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Anaemia 203
Table 5.6 Causes of aplastic anaemia
Idiopathic acquired (67% of cases)
Inherited, e.g. Fanconi’s anaemia (autosomal recessive)
Cytotoxic drugs and radiation
Idiosyncratic drug reaction, e.g. phenytoin, carbamazepine, carbimazole,
NSAIDs
Chemicals: benzene, insecticides
Infections, e.g. EBV, HIV, hepatitis, tuberculosis
Paroxysmal nocturnal haemoglobinuria
Miscellaneous, e.g. pregnancy
EBV, Epstein–Barr virus; HIV, human immunodeficiency virus; NSAIDs, non-steroidal
anti-inflammatory drugs.
Anaemia caused by marrow failure (aplastic anaemia)
Aplastic anaemia is defined as pancytopenia (deficiency of all cell elements
of the blood) with hypocellularity (aplasia) of the bone marrow. It is an
uncommon but serious condition which may be inherited but is more commonly acquired. There is a reduction in the number of pluripotent stem cells
together with a fault in those remaining or an immune reaction against them
so that they are unable to repopulate the bone marrow. Failure of only one
cell line may also occur, resulting in isolated deficiencies, e.g. red cell aplasia.
Aetiology
Aplastic anaemia can be induced by a variety of disorders (Table 5.6). Many
drugs have been associated with the development of aplastic anaemia,
and this occurs as a predictable dose-related effect (e.g. chemotherapeutic
agents) or as an idiosyncratic reaction (e.g. chloramphenicol, phenytoin, nonsteroidal anti-inflammatory drugs [NSAIDs]).
Clinical features
The clinical manifestations of marrow failure from any cause are anaemia,
bleeding and infection. Physical findings include bruising, bleeding gums and
epistaxis. Mouth infections are common.
Investigations
• Blood count shows pancytopenia with low or absent reticulocytes.
• Bone marrow examination shows a hypocellular marrow with increased
fat spaces.
Differential diagnosis
This is from other causes of pancytopenia (Table 5.7). A bone marrow
trephine biopsy is essential for assessment of the bone marrow cellularity.
204 Haematological disease
Table 5.7 Causes of pancytopenia
Aplastic anaemia (see Table 5.6)
Drugs
Megaloblastic anaemia
Bone marrow infiltration or replacement: lymphoma, acute leukaemia,
myeloma, secondary carcinoma, myelofibrosis
Hypersplenism
Systemic lupus erythematosus
Disseminated tuberculosis
Paroxysmal nocturnal haemoglobinuria
Overwhelming sepsis
Management
Treatment includes withdrawal of the offending agent, supportive care and
some form of definitive therapy (see later). Blood and platelet transfusions are
used cautiously in patients who are candidates for bone marrow transplantation (BMT) to avoid sensitization. Patients with severe neutropenia are at risk
of serious infections with bacteria, fungi (e.g. Candida and aspergillosis) and
viruses (herpesvirus). Fever in a neutropenic patient is a medical emergency
(Emergency Box 5.1).
The course of aplastic anaemia is very variable, ranging from a rapid
spontaneous remission to a persistent, increasingly severe pancytopenia,
which may lead to death through haemorrhage or infection. Features that
indicate a poor prognosis are neutrophil count <0.5 × 109/L, platelet count
<20 × 109/L and a reticulocyte count of <40 × 109/L.
In those patients who do not undergo spontaneous recovery the options
for treatment are as follows:
• BMT from a human leucocyte antigen (HLA)-identical sibling donor is the
treatment of choice for patients under 40 years of age.
• Immunosuppressive therapy with antilymphocyte globulin and ciclosporin
is used for young patients who lack an HLA-identical donor, patients over
the age of 40 years (BMT is not indicated because of the high risk of
graft-versus-host disease) and transfusion-dependent patients.
HAEMOLYTIC ANAEMIA
Haemolytic anaemia results from increased destruction of red cells with a
reduction of the circulating lifespan (normally 120 days). There is a compensatory increase in bone marrow activity with premature release of immature
red cells (reticulocytes, p. 194).
Red cell destruction may be intravascular (within the blood vessels) but
is more commonly extravascular (within the reticuloendothelial system,
Haemolytic Anaemia 205
Emergency Box 5.1 Assessment and treatment of
suspected neutropenic sepsis
Suspect neutropenic sepsis in a neutropenic patient (neutrophil count
<1 × 109/L) who is pyrexial or has new-onset confusion, tachycardia,
hypotension, dyspnoea or hypothermia.
Assessment
• History and physical examination including mucous membranes, oropharynx
(?thrush, erythema), surgical sites and intravenous lines
Investigations
• Bloods: Full blood count and differential white cell count, C-reactive
protein, urea and electrolytes, liver biochemistry, clotting, blood cultures
• Radiology: Chest X-ray. Consider further imaging if localizing signs, e.g.
computed tomography (CT) scan of abdomen and pelvis
• Microbiology: Microscopy and culture of peripheral blood (as above) and
taken from central lines, sputum, urine, stool (if diarrhoea)
Antibiotics
• Seek expert help from microbiologist and oncologist
• Start empirical intravenous antibiotic treatment, e.g. piperacillin and
aminoglycoside, to cover Gram-negative organisms and Pseudomonas
• Add vancomycin if clinical deterioration, fever persists or suspected
methicillin-resistant Staphylococcus aureus (MRSA) infection
• Subsequent treatment is adjusted on the basis of cultured organisms and
clinical progress
• Swap to oral antibiotics when apyrexial for 48 hours and continue for
10–14 days
mainly the spleen). The causes of haemolytic anaemia in adults are listed
in Table 5.8.
Intravascular haemolysis is suggested by:
• Raised levels of plasma Hb as red cells are broken down.
• Very low or absent haptoglobins: Free Hb binds to plasma haptoglobins;
the bound complex is rapidly removed by the liver, leading to low plasma
haptoglobin levels.
• Positive Schumm’s test: Hb appears in the plasma as the oxidized form,
methaemoglobin, which dissociates into ferrihaem and globin. Binding of
ferrihaem to albumin forms methaemalbumin and this can be detected in
the plasma (Schumm’s test).
• Haemosiderinuria: Unbound Hb appears in the urine as haemoglobinuria.
Some Hb is broken down in the renal tubular cells and appears as
haemosiderin in the urine.
206 Haematological disease
Table 5.8 Causes of haemolytic anaemia
Inherited Acquired
Red cell membrane defect
Hereditary spherocytosis
Hereditary elliptocytosis
Hb abnormalities
Thalassaemia
Sickle cell disease
Metabolic defects
G6PD deficiency
Pyruvate kinase deficiency
Pyrimidine kinase
deficiency
G6PD, glucose-6-phosphate dehydrogenase deficiency.
Fig. 5.2 shows an approach to investigating the patient with suspected
haemolytic anaemia
Immune
Autoantibodies
Alloimmune
Drug-induced antibodies
Non-immune
Paroxysmal nocturnal haemoglobinuria
Mechanical destruction: microangiopathic
Haemolytic anaemia, damaged artificial
heart valves, march haemoglobinuria
Secondary to systemic disease, e.g. liver
failure
Infections, e.g. malaria
Drugs/chemicals
Hypersplenism
INHERITED HAEMOLYTIC ANAEMIAS
Inherited haemolytic anaemias are due to defects in one or more components
of the mature red blood cell:
• Cell membrane
• Haemoglobin
• Metabolic machinery of the red blood cell.
Membrane defects
Hereditary spherocytosis
This is the most common inherited haemolytic anaemia in northern
Europeans, and can be inherited in either an autosomal dominant or
recessive manner. A defect in the red cell membrane causes an increased
permeability to sodium; the red cells become spherical in shape, are more
rigid and less deformable than normal red cells, and are destroyed prematurely in the spleen. Common causes of hereditary spherocytosis include
deficiencies of the red cell structural membrane proteins spectrin or ankyrin.
Clinical features
The clinical severity varies from symptom-free carrier to severe haemolysis
with anaemia, jaundice and splenomegaly. As in many haemolytic anaemias,
Inherited Haemolytic Anaemias 207
Haemolysis
Increased red cell production
• Reticulocytosis/polychromasia
• Erythroid hyperplasia of bone
marrow
Abnormal red cells
Haemoglobin
electrophoresis
Thalas-
Sickle
saemia
cell
disease
Drugs, e.g.
• Methyldopa
• Quinine
• NSAIDs
• Interferon
• Ribavarin
IgG – warm IgM – cold
Hb
variants
Autoimmune
haemolytic
anaemia
Spherocytes Other
DCT
+ve
Increased red cell breakdown
• Anaemia
• Serum bilirubin
• LDH
• Urobilinogen
• +ve urinary haemosiderin
• Plasma haptoglobulin
Blood film
• Bite cells
• Blister cells
• Heinz bodies
Enzyme defects,
e.g.
DCT
• G6PD
-
ve
• Pyruvate kinase
• Pyrimidine 5'
nucleotidase
Hereditary
spherocytosis
Malaria,
Clostridium
welchii
Fragmentation
Microangiopathic
haemolytic
anaemia, e.g.
• Eclampsia
• Haemolytic
uraemic syndrome
• Thrombotic
thrombocytopenic
purpura
• DIC
Fig. 5.2 An approach to investigation of suspected haemolytic anaemia.
DCT, directCoombs’ test; DIC, disseminated intravascular coagulation;
G6PD, glucose-6- phosphate dehydrogenase; IgG, immunoglobulin G; IgM,
immunoglobulin M; LDH, lactate dehydrogenase; NSAIDs, non-steroidal antiinflammatory drugs.
the course of the disease may be interrupted by aplastic, haemolytic and
megaloblastic crises. Aplastic anaemia usually occurs after infections,
particularly with erythro(parvo)virus, whereas megaloblastic anaemia is the
result of folate depletion caused by hyperactivity of the bone marrow. Chronic
haemolysis may lead to the development of pigment gallstones.
Investigations
• Blood count demonstrates reticulocytosis and anaemia, which is usually
mild.
• The blood film shows spherocytes and reticulocytes.
208 Haematological disease
• Haemolysis is evident (e.g. the serum bilirubin and urinary urobilinogen
will be raised).
The diagnosis is usually straightforward and made on the basis of
clinical features, family history, laboratory investigation (as above) and
exclusion of other causes of haemolytic anaemia, particularly autoimmune
haemolytic anaemia (which is virtually ruled out by a negative direct
antiglobulin test).
Management
Splenectomy is indicated in hereditary spherocytosis to relieve symptoms
due to anaemia or splenomegaly. This is usually postponed until after childhood to minimize the risk of overwhelming infections (p. 221–222).
Hereditary elliptocytosis
Hereditary elliptocytosis is similar to spherocytosis, but the red cells are elliptical in shape. It is milder clinically and usually does not require splenectomy.
Haemoglobin abnormalities
Normal adult Hb is made up of haem and two polypeptide globin chains,
α and β. The haemoglobinopathies can be classified into abnormal chain
production (e.g. thalassaemia), or abnormal chain structure (e.g. sickle cell
anaemia) (Table 5.9).
Table 5.9 Types of haemoglobin
Hb Structure Comment
Normal
Abnormal
chain
production
Abnormal
chain
structure
A
A
2
F
H
Barts
S
C
α2β
α2δ
α2γ
β
γ
α2β
α2β
4
4
97% of adult haemoglobin (Hb)
2
2% of adult Hb; elevated in
2
β-thalassaemia
Normal Hb in foetus from 3rd to 9th
2
month; increased in β-thalassaemia
Found in α-thalassaemia,
biologically useless
Found in α-thalassaemia,
biologically useless
Substitution of valine for glutamic
2
acid in position 6 of β chain
Substitution of lysine for glutamic
2
acid in position 6 of β chain
Inherited Haemolytic Anaemias 209
Thalassaemia
In normal Hb there is balanced (1:1) production of α and β chains. The thalassaemias are a group of disorders arising from one or multiple gene defects,
resulting in a reduced rate of production of one or more globin chains. The
imbalanced globin chain production leads to precipitation of globin chains
within red cells or precursors. This results in cell damage, death of red cell
precursors in the bone marrow (ineffective erythropoiesis) and haemolysis. The
thalassaemias affect people throughout the world. There are two main types:
• α-Thalassaemia: reduced α chain synthesis
• β-Thalassaemia: reduced β chain synthesis.
β-Thalassaemia
In homozygous β-thalassaemia there is little or no β chain production, resulting in excess α chains. These combine with whatever δ and γ chains are
produced, leading to increased Hb A2 and Hb F. Clinical syndromes in thalassaemia have moved away from ‘major’ and ‘minor’ descriptions to focus
on whether or not they are transfusion dependent:
• β-Thalassaemia trait (carrier). This is the asymptomatic heterozygous
carrier state. Anaemia is mild or absent, with a low MCV and MCH. This
condition is distinguished from iron deficiency as iron stores and serum
ferritin levels are normal.
• Non-transfusion-dependent thalassaemia. This includes patients with
moderate anaemia (Hb 70–100 g/L) that do not require regular blood
transfusions. Splenomegaly, bone deformities, recurrent leg ulcers and
gallstones are other features. This may be caused by a combination of
homozygous β- and α-thalassaemias.
• Transfusion-dependent thalassaemia. This presents in the first year
of life with severe anaemia, failure to thrive and recurrent infections.
Hypertrophy of the ineffective bone marrow leads to bony abnormalities:
the thalassaemic facies, with an enlarged maxilla and prominent frontal
and parietal bones. Resumption of haemopoiesis in the spleen and liver
(extramedullary haemopoiesis), the chief sites of red cell production in
fetal life, leads to hepatosplenomegaly.
Investigations
In homozygous disease, blood count and film show a hypochromic/microcytic
anaemia, raised reticulocyte count and nucleated red cells in the peripheral
circulation.
The diagnosis is made by Hb electrophoresis, which shows an increase in
Hb F and absent or markedly reduced Hb A.
Management
In homozygous patients, the mainstay of treatment is blood transfusion, aiming to keep the Hb above 100 g/L, thus suppressing ineffective
210 Haematological disease
erythropoiesis, preventing bony abnormalities and allowing normal development. Long-term folic acid supplements are required. Iron overload
caused by repeated blood transfusions may lead to damage of the endocrine glands, liver, pancreas and heart, with death in the second decade
from cardiac failure. Treatment with iron-chelating agents (subcutaneous
desferrioxamine, oral deferasirox or deferiprone) decreases iron loading.
Ascorbic acid 200 mg daily increases the urinary excretion of iron in
response to desferrioxamine. BMT has been used in young patients with
HLA-matched siblings.
α-Thalassaemia
The clinical manifestations of this disorder vary from a mild anaemia with
microcytosis to a severe condition incompatible with life. There are four
α-globin genes per cell. The manifestations depend on whether one, two,
three or all four of the genes are deleted, and thus whether a chain synthesis
is partial or completely absent. In the most severe form, where there is complete absence of α-globin (Hb Barts), infants are stillborn (hydrops fetalis).
Sickle syndromes
Sickle syndromes are a family of haemoglobin disorders in which the sickle
β-globin gene is inherited. The sickle β gene is spread widely throughout
Africa (25% carry the gene), India, the Middle East and Mediterranean countries. In the homozygous state (sickle cell anaemia) both genes are abnormal
(Hb SS), whereas in the heterozygous state (sickle cell trait, Hb AS) only one
chromosome carries the abnormal gene. Inheritance of the HbS gene from
one parent and HbC from the other parent gives rise to Hb SC disease, which
tends to run a milder clinical course than sickle cell disease but with more
thromboses.
In the deoxygenated state Hb S molecules are insoluble and polymerize.
This results in increased rigidity of the red cells, causing the classic sickle
appearance (Fig. 5.3). Sickling can produce:
• Premature destruction of red cells (haemolysis)
• Obstruction of the microcirculation (vaso-occlusion), leading to tissue
infarction.
Sickling is precipitated by hypoxia, dehydration, infection, acidosis and
cold.
Sickle cell anaemia
Clinical features
As the production of Hb F is normal, the disease is usually not manifest until
Hb F decreases to adult levels at about 6 months of age. There is extreme
phenotypic variation, with some patients having few or no symptoms and
others having recurrent crises and a markedly reduced life expectancy.
Inherited Haemolytic Anaemias 211
Fig. 5.3 Sickle cells (arrowed) and target cells (‘Mexican hat cells’).
Vaso-occlusion. In early childhood, acute pain in the hands and feet
(dactylitis) is due to occlusion of the small vessels and avascular necrosis of bone
marrow. In adults, bone pain most commonly affects the long bones, ribs, spine
and pelvis. The frequency of attacks varies from daily to perhaps once a year.
Anaemia. Most patients have a steady-state Hb of 60–80 g/L with a high
reticulocyte count (10%–20%). They often do not have symptoms of anaemia
because Hb S releases oxygen to the tissues more easily than normal Hb. A
rapid fall in the Hb can occur due to:
• Splenic sequestration. The spleen becomes engorged with red cells,
leading to an acute fall in Hb and rapid enlargement of the spleen. Liver
sequestration can also occur.
• Bone marrow aplasia most commonly due to parvovirus B19 infection,
which destroys erythrocyte precursors.
• Further haemolysis due to drugs or acute infection.
Long-term problems. Avascular necrosis of bones results in shortened,
deformed bones in children. Other complications of vaso-occlusion include
splenic atrophy (resulting in susceptibility to infection with pneumococcus,
Salmonella species and Haemophilus), retinal ischaemia (which may precipitate
proliferative sickle retinopathy and visual loss) and cerebral infarction (causing
fits and strokes). Transcranial Doppler ultrasound measures mean velocity of
blood flow in the large intracranial vessels and is used to screen for patients at
high risk of stroke and offer them prophylactic transfusion. Sequestration of red
cells within the corpora cavernosa causes priapism (prolonged painful erections)
and eventual impotence. Chronic haemolysis is associated with increased
formation of pigment gallstones. Other complications of sickle cell disease
include chronic kidney disease, leg ulcers, osteomyelitis, myocardial infarctions,
cardiomyopathy, pulmonary hypertension and acute chest syndrome. Acute
chest syndrome is a medical emergency and is characterized by fever, cough,
dyspnoea and pulmonary infiltrates on the chest X-ray. It is caused by infection,
fat embolism from necrotic bone marrow or pulmonary infarction due to
sequestration of sickle cells. Pulmonary hypertension and chronic lung disease
are the most common causes of death in adults with sickle cell disease.
212 Haematological disease
Investigations
Sickle cell disease is diagnosed by screening in the neonate (using cord
blood or the heel prick test), in the fetus of at-risk couples through prenatal
diagnosis and in children and adults from high-risk areas before undergoing
surgery. In Africa many patients are still diagnosed only when they present
with complications.
• Blood count: Hb (60–80 g/L) is low with a high reticulocyte count.
• Blood film shows sickled erythrocytes (Fig. 5.3).
• Diagnosis is made with Hb electrophoresis showing 80%–95% Hb SS
and absent Hb A.
• Sickle solubility test: sickling is induced in vitro with sodium dithionite.
Management
Precipitating factors should be avoided or treated promptly. Folic acid is
given to all patients with haemolysis. Infection prophylaxis is with penicillin 500 mg daily and vaccination with pneumococcal, meningococcal and
Haemophilus influenzae type b vaccine, as patients lack a functioning
spleen.
Most patients with a painful crisis are managed in the community, but
hospital admission is necessary when the pain is not controlled by non-opiate
analgesia or if there are complications (Table 5.10). The management of a
painful sickle crisis is summarized in Emergency Box 5.2.
Blood transfusions are not routinely given in steady-state anaemia and
are reserved for certain situations including after transient ischaemic attacks
and stroke, acute chest syndrome, splenic sequestration crisis and aplastic
crises, as well as before elective operations and during pregnancy.
Table 5.10 Complications of sickle cell anaemia requiring
inpatient management
Pain – uncontrolled by non-opiate analgesia
Swollen painful joints
Acute sickle chest syndrome or pneumonia
Mesenteric sickling and bowel ischaemia
Splenic or hepatic sequestration
Central nervous system deficit
Cholecystitis (pigment stones)
Cardiac arrhythmias
Renal papillary necrosis resulting in colic or severe haematuria
Hyphema (layer of red cells in anterior chamber of eye) or retinal detachment
Priapism