, chest, or abdomen; priapism; lower-extremity skin ulcers; or an acute pneumonia-
like syndrome suggest sickle cell anaemia.
• There may be a previous history of autoimmune disease (e.g., SLE, rheumatoid arthritis, or
scleroderma) or lymphoproliferative disorders (usually non-Hodgkin's lymphoma or chronic
lymphocytic leukaemia), which can lead to autoimmune haemolytic anaemia. Note that autoimmune
diseases may also cause pure red cell aplasia, in which case the reticulocyte count would be low, with
normal lactate dehydrogenase, haptoglobin, and bilirubin levels.
• Recent blood transfusion may indicate haemolysis due to a transfusion reaction.
• Occupational or home exposure to lead should prompt suspicion of lead toxicity.
Examination

• Features of microangiopathic disease: there may be purpura or ecchymoses due to bleeding. Systolic
BP >210 mmHg and diastolic BP >130 mmHg indicate malignant hypertension; associated signs
may include new murmurs, S3 on auscultation of the heart, jugular venous distension, rales or
lower-extremity oedema, oliguria or polyuria, focal neurological signs, and hypertensive retinopathy.
Cutaneous reddish-brown or violaceous vascular lesions may indicate haemangioma.[31]

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 Assessment of anaemia Diagnosis
• Splenomegaly is seen in hereditary spherocytosis. Clinical features of underlying autoimmune
diseases may be present. Lymphadenopathy may indicate infectious mononucleosis, leukaemia,
lymphoma, or autoimmune disease.
Initial investigations

• The FBC and peripheral blood smear should be examined for clues to the underlying cause. A
thrombocytopenia with schistocytes strongly suggests a microangiopathic haemolytic anaemia.
Spherocytes suggest autoimmune haemolytic anaemia or hereditary spherocytosis. Hereditary
spherocytosis is also associated with increased mean corpuscular Hb. Sickling of RBCs is diagnostic
of sickle cell anaemia.[27] Heinz bodies, eccentrocytes, or bite cells are seen in G6PD deficiency.
• If haemolytic anaemia is suspected, serum lactate dehydrogenase, haptoglobin, and bilirubin should
be measured. Elevated lactate dehydrogenase and bilirubin levels with a decreased haptoglobin are
strongly suggestive of a haemolytic anaemia. Clinical jaundice is seen once bilirubin levels rise above
34.2 to 68.4 mmol/L (2-4 mg/dL).
Tests to consider in suspected microangiopathic haemolytic anaemias

• Serum creatinine, which may be elevated in patients with haemolytic uraemic syndrome or malignant
hypertension. Kidney biopsy provides a definitive diagnosis of haemolytic uraemic syndrome.
• Prothrombin time and activated partial prothrombin time, which are prolonged in DIC but normal
in other microangiopathic haemolytic anaemias. DIC panel shows elevated D-dimers and fibrin
degradation products with low fibrinogen in patients with DIC. X-rays and MRI scanning of suspected
regions reveal internal haemangiomas.
Tests to consider in other haemolytic anaemias

• Direct antiglobulin (Coombs') test, which is positive in autoimmune haemolytic anaemia.

• Tests to identify hereditary causes. Sickle cell anaemia is diagnosed on FBC. Osmotic fragility test is
positive in hereditary spherocytosis; cells lyse on exposure to hypo-osmotic solution. G6PD assays
identify deficiencies of the enzyme.
• Tests to identify infection. Monospot test or EBV IgM is positive in infectious mononucleosis. CMV IgM
DIAGNOSIS

is positive in CMV infection. Double-sandwich IgM ELISA or IgG avidity test is positive for IgM in acute
toxoplasmosis. Splenic or bone marrow aspirate shows amastigotes of the parasite in leishmaniasis.
• Blood lead levels, which are elevated in lead toxicity.

[VIDEO: Venepuncture and phlebotomy animated demonstration ]

Macrocytic anaemia: megaloblastic

Potential diagnoses

• The main causes to consider are vitamin B12 or folate deficiency, or drugs that interfere with DNA
synthesis. Autoimmune thyroid disease may coexist with pernicious anaemia and atrophic gastritis,
which decrease B12 absorption. Therefore, screening for B12 deficiency when the aetiology of
hypothyroidism is thought to be autoimmune is recommended.[62]
• Discontinuation of causative medications leads to resolution of the anaemia.

History

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Assessment of anaemia Diagnosis

• Poor intake due to malnutrition, alcohol abuse, or strict vegan or low-protein diets can produce
deficiency of vitamin B12 and/or folate.
• A history of coeliac disease, tropical sprue, Crohn's disease, previous gastric or intestinal surgery, or
bacterial overgrowth may indicate malabsorption.
• A swollen, red, painful tongue; angular stomatitis; patchy hyperpigmentation of the skin and mucous
membranes; and a persistent mild pyrexia are symptoms of folate deficiency.
• Drug history: known causative medications include purine analogues, pyrimidine analogues,
reductase inhibitors, methotrexate, trimethoprim, anticonvulsants, oral contraceptives, cycloserine, p-
aminosalicylic acid, metformin, colchicine, neomycin, and biguanides. Hydroxyurea, in particular, is
known to cause oval macrocytosis with MCV >110 femtolitres (fL).
Initial investigations

• Serum vitamin B12 levels are decreased and serum methylmalonic acid levels are elevated in vitamin
B12 deficiency. The latter is more sensitive and should be used to definitively exclude vitamin B12
deficiency. An MCV of >115 fL is typically seen in nutritional deficiency.
• Serum folate levels are low in folate deficiency. If folate levels are low, serum vitamin B12 and
methylmalonic acid levels should be measured to exclude concurrent vitamin B12 deficiency before
folate levels are corrected. Normal serum homocysteine levels make folate deficiency unlikely. RBC
folate is a more accurate indicator of folate deficiency than serum folate level.
• Anti-intrinsic factor and parietal cell antibodies are positive in pernicious anaemia.

Macrocytic anaemia: non-megaloblastic

Potential diagnoses

• Causes to consider include alcohol abuse, myelodysplastic syndrome, chronic liver disease, and
congenital bone marrow failure syndromes.
History

DIAGNOSIS
• High alcohol intake indicates alcohol-induced anaemia, which usually persists for months after total
abstinence. A history of chronic liver disease indicates liver disease-induced anaemia.
• History of prior exposure to petroleum distillates (especially benzene), chemotherapy, or radiotherapy
should prompt suspicion of myelodysplastic syndrome.
• A history of fever, chills, fatigue, weakness, recurrent infection, anorexia, night sweats, shortness of
breath, and easy bruising should prompt suspicion of myelodysplastic syndrome.
• Recurrent infections in an infant should prompt suspicion of congenital bone marrow failure
syndromes.
Examination

• May reveal stigmata of chronic alcoholism or chronic liver disease.

• Dyskeratosis congenita is characterised by the triad of abnormal nails, reticulated skin rash, and
leukoplakia.
• Skeletal abnormalities and growth retardation are seen in Shwachman-Diamond syndrome.

Investigations

• FBC shows associated neutropenia and thrombocytopenia with macro-ovalocytes in myelodysplastic

syndrome.

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 Assessment of anaemia Diagnosis
• Bone marrow aspiration and biopsy shows myeloblasts with immature precursors in myelodysplastic
syndrome. Diagnostic features of congenital bone marrow failure syndromes are also identified.
• Cytogenetics reveal chromosomal translocations in myelodysplastic syndrome.
• Additional tests for congenital bone marrow syndromes: diepoxybutane or mitomycin-c fragility test is
positive in Fanconi anaemia. Genetic testing reveals underlying mutations.
DIAGNOSIS

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Assessment of anaemia Diagnosis

Differential diagnosis overview

Common

Trauma

Acute GI bleeding

Rupture of a vascular aneurysm

Surgery

Menorrhagia

Iron deficiency

Vitamin B12 deficiency

Folate deficiency

Myelodysplastic syndrome

Acute lymphocytic leukaemia

Acute myelogenous leukaemia

Chronic myelogenous leukaemia

DIAGNOSIS
Hairy cell leukaemia

Acquired aplastic anaemia

Infiltration by secondary malignancy

Pure red cell aplasia

Drug toxicity

Anaemia of chronic disease

Chronic kidney disease

Chronic liver disease

Pregnancy

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 Assessment of anaemia Diagnosis

Uncommon

Generalised malnutrition

Cytotoxic chemotherapy

Radiotherapy

Alcohol abuse

Lead toxicity

Hypothyroidism

Autoimmune haemolytic anaemia (AIHA)

Transfusion reaction

Malaria

Viral hepatitis

Toxoplasmosis

Leishmaniasis

Parvovirus B19 infection

Infectious mononucleosis
DIAGNOSIS

Cytomegalovirus (CMV)

Sickle cell anaemia

Thalassaemias

Hereditary spherocytosis

Glucose-6-phosphate dehydrogenase deficiency (G6PD)

Bone marrow failure syndromes

Haemolytic uraemic syndrome

Disseminated intravascular coagulation (DIC)

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Assessment of anaemia Diagnosis

Uncommon

Thrombotic thrombocytopenic purpura

Haemangioma

Malignant hypertension

Prosthetic valves and surfaces

Cutaneous burns

DIAGNOSIS

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 Assessment of anaemia Diagnosis

Differential diagnosis

Common

◊ Trauma

History Exam 1st Test Other tests

history of trauma evidence of injury »FBC: normal or »diagnostic

(including gunshot (wounds, bruises, decreased Hct; laparotomy:
wounds, major deformities), decreased Hb; reactive identification of
fractures, crush hypotension, pallor, leukocytosis and bleeding source
injuries); history of prior tachycardia, dyspnoea/ thrombocytosis due »CT scan of affected
bleeding episodes; or air hunger, altered to a stress response, body region:
use of anticoagulants mental status or thrombocytopenia identification of internal
or non-steroidal anti- confusion; flat neck from dilutional effect of injuries
inflammatory drugs veins when supine multiple transfusions
(NSAIDs) indicate at least 30% to »reticulocyte count:
40% total body volume >2%
loss
»prothrombin time/
activated partial
thromboplastin
time: usually normal;
prolonged with
anticoagulants,
underlying defects
in haemostasis,
or consumptive
coagulopathy
Consumptive
coagulopathy may
be due to repeated
DIAGNOSIS

blood transfusions
or to disseminated
intravascular
coagulation.

»joint or spine x-
rays: identification of
fractures

◊ Acute GI bleeding

History Exam 1st Test Other tests

history of prior hypotension, pallor, »FBC: normal or

episodes of GI tachycardia, dyspnoea/ decreased Hct;
bleeding, gastritis, air hunger, altered decreased Hb; reactive
non-steroidal mental status or leukocytosis and
anti-inflammatory confusion; flat neck thrombocytosis due to a
drug (NSAID) or veins when supine stress response
corticosteroid use, indicate at least

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Assessment of anaemia Diagnosis

Common

◊ Acute GI bleeding

History Exam 1st Test Other tests

alcohol use, cirrhosis, 30% to 40% total »reticulocyte count:
anticoagulants; rectal blood volume loss; >2%
bleeding, melaena, ascites, hepatomegaly/ »prothrombin
haematemesis, splenomegaly, time (PTT)/
abdominal pain cirrhotic hard liver, activated partial
caput medusae, thromboplastin
gynaecomastia, time: usually normal;
melaena, or bright prolonged in cirrhosis,
red blood on rectal anticoagulant therapy,
examination or underlying defects in
haemostasis; elevated
urea may be seen
»upper GI
endoscopy: bleeding
varices or ulcers if
source is from upper GI
tract
»colonoscopy:
visualisation of bleeding
lesion or mass

◊ Rupture of a vascular aneurysm

History Exam 1st Test Other tests

sudden tearing hypotension, pallor, »FBC: normal or »chest x-ray: may

pain may be tachycardia, dyspnoea/ decreased Hct; show widened

DIAGNOSIS
accompanied by loss air hunger, altered decreased Hb; reactive mediastinum in thoracic
of consciousness if mental status or leukocytosis and aortic aneurysm
major vessel involved; confusion; flat neck thrombocytosis due to a [Fig-6]
history of hypertension, veins when supine stress response
collagen disorders, indicate at least 30% »reticulocyte count:
trauma, cocaine or to 40% total blood >2%
amphetamine use volume loss; wide pulse
pressure or absent »ultrasonography
distal pulses; may of affected region:
rapidly progress to shows extent and
circulatory collapse and nature of aneurysm
death Intravascular
ultrasound is more
accurate if patient is
stable.

»CT scan of affected

region: shows extent
and nature of aneurysm

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 Assessment of anaemia Diagnosis

Common

◊ Rupture of a vascular aneurysm

History Exam 1st Test Other tests

Spiral CT or MRI are
better if patient is
stable.
[Fig-5]

◊ Surgery

History Exam 1st Test Other tests

recent surgery with hypotension, pallor, »FBC: normal or »reticulocyte count:

at least moderate tachycardia, continuous decreased Hct; >2%
blood loss; history of bleeding from surgical decreased Hb; reactive »ultrasound of
bleeding disorders or wound, petechiae, leukocytosis and affected region:
excessive bruising; use purpura; severe thrombocytosis due to a shows source and
of antibiotics bleeding produces stress response extent of bleeding
dyspnoea/air hunger,
altered mental status »CT scan of affected
or confusion; flat neck region: shows source
veins when supine and extent of bleeding
indicate at least 30% to »diagnostic
40% total blood volume laparotomy: shows
loss source and extent of
bleeding

◊ Menorrhagia
DIAGNOSIS

History Exam 1st Test Other tests

excessive menstrual pallor, adnexal masses »FBC: chronic »pregnancy test:

bleeding lasting >7 or fibroids microcytic anaemia with negative
days; fatigue, dyspnoea normal WBC; reactive »prothrombin time/
on exertion, pica; use thrombocytosis if iron activated partial
of hormone therapy, deficient thromboplastin
history of fibroids »serum ferritin: time: usually normal;
<33 picomol/L (<15 prolonged with
micrograms/L) if iron anticoagulants,
deficient underlying defects
in haemostasis,
or consumptive
coagulopathy
»TSH/free T4: elevated
TSH with low free T4 in
hypothyroidism
»transvaginal
ultrasound: may see

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Assessment of anaemia Diagnosis

Common

◊ Menorrhagia

History Exam 1st Test Other tests

hyperplasia, dysplasia,
fibroids, or polyps
Endometrial carcinoma
should be excluded in
patients >40 years.

◊ Iron deficiency

History Exam 1st Test Other tests

hx of poor dietary iron pallor, dyspnoea, »FBC with peripheral »upper GI

intake, coeliac disease, poor exercise smear: microcytic endoscopy:
Crohn's disease, tolerance, koilonychia, anaemia with identification of source
ulcerative colitis, angular cheilosis, thrombocytosis of upper GI bleeding;
small bowel resection, glossitis, thinning hair, »serum iron studies: high gastric pH in
peptic ulcer disease, systolic flow murmur; achlorhydria
low serum iron, high
regular running, haemorrhoids, fresh total iron-binding »colonoscopy:
chronic blood loss blood or melaena on capacity, low ferritin, identification of source
(melaena, haematuria, rectal examination; high soluble transferrin of lower GI bleeding or
menorrhagia, evidence of pregnancy; receptor chronic inflammation
haemoptysis, frequent adnexal masses or
blood donation, self- fibroids »immunoglobulin »flow cytometry:
harm), pica, salicylate A-tissue identification of
ingestion, gastric transglutaminase paroxysmal nocturnal
bypass, hookworm (IgA-tTG) test: positive haemoglobinuria
infestation, pregnancy, in coeliac disease »transvaginal
or menorrhagia »faecal occult blood: ultrasound: may see

DIAGNOSIS
positive if GI bleeding hyperplasia, dysplasia,
fibroids, or polyps
Endometrial carcinoma
should be excluded
in patients aged >40
years.

»stool microscopy:
visualisation of
hookworm, whipworm,
or Schistosoma eggs
»Helicobacter pylori
test: positive result if H
pylori present
In the setting of
persistent iron
deficiency anaemia,
after negative
endoscopy, testing

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 Assessment of anaemia Diagnosis

Common

◊ Iron deficiency

History Exam 1st Test Other tests

for H pylori may
be considered
after malignancies,
B12 deficiency,
and idiopathic
thrombocytopenic
purpura have been
excluded.[57]

◊ Vitamin B12 deficiency

History Exam 1st Test Other tests

hx of coeliac or Crohn's impaired vibration »FBC with peripheral

disease, autoimmune sense and extremity smear: megaloblastic
thyroid disease, numbness, vitiligo, macrocytic anaemia;
gastric bypass, chronic glossitis, poor balance basophilic stippling may
antibiotic use (intestinal or co-ordination, be seen
bacterial overgrowth tachycardia, pallor, »serum vitamin B12
syndrome), vegan hepatosplenomegaly levels: low
diet or alcohol abuse;
fatigue, palpitations, »serum
distal paraesthesias, methylmalonic acid
depression, confusion, levels: elevated
tinnitus, dementia Confirms deficiency
if B12 levels are
DIAGNOSIS

borderline.

»anti-intrinsic factor
antibodies: positive in
pernicious anaemia
»antiparietal cell
antibodies: positive in
pernicious anaemia

◊ Folate deficiency

History Exam 1st Test Other tests

hx of coeliac or Crohn's mild persistent pyrexia, »FBC with peripheral »serum

disease, gastric tachycardia, pallor, smear: megaloblastic homocysteine levels:
bypass, haemodialysis, hepatosplenomegaly, macrocytic anaemia; high
pregnancy, alcohol glossitis, angular basophilic stippling may
abuse, or use of anti- stomatitis, patchy be seen
seizure medications; hyperpigmentation »serum folate: low

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Assessment of anaemia Diagnosis

Common

◊ Folate deficiency

History Exam 1st Test Other tests

fatigue, palpitations, of skin and mucous »serum vitamin B12
headaches membranes levels: normal; low in
combined vitamin B12
and folate deficiency
Neurological symptoms
will worsen if folate
is corrected in the
presence of low vitamin
B12.

◊ Myelodysplastic syndrome

History Exam 1st Test Other tests

history of prior pallor, petechiae, »FBC: macrocytic »bone marrow

exposure to purpura anaemia with aspiration and
petroleum distillates leukopenia, macro- biopsy: myeloblasts
(especially benzene), ovalocytes; associated with immature
chemotherapy, cytopenias include precursors
or radiotherapy; neutropenia and »cytogenetics of
fever, chills, fatigue, thrombocytopenia bone marrow biopsy:
weakness, recurrent multiple chromosomal
infection, anorexia, translocations possible,
night sweats, shortness especially 5q-, 7q-, or
of breath, easy bruising trisomy 8 (+8)

DIAGNOSIS
◊ Acute lymphocytic leukaemia

History Exam 1st Test Other tests

malaise, fatigue, easy pallor, petechiae, »FBC with peripheral »bone marrow
bruising or bleeding, purpura, tachycardia, smear: pancytopenia, aspirate and biopsy:
recurrent infections, hepatosplenomegaly, with ≥20% blasts; ≥20% blasts
fever, arthralgias, lymphadenopathy, normocytic Immunohistochemistry,
infection, anorexia, painless scrotal anaemia; may see cytochemistry, and
night sweats, shortness enlargement, bleeding hypereosinophilia
of breath, bony gums cytogenetics help to
Up to 10% of patients
tenderness, epistaxis, further classify disease.
do not have peripherally
bleeding gums, gingival
hyperplasia circulating blasts.

»reticulocyte count:
<2%

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 Assessment of anaemia Diagnosis

Common

◊ Acute myelogenous leukaemia

History Exam 1st Test Other tests

history of prior pallor, petechia, »FBC with peripheral »bone marrow

chemotherapy or purpura, dyspnoea, smear: pancytopenia, aspirate and biopsy:
radiotherapy; malaise, tachycardia with ≥20% blasts; ≥20% blasts
night sweats, fatigue, normocytic Immunohistochemistry,
easy bruising or anaemia; may see cytochemistry, and
bleeding, recurrent hypereosinophilia
infections, fever, bony cytogenetics help to
Cytoplasmic granules
tenderness, epistaxis, further classify disease.
indicate myeloid lineage
bleeding gums, gingival
hyperplasia of blasts. May also see
Auer's rods.
[Fig-7]

»reticulocyte count:
<2%

◊ Chronic myelogenous leukaemia

History Exam 1st Test Other tests

usually in middle-aged tender splenomegaly, »FBC with peripheral »cytogenetics:

patients; fatigue, weight painful sternum, smear: normocytic t(19;22) Philadelphia
loss, night sweats, lymphadenopathy, anaemia; myeloid chromosome - bcr-abl
early satiety, petechiae, splenomegaly maturing cells, elevated translocation
purpura, recurrent basophils, and »serum uric acid:
fevers, bone pain, eosinophils elevated
gouty arthritis »reticulocyte count: Due to elevated
DIAGNOSIS

<2% leukocyte count and

»bone marrow turnover.
aspirate and
biopsy: hypercellular
with granulocytic
hyperplasia

◊ Hairy cell leukaemia

History Exam 1st Test Other tests

weakness, fatigue, massive splenomegaly »FBC with peripheral »bone marrow

weight loss, night smear: pancytopenia aspirate and biopsy:
sweats, early satiety, with normocytic core biopsy shows
petechiae, purpura, anaemia hairy cells
recurrent fevers, Characteristic [Fig-8]
abdominal discomfort mononuclear 'hairy'
or fullness due to large
spleen cells, which stain
positive for tartrate-

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Assessment of anaemia Diagnosis

Common

◊ Hairy cell leukaemia

History Exam 1st Test Other tests

resistant acid
phosphatase (TRAP)

»reticulocyte count:
<2%

◊ Acquired aplastic anaemia

History Exam 1st Test Other tests

history of hepatitis, pallor, petechiae, »FBC with peripheral »bone marrow

HIV, benzene purpura, dyspnoea, smear: pancytopenia aspirate and biopsy:
exposure, use of known tachycardia with mild macrocytosis; hypocellular with
causative medications, normocytic anaemia decrease in all
radiation exposure, »reticulocyte count: elements, replaced
paroxysmal nocturnal mostly by fat cells; no
<2%
haemoglobinuria; infiltration by fibrosis or
malaise, fatigue, easy malignant cells
bruising or bleeding, »serum vitamin B12:
recurrent infections, normal
fever
»folate: normal

◊ Infiltration by secondary malignancy

History Exam 1st Test Other tests

DIAGNOSIS
weight loss, malaise, pallor, petechiae, »FBC with peripheral
fevers, fatigue, purpura, tachycardia, smear: pancytopenia,
dyspnoea, easy abnormal lung teardrop cells,
bleeding or bruising examination (if lung poikilocytes; normocytic
cancer), breast mass anaemia
(if breast cancer), »reticulocyte count:
bruising, cachexia <2%
»bone marrow
aspirate and biopsy:
infiltration of marrow
space by malignant
cells
Provide history
to pathologist so
appropriate stains
can be ordered if
metastatic malignancy
is suspected.

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 Assessment of anaemia Diagnosis

Common

◊ Pure red cell aplasia

History Exam 1st Test Other tests

self-limiting disease: clinical signs of »FBC: normocytic »thick and thin

history of use of underlying infection or anaemia peripheral smear:
known causative autoimmune disease intracellular parasites
»reticulocyte count:
medications, clinical seen with Wright's or
<2%
features of causative Giemsa staining in
infections (parvovirus »trial of malaria infection
B19, infectious discontinuation
»serum IgM + IgG
mononucleosis, viral of causative
anti-HAV: positive in
hepatitis, malaria, medication: anaemia
hepatitis A infection
respiratory infections, resolves
gastroenteritis, primary »serum IgM + IgG
»antiparvovirus B19
atypical pneumonia, HBcAb: positive in
antibodies: positive in
mumps); chronic hepatitis B infection
parvovirus infection
disease: history The most common »serum HBsAg:
of autoimmune positive in hepatitis B
disease (SLE, infectious cause.
infection
rheumatoid arthritis,
dermatomyositis, »serum IgM + IgG
scleroderma, anti-HCV: positive in
polyarteritis nodosa), hepatitis C infection
persistent infection, or »antinuclear
thymoma antibodies: positive in
SLE or scleroderma
»ds-DNA, Smith's
antigen: positive in
SLE
»rheumatoid factor:
positive in rheumatoid
DIAGNOSIS

arthritis
»serum CK: elevated
in dermatomyositis
»chest x-ray: infiltrates
in atypical pneumonia;
smooth mass in
thymoma, typically
projecting into one of
the hemi-thoraces and
obscuring the aortic
arch, or silhouette sign

◊ Drug toxicity

History Exam 1st Test Other tests

known or suspected pallor, jaundice (with »FBC with peripheral »serum bilirubin:
ingestion of causative haemolytic anaemia smear: typically elevated in haemolytic
drug prior to onset of only), dyspnoea normocytic anaemia; anaemia
inhibitors of DNA

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Assessment of anaemia Diagnosis

Common

◊ Drug toxicity

History Exam 1st Test Other tests

anaemia, poor exercise synthesis, folate,
tolerance or vitamin B12
produce megaloblastic
macrocytic anaemia
»reticulocyte count:
<2% if drugs suppress
bone marrow; >2%
if drugs produce
haemolysis
»trial of
discontinuation
of causative
medication: anaemia
resolves

◊ Anaemia of chronic disease

History Exam 1st Test Other tests

hx of known chronic pallor, fatigue, »FBC: microcytic »serum

inflammatory, dyspnoea; specific anaemia erythropoietin level:
autoimmune, or signs of underlying normal or elevated;
»serum iron studies:
infectious states; disease often decreased in
low serum iron, low
sustained physiological total iron-binding chronic kidney disease
stress, renal failure; Elevation, if present,
capacity and ferritin;
vasculitis or collagen is usually inadequate
ferritin normal or
vascular diseases, poor elevated in acute-phase to compensate for the

DIAGNOSIS
exercise tolerance; reaction
anaemia correlates with degree of anaemia.
severity of inflammatory
process

◊ Chronic kidney disease

History Exam 1st Test Other tests

chronic kidney disease, pallor, fatigue, »FBC: normocytic or »serum calcium

poor exercise tolerance; dyspnoea; signs of microcytic anaemia with level: decreased in
features of secondary renal failure: jaundice, thrombocytosis associated secondary
hypoparathyroidism: skin bruising, lung hyperparathyroidism
»reticulocyte count:
muscle cramps, bone rales, pericardial <2% »serum intact
pain rub, oedema, poor parathyroid
concentration or »serum creatinine:
hormone level:
memory, myoclonus; elevated
increased in
positive Chvostek's »urinalysis: associated secondary
sign or Trousseau's haematuria and/or hyperparathyroidism
sign in associated proteinuria
hyperparathyroidism

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 Assessment of anaemia Diagnosis

Common

◊ Chronic kidney disease

History Exam 1st Test Other tests

»serum iron studies: »renal ultrasound:
low serum iron and small kidney size;
ferritin, high total iron- presence of obstruction
binding capacity in iron or hydronephrosis;
deficiency kidney stones
»serum »kidney biopsy:
erythropoietin level: identification of
normal or decreased underlying kidney
pathology

◊ Chronic liver disease

History Exam 1st Test Other tests

hx of chronic liver pallor, fatigue, »FBC: non- »abdominal

disease, poor exercise dyspnoea, jaundice, megaloblastic ultrasound, CT, or
tolerance; may be lower-extremity macrocytic anaemia; MRI scanning: liver
asymptomatic or with swelling; hand and nail thrombocytopenia may surface nodularity,
fatigue, weakness, features: leukonychia, be present small liver, possible
weight loss, recurrent palmar erythema, hypertrophy of left/
»prothrombin time:
infections, decreased finger clubbing, spider caudate lobe, evidence
decreased in hepatic
libido; altered mental angiomata; facial of ascites or collateral
synthetic dysfunction
status in hepatic features: telangiectasia, circulation
encephalopathy bruising, rhinophyma, »LFTs: abnormal;
»liver biopsy:
parotid gland pattern depends on
diagnosis of underlying
swelling, paper-dollar underlying cause
cause or subsequent
appearance of skin, cirrhosis
seborrhoeic dermatitis,
DIAGNOSIS

xanthelasma;
abdominal features:
caput medusae,
bruising, hepatomegaly,
splenomegaly,
abdominal distension;
in males, loss of
secondary sexual hair
and testicular atrophy

◊ Pregnancy

History Exam 1st Test Other tests

pregnancy, especially in abdominal distension »FBC: microcytic »serum iron studies:

third trimester consistent with anaemia with low serum iron, high
pregnancy thrombocytosis total iron-binding
in iron deficiency; capacity, low ferritin,
megaloblastic high soluble transferrin
receptor in iron
deficiency

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Assessment of anaemia Diagnosis

Common

◊ Pregnancy

History Exam 1st Test Other tests

macrocytic anaemia in »serum folate: low in
folate deficiency folate deficiency

Uncommon

◊ Generalised malnutrition

History Exam 1st Test Other tests

protein calorie loss of subcutaneous »FBC with »serum vitamin B12:

deprivation; fat, apathy and lethargy, peripheral smear: low
malabsorption depigmentation, microcytic anaemia »serum folate: low
syndrome; neglect; hx enlarged abdomen, in iron deficiency;
of an eating disorder winged scapula, flaky megaloblastic »serum copper level:
skin, bipedal oedema macrocytic anaemia in low
vitamin B12 and folate Copper deficiency
deficiency; normocytic needs to be considered
anaemia with combined
in patients on
vitamin and mineral
deficiencies prolonged total
parenteral nutrition.
»serum iron studies:
low serum iron, high
total iron-binding
capacity, and low
ferritin in iron deficiency

◊ Cytotoxic chemotherapy

DIAGNOSIS
History Exam 1st Test Other tests

hx of myelosuppressive pallor, lethargy, »FBC: pancytopenia

chemotherapy; fatigue; dyspnoea with a normocytic
headaches; poor anaemia
exercise tolerance Counts usually reach
nadir 7 to 10 days
after administration of
chemotherapy.

»reticulocyte count:
<2%

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 Assessment of anaemia Diagnosis

Uncommon

◊ Radiotherapy

History Exam 1st Test Other tests

hx of recent radiation pallor, lethargy, »FBC: anaemia

exposure, especially to dyspnoea, skin (pancytopenia)
pelvic or sternal areas; erythema on radiation »reticulocyte count:
fatigue, headaches, sites <2%
poor exercise tolerance

◊ Alcohol abuse

History Exam 1st Test Other tests

hx of chronic high overweight status, »FBC: macrocytic »diagnostic

alcohol intake increased prominence anaemia interview: diagnosis of
of superficial cutaneous alcohol dependence
vasculature, peripheral »alcohol level
neuropathy, alterations (breath and blood):
in normal dentition elevated
and halitosis, possible
signs of liver disease:
hepatomegaly or small
liver, jaundice, ascites

◊ Lead toxicity

History Exam 1st Test Other tests

hx of occupational or blue gingival line »FBC with peripheral

DIAGNOSIS

recreational exposure (Burton's line), smear: normocytic

to lead products or old hypertension, gout anaemia with basophilic
paint; neuropsychiatric (saturnine gout); wrist stippling; microcytic
disturbance, insomnia, or foot drop anaemia if associated
abdominal pain, poor iron deficiency is
appetite, pica present
»reticulocyte count:
>2%
»whole blood lead
level: elevated

◊ Hypothyroidism

History Exam 1st Test Other tests

weakness, lethargy, pallor; dyspnoea; »FBC: non-

slow speech, feeling coarse, dry skin; megaloblastic
cold, forgetfulness, eyelid oedema; thick macrocytic anaemia
constipation, weight tongue; facial oedema; »serum TSH: elevated
bradycardia

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Assessment of anaemia Diagnosis

Uncommon

◊ Hypothyroidism

History Exam 1st Test Other tests

gain, poor exercise »serum T4: reduced
tolerance

◊ Autoimmune haemolytic anaemia (AIHA)

History Exam 1st Test Other tests

hx of autoimmune pallor, lethargy, »FBC with peripheral

diseases (SLE, dyspnoea, tachycardia, smear: normocytic
rheumatoid arthritis, jaundice, splenomegaly anaemia, with
or scleroderma), (especially if spherocytes
lymphoproliferative extravascular »reticulocyte count:
disorders (non- haemolysis) >2%; usually 4%
Hodgkin's lymphoma
The high reticulocyte
or chronic lymphocytic
leukaemia), recent count may incorrectly
viral illness, or increase mean
mononucleosis; may corpuscular volume
be asymptomatic;
(MCV) on automated
symptoms include
weakness, fatigue, counters.
headaches, poor [Fig-9]
exercise tolerance, prior
gallstones, dark urine, »lactate
clay-coloured stools dehydrogenase
(LDH): high
»haptoglobin: low

DIAGNOSIS
»direct antiglobulin
(Coombs') test:
usually positive;
negative in 5% to 10%
of cases
»serum bilirubin:
high

◊ Transfusion reaction

History Exam 1st Test Other tests

multiple prior pallor, lethargy, »ABO typing: »direct antiglobulin

transfusions; fever, dyspnoea, dark urine, discrepancy to blood (Coombs') test:
back pain, and jaundice used for transfusion IgG anti-A, anti-B, or
dyspnoea, usually Most commonly a anti-AB detected on
within 6 hours of clerical error. Stop circulating red cells
transfusion
transfusion immediately »serum bilirubin:
high
and stabilise patient.

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 Assessment of anaemia Diagnosis

Uncommon

◊ Transfusion reaction

History Exam 1st Test Other tests

»inspection
of plasma in
centrifuged,
anticoagulated
venous blood
sample: clear
or pink-red within
first few hours of
haemoglobinaemia
»inspection
of centrifuged
urine: clear red in
haemoglobinaemia

◊ Malaria

History Exam 1st Test Other tests

history of mosquito bite jaundice or pallor, »FBC: normocytic »serum bilirubin:

or habitation in malaria- splenomegaly, anaemia ± elevated
prone region; fatigue, dyspnoea, high flow thrombocytopenia and
dyspnoea, fevers and cardiac murmur, leukopenia
prostration, decreased pulmonary oedema, »reticulocyte count:
exercise tolerance, dark urine, fevers >2%; usually 4%
headaches, malaise;
symptoms usually cycle »thick and thin
every 48 to 72 hours, peripheral smear:
coinciding with RBC intracellular parasites
DIAGNOSIS

destruction seen with Wright's or

Giemsa staining
Banana-shaped
gametocytes or multiple
signet-ring forms in
RBCs are typical for
Plasmodium falciparum
, which requires
hospital admission.

◊ Viral hepatitis

History Exam 1st Test Other tests

perinatal exposure, jaundice, »FBC: normocytic

direct body fluid hepatomegaly, RUQ anaemia
transmission, exposure pain, acholic stools, »reticulocyte count:
to food-borne outbreak maculopapular or <2%
(in hepatitis A); nausea, urticarial skin rash (in

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Assessment of anaemia Diagnosis

Uncommon

◊ Viral hepatitis

History Exam 1st Test Other tests

vomiting, abdominal hepatitis B); usually »serum
pain, fever, malaise, normal in hepatitis C aminotransferases:
fatigue and headache, elevated
dark urine, acholic »serum IgM + IgG
(clay-coloured) stools, anti-HAV: positive in
jaundice, pruritus (in hepatitis A infection
hepatitis B); hepatitis C
is usually asymptomatic »serum IgM + IgG
HBcAb: positive in
hepatitis B infection
»serum HBsAg:
positive in hepatitis B
infection
»serum IgM + IgG
anti-HCV: positive in
hepatitis C infection

◊ Toxoplasmosis

History Exam 1st Test Other tests

usually seen jaundice, fever, »FBC: normocytic »PCR for

in pregnant or fatigue, lethargy, rash, anaemia and Toxoplasma gondii:
immunosuppressed hepatosplenomegaly; thrombocytopenia; may positive
patients and newborns; newborns infected see leukocytosis and
history of exposure to in utero may have eosinophilia
domestic cats, sheep, chorioretinitis, »reticulocyte count:

DIAGNOSIS
or cattle, or to raw meat microcephaly, seizures, >2%; usually 4%
mental retardation
»double-sandwich
IgM ELISA or IgG
avidity test: IgM
detected in acute
infection; IgG detected
in chronic or previous
exposure
IgM may persist long
after infection; its
absence excludes
infection.

»Sabin-Feldman dye
test: IgG antibodies
positive

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 Assessment of anaemia Diagnosis

Uncommon

◊ Leishmaniasis

History Exam 1st Test Other tests

hx of exposure to pallor, jaundice, »FBC: normocytic »reticulocyte count:

sandfly bite, especially hepatosplenomegaly, anaemia, >2%
in tropical or subtropical lymphadenopathy, thrombocytopenia, »splenic or
zones; AIDS, diarrhoea, skin leukopenia, bone marrow
immunosuppression, ulcerations, erythroblastosis aspirate: presence
or malnutrition; nasopharyngeal of amastigotes of the
fatigue and anorexia; ulcerations parasite
prolonged, persistent,
Splenic aspirate is most
low-grade intermittent
fevers; failure to thrive, sensitive.
distended abdomen
»direct antiglobulin
(Coombs') test:
positive

◊ Parvovirus B19 infection

History Exam 1st Test Other tests

acute infection: acute infection: »FBC: normocytic »antiparvovirus B19

characteristic skin 'slapped cheek' anaemia antibodies: positive
rash with or without appearance followed Used to exclude
»reticulocyte count:
arthralgia by a reticular parvovirus when typical
<2%
erythematous eruption
on extremities, and clinical features are
arthritis of hands, absent.
wrists, knees, or ankles
DIAGNOSIS

◊ Infectious mononucleosis

History Exam 1st Test Other tests

fatigue, malaise, sore fever, »FBC with peripheral »lactate

throat, nausea, ocular lymphadenopathy, smear: normocytic dehydrogenase
pain, photophobia pharyngitis, rash, anaemia, with (LDH): high
tender splenomegaly, spherocytes and »haptoglobin: low
palatal petechiae, atypical lymphocytes
periorbital oedema, »monospot test or
»reticulocyte count:
jaundice Epstein-Barr virus
>2% and usually 4% in (EBV) IgM: positive
haemolytic anaemia,
<2% in pure red cell
aplasia

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Assessment of anaemia Diagnosis

Uncommon

◊ Cytomegalovirus (CMV)

History Exam 1st Test Other tests

infection is usually usually normal; »FBC: normocytic »lactate

asymptomatic; a jaundice occurs due to anaemia dehydrogenase
maculopapular rash haemolytic anaemia; (LDH): high
»reticulocyte count:
following administration symptomatic infection >2%; usually 4% »haptoglobin: low
of antibiotics may produces fever,
occur; fatigue occurs lymphadenopathy, »monospot test or
due to anaemia; pharyngitis, rash, Epstein-Barr virus
symptomatic infection tender splenomegaly, (EBV) IgM: negative
is a sign of underlying palatal petechiae, Rules out EBV,
immunosuppression periorbital oedema which is clinically
indistinguishable from
CMV.

»CMV IgM: positive

◊ Sickle cell anaemia

History Exam 1st Test Other tests

known diagnosis of high fever, pallor, »FBC with peripheral

sickle cell disease in lethargy, dyspnoea, smear: normocytic
patient and/or parents; jaundice during acute anaemia with sickle
prior painful vaso- crisis cells
occlusive crises; Pancytopenia occurs in
fatigue, poor exercise aplastic crisis (usually
tolerance, persistent
pain in skeleton, chest, self-limiting).

DIAGNOSIS
or abdomen, priapism, [Fig-10]
gallstones, stroke,
lower-extremity skin »reticulocyte count:
ulcers, pneumonia-like >2%
syndrome »haemoglobin (Hb)
isoelectric focusing:
elevated HbS/A ratio
(close to 100/0)
»LDH: elevated
»serum bilirubin:
elevated

◊ Thalassaemias

History Exam 1st Test Other tests

family history of splenomegaly, »FBC with peripheral »serum ferritin:

blood disorders, jaundice, abdominal smear: microcytic elevated in iron
especially requiring distension, icterus; anaemia with mean overload
repeated transfusions; skeletal abnormalities, corpuscular volume

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 Assessment of anaemia Diagnosis

Uncommon

◊ Thalassaemias

History Exam 1st Test Other tests

Mediterranean, Middle large head, chipmunk (MCV) typically
Eastern, or Southeast facies, and misaligned closer to 70 fL, low
Asian descent; variable teeth seen in beta- mean corpuscular
severity ranging from thalassaemia haemoglobin (Hb);
asymptomatic to severe intermedia and major target cells seen
transfusion-dependent »Hb electrophoresis:
symptoms elevated HbF; other
Hb patterns consistent
with respective
thalassaemias

◊ Hereditary spherocytosis

History Exam 1st Test Other tests

family history of may be normal or »FBC with peripheral »direct antiglobulin

blood disorder, show pallor, jaundice, smear: normocytic (Coombs') test:
splenectomy, or lower leg skin ulcers, anaemia, with negative
pigmented gallstones; splenomegaly increased mean Excludes immune-
may be asymptomatic corpuscular mediated haemolytic
if extramedullary haemoglobin and
haematopoiesis spherocytes anaemias.
compensates »reticulocyte count:
>2%
»osmotic fragility
test: positive (cells lyse
on exposure to hypo-
DIAGNOSIS

osmotic solution)

◊ Glucose-6-phosphate dehydrogenase deficiency (G6PD)

History Exam 1st Test Other tests

usually in males of pallor, jaundice, mild »FBC with peripheral »G6PD enzyme
African, Mediterranean, dyspnoea smear: normocytic assays: quantitative
Sardinian, or Sephardic anaemia with Heinz or qualitative
Jewish descent; self- bodies, eccentrocytes, abnormalities
limiting episodes of or bite cells May be falsely negative
acute haemolysis Heinz bodies are during the acute
when exposed to rapidly cleared by the
oxidant stress; life- haemolytic event,
threatening symptoms spleen within 24 hours, owing to the destruction
more common with the resulting in 'bite cells'. of affected cells.
Mediterranean variant
»reticulocyte count: »serum bilirubin:
>2% elevated indirect
»serum haptoglobin: bilirubin
decreased

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Assessment of anaemia Diagnosis

Uncommon

◊ Glucose-6-phosphate dehydrogenase deficiency (G6PD)

History Exam 1st Test Other tests

»lactate »direct antiglobulin
dehydrogenase (Coombs') test:
(LDH): elevated negative
Distinguishes
glucose-6-phosphate
dehydrogenase
deficiency from immune
haemolytic anaemias.

◊ Bone marrow failure syndromes

History Exam 1st Test Other tests

recurrent infection ill-appearing, with »FBC with peripheral »bone marrow

shortly after birth, weight loss, pallor, smear: pancytopenia aspiration and
fever, easy bleeding lethargy, dyspnoea, with normocytic or biopsy: varies
or bruising, organ petechiae, purpura, macrocytic anaemia depending on
abnormalities, short and/or thrush Causes include underlying cause
stature Fanconi anaemia, »diepox ybutane or
dyskeratosis congenita, mitomycin-c fragility
test: positive in Fanconi
and Shwachman-
anaemia
Diamond syndrome.
»genetic testing:
»reticulocyte count: characteristic genetic
<2% mutations detected

DIAGNOSIS
◊ Haemolytic uraemic syndrome

History Exam 1st Test Other tests

acute renal failure pallor, lethargy, »FBC with »prothrombin time/

usually following dyspnoea, petechiae, peripheral smear: activated partial
an enteric bacterial purpura, bloody normocytic anaemia, thromboplastin time:
infection ( Escherichia diarrhoea; usually self- thrombocytopenia, normal
coli 0157:H7) with limiting in children schistocytes Excludes disseminated
bloody diarrhoea, intravascular
»erythrocyte count:
or Streptococcus >2% coagulation (DIC).
pneumoniae
»serum haptoglobin:
decreased
»lactate
dehydrogenase
(LDH): elevated
»serum bilirubin:
elevated

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 Assessment of anaemia Diagnosis

Uncommon

◊ Haemolytic uraemic syndrome

History Exam 1st Test Other tests

»direct antiglobulin
(Coombs') test:
negative
Excludes immune-
mediated haemolytic
anaemias.

»kidney biopsy:
hyaline arteriolar
thrombi in absence of
inflammatory changes
in vessel wall

◊ Disseminated intravascular coagulation (DIC)

History Exam 1st Test Other tests

ongoing severe diffuse bleeding, »FBC with

infection, sepsis especially from peripheral smear:
(typically gram- puncture sites or minor normocytic anaemia,
negative), malignancy, trauma; unprovoked thrombocytopenia,
obstetric emergency, clots; clinical signs of schistocytes
trauma, burns, underlying cause »prothrombin time:
envenomations, drug prolonged
overdose, any cause of
endothelial damage »activated partial
thromboplastin time:
varies depending on
DIAGNOSIS

factor VII levels

»DIC panel: elevated
D-dimer and fibrin
degradation products
with low fibrinogen
Fibrinogen may be
normal or elevated
as an acute-phase
reactant.

◊ Thrombotic thrombocytopenic purpura

History Exam 1st Test Other tests

non-specific prodrome pallor, lethargy, »FBC with peripheral

followed by headache, dyspnoea, purpura, smear: normocytic
confusion, focal ecchymoses anaemia with
weakness, seizures, schistocytes
coma; menorrhagia

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Assessment of anaemia Diagnosis

Uncommon

◊ Thrombotic thrombocytopenic purpura

History Exam 1st Test Other tests

may be seen due to »reticulocyte count:
bleeding >2%
»direct antiglobulin
(Coombs') test:
negative
Excludes immune-
mediated haemolytic
anaemias.

◊ Haemangioma

History Exam 1st Test Other tests

typically young child or depends on location »FBC with »x-ray of suspected

infant with expanding of lesion(s), which are peripheral smear: region: soft-tissue
vascular skin lesion; typically reddish-brown normocytic anaemia, shadows, phleboliths
may also be hepatic or or violaceous; other thrombocytopenia »MRI of suspected
in other visceral site symptoms consistent Platelet sequestration region: increased
with anaemia in enlarging signal on both T1- and
haemangiomas T2-weighted images
with areas of signal
(Kasabach-Merritt
void
syndrome) can
cause life-threatening
bleeding.

DIAGNOSIS
»reticulocyte count:
>2%

◊ Malignant hypertension

History Exam 1st Test Other tests

history of essential systolic BP >210 »FBC with peripheral »chest x-ray:

hypertension, renal mmHg and diastolic smear: normocytic evidence of pulmonary
disease, or eclampsia; BP >130 mmHg, anaemia with oedema indicating left
older age, male lethargy, new murmurs, schistocytes ventricular failure
gender, black ethnicity; S3 on auscultation »reticulocyte count: »head CT or MRI:
dizziness, headache, of heart, jugular >2% evidence of infarct or
mental status changes, venous distension, haemorrhage
loss of sensation or rales or lower- »ECG: evidence of
motor strength, chest extremity oedema, ischaemia or infarct
pain or pressure, oliguria or polyuria, such as ST- or T-wave
dyspnoea, oedema focal neurological changes
signs, hypertensive
retinopathy

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 Assessment of anaemia Diagnosis

Uncommon

◊ Malignant hypertension

History Exam 1st Test Other tests

»serum creatinine:
elevated with renal
failure

◊ Prosthetic valves and surfaces

History Exam 1st Test Other tests

history of aortic or pallor, lethargy, »FBC with peripheral

mitral metallic valve dyspnoea, petechiae, smear: normocytic
replacement, with purpura, jaundice anaemia with
anticoagulation; schistocytes
weakness, fatigue, »reticulocyte count:
headaches; poor >2%
exercise tolerance, prior
gallstones, dark urine »direct antiglobulin
(Coombs') test:
negative
Excludes immune-
mediated haemolytic
anaemias.

◊ Cutaneous burns

History Exam 1st Test Other tests

DIAGNOSIS

burn injury to at least epidermal or dermal »FBC with peripheral »reticulocyte count:
10% of total body loss consistent with smear: normocytic >2%
surface area (TBSA); burn injury anaemia with
multiple surgical thrombocytopenia;
procedures schistocytes from
peripheral destruction
seen on blood smear

Diagnostic guidelines

Europe

Paediatric amendment to adult BSH Guidelines for aplastic anaemia

Published by: British Society for Haematology (BSH)

Last published: 2018

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Assessment of anaemia Diagnosis

Europe

Guidelines on the management of drug-induced immune and secondary

autoimmune, haemolytic anaemia

Published by: British Society for Haematology

Last published: 2017

The diagnosis and management of primary autoimmune haemolytic anaemia

Published by: British Society for Haematology

Last published: 2016

Guidelines for the diagnosis and management of adult aplastic anaemia

Published by: British Society for Haematology

Last published: 2015

Chronic kidney disease: managing anaemia

Published by: National Institute for Health and Care Excellence

Last published: 2015

North America

Clinical practice guidelines from the AABB: red blood cell transfusion
thresholds and storage

Published by: AABB (formerly known as American Association of Blood Banks)

DIAGNOSIS
Last published: 2016

Clinical practice guidelines for evaluation of anemia

Published by: Canadian Society of Nephrology

Last published: 2008

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 Assessment of anaemia References

Key articles
• Report of WHO/UNICEF/UNU consultation on indicators and strategies for iron deficiency and anemia
REFERENCES

programmes. In: WHO/UNICEF/UNU consultation. Geneva, Switzerland: WHO; 1994.

• Brown RG. Anemia. In: Taylor RB, ed. Family medicine: principles and practice. 4th ed. New York, NY:
Springer-Verlag; 1994:997-1005.

• Zuckerman KS. Approach to the anemias. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed.
Philadelphia, PA: Saunders Elsevier; 2007: chapter 162.

• Glader BE. Hemolytic anemia in children. Clin Lab Med. 1999;19:87-111,vi. Abstract

• Ginder GD. Microcytic and hypochromic anemias. In: Goldman L, Ausiello DA, eds. Cecil Medicine.
23rd ed. Philadelphia, PA: Saunders Elsevier; 2007: chapter 163.

• Killick SB, Bown N, Cavenagh J, et al; British Society for Standards in Haematology. Guidelines for the
diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172:187-207. Full text
Abstract

• Killick SB, Bown N, Cavenagh J, et al; British Society for Standards in Haematology. Guidelines for the
diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172:187-207. Full text
Abstract

References
1. Report of WHO/UNICEF/UNU consultation on indicators and strategies for iron deficiency and anemia
programmes. In: WHO/UNICEF/UNU consultation. Geneva, Switzerland: WHO; 1994.

2. Lee GR, Foerster J, Lukens J. Wintrobe's clinical hematology. 10th ed. Baltimore, MD: Lippincott,
Williams & Wilkins; 1999.

3. Beutler E, Lichtman MA, Coller BS, et al. Williams hematology. 6th ed. New York, NY: McGraw-Hill;
2000.

4. Brown RG. Anemia. In: Taylor RB, ed. Family medicine: principles and practice. 4th ed. New York, NY:
Springer-Verlag; 1994:997-1005.

5. Thein M, Ershler WB, Artz AS, et al. Diminished quality of life and physical function in community-
dwelling elderly with anemia. Medicine (Baltimore). 2009;88:107-114. Abstract

6. Zuckerman KS. Approach to the anemias. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed.
Philadelphia, PA: Saunders Elsevier; 2007: chapter 162.

7. Glader BE. Hemolytic anemia in children. Clin Lab Med. 1999;19:87-111,vi. Abstract

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Assessment of anaemia References
8. Ginder GD. Microcytic and hypochromic anemias. In: Goldman L, Ausiello DA, eds. Cecil Medicine.
23rd ed. Philadelphia, PA: Saunders Elsevier; 2007: chapter 163.

REFERENCES
9. Brill JR, Baumgardner DJ. Normocytic anemia. Am Fam Physician. 2000;62:2255-2264. Full text
Abstract

10. Davenport J. Macrocytic anemia. Am Fam Physician. 1996;53:155-162. Abstract

11. Gasche C, Berstad A, Befrits R, et al. Guidelines on the diagnosis and management of iron deficiency
and anemia in inflammatory bowel diseases. Inflamm Bowel Dis. 2007;13:1545-1553. Abstract

12. Madore F, White CT, Foley RN, et al; Canadian Society of Nephrology. Clinical practice guidelines
for assessment and management of iron deficiency. Kidney Int Suppl. 2008;110:S7-S11. Full text
Abstract

13. Conrad ME, Umbreit JN. Iron absorption and transport - an update. Am J Hematol. 2000;64:287-298.
Full text Abstract

14. Centers for Disease Control and Prevention (CDC). Iron deficiency: United States, 1999-2000. MMWR
Morb Mortal Wkly Rep. 2002;51:897-899. Full text Abstract

15. den Elzen WP, van der Weele GM, Gussekloo J, et al. Subnormal vitamin B12 concentrations and
anaemia in older people: a systematic review. BMC Geriatrics. 2010;10:42. Full text Abstract

16. Fernando OV, Grimsley EW. Prevalence of folate deficiency and macrocytosis in patients with and
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58 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 19, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
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Assessment of anaemia Images

Images

IMAGES
Figure 1: Microcytic anaemia
From the collection of Dr Robert Zaiden; used with permission

Figure 2: Megaloblastic macrocytic anaemia

From the collection of Dr Robert Zaiden; used with permission

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IMAGES Assessment of anaemia Images

Figure 3: Classification of anaemia: MCV, mean corpuscular volume; fL, femtolitres

Created by the BMJ Knowledge Centre

Figure 4: Algorithm for the assessment of anaemia

Created by the BMJ Knowledge Centre

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Assessment of anaemia Images

IMAGES
Figure 5: CT scan of a ruptured abdominal aortic aneurysm
University of Michigan, specifically the cases of Dr Gilbert R. Upchurch reflecting the Departments of
Vascular Surgery and Radiology

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IMAGES Assessment of anaemia Images

Figure 6: CXR showing a widened mediastinum

From the collection of Professor James Brown; used with permission

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Assessment of anaemia Images

IMAGES
Figure 7: Peripheral blood film of a patient with acute myelogenous leukaemia showing myeloid blasts with an
Auer rod
From the collection of Dr Kavita Raj and Dr Priyanka Mehta; used with patient consent

Figure 8: Cytospin prepared from bone marrow aspirate illustrates the typical cell cytology, with oval- to bean-
shaped nuclei and moderate amounts of cytoplasm with irregular cytoplasmic borders (Wright Giemsa 100x
oil)
From the collection of Lynn Moscinski, MD; used with permission

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 Assessment of anaemia Images
Figure 9: Peripheral blood smear with spherocytes, reticulocytes, and a nucleated RBC
From the collection of John Densmore, Department of Medicine, University of Virginia; used with permission
IMAGES

Figure 10: Red cells in sickle cell disease

From the personal collection of Sophie Lanzkron, MD; used with permission

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Contributors:

// Authors:

Robert Zaiden, MD
Hematologist Oncologist
Baptist MD Anderson Cancer Center, Jacksonville, FL
DISCLOSURES: RZ declares that he has no competing interests.

// Acknowledgements:
Dr Robert Zaiden would like to gratefully acknowledge Dr Fauzia Rana, a previous contributor to this
monograph. FR declares that she has no competing interests.

// Peer Reviewers:

Christoph Pechlaner, MD
Associate Professor of Medicine
Innsbruck Medical University, Innsbruck, Austria
DISCLOSURES: CP declares that he has no competing interests.

John Densmore, MD, PhD

Associate Professor of Clinical Medicine
Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA
DISCLOSURES: JD declares that he has no competing interests.

Carlos Aravena, MD
Internal Medicine Instructor
Member of Evidence Based Medicine Unit, Catholic University of Chile, Santiago, Chile
DISCLOSURES: CA declares that he has no competing interests.