Table 2.3 Normal haemoglobins in adult blood.
HbA
Hb F
Hb A2
Structu
re
α2β2
α2γ2
α2δ2
Normal
(%)
96–98
0.5–0.8
1.5–3.2
Anaemia
Key facts and checkpoints
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In Australia, most people with anaemia will have iron deficiency
5% for children to
20% for menstruating females.
Elderly 30-45% Anaemia of chronic disorders. 15-30% IDA
The incidence of haemoglobinopathy traits, especially thalassaemia, is increasing in
multicultural Western societies.
If a patient presents with precipitation or aggravation of myocardial ischaemia, heart
failure or intermittent claudication, consider the possibility of anaemia.
The serum ferritin level, which is low in cases of iron-deficiency anaemia, is probably the
best test to monitor iron-deficiency anaemia as its level reflects the amount of stored
iron.
Normal reference values for peripheral blood: adults
male
female
Haemoglobin (g/L)
130–180
115–165
Red cells (× 1012/L)
4.5–6
4–5.5
PCV (haematocrit)
40–53
35–47
MCV (fL)
80–100
Platelets (× 109/L)
150–400
White cell count (× 109/L)
4–11
Neutrophils
2.5–7.5
Lymphocytes
1.5–4
Monocytes
0.2–1
Eosinophils
<0.5
Reticulocytes (%)
0.5–2
ESR (mm/hour)
<20 mm <35 mm if >70 years
Haemoglobin (g/L)
Red cells (erythrocytes) (× 1012/L)
PCV (haematocrit) (%)
Mean cell volume (MCV) (fL)
Mean cell haemoglobin (MCH)
(pg)
Reticulocyte count (×109/L)
Males
Females
135.0–175.0
4.5–6.5
40–52
80–95
115.0–155.0
3.9–5.6
36–48
27–34
50–150
White cells (leucocytes)
Total (×109/L)
Neutrophils (×109/L)
Lymphocytes (×109/L)
Monocytes (×109/L)
Eosinophils (×109/L)
Basophils (×109/L)
Platelets (×109/L)
Serum iron (μmol/L)
4.0–11.0
1.8–7.5
1.5–3.5
0.2–0.8
0.04–0.44
0.01–0.1
150–400
10–30
anaemia
DxT→ fatigue + palpitations + exertional dyspnoea
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Clinical features
Patients with anaemia may be asymptomatic. When symptoms develop they are usually non- specific.
Symptoms:
tiredness/fatigue muscle weakness
headache and tinnitus lack of concentration faintness/dizziness dyspnoea on exertion palpitations
angina on effort
intermittent claudication
pica—usually brittle and crunchy food, e.g. ice (iron-deficiency anaemia)
Signs
Non-specific signs include pallor, tachycardia, systolic flow murmur and angular cheilosis. If severe, signs can
include ankle oedema and cardiac failure.
• Specific signs include
• jaundice—haemolytic anaemia
• koilonychias (spoon-shaped nails)—iron-deficiency anaemia.
History
• The history may indicate the nature of the problem:
• iron deficiency: inadequate diet, pregnancy, GIT loss, menorrhagia,
NSAID and anticoagulant ingestion
• folate deficiency: inadequate diet especially with pregnancy and
alcoholism, small bowel disease
• vitamin B12 deficiency: previous gastric surgery, ileal disease or
surgery, pernicious anaemia, selective diets (e.g. vegetarian, fad)
• haemolysis: abrupt onset anaemia with mild jaundice possibly lead
toxicity, especially in children
Classification of anaemia
• The various types of anaemia are classified in terms of the red cell size—
the mean corpuscular volume (MCV):
• microcytic—MCV ≤ 80 fL
• macrocytic—MCV >100 fL
• normocytic—MCV 80–100 fL
• anaemia of chronic disorders (chronic infection, inflammation and
malignancy) can occasionally be microcytic as well as normocytic;
• the anaemia of hypothyroidism can be macrocytic in addition to the more
likely normocytic;
• the anaemia of bone marrow disorder or infiltration can also be
occasionally macrocytic.
Classification of anaemia by mean RBC volume
(MCV) with selected causes
Microcytic (MCV < 80 fL)
Microcytic (MCV > 100 fL) Normocytic (MCV 80–100
fL)
Iron deficiency
Thalassaemia
Anaemia of chronic
disease Sideroblastic
anaemia
Vitamin B12 deficiency
Folate deficiency
Myelodysplastic disorders
Cytotoxic drugs
Liver disease/alcoholism
Kidney disease
Anaemia of chronic
disease Endocrine
failure/hypothyroidism
Haemolysis
Aplastic anaemia
Classification of anaemia.
Microcytic, hypochromic
Normocytic, normochromic
Macrocytic
MCV <80fL
MCV 80–95fL
MCV >95fL
MCH <27pg
MCH ≥27pg
Megaloblastic: vitamin B12 or
folate deficiency
Non‐megaloblastic: alcohol, liver
disease, myelodysplasia, aplastic
anaemia, etc. (see Table 5.10)
Iron deficiency
Many haemolytic anaemias
Thalassaemia
Anaemia of chronic disease
(some cases)
Lead poisoning
Sideroblastic anaemia (some
cases)
Anaemia of chronic disease
(some cases)
After acute blood loss
Factors impairing the normal reticulocyte response to anaemia.
Marrow diseases, e.g. hypoplasia, infiltration by carcinoma, lymphoma,
myeloma, acute leukaemia, tuberculosis
Deficiency of iron, vitamin B12 or folate
Lack of erythropoietin, e.g. renal disease
Reduced tissue O2 consumption, e.g. myxoedema, protein deficiency
Ineffective erythropoiesis, e.g. thalassaemia major, megaloblastic
anaemia, myelodysplasia, myelofibrosis
Chronic inflammatory or malignant disease
Untitled 2
IRON DEFICIENCY ANAEMIA
Microcytic anaemia—MCV ≤80 FL
• The main causes of microcytic anaemia are iron deficiency and
haemoglobulinopathy, particularly thalassaemia. Consider lead
poisoning.
• Iron-deficiency anaemia
• Iron deficiency is the most common cause of anaemia worldwide. It is
the biggest cause of microcytic anaemia, with the main differential
diagnosis of microcytic anaemia being a haemoglobinopathy such as
thalassaemia. However, it is caused by bleeding until proved
otherwise.
•
Clinical and laboratory features
An understanding of the interpretation of iron studies is important in
management.
• Microcytic anaemia
• Serum ferritin level low (NR: F 15–200 mcg/L: M 30–300 mcg/L) <15
• Serum iron level low
• Increased transferrin level
• Microcytic hypochromic red cells
• MCV ↓, MCH ↓, MCHC ↓
• Reduced transferrin saturation
• Response to iron therapy
Non-haematological effects of chronic iron
deficiency
• Angular cheilosis/stomatitis
• Glossitis
• Oesophageal webs
• Atrophic gastritis
• Brittle nails and koilonychias
Causes
• Blood loss
• Menorrhagia
• Gastrointestinal bleeding (e.g. carcinoma, haemorrhoids, peptic ulcer, hiatus hernia, GORD, NSAID therapy)
• Frequent blood donations
• Malignancy
• Hookworm (common in tropics)
• Increased physiological requirements
• Prematurity, infant growth
• Adolescent growth
• Pregnancy
• Malabsorption
• Coeliac disease
• Postgastrectomy
• Dietary
• Inadequate intake
Special diets (e.g. fad, vegetarianism)
• Pica—eating unnatural food, e.g. dirt, ashes
Investigations
• Investigations are based on the
• history
• physical examination, including the rectal examination.
• If GIT bleeding is suspected, the faecal occult blood test is not
considered very valuable but appropriate investigations include
gastroscopy and colonoscopy, small bowel biopsy and small bowel
enema.
Haematological investigations: typical findings
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Microcytic, hypochromic red cells
Anisocytosis (variation in size), poikilocytosis (shape)—pencil-shaped rods
Low serum iron level
Raised iron-binding capacity
Serum ferritin level low (the most useful index)
Soluble transferrin receptor factor—this factor is increased in iron
deficiency, but not in chronic disease. Therefore, it is very helpful in
differentiating iron deficiency from other forms. It is an indirect marker of
what is happening in the bone marrow.
The state of the iron stores is assessed by considering the serum iron, the
serum ferritin and the serum transferrin levels in combination
• Typically, in
• iron deficiency, the serum iron and ferritin levels are low and
the transferrin high,
• but the serum iron level is also low in all infections— severe,
mild and even subclinical—as well as in inflammatory states,
malignancy and other chronic conditions.
• Serum ferritin estimations are spuriously raised in liver disease
of all types, chronic inflammatory conditions and malignancy;
• transferrin is normally raised in pregnancy. Since each of
these estimations can be altered in conditions other than iron
deficiency, all three quantities have to be considered together
to establish the iron status
The interpretation of iron studies
Condition
Serum Fe
TIBC
% Transferrin Ferritin
saturation
Iron deficiency
↓
N or ↑
↓ <10%
↓↓
β-thalassaemia
N or ↑
N
N or ↑
N or ↑
Anaemia of chronic
disease
↓
N or ↓
↓
N or ↑
Sideroblastic anaemia
N or ↑
N
N or ↑
↑
↓
↑↑
↑↑
Haemochromatosi ↑
s
Treatment
• Correct the identified cause
• Diet—iron-rich foods, vitamin C-rich foods (Iron is present in meat and
legumes as Fe+ + + and therefore requires gastric acid for conversion to Fe++. )
• Elemental iron supplements 100–200 mg daily (adults).
• Iron preparations:
oral iron (ferrous sulphate 1–2 tablets daily between meals for 6 months), e.g.
Ferro- Gradumet or Ferro-grad C (avoid taking with milk) with orange juice or
ascorbic acid until Hb is normal
parenteral iron preferably by IV infusion is probably best reserved for special
circumstances such as a failed trial of oral iron for symptomatic iron-deficiency
anaemia (there is a risk of an allergic reaction, a serum sickness-like illness for
48 hours and post- infusion skin staining around the cannula site). Cover with
an antihistamine or IV hydrocortisone 30 minutes beforehand. Infusion is best
with ferric carboxymaltose in 0.9% (N) saline.
Avoid blood transfusions if possible. IM iron is not recommended.
Optimal adult diet for iron deficiency
Adults should limit milk intake to 500 mL a day while on iron tablets Avoid excess caffeine,
faT diets and excess processed bread
Eat ample iron-rich foods (especially protein)
Protein foods
Meats—beef (especially), veal, pork, liver, poultry Fish and shellfish (e.g. oysters, sardines,
tuna) Seeds (e.g. sesame, pumpkin)
Eggs, especially egg yolk
Fruits
Dried fruit (e.g. prunes, figs, raisins, currants, peaches) Juices (e.g. prune, blackberry)
Most fresh fruit
Vegetables
Greens (e.g. spinach, silver beet, lettuce) Dried peas and beans (e.g. kidney beans)
Pumpkin, sweet potatoes
Grains
Iron-fortified breads and dry cereals Oatmeal cereal
or better iron absorption, add foods rich in vitamin C (e.g. citrus fruits, cantaloupe,
Brussels sprouts, broccoli, cauliflower)
Response
• Anaemia responds after about 2 weeks and is usually corrected after 2
months (if underlying cause addressed).
• Oral iron is continued for 3 to 6 months to replenish stores.
• Monitor progress with regular serum ferritin levels.
• A serum ferritin level >50 mcg/L generally indicates adequate stores.
Failure of iron therapy
• poor compliance
• continuing blood loss
• malabsorption (e.g. severe coeliac disease)
• incorrect diagnosis (e.g. thalassaemia minor, chronic disease)
• bone marrow infiltration
Anaemia of chronic disorders
• One of the most common anaemias occurs in patients with a variety of
chronic inflammatory and malignant diseases (Table 3.6). The characteristic
features are:
• 1 Normochromic, normocytic or mildly hypochromic (MCV rarely <75 fL)
indices and red cell morphology.
• 2 Mild and non‐progressive anaemia (haemoglobin rarely <90g/L) – the
severity being related to the severity of the disease.
• 3 Both the serum iron and TIBC are reduced.
4 The serum ferritin is normal or raised.
5 Bone marrow storage (reticuloendothelial) iron is normal
• but erythroblast iron is reduced
• pathogenesis of this anaemia appears to be related to decreased
release of iron from macrophages to plasma because of raised serum
hepcidin levels, reduced red cell lifespan and an inadequate
erythropoietin response to anaemia caused by the effects of
cytokines such as IL‐1 and tumour necrosis factor (TNF) on
erythropoiesis.
Causes of the anaemia of chronic disorders.
Chronic inflammatory diseases
Infections (e.g. pulmonary abscess, tuberculosis, osteomyelitis, pneumonia,
bacterial endocarditis)
Non‐infectious (e.g. rheumatoid arthritis, systemic lupus erythematosus and other
connective tissue diseases, sarcoidosis, inflammatory bowel disease, liver
disease)
Malignant diseases
Carcinoma, lymphoma, sarcoma
Laboratory diagnosis of a hypochromic anaemia.
Iron deficiency
Chronic
inflammation or
malignancy
Thalassaemia trait Sideroblastic
(α or β)
anaemia
MCV/ MCH
Reduced in relation
Normal or mild
to severity of
reduction
anaemia
Reduced; very low
for degree of
anaemia
Usually low in
congenital type but
MCV usually raised
in acquired type
Serum iron
Reduced
Reduced
Normal
Raised
TIBC
Raised
Reduced
Normal
Normal
Serum ferritin
Reduced
Normal or raised
Normal
Raised
Bone marrow iron
stores
Absent
Present
Present
Present
Erythroblast iron
Absent
Absent
Present
Ring forms
Haemoglobin
electrophoresis
Normal
Normal
Hb A2 raised in β
form
Normal
Sideroblastic anaemia
Classification of sideroblastic anaemia.
Hereditary
X chromosome linked ALA‐S mutation or rarely with spinocerebellar degeneration and ataxia
Usually occurs in males, transmitted by females; also occurs rarely in females
Other rare types (see text)
Acquired
Primary
Myelodysplasia (refractory anaemia with ring sideroblasts) (see p. 178)
N.B. Ring sideroblast formation (<15% of erythroblasts) may also occur in the bone marrow in:
other malignant diseases of the marrow (e.g. other types of myelodysplasia, myelofibrosis, myeloid
leukaemia, myeloma) drugs, e.g. antituberculous (isoniazid, cycloserine), alcohol, lead
other benign conditions (e.g. haemolytic anaemia, megaloblastic anaemia, malabsorption, rheumatoid
arthritis)
ALA‐S, δ‐aminolaevulinic acid synthase.
Lead poisoning
• Lead inhibits both haem and globin synthesis at a number of points.
In addition it interferes with the breakdown of RNA by inhibiting the
enzyme pyrimidine 5′ nucleotidase, causing accumulation of
denatured RNA in red cells, the RNA giving an appearance called
basophilic stippling on the ordinary (Romanowsky) stain (see Fig.
2.17). The anaemia may be hypochromic or predominantly
haemolytic, and the bone marrow may show ring sideroblasts. Free
erythrocyte protopor phyrin is raised.
Haemochromatosis
• Hereditary haemochromatosis (HHC), which is a disorder of iron overload, is the most
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common serious single gene genetic disorder in our population.
It is a common condition in which the total body iron concentration is increased to 20–
60 g (normal 4 g).
The excess iron is deposited in and can damage several organs:
liver—cirrhosis (10% develop cancer)
pancreas—‘bronze’ diabetes
skin—bronze or leaden grey colour
heart—restrictive cardiomyopathy,
pituitary—hypogonadism, impotence
joints—arthralgia (especially hands), chondrocalcinosis
It is usually hereditary (autosomal recessive = AR) or may be secondary to chronic
haemolysis and multiple transfusions.
Note: Hereditary haemochromatosis is the genetic condition; haemosiderosis is the
secondary condition.
Genetic profile
• Being an autosomal recessive disorder, the patient must inherit two altered (mutated)
copies of the gene. It is a problem mainly affecting Caucasians, usually from middle age
onwards.
• About 1 in 10 people are silent carriers of one mutated gene, while 1 in 200 are
homozygous and are at risk of developing haemochromatosis.
• These people can have it to a variable extent (the penetrance factor), and some are
asymptomatic while others have a serious problem. It is rare for symptoms to manifest
before the third decade.
• The two common identified specific mutations in the HFE gene are C282Y and H63D
(another is S65C):
• homozygous C282Y—high risk for HHC
• homozygous H63D—unlikely to develop clinical HHC
• heterozygous C282Y and H63D—milder form of HHC
Clinical features
• Most patients are asymptomatic but may have extreme lethargy,
abdominal discomfort, signs of chronic liver disease, polyuria and
polydipsia, arthralgia, erectile dysfunction, loss of libido and joint
signs.
• Signs: look for hepatomegaly, very tanned skin, cardiac arrhythmias,
joint swelling, testicular atrophy.
The key diagnostic sensitive markers are serum transferrin saturation
and the serum ferritin level. The serum iron level is not a good
indicator. An elevated ferritin level is not diagnostic of HHC but is the
best serum marker of iron overload.
Diagnosis
• Increased serum transferrin saturation: >50% (F); >60% (M)
• Increased serum ferritin level: >200 mcg/L (F); >300 mcg/L (M) CT,
MRI or FerriScan—increased iron deposition in liver
• Liver biopsy (if liver function test enzymes are abnormal or ferritin
>1000 mcg/L or hepatomegaly)—FerriScan now preferred
• Genetic studies: HFE gene—a C282Y and/or H63D mutation
• Screen first-degree relatives (serum ferritin levels and serum
transferrin saturation in older relatives and genetic testing in younger
ones). No need to screen before adulthood. HbEPG gene for
pregnant patient and partner.
• Routine screening not recommended
Note: Full blood count (FBE) and erythrocyte sedimentation rate are
normal.
Management
• Refer for specialist care
• Weekly venesection 500 mL (250 mg iron) until serum iron
stores are normal (may take at least 2 years), then every 3–4
months to keep serum ferritin level <100 mcg/L (usually 40–80
mcg/L), serum transferrin saturation <50% and iron levels
normal
• Desferrioxamine can be used but not as effective as
venesection
• Normal, healthy low-iron diet
• Avoid or limit alcohol
• Avoid iron tablets and vitamin C
• Life expectancy is normal if treated before cirrhosis or diabetes
Megaloblastic anaemias and other macrocytic
anaemias
•MEGALOBLASTIC ANAEMIAS
Causes of megaloblastic anaemia.
Vitamin B12 deficiency
Folate deficiency
Abnormalities of vitamin B12 or folate metabolism (e.g.
transcobalamin deficiency, nitrous oxide, antifolate drugs)
Other defects of DNA synthesis
Congenital enzyme deficiencies (e.g. orotic aciduria)
Acquired enzyme deficiencies (e.g. alcohol, therapy with
hydroxyurea, cytosine arabinoside)
Vitamin B12 and folate: nutritional aspects.
Vitamin B12
Folate
Normal daily dietary intake
7–30 μg
200–250 μg
Main foods
Animal produce only
Most, especially liver, greens and
yeast
Cooking
Little effect
Easily destroyed
Minimal adult daily requirement
1–2 μg
100–150 μg
Body stores
2–3mg (sufficient for 2–4 years)
10–12mg (sufficient for 4 months)
Absorption Site
Mechanism Limit
Ileum
Intrinsic factor 2–3 μg/day
Duodenum and jejunum
Conversion to methyltetrahydrofolate
50–80% of dietary content
Enterohepatic circulation
5–10 μg/day
90 μg/day
Transport in plasma
Most bound to haptocorrin; TC
essential for cell uptake
Weakly bound to albumin
Major intracellular physiological forms Methyl‐ and deoxyadenosylcobalamin Reduced polyglutamate derivatives
Causes of severe vitamin B12 deficiency.
Nutritional
Especially vegans
Malabsorption
Gastric causes
Pernicious anaemia
Congenital lack or abnormality of intrinsic factor Total or partial gastrectomy
Intestinal causes
Intestinal stagnant loop syndrome – jejunal diverticulosis, blind‐loop, stricture, etc.
Chronic tropical sprue
Ileal resection and Crohn’s disease
Congenital selective malabsorption with proteinuria (autosomal recessive megaloblastic anaemia)
Fish tapeworm
Causes of mild vitamin B12 deficiency include poor diet and other causes of malabsorption of vitamin B12
(malabsorption of food B12 caused by atrophic gastritis particularly in the elderly, therapy with proton pump
inhibitors or metformin), severe pancreatitis, gluten‐induced enteropathy and HIV infection. These
• Vitamin B12 neuropathy (subacute combined degeneration of the cord)
• Severe B12 deficiency can cause a progressive neuropathy affect- ing the
peripheral sensory nerves and posterior and lateral columns (Fig. 5.9). The
neuropathy is symmetrical and affects the lower limbs more than the upper
limbs. The patient notices tingling in the feet, difficulty in walking and may fall
over in the
• dark. Rarely, optic atrophy or severe psychiatric symptoms are present.
Anaemia may be severe, mild or even absent, but the blood film and bone
marrow appearances are always abnormal. The peripheral neuropathy is
usually reversible with B12 therapy but spinal cord recovery is incomplete,
especially if the neu- ropathy has been present for more than a few weeks or
months.
• The cause of the neuropathy is likely to be related to the accumulation of
S‐adenosyl homocysteine and reduced levels of S‐adenosyl methionine in
nervous tissue resulting in defec- tive methylation of myelin and other
substrates. Folate and B12 deficiency has been associated with reduced
cognitive function and Alzheimer’s disease but no benefit has been shown for
pro- phylactic folic acid or B12.
Causes of folate deficiency.
Nutritional
Especially old age, institutions, poverty, famine, special diets, goat’s milk anaemia, etc.
Malabsorption
Tropical sprue, gluten‐induced enteropathy (adult or child). Possible contributory factor to folate
deficiency in some patients with partial gastrectomy, extensive jejunal resection or Crohn’s disease
Excess utilization
Physiological
Pregnancy and lactation, prematurity
Pathological
Haematological diseases: haemolytic anaemias, myelofibrosis
Malignant disease: carcinoma, lymphoma, myeloma Inflammatory diseases: Crohn’s disease,
tuberculosis, rheumatoid arthritis, psoriasis, exfoliative dermatitis, malaria
Excess urinary folate loss
Active liver disease, congestive heart failure
Drugs
Anticonvulsants, sulfasalazine
Mixed
Treatment of megaloblastic anaemia.
Vitamin B12 deficiency
Folate deficiency
Compound
Hydroxocobalamin
Folic acid
Route
Intramuscular*
Oral
Dose
1000μg
5mg
Initial dose
6 × 1000μg over 2–3 weeks Daily for 4 months
Maintenance
Prophylactic
1000μg every 3 months
Depends on underlying
disease; life‐long therapy
may be needed in chronic
inherited haemolytic
anaemias, myelofibrosis,
renal dialysis
Total gastrectomy Ileal
Pregnancy, severe
haemolytic anaemias,
• Macrocytic anaemias show an increased size of circulating red cells (MCV >98 fL). Causes
include vitamin B12 (B12, cobalamin) or folate deficiency, alcohol, liver disease,
hypothyroidism, myelodysplasia, paraproteinaemia, cytotoxic drugs, aplastic anaemia,
pregnancy and the neonatal period.
• B12 or folate deficiency cause megaloblastic anaemia, in which the bone marrow
erythroblasts have a typical abnormal appearance.
• Folates take part in biochemical reactions in DNA synthesis. B12 has an indirect role by its
involvement in folate metabolism.
• B12 deficiency may also cause a neuropathy due to damage to the spinal cord and
peripheral nerves.
• B12 deficiency is usually caused by B12 malabsorption brought about by pernicious anaemia
in which there is autoimmune gastritis, resulting in severe deficiency of intrinsic factor, a
glycoprotein made in the stomach which facilitates B12 absorption by the ileum.
• ■ Other gastrointestinal diseases as well as a vegan diet may cause B12 deficiency.
• ■ Folate deficiency may be caused by a poor diet, malabsorption (e.g. gluten‐induced
enteropathy) or excess cell turnover (e.g. pregnancy, haemolytic anaemias, malignancy).
• ■ Treatment of B12 deficiency is usually with injections of hydroxocobalamin and of folate
deficiency with oral folic (pteroylglutamic) acid.
• ■ Rare causes of megaloblastic anaemia include inborn errors of B12 or folate transport or
metabolism, and defects of DNA synthesis not related to B12 or folate.
Pernicious anaemia (PA)
• This is caused by autoimmune attack on the gastric mucosa leading to
atrophy of the stomach. The wall of the stomach becomes thin, with a
plasma cell and lymphoid infiltrate of the lamina propria. Intestinal
metaplasia may occur. There is achlorhydria and secretion of IF is
absent or almost absent. Serum gastrin levels are raised. Helicobater
pylori infection may initiate an autoimmune gastritis which presents
in younger subjects as iron deficiency and in the elderly as PA.
Pernicious anaemia: associations.
Female
Vitiligo
Blue eyes
Myxoedema
Early greying
Hashimoto’s disease
Northern European
Thyrotoxicosis
Familial
Addison’s disease
Blood group A
Hypoparathyroidism
Hypogammaglobulinaemia
Carcinoma of the stomach
Causes of macrocytosis other than megaloblastic anaemia.
Alcohol
Liver disease
Myxoedema
Myelodysplastic syndromes
Antimetabolite drugs, e.g. hydroxycarbamide
Aplastic anaemia
Pregnancy
Smoking
Reticulocytosis
Myeloma and paraproteinaemia
•Hemolytic anaemia
Intravascular and extravascular haemolysis
• Hemolytic anemias are characterized by an excessive breakdown
of red blood cells (RBCs). They can be classified according to the
cause of hemolysis (intrinsic or extrinsic) and by the location of
hemolysis (intravascular or extravascular)
• There are two mechanisms whereby red cells are destroyed in
haemolytic anaemia. There may be excessive removal of red cells by
cells of the RE system (extravascular haemolysis) or they may be
broken down directly in the circulation (intravascular haemolysis)
Laboratory findings
• The laboratory findings are conveniently divided into three groups.
• 1 Features of increased red cell breakdown:
(a) serum bilirubin raised, unconjugated and bound to albumin;
(b) urine urinobilinogen increased;
(c) serum haptoglobins absent because the haptoglobins become saturated with
haemoglobin and the complex is removed by RE cells.
2 Features of increased red cell production:
a)reticulocytosis;
b)bone marrow erythroid hyperplasia; the normal marrow myeloid:erythoid ratio of 2:1 to
12:1 is reduced to 1 : 1 or reversed.
3 Damaged red cells:
a) morphology (e.g. microspherocytes, elliptocytes, fragments);
(b) osmotic fragility;
(c) specific enzyme, protein or DNA tests.
Causes of intravascular haemolysis.
Mismatched blood transfusion (usually ABO)
G6PD deficiency with oxidant stress
Red cell fragmentation syndromes
Some severe autoimmune haemolytic anaemias
Some drug‐ and infection‐induced haemolytic anaemias
Paroxysmal nocturnal haemoglobinuria
March haemoglobinuria
Unstable haemoglobin
G6PD, glucose‐6‐phosphate dehydrogenase
• The main laboratory features of intravascular haemolysis therefore
are (Fig. 6.3):
• 1 Haemoglobinaemia and haemoglobinuria.
2 Haemosiderinuria.
3 Methaemalbuminaemia (detected spectrophotometrically).
Classification of haemolytic anaemias.
Hereditary
Acquired
Membrane
Hereditary spherocytosis, hereditary
elliptocytosis
Metabolism
G6PD deficiency, pyruvate kinase
deficiency
Haemoglobin
Genetic abnormalities (Hb S, Hb C,
unstable); see Chapter 7
Immune
Autoimmune
Warm antibody type (see Table 6.5)
Cold antibody type
Alloimmune
Haemolytic transfusion reactions Haemolytic
disease of the newborn Allografts, especially
marrow transplantation Drug associated
Red cell fragmentation syndromes
See Table 6.6
March haemoglobinuria
Infections
Malaria, clostridia
Chemical and physical agents
Especially drugs, industrial/domestic substances,
burns Secondary
Liver and renal disease
Paroxysmal nocturnal haemoglobinuria (see
Chapter 22)
• Hereditary haemolytic anaemias
Hereditary spherocytosis
• This is the commonest cause of inherited haemolytic anaemia in
northern Europeans.
• It is an autosomal dominant disorder of variable severity, although in
25% of patients neither parent is affected, suggesting spontaneous
mutation in some instances.
• Jaundice may present at birth or be delayed or occur not at all.
• Splenomegaly is a feature and
• splenectomy is considered to be the treatment of choice in severe
cases.
• Maintenance of folic acid levels is important.
Glucose-6-phosphate dehydrogenase deficiency
• G6PD deficiency is a common disorder affecting
over 400 million people worldwide.
• It is the most common red cell enzyme defect that
causes episodic haemolytic anaemia because of the
decreased ability of red blood cells to cope with
oxidative stresses.
• It is an X-linked recessive inherited disorder with a
high prevalence among people of African,
Mediterranean or Asian ancestry.
• In some countries such as Malaysia there is a
national screening program.
The important clinical features are:
• asymptomatic in many
• neonatal jaundice—infants at risk should be observed after delivery (at
least 5 days)
• episodic acute haemolytic anaemia—triggered by antioxidants and
infections, and drugs, especially antimalarials, sulfonamides,
nitrofurantoin, quinolones, traditional medicines, vitamins C and K, high
dose aspirin, fava (broad) beans and naphthalene (e.g. moth balls)
• There is no specific treatment. Known precipitants should be avoided.
Avoid penicillin and probenecid.
• Diagnosis is by G6PD assay and a blood film during an attack.
Agents that may cause haemolytic anaemia in glucose‐6‐phosphate
dehydrogenase (G6PD) deficiency.
Infections and other acute illnesses (e.g. diabetic ketoacidosis)
Drugs
Antimalarials (e.g. primaquine, pamaquine, chloroquine, Fansidar, Maloprim)
Sulphonamides and sulphones (e.g. co‐trimoxazole, sulfanilamide, dapsone,
sufasalazine)
Other antibacterial agents (e.g. nitrofurans, chloramphenicol)
Analgesics (e.g. aspirin), moderate doses are safe
Antihelminths (e.g. β‐naphthol, stibophen)
Miscellaneous (e.g. vitamin K analogues, naphthalene (mothballs), probenecid)
Fava beans (possibly other vegetables)
N.B. Many common drugs have been reported to precipitate haemolysis in G6PD deficiency in some patients
(e.g. aspirin, quinine and penicillin) but not at conventional dosage.
Acquired haemolytic anaemias
• Immune haemolytic anaemias
• Autoimmune haemolytic anaemias
Immune haemolytic anaemias: classification.
Warm type
Cold type
Autoimmune
Idiopathic
Secondary
SLE, other ‘autoimmune’ diseases CLL,
lymphomas
Drugs (e.g. methyldopa)
Idiopathic
Secondary
Infections – Mycoplasma pneumonia,
infectious mononucleosis Lymphoma
Paroxysmal cold haemoglobinuria (rare,
sometimes associated with infections, e.g.
syphilis)
Alloimmune
Induced by red cell antigens
Haemolytic transfusion reactions
Haemolytic disease of the newborn post
stem cell grafts
Drug induced
Drug–red cell membrane complex Immune
Hemolytic anaemia
• hemolytic anaemia are those with a red cell membrane defect and
include
• hereditary spherocytosis,
• hereditary elliptocytosis and
• hereditary stomatocytosis.
• Haemolytic anaemia is caused by shortening of the red cell life. The red cells may
break down in the reticuloendothelial system (extravascular) or in the circulation
(intravascular).
• Haemolytic anaemia may be caused by inherited red cell defects, which are usually
intrinsic to the red cell, or to acquired causes, which are usually caused by an
abnormality of the red cell environment.
• Features of extravascular haemolysis include jaundice, gallstones and splenomegaly
with raised reticulocytes, unconjugated bilirubin and absent haptoglobins.
• In intravascular haemolysis (e.g. caused by ABO mismatched blood transfusion), there
is haemoglobinaemia, methaemalbuminaemia, haemoglobinuria and
haemosiderinuria.
• ■ Genetic defects include those of the red cell membrane (e.g. hereditary
spherocytosis), enzyme deficiencies (e.g. glucose‐6‐phosphate dehydrogenase or
pyruvate kinase deficiency) or haemoglobin defects (e.g. sickle cell anaemia, see
Chapter 7).
• ■ Acquired causes of haemolytic anaemia include
warm or cold, auto‐ or allo‐antibodies to red cells, red cell fragmentation syndromes,
infections, toxins and paroxysmal nocturnal haemoglobinuria
Microangiopathic hemolytic anemia
• MAHA
• A type of hemolytic anemia that is the result of mechanical damage
to erythrocytes by microthrombi in small blood vessels.
• Characterized by schistocytes on the peripheral blood smear.
• Common causes include,
oThrombotic thrombocytopenic purpura
oHemolytic uremic syndrome
oDisseminated intravascular coagulation
oHELLP syndrome.
• If the patient has severe symptoms of anemia or a lifethreatening cause is suspected (i.e., TTP/HUS, disseminated
intravascular coagulation, HELLP syndrome, acute hemolytic
transfusion reaction), proceed directly to treatment in parallel with
diagnostic evaluation.
Hereditary haemoglobinopathies
• The commonest haemoglobinopathies are the thalassaemias, which
are caused by a deficiency in the quality of globin chains, whereas
other haemoglobinopathies are caused by structural variations in the
globin chain. These conditions include HbS (sickle cell), HbC, HbD,
HbE, HbO and HbLepore.
Thalassaemia
Four gene deletion α‐thalassaemia
β0-Thalassaemia trait
Thalassaemia major
β+‐Thalassaemia trait
Transfusion dependent, homozygous
β0‐thalassaemia or other combinations of β‐thalassaemia trait
Thalassaemia intermedia (non‐transfusion dependent thalassaemia)
α0‐Thalassaemia trait
See Table 7.3
α+‐Thalassaemia trait
Genetic
Type
Haplotype
Heterozygous
Homozygous
thalassaemia trait (minor)*
– –/
MCV, MCH low
Hydrops fetalis
MCV, MCH minimally
reduced
As heterozygous
α0‐thalassaemia† Compound
heterozygote α0α+ (– –/–α) is
haemoglobin H disease
α‐Thalassaemias†
α0
α+
–α/
Thalassaemia
• This inherited condition is seen mainly (although not exclusively) in people from the
Mediterranean basin, the Middle East, north and central India and South-East Asia, including
south China.
• The heterozygous form is usually asymptomatic; patients show little if any anaemia and
require no treatment. The condition is relatively common in people from these areas.
• The homozygous form is a very severe congenital anaemia needing lifelong transfusional
support but is comparatively rare, even among the populations prone to thalassaemia
• The key to the diagnosis of heterozygous thalassaemia minor is significant microcytosis quite
out of proportion to the normal Hb or slight anaemia, and confirmed by finding a raised
HbA2 on Hb electrophoresis.
• DNA screening analysis is now available.
• The importance of recognising the condition lies in distinguishing it from iron-deficiency
anaemia, for iron does not help people with thalassaemia and is theoretically
contraindicated. Even more importantly, it lies in recognising the risk that, if both parents
have thalassaemia minor, they run a one in four chance of having a baby with thalassaemia
major in every pregnancy, with devastating consequences for both the affected child and the
whole family.
• Treatment of thalassaemia major is transfusion to a high normal Hb with packed cells plus
desferrioxamine.
Thalassemia
• the most common human single-gene disorders in the world, are a group of
hereditary disorders characterised by a defect in the synthesis of one or
more of the globin chains (α or β)—there are two of each (α2, β2).
• This causes defective haemoglobin synthesis leading to hypochromic
microcytic anaemia.
• α-thalassaemia is usually seen in people of Asian origin.
• β-thalassaemia is seen in certain ethnic groups from the Mediterranean, the
Middle East, South- East Asia and the Indian subcontinent.
• However, in our multicultural communities one cannot assume a person’s
origins.
• It is recommended that all women of child-bearing age be screened for
thalassaemia.
• The thalassaemias are described as ‘trait’ when there are laboratory features
without clinical expression.
Genetic profile
• α-thalassaemia is usually due to the deletion of one or more of the four genes for
α-globin,
• the severity depending on the number of genes deleted:
• deletion of all four genes—α-thalassaemia (hydrops fetalis);
• of three genes—haemoglobin H disease, which results in lifelong anaemia of mildto-moderate degree;
• of one or two genes—a symptomless carrier.
• In β-thalassaemia, the β-chains are produced in decreased quantity rather than
having large deletions. People who have two mutations (one in each β-globin gene)
have β-thalassaemia major.
• β-thalassaemia minor—a single mutation (heterozygous)—the carrier or trait state
• β-thalassaemia major—two mutations (homozygous)—the person who has the
disorder
• If both parents are carriers, there is a 1 in 4 chance that their child will have the
disorder.
Clinical features
• Carriers are clinically asymptomatic and do not need treatment apart
from counselling.
• Patients with thalassaemia major present with symptoms of severe
anaemia (haemolytic anaemia).
• Without treatment, children with thalassaemia major are lethargic and
inactive, show a failure to thrive or to grow normally, and delayed
puberty, hepatosplenomegaly and jaundice.
• Signs usually appear after 6 months and death from cardiac failure
used to be common but with regular blood transfusions and ironchelating treatment people can now live in good health.
DxT pallor + jaundice + hepatosplenomegaly → thalassaemia
major
• Diagnosis
• FBE: in most carriers the mean corpuscular haemoglobin/mean
corpuscular volume is low but can be normal. There is usually mild
hypochromic microcytic anaemia but this is severe with the
homozygous type.
• Haemoglobin electrophoresis: measures relative amounts of normal
adult haemoglobin (HbA) and other variants (e.g. HbA2, HbF). This will
detect most carriers.
• Serum ferritin level: helps distinguish from iron deficiency, which has a
similar blood film.
• DNA analysis: for mutation detection (mainly used to detect or confirm
carriers).
Treatment for thalassaemia major
• Treatment is based on a regular blood transfusion schedule for
anaemia.
• Avoid iron supplements.
• Folate supplementation and a low-iron diet are advisable.
• Excess iron is removed by iron chelation (e.g. desferrioxamine).
• Allogeneic bone marrow transplantation has been used with success.
• Splenectomy may be appropriate.
Sickle-cell disorders
• The most important abnormality in the haemoglobin (Hb) chain is sickle-cell
haemoglobin (HbS), which results from a single base mutation of adenine to
thymine, leading to a substitution of valine for glutamine at position 6 on
the β-globin chain.
• The defective Hb causes the red cells to become deformed in shape—
‘sickled’.
• The sickled cells tend to flow poorly and clog the microcirculation, resulting
in hypoxia, which compounds the sickling. Such attacks, which result in
tissue infarction, are called ‘crises’.
• Sickling is precipitated by infection, hypoxia, dehydration, cold and acidosis,
and may complicate operations.
• The autosomal recessive disorder occurs mainly in Africans (25% carry the
gene), but it is also found in India, South-East Asia, the Middle East and
southern Europe.
• Heterozygous state for HbS = sickle-cell trait
• Homozygous state = sickle-cell anaemia/disease
• Sickle-cell anaemia
• This varies from being mild or asymptomatic to a severe haemolytic anaemia
and recurrent painful crises.
• It may present in children with anaemia and mild jaundice.
• Children may develop digits of varying lengths from the hand-and-foot
syndrome due to infarcts of small bones.
• Features of infarctive sickle crises include:
• bone pain (usually limb bones)
• abdominal pain
• chest—pleuritic pain kidney—haematuria
• spleen—painful infarcts
• precipitated by cold, hypoxia, dehydration or infection
•
•
•
•
•
•
Hb electrophoresis is needed to confirm the diagnosis.
Long-term problems ;
chronic leg ulcers, susceptibility to infection,
aseptic necrosis of bone (especially head of femur),
blindness and chronic kidney disease. T
he prognosis is variable. Children in Africa often die within the first year of
life. Infection is the commonest cause of death.
• Sickle-cell trait
• People with this usually have no symptoms unless they are exposed to
prolonged hypoxia, such as anaesthesia and flying in non-pressurised
aircraft. The disorder is protective against malaria.
Classification of bleeding disorders
Vascular disorders
Inherited
• Hereditary haemorrhagic telangiectasia
• Connective tissue disease, e.g. Marfan syndrome
• Easy bruising syndrome
Acquired
• Senile purpura
• Infection, e.g. dengue, meningococcal
• Henoch-Schonlein purpura
• Corticosteroid purpura
• Vitamin C deficiency (scurvy)
• Painful bruising syndrome
Platelet disorders
Inherited
Fanconi syndrome
Glanzmann disease
Acquired (immune)
Idiopathic thrombocytopenic purpura
Aplastic anaemia
Drug induced thrombocytopenia, e.g. heparin
Thrombotic thrombocytopenia purpura
Post-transfusion purpura
Non-immune
Disseminated intravascular coagulation
Myeloproliferative disorders
Kidney failure/uraemia
Bone marrow replacement (e.g. leukaemia) or failure
Coagulation disorders
•
•
•
•
•
•
•
•
•
•
Inherited
Haemophilia A
Haemophilia B
von Willebrand disease (types 1, 2 and 3)
Acquired
Disseminated intravascular coagulation (DIC)
Vitamin K deficiency
Oral anticoagulation therapy or overdose
Acquired haemophilia
Liver disease
The coagulation factors.
Factor number
Descriptive
name
Active form
I
Fibrinogen
Fibrin subunit
II
Prothrombin
Serine protease
III
Tissue factor
Receptor/cofact
or*
V
Labile factor
Cofactor
VII
Proconvertin
Serine protease
VIII
Antihaemophilic
factor
Cofactor
Table 3.7 Laboratory diagnosis of a hypochromic anaemia.
Iron deficiency
Chronic inflammation
or malignancy
Thalassaemia trait (α
or β)
Sideroblastic anaemia
MCV/ MCH
Reduced in relation to
severity of anaemia
Normal or mild
reduction
Reduced; very low for
degree of anaemia
Usually low in
congenital type but
MCV usually raised in
acquired type
Serum iron
Reduced
Reduced
Normal
Raised
TIBC
Raised
Reduced
Normal
Normal
Serum ferritin
Reduced
Normal or raised
Normal
Raised
Bone marrow iron
stores
Absent
Present
Present
Present
Erythroblast iron
Absent
Absent
Present
Ring forms
Haemoglobin
electrophoresis
Normal
Normal
Hb A2 raised in β form
Normal
MCH, mean corpuscular haemoglobin; MCV, mean corpuscular volume; TIBC, total iron‐binding capacity.
• Aplastic anaemia
• Aplastic (hypoplastic) anaemia is defined as pancytopenia resulting
from hypoplasia of the bone marrow (Fig 22.1). It is classified into
primary (congenital or acquired) or secondary types
Causes of pancytopenia.
Decreased bone marrow function
Aplasia (reduction of haemopoietic stem cells)
Acute leukaemia, myelodysplasia, myeloma
Infiltration with lymphoma, solid tumours, tuberculosis
Megaloblastic anaemia
Paroxysmal nocturnal haemoglobinuria
Myelofibrosis
Haemophagocytic syndrome
Increased peripheral destruction
Splenomegaly
Causes of aplastic anaemia.
Primary
Secondary
Congenital (Fanconi and non-Fanconi
types)
Ionizing radiation: accidental exposure
(radiotherapy, radioactive isotopes,)
Idiopathic acquired
Chemicals: benzene, organophosphates
and other organic solvents, DDT and other
pesticides, recreational drugs (ecstasy)
Drugs: Those that regularly cause marrow
depression (e.g. busulfan, melphalan,
cyclophosphamide, anthracyclines,
nitrosoureas)
Those that occasionally or rarely cause
marrow depression (e.g. chloramphenicol,
sulphonamides, gold, anti-inflammatory,
antithyroid, psychotrophic, anticonvulsant/
antidepressant drugs)
Viruses: viral hepatitis (non-A, non-B,
non-C, non-G in most cases), EBV
Autoimmune diseases: systemic lupus
erythematosus
Transfusion associated GVHD (see p.
342)
Screening tests used in the diagnosis of coagulation disorders (see also Fig. 24.10)
Screening tests
Abnormalities indicated by
prolongation
Most common cause of
coagulation disorder
Thrombin time (TT)
Deficiency or abnormality of
fibrinogen or inhibition of thrombin DIC Heparin therapy
by heparin or FDPs
Prothrombin time (PT)
Deficiency or inhibition of one
or more of the following
coagulation factors: VII, X, V, II,
fibrinogen
Liver disease Warfarin therapy
DIC
Activated partial thromboplastin
time (APTT or PTTK)
Deficiency or inhibition of one or
more of the following coagulation
factors: XII, XI, IX (Christmas
disease), VIII (haemophilia), X, V,
II, fibrinogen
Haemophilia, Christmas disease
(+ conditions above)
Fibrinogen quantitation
Fibrinogen deficiency
DIC, liver disease
DIC, disseminated intravascular coagulation; FDPs, fibrin degradation products.
N.B. Platelet count and the tests of platelet function are also used in screening patients with a bleeding disorder (
• Normal haemostasis requires vasoconstriction, platelet aggregation and blood
coagulation. The
intact endothelial cell separates collagen and other subendothelial connective tissues
that would stimulate platelet aggregation from circulating blood. The endothelial cells
also produce prostacyclin, nitric oxide and an ectonucleotidase, which inhibit platelet
aggregation.
• Platelets are produced from megakaryocytes in the bone marrow stimulated by
thrombopoietin. They have surface glycoproteins which facilitate direct adherence to
subendothelial tissues and also, via von Willebrand factor, to collagen, to other platelets
(aggregation) and to fibrinogen. Platelets contain different types of storage granules
which are released after platelet activation.
• ■ Blood coagulation in vivo in response to vascular injury commences with tissue factor
binding to clotting factor VII and this initiates a cascade which results in thrombin
generation. Thrombin then activates cofactors VIII and V and factor XI which greatly
amplify the coagulation pathway resulting in a fibrin clot.
• ■ Coagulation factor inhibitors include antithrombin, protein C and protein S.
• ■ Dissolution of fibrin clots (fibrinolysis) occurs by activation of plasminogen to plasmin.
• ■ Tests of haemostatic function include the thrombin time (TT), prothrombin time (PT),
activated partial thromboplastin time (APTT) as well as individual coagulation factor
assays and assay of von Willebrand factor. Tests of platelet function include the PFA‐100
and platelet aggregation tests.
Causes of thrombocytopenia.
Failure of platelet production
Selective megakaryocyte depression rare congenital defects (see text) drugs, chemicals, viral infections
Part of general bone marrow failure cytotoxic drugs
radiotherapy
aplastic anaemia
leukaemia
myelodysplastic syndromes
myelofibrosis
marrow infiltration (e.g. carcinoma, lymphoma, Gaucher’s disease)
multiple myeloma
megaloblastic anaemia
HIV infection
Increased consumption of platelets
Immune
autoimmune
idiopathic
associated with systemic lupus erythematosus, chronic lymphocytic leukaemia or lymphoma;
infections: Helicobacter pylori, HIV, other viruses, malaria drug‐induced, e.g. heparin
post‐transfusional purpura
feto‐maternal alloimmune thrombocytopenia
Thrombocytopenia as a result of drugs or toxins.
Bone marrow suppression
Predictable (dose‐related)
ionizing radiation, cytotoxic drugs, ethanol
Occasional
chloramphenicol, co‐trimoxazole, idoxuridine, penicillamine, organic arsenicals,
benzene, etc.
Immune mechanisms (proven or probable) Analgesics, anti‐inflammatory drugs
gold salts Antimicrobials
penicillins, rifamycin, sulphonamides, trimethoprim, para‐
aminosalicylate Sedatives, anticonvulsants
diazepam, sodium valproate, carbamazepine Diuretics
acetazolamide, chlorathiazides, furosemide Antidiabetics
chlorpropamide, tolbutamide Others
digitoxin, heparin, methyldopa, oxyprenolol, quinine, quinidine
Thrombotic thrombocytopenic purpura (TTP)
• TTP has traditionally been described as a pentad of
• thrombocytopenia, microangiopathic haemolytic anaemia,
neurological abnormalities, renal failure and fever.
Main clinical and laboratory findings in haemophilia A, factor IX deficiency (haemophilia B, Christmas disease) and von
Willebrand disease.
Inheritance
Haemophilia
A
Factor IX
deficiency
von
Willebrand
disease
Sex‐linked
Sex‐linked
Dominant
(incomplete)
Main sites of
haemorrhage
Muscle, joints,
post‐ trauma or
postoperative
Muscle, joints,
post‐trauma or
postoperative
Mucous
membranes,
skin cuts,
post‐trauma or
postoperative
Platelet count
Normal
Normal
Normal
PFA‐100
Normal
Normal
Prolonged
Prothrombin
time
Normal
Normal
Normal
Partial
thromboplastin
time
Prolonged
Prolonged
Prolonged or
normal
Haemostasis tests: typical results in acquired bleeding disorders.
Platelet
count
Prothromb
in time
Activated
partial
thrombopl
astin time
T
ti
Liver
disease
Low
Prolonged
Prolonged
N
(r
pr
DIC
Low
Prolonged
Prolonged
G
pr
Massive
transfusion
Low
Prolonged
Prolonged
N
Coumarin
anticoagula
nts
Normal
Grossly
prolonged
Prolonged
N
Heparin
Normal
(rarely low)
Mildly
prolonged
Prolonged
P
Circulating
Indications for the use of fresh frozen plasma (National Institutes of Health Consensus
Guidelines).
Coagulation factor deficiency (PCC where specific or combined factor concentrate is
not available)
Reversal of warfarin effect (only if PCC is unavailable)
Multiple coagulation defects (e.g. in patients with liver disease, DIC) (PCC are much
better, plasma is virtually useless)
Massive blood transfusion with coagulopathy and clinical bleeding
Thrombotic thrombocytopenic purpura
Some patients with immunodeficiency syndromes
DIC, disseminated intravascular coagulation; PCC, prothrombin complex concentrates.
Venous thrombosis Pathogenesis and risk factors
• Virchow’s triad suggests that there are three components that are
important in thrombus formation:
1 Slowing down of blood flow;
2 Hypercoagulability of the blood;
3 Vessel wall damage.