Haematology SBAs

Question 1

A 22-year-old motorcyclist is involved in a road traffic accident, and is transfused
two units of blood. Four hours later he develops acute shortness of breath
and hypoxia, and despite attempts at ventilation deteriorates rapidly and goes
into respiratory arrest. An autopsy shows evidence of massive pulmonary oedema
with granulocyte aggregation within the pulmonary microvasculature. The
most likely diagnosis is:

A Anaphylaxis

B ABO incompatible blood transfusion

C Fluid overload

D Transfusion related acute lung injury

E Air embolism

Answer 1

D Transfusion related acute lung injury

Transfusion related acute lung injury (TRALI) (D) is rare but is one of
the leading causes of transfusion related mortality. It can present with
acute shortness of break and hypoxia, as in this case, typically within
6 hours of receiving the transfusion. The classic presentation to look
out for is that of non-cardiogenic pulmonary oedema, i.e. pulmonary
oedema that is not due to fluid overload.
The underlying mechanism is not fully understood, but it is thought to
involve HLA antibodies in the blood donor reacting with corresponding
HLA antigens on the patient’s white blood cells. This leads to the formation
of aggregates of white blood cells which become stuck in small
pulmonary capillaries. The release of proteolytic enzymes from neutrophils
and toxic oxygen metabolites causes lung damage, and subsequent
non-cardiogenic pulmonary oedema which can be fatal. Treatment is
essentially supportive, and includes stopping the transfusion, giving
IV fluids and ventilation if needed. TRALI can occur with platelets and
FFP, as well as with packed red cells as in this case. You might find it
helpful to remember the mechanism by rearranging ‘TRALI’ to form the
word ‘TRAIL’, and think of the blood donor leaving a ‘trail’ of antibodies
in the recipient.

Question 2

A 43-year-old woman is transfused three units of blood as an emergency following
prolonged haematemesis. A few minutes later she becomes restless, and
complains of chest pain. On examination she is pyrexial and tachycardic with
a blood pressure of 95/60. There is bleeding at the site where her cannula is
inserted,
and urinalysis reveals haemoglobinuria. The most likely diagnosis is:

A Anaphylaxis

B ABO incompatible blood transfusion

C Myocardial infarction

D Graft versus host disease

E Bacterial contamination

Answer 2

B ABO incompatible blood transfusion

An ABO incompatible blood transfusion (B) can occur immediately
after a transfusion has been given. For example, if group A, B or AB
blood is given to a group O patient, the patient’s anti-A and anti-B
antibodies attack the blood cells in the donor blood. The most severe
form of reaction is thought to occur if group A red cells are transfused
to a group O patient. Even just a few millilitres of blood can trigger a
severe reaction within a few minutes. These reactions can also occur
with platelets or fresh frozen plasma because they also contain anti-red
cell antibodies.
Symptoms can include chills, fever, pain in the back, chest or along
the IV line, hypotension, dark urine (intravascular haemolysis), and
uncontrolled bleeding due to DIC. In this case, the management involves
stopping the transfusion immediately and taking blood samples for
FBC, biochemistry, coagulation, repeat x-match, blood cultures and
direct antiglobulin test, and contacting the haematology doctor as soon
as possible. The blood bank should also be urgently informed because
another patient may have also been given incompatible blood. These
patients require fluid resuscitation and possibly inotropic support. They
should be transferred to ICU if possible.

Question 3

An 83-year-old woman with myelodysplasia is found to have a haemoglobin of
6.2 on admission. She is transfused two units of blood, and is discharged 2 days
later. Six days after her admission her carer calls the GP with concerns that she
is feverish and her skin looks slightly yellow. She is readmitted to hospital where
blood tests reveal the following: bilirubin 35, ALT 15 (N 5–35), ALP 82
(N 20–140), Hb 7.3 g/dL, platelets 264 × 109/L. The most likely diagnosis is:

A Febrile haemolytic transfusion reaction

B Hepatitis B

C Graft versus host disease

D Post-transfusion purpura

E Delayed haemolytic transfusion reaction

Answer 3

E Delayed haemolytic transfusion reaction

Delayed haemolytic transfusion reactions (E) can occur more than 24
hours after a transfusion is given. They occur when patients are sensitized
from previous transfusions or pregnancies, and therefore have
antibodies against red cell antigens which are not picked up by routine
blood bank screening if they are below the detectable limits. The most
frequent causes are the antibodies of the Kidd (Jk) and Rh systems.
Clinical features might include falling haemoglobin concentration, a
smaller rise in haemoglobin than expected following a transfusion as in
this case, fever, jaundice and rarely haemoglobinuria or renal failure. A
blood film may show a raised reticulocyte count. Management of these
reactions includes monitoring renal function, sending a repeat group
and antibody screen and cross-match and further transfusion if needed.
The blood bank should be notified too, and further specific treatment
might not be needed unless renal failure develops.

Question 4

An 8-year-old boy is brought to his GP by his father, who reports that he has
been feeling progressively more tired over the past few months. On examination
the GP notices a slight yellowing of his sclera, and the presence of splenomegaly.
His father recollects that he himself was told he had a problem with his blood
cells as a child, but has never been affected by it. A peripheral blood film shows
a raised reticulocyte count and spherocytes. He is likely to have a positive:

A Coombs test

B Osmotic fragility test

C G6PD test

D Sickle cell screen

E Schilling test

Answer 4

B Osmotic fragility test

Hereditary spherocytosis is a type of autosomal dominant inherited
haemolytic anaemia. It occurs due to an increase in the fragility of
the red blood cell membrane due to dysfunctional skeletal proteins in
the membrane, such as spectrin, ankyrin and band 4.2. Most patients
develop
a haemolytic state that is partially compensated. Clinical
features
can include tiredness from anaemia, as in this case, and the
presence of jaundice and splenomegaly on examination. They can also
develop pigment gallstones from the haemolysis. As with this child,
there is often a positive family history. A blood film can show the presence of spherocytes and reticulocytes,
and a Coombs test is negative. They may have a positive osmotic fragility
test (B), but remember that this is just used to confirm that there are
spherocytes present, not that the cause is hereditary spherocytosis. With
this test, because the membrane is more permeable to salt and water,
the spherocytes rupture in a mildly hypotonic solution. Do not forget
that spherocytes may also be found in autoimmune haemolytic anaemia.

Question 5

A 33-year-old Turkish man presents with extreme tiredness and shortness of
breath after being started on a course of anti-malarial tablets. A full blood count
reveals an Hb of 6.8. His Coombs test is negative. The cell type most likely to be
found on his blood film is:

A Heinz bodies

B Pencil cells

C Target cells

D Spherocytes

E Sickle cells

Answer 5

A Heinz bodies

This man is suffering from glucose-6-phosphate dehydrogenase (G6PD)
deficiency, an X-linked recessive disorder that is common in people
from the Mediterranean, South East Asia, Middle East and West Africa. This enzyme is responsible for maintaining levels of glutathione
from the pentose phosphate pathway, which protects against oxidant
free radicals. Oxidative stress, for example in the form of chemicals,
food or infection, can put people with this condition at risk of severe
haemolytic
anaemia. Drugs to be avoided in these patients include
anti-malarials,
such as primaquine, and others such as sulphonamides,
vitamin K and dapsone. The exam favourite of broad beans can lead to
a reaction called favism in these patients.

Question 6

A 25-year-old student is treated for infectious mononucleosis following a positive
Paul Bunnell test. A blood film reveals target cells, Howell–Jolly bodies and
atypical lymphocytes. Together, these suggest that he has features of:

A Bone marrow suppression

B Hyposplenism

C Disseminated intravascular coagulation

D Haemolytic anaemia

E Liver failure

Answer 6

B Hyposplenism

Up to half of all patients might develop splenomegaly in infectious
mononucleosis. This does not often cause symptoms but can lead to
splenic rupture, either spontaneously or following minor trauma, and
may necessitate treatment with splenectomy. Postoperatively a combination
of features on a blood film might suggest hyposplenism:
• Howell–Jolly bodies: these are small fragments of non-functional
nuclei that are normally removed by the spleen, so might be seen on
a blood film in hyposplenism. They may also be seen in megaloblastic
and iron-deficiency anaemias
• Target cells: these have a central dense area with a ring of pallor,
and can occur in the three Hs: hepatic pathology, hyposplenism and
haemoglobinopathies
• Occasional nucleated red blood cells
• Lymphocytosis
• Macrocytosis
• Acanthocytes: spiculated red cells that are found in hyposplenism,
α-β-lipoproteinaemia, chronic liver disease and α-thalassaemia trait

Question 7

A 4-year-old Afro-Caribbean boy has chest and abdominal pain. His blood tests
reveal an Hb of 6.1 g/dL, with an MCV of 65. A blood film shows the presence of
sickle cells. The most likely diagnosis is:

A Sickle cell trait

B Sickle cell anaemia

C Sickle cell/b-thalassaemia

D Sickle cell/haemoglobin C

E b-Thalassaemia

Answer 7

B Sickle cell anaemia

This boy is suffering from sickle cell anaemia (B), an autosomal recessive
haemoglobinopathy. The term sickle cell disease actually comprises
several different states: sickle cell anaemia, but also compound
heterozygous states including sickle cell/haemoglobin C (D) and sickle
cell/b-thalassaemia (C).
Do not forget that the haemoglobin molecule consists of four chains,
and there are three different forms: haemaglobin A (α2β2), haemoglobin
A2 (α2d2) and haemoglobin F (α2ϒ2). The proportions of the different
forms vary with age – haemoglobin F predominates before birth,
but concentrations of haemaglobin A and A2 increase after birth, with
haemoglobin A predominating. In sickle-cell anaemia a point mutation
in the β-globin chain of haemoglobin (found on chromosome 11)
results in the hydrophilic amino acid glutamic acid being replaced by
the hydrophobic amino acid valine at the sixth position. This promotes
aggregation of the haemoglobin chains in conditions of low oxygen,
distorting the red blood cells so they adopt a sickle shape. These cells
become adherent to the endothelieum of post capillary venules, causing
retrograde capillary obstruction which can lead to painful crises.

Question 8

A 7-year-old child has known sickle cell disease. He presents with a 5-day history
of fever, shortness of breath and extreme fatigue. His mother reports that
his younger brother, who also has sickle cell disease, has been feeling unwell too
recently. A blood test for the patient reveals a severe anaemia and low reticulocyte
count. He has most likely developed:

A Splenic sequestration

B Pneumococcal infection

C Vaso-occlusive crisis

D Folic acid deficiency

E Parvovirus B19 infection

Answer 8

E Parvovirus B19 infection

Aplastic crises caused by parvovirus B19 infection (E) can occur in
patients with sickle cell disease. They can present with acute worsening
of the patient’s baseline anaemia, which might manifest as shortness of
breath and fatigue as in this case. The fever points to an infectious cause.
The virus affects erythropoiesis by invading erythrocyte precursors and
destroying them. Infants and children with sickle cell disease initially
have no immunity to parvovirus B19, and their first exposure can lead
to pure red cell aplasia. In a normal individual the virus blocks red
cell production for 2 or 3 days with little consequence, but it can be
life threatening in sickle cell patients in whom the red cell life span is
already shortened. This can lead to profound anaemia over the course
of just a few days, and a dramatic drop in the reticulocyte count. Serum
IgM antibodies to parvovirus B19 can confirm the diagnosis, and blood
transfusion may be required.

Question 9

A 26-year-old pregnant woman is found to have an Hb of 9.5 g/dL on a routine
blood test, with an MCV of 70. Serum electrophoresis reveals an Hb A2 of
3.9 per cent and Hb A of 96.1 per cent. Her ferritin levels are normal. The most
likely diagnosis is:

A Iron deficiency anaemia

B Cooley’s anaemia

C b-Thalassaemia intermedia

D b-Thalassaemia minor

E a-Thalassaemia

Answer 9

D b-Thalassaemia minor

In b-thalassaemia minor (D) only one of the b-globulin alleles is mutated,
so these individuals usually only have a well-tolerated microcytic anaemia
(Hb >9 g/dL) which is clinically asymptomatic. They might be picked
up on a routine blood test, with a low MCH and significantly low MCV
(3.5–4 per
cent to compensate for the reduced amount of normal haemoglobin, and
they might have a slight increase in Hb F. It can worsen in pregnancy, as
in this case.

Question 10

A 24-year-old unemployed man presents to his GP with a 4-week history of
flu-like symptoms and a persistent dry cough. On examination he has a maculopapular
rash. A blood film reveals a haemolytic anaemia, and he is positive for
cold agglutinins. The most likely organism implicated is:

A Streptococcus pneumoniae

B Mycoplasma pneumoniae

C Legionella pneumophilia

D Chlamydophila psittaci

E Borrelia burgdorferi

Answer 10

B Mycoplasma pneumoniae

Autoimmune haemolytic anaemia is a form of mainly extravascular
haemolysis, which is mediated by autoantibodies. It is classified into
warm and cold autoimmune haemolytic anaemia, according to the optimal
temperature at which the antibodies bind to red blood cells. This
activates the classical pathway in the complement system, resulting
in haemolysis. Cold AIHA is mediated by IgM antibodies, and as the
name suggests these antibodies bind optimally at lower temperatures
(28–31°C), resulting in anaemia that is aggravated in cold conditions. In
severe cases, patients may suffer from Raynaud’s or acrocyanosis (purplish
discolouration of peripheries). Most cases are idiopathic, but there
are some specific causes worth remembering, as ‘Cold LID’:
• Lymphoproliferative disease, e.g. CLL, lymphomas
• Infections – mycoplasma, as in this case (B), EBV
• Do not know, i.e. idiopathic!
This patient has typical features of mycoplasma pneumonia including a protracted
history of flu-like symptoms (such as myalgia, arthralgia, headache)
and a non-productive cough. Treatment includes avoiding cold conditions,
use of chlorambucil, and treating the underlying cause. The other infectious
agents listed here do not typically cause a cold haemolytic anaemia.

Question 11

A 7-year-old boy is taken ill from school on a cold December day, with a presumed
viral infection. On returning home that day, he beings to feel even more
unwell with a very high fever, headache and abdominal pain. His father begins to
worry that his skin has taken on a yellow tinge, and the boy says his urine is now
a dark reddy-brown colour. He is taken to the GP and after several tests the presence
of ‘Donath–Landsteiner antibodies’ is reported. This child is suffering from:

A Paroxysmal cold haemoglobinuria

B Paroxysmal nocturnal haemoglobinuria

C Sickle cell disease

D Acute intermittent porphyria

E Epstein–Barr virus

Answer 11

A Paroxysmal cold haemoglobinuria

Paroxysmal cold haemoglobinuria (A) is a rare form of autoimmune
haemolytic anaemia. It usually affects children in the acute setting after
an infection, and the key in this case is the presence of sudden haemoglobinuria
and jaundice after exposure to a cold temperatures. IgG
autoantibodies usually form after an infection, and bind to red blood cell
surface antigens, inducing variable degrees of intravascular haemolysis in
the cold. The antibodies are known as ‘Donath–Landsteiner antibodies’. Analysis of the urine will confirm the presence of haemaglobinuria, and
blood tests often reveal a normocytic or macrocytic anaemia. It is possible
to test indirectly for the IgG antiglobulins at a low temperature, as
in this case. Blood transfusion may be required if the anaemia is severe,
but in children who have an acute onset with an antecedent infection, it
is usually a transient and self limiting condition.

Question 12

A 21-year-old student has recently been diagnosed with coeliac disease. She
presents to her GP complaining of increased tiredness and shortness of breath
on climbing stairs. Which of the following are most likely to be raised in this
patient?

A Serum iron

B Haematocrit

C Transferrin

D Ferritin

E Mean cell haemoglobin

Answer 12

C Transferrin

This patient is suffering from iron deficiency anaemia, a common complication
in coeliac disease. The tiredness and shortness of breath are
common symptoms. Causes can include blood loss (e.g. upper or lower
GI bleeding, menstruation), malabsorption (as in this case), dietary deficiency
(rare in adults but can be seen in children) or infestation with
parasitic worms (the most common cause worldwide). Blood tests characteristically
reveal a low mean cell volume, mean cell haemoglobin
(E) and mean cell haemoglobin concentration. A blood film may reveal
hypochromic red blood cells with anisocytosis (variation in cell size)
and poikilocytosis (variation in cell shape). The red blood cell distribution
width (RDW) (a measure of the variation of the width of red blood
cells) may be increased initially.

Question 13

A 34-year-old woman with known Addison’s disease is brought to the GP by her
husband, as he is concerned that she keeps falling over at night. On examination
the GP notes that she has conjunctival pallor. A thorough neurological examination
reveals absent knee jerks, absent ankle jerks and extensor plantars bilaterally. Which
of the following is the most sensitive test for the condition she has developed?

A Anti-intrinsic factor antibodies

B Anti-endomysial cell antibodies

C Anti-smooth muscle antibodies

D Anti-parietal cell antibodies

E Anti-voltage gated calcium channel antibodies

Answer 13

D Anti-parietal cell antibodies

This woman has developed pernicious anaemia leading to vitamin B12
deficiency. It can be associated with other autoimmune conditions, such
as Addison’s disease or thyroid disease. Specifically, she has developed
a condition called subacute combined degeneration of the cord (SACD)
which has led to symmetrical loss of dorsal columns (resulting in loss
of touch and proprioception leading to ataxia, and LMN signs) and corticospinal
tract loss (leading to UMN signs), with sparing of pain and
temperature sensation (which is carried by spinothalamic tracts). The
ataxia and loss of joint position sense have resulted in her falling at
night, which may be exacerbated by optic atrophy – another manifestation
of vitamin B12 deficiency.
Remember that vitamin B12 is found in meat, fish and dairy products.
More common causes of vitamin B12 deficiency can be related to diet
(e.g. vegans) or to malabsorption. It is absorbed in the terminal ileum
after binding to intrinsic factor produced by the parietal cells in the
stomach. Causes of malabsorption can therefore be related to the stomach
(e.g. post gastrectomy, pernicious anaemia), or due to the terminal ileum
(e.g. Crohn’s, resection of the terminal ileum, bacterial overgrowth).

Question 14

A 58-year-old woman is referred to a haematology clinic following repeated chest infections and epistaxis. On examination the doctor notes that she has conjunctival pallor and some petechial rashes on her forearms, but no organomegaly.
Her blood tests reveal a pancytopenia, and an MCV of 112. Her drug
history includes omeprazole, carbamazepine, gliclazide, metformin, paracetamol,
and simvastatin. A bone marrow biopsy reveals a hypocellular marrow. The most
likely diagnosis is:

A Aplastic anaemia

B Myelodysplasia

C Hypothyroidism

D Chronic myeloid leukaemia

E Myeloma

Answer 14

A Aplastic anaemia

14 A Causes of macrocytosis can be divided into:
1 Megaloblastic, e.g. folate and B12 deficiency
2 Non-megalobastic, causes of which can be remembered as RALPH =
reticulocytosis (e.g. in haemolysis), alcohol, liver disease, pregnancy
and hypothyroidism)
3 Other haematological disorders, e.g. myelodysplasia, aplastic anaemia,
myeloma, myeloproliferative disorders
This woman is suffering from aplastic anaemia (A), where the bone
marrow stops producing cells leading to a pancytopenia. Bone marrow
examination is needed to confirm the diagnosis, and shows a hypocellular
bone marrow. Causes of aplastic anaemia can be primary or secondary.
Primary causes can be congenital (e.g. Fanconi’s anaemia) or idiopathic
acquired aplastic anaemia. Secondary causes include drugs (all
the Cs – cytotoxics, carbamazepine, chloramphenicol, anticonvulsants such as phenytoin), ionizing radiation and viruses (e.g. hepatitis, EBV).
This woman’s aplastic anaemia is secondary to long-term carbamazepine
therapy for hypothyroidism

Question 15

A 50-year-old diabetic man sees his GP complaining of generalized tiredness and
a painful right knee. He is found on examination to have five finger breadths of
hepatomegaly. An X-ray of his right knee is reported as showing chondrocalcinosis.
His blood tests are likely to reveal:

A Raised MCV

B Raised total iron binding capacity

C Reduced serum ferritin

D Reduced iron level

E Raised transferrin saturation

Answer 15

E Raised transferrin saturation

This man has hereditary haemachromatosis, an inherited disorder of
iron metabolism. It is particularly common in those of Celtic descent,
and the gene responsible for the majority of cases is the HFE gene on
chromosome 6.
Increased iron absorption leads to deposition to multiple organs including:
• the liver (hepatomegaly, deranged LFTs)
• joints (arthralgia, chondrocalcinosis)
• pancreas (diabetes)
• heart (dilated cardiomyopathy)
• pituitary gland (hypogonadism and impotence)
• adrenals (adrenal insufficiency)
• skin (slate grey skin pigmentation)
Blood tests can show deranged LFTs as in this case, as well as a raised
serum ferritin, raised serum iron, reduced or normal total iron binding
capacity and raised transferrin saturation (E) (>80 per cent).

Question 16

A 64-year-old woman is seen in the haematology clinic with generalized bone
pain and recurrent infections. Following a set of blood tests, a skeletal survey
reveals multiple lytic lesions and a bone marrow biopsy reports the presence of
>10 per cent plasma cells. Her blood tests are most likely to have shown:

A Raised calcium, normal alkaline phosphatase, raised ESR

B Normal calcium, raised alkaline phosphatase, normal
ESR

C Raised calcium, raised alkaline phosphatase, raised ESR

D Raised calcium, normal alkaline phosphatase, raised CRP

E Normal calcium, normal alkaline phosphatase, raised CRP

Answer 16

A Raised calcium, normal alkaline phosphatase, raised ESR

This woman has multiple myeloma, a cancer of plasma cells. The symptoms
can be remembered using the mnemonic BRAIN: Bone pain (due to
osteoclast activation leading to hypercalcaemia and the presence of lytic
lesions on a skeletal survey, characteristically with a ‘pepperpot skull’
appearance), Renal failure (which can be secondary to one or a combination
of: hypercalcaemia, tubular damage from light chain secretion,
or secondary amyloidosis), Anaemia (typically normocytic), Infections
(particularly pneumonias and pyelonephritis), and Neurological symptoms
(such as a headache and visual changes from hyperviscosity, or
confusion and weakness from the hypercalcaemia).
The diagnostic criteria for symptomatic myeloma are as follows:
• Clonal plasma cells >10 per cent on bone marrow biopsy
• A paraprotein in the serum or urine – most commonly IgG
• Evidence of end-organ damage related to the plasma cell disorder
(commonly referred to by the acronym ‘CRAB’):
• Calcium – high
• Renal insufficiency
• Anaemia
• Bone lesions (e.g. lytic lesions, or osteoporosis with compression
factors)

Blood tests may reveal a high calcium but the alkaline phosphatase
is often normal (A) (in contrast to other malignancies, with osteolytic
metastases and raised alkaline phosphatase).

Question 17

A 67-year-old woman presented with polyuria and polydipsia on a background
of ongoing bone pain. Her blood tests revealed a high calcium, and a serum
electrophoresis was sent. Her serum paraprotein was 25 g/L and a bone marrow
biopsy revealed 6 per cent clonal plasma cells. The most likely diagnosis is:

A Plasma cell dyscrasia

B Monoclonal gammopathy of undetermined significance

C Smouldering myeloma

D Multiple myeloma

E Hypercalcaemia with no evidence of underlying malignancy

Answer 17

D Multiple myeloma

This question tests your understanding of the diagnostic criteria for
plasma cell disorders. Do not forget that:

1 Symptomatic myeloma (D):
• Clonal plasma cells on bone marrow biopsy
• Paraprotein in either serum or urine
• Evidence of end-organ damage attributed to the plasma cell
disorder, commonly remembered using the acronym ‘CRAB’
(Calcium – high, Renal insufficiency, Anaemia and Bone lesions)

2 Asymptomatic (smouldering) myeloma (C):
• Serum paraprotein >30 g/L AND/OR
• Clonal plasma cells >10 per cent on bone marrow biopsy AND
• NO myeloma-related organ or tissue impairment

3 Monoclonal gammopathy of undetermined significance (MGUS) (B):
• Serum paraprotein

Question 18

A 39-year-old motorcyclist is admitted following a road traffic accident complicated
by severe burns. Several days later he is due to go home, when oozing
is noted from his cannula site and he has several nose bleeds. Repeat blood
tests reveal an Hb of 12.2 g/dL, WCC of 11.2 × 109/L, and platelets of 28 × 109/L.
A coagulation screen shows a prolonged APTT and PT. He also has a reduced
fibrinogen and raised D-dimers. The most likely diagnosis is:

A Liver failure

B Disseminated intravascular coagulation

C Thrombotic thrombocytopenic purpura

D Aplastic anaemia

E Heparin induced thrombocytopenia

Answer 18

B Disseminated intravascular coagulation

This man has developed disseminated intravascular coagulation (DIC)
(B) following his severe burns. DIC is widespread pathological activation
of the clotting cascade in response to various insults. The cascade
is activated in various ways: one mechanism is the release of a transmembrane
glycoprotein called ‘tissue factor’ in response to cytokines or
vascular damage. This results in fibrin formation, which can eventually
cause occlusion of small and medium sized vessels and lead to organ
failure. At the same time, depletion of platelets and coagulation proteins
can result in bleeding (as in this case).
It can be caused by a wide range of factors, which can be remembered
using the mnemonic ‘I’M STONeD!’: Immunological (e.g. severe allergic
reactions, haemolytic transfusion reactions), Miscellaneous (e.g. aortic
aneurysm, liver disease), Sepsis, Trauma (including serious tissue injury,
burns, extensive surgery), Obstetric (e.g. amniotic fluid embolism, placental
abruption), Neoplastic (myeloproliferative disorders as well as
solid tumours such as pancreatic cancer), and Drugs and toxins.

Question 19

A 46-year-old woman is brought to accident and emergency by her daughter,
who reports that she had been feeling unwell for a few days with a fever and is
now hallucinating. On examination she has a temperature of 38.9°C, is noted to
be pale and has widespread purpura over both arms. Blood tests reveal an Hb of
9.1 g/dL, platelet count of 60 × 109/L, creatinine of 226 and urea 16.7. A blood film
is reported as showing the presence of shistocytes. The most likely diagnosis is:

A Weil’s disease

B Glandular fever

C Idiopathic thrombocytopenic purpura

D Thrombotic thombocytopenic purpura

E Haemolytic uraemic syndrome

Answer 19

D Thrombotic thombocytopenic purpura

This woman has thrombotic thrombocytopenic purpura (TTP) (D), a rare
but potentially fatal haematological emergency. It consists of six key
features:
1 MAHA
2 A fever
3 Renal failure
4 Fluctuating CNS signs, e.g. seizures, hallucinations, hemiparesis,
decreased consciousness
5 Haematuria/proteinuria
6 Low platelet count
You can remember these as ‘MARCH with low platelets’.
TTP typically affects adults and is thought to occur due to a deficiency
of a protease that is responsible for cleaving multimers of von
Willebrand factor. The resulting formation of large vWF multimers
stimulates platelet aggregation and fibrin deposition in small vessels.
This in turn causes microthrombi to form in blood vessels, impeding
the blood supply to major organs such as the kidneys, heart and brain.
Haemolysis occurs and shistocytes form because of the sheer stress on
red blood cells as they pass through the microscopic clots.

Question 20

A 28-year-old woman in her 29th week of pregnancy comes to accident and
emergency with epigastric pain, nausea and vomiting. She also complains that
her hands and feet have been swelling up. On examination her blood pressure
is 165/96, HR 125 bpm, and she is apyrexial. She is noted to have yellowing of
her sclera and right upper quadrant tenderness. Blood tests reveal an Hb of 10.1,
platelets 96, WCC 11.3, LDH 820 (N 70–250), AST 115 (N 5–35), and ALT 102
(N 5–35). Her coagulation screen is normal and a blood film is reported as
showing
the presence of schistocytes. The most likely diagnosis is:

A Hepatitis

B Thrombotic thrombocytopenic purpura

C Pre-eclampsia

D Acute fatty liver of pregnancy

E HELLP syndrome

Answer 20

E HELLP syndrome

‘HELLP’ syndrome (E) is a potentially fatal occurrence in pregnancy,
characterized by a triad of features:
1 H – haemolysis
2 EL – elevated liver enzymes
3 LP – low platelet count
In a similar way to DIC, generalized activation of the clotting cascade
is triggered which can only be terminated with delivery. Platelet consumption
and MAHA occurs, and liver ischaemia can lead to periportal
necrosis and, in severe cases, formation of a subcapsular haematoma
which can rupture.
It usually presents in the third trimester, but can happen even up to a
week after delivery. Often patients with HELLP have had pregnancy-induced
hypertension or pre-eclampsia prior to its development.
Common symptoms are often vague, and can include nausea and vomiting,
epigastric pain, peripheral swelling, paraesthesia, headaches and
visual problems. On examination patients may be noted to have peripheral
oedema, upper abdominal tenderness, jaundice and hepatomegaly.
Complications can include liver and renal failure, pulmonary oedema, DIC and placental abruption. Clotting studies may be normal as in this
case, unless DIC has occurred. The only effective treatment is delivery,
but other supportive treatment includes control of the hypertension,
seizure
prophylaxis and corticosteroid use.

Question 21

A 56-year-old woman with known cirrhosis presents with falls. On examination
she is clinically jaundiced and rectal examination reveals malaena. Blood tests
reveal an INR of 2.2. She is diagnosed with decompensated chronic liver disease.
Which of the following is not a vitamin K dependent clotting factor?

A Thrombin

B Factor VII

C Factor VIII

D Protein C

E Factor X

Answer 21

C Factor VIII

The vitamin K dependent clotting factors include II, VII, IX and X.
Vitamin K is also required for the production for protein C, protein S
and protein Z, although these are strictly not clotting factors, rather
anticoagulant factors. Vitamin K is a fat soluble vitamin found in
green leafy vegetables such as spinach, cabbage and cauliflower. It
is absorbed in the small bowel and is important in the production of
functional clotting factors in the liver. This patient’s acute chronic liver
failure has meant she is no longer producing functional clotting factors,
represented
as a raised INR.
Vitamin K is recycled in the liver and its oxidation is coupled with the
post-translational modification of glutamate residues to form gammacarboxyglutamate.
Vitamin K is firstly reduced by vitamin K epoxide
reductase to form vitamin K hydroquinone. This reduced form is oxidized
by vitamin K dependent carboxylase to form vitamin K epoxide.
This reaction is coupled with gamma-glutamyl carboxylase; the enzyme
responsible for post-translational modification of the vitamin K dependent
factors. Vitamin K epoxide is then reconverted to vitamin K by
vitamin K epoxide reductase; thus completing the cycle. If the patient
were to be given vitamin K metabolism antagonists, e.g. warfarin, the
clotting factors produced would still be immunologically identical (these
are also known as Proteins Induced by Vitamin K Absence/Antagonism
– PIVKA) but would lack efficacy as they are unable to interact with
calcium or platelet factor 3.

Question 22

A 46-year-old man presents with pain and swelling in the right calf 2 weeks
after being fitted with a plaster cast to his leg after a fall. The calf is tender,
erythematous and swollen. He is also a heavy smoker and slightly overweight.
His admitting physician suspects a deep vein thrombosis (DVT) and books an
ultrasound of the calf. A deep vein thrombosis is confirmed and 5 mg warfarin is
started the next day. Two days later, the same patient develops pain and swelling
in the other calf, an ultrasound confirms a further deep vein thrombosis in the
contralateral leg. What factor is least likely to contribute to the development of
the second DVT?

A Smoking

B Warfarin

C Previous DVT

D Being slightly overweight

E Plaster cast

Answer 22

D Being slightly overweight

Although obesity is associated with risk of development of DVT, this
man is described as slightly overweight (D). Thus, in comparison to the
other risk factors presented, it probably represents the lowest attributable
risk to the second DVT.

Question 23

A 54-year-old man presents with haematemesis. He has known varices and is
currently vomiting large amounts of bright red blood. The admitting doctor takes
some blood for fast analysis and confirms a haemoglobin of 4 g/dL. The patient’s
haematemesis continues and he is transfused a total of 20 units of blood and
eight units of fresh frozen plasma in the next 24 hours. The patient underwent
gastroscopy which revealed bleeding oesophageal varices which were successfully
treated by endoscopic banding. His post-transfusion bloods are the following:

Hb 9.2 g/dL
White cells 8.0 × 109/L
Platelets 57 × 109/L
Prothrombin time normal
Activated partial thromboplastin time normal
Fibrinogen >1.0 g/L

What is the most likely cause of his thrombocytopenia?

A Disseminated intravascular coagulopathy

B Alcohol excess

C Massive blood transfusion

D Megaloblastic anaemia

E Hypersplenism

Answer 23

C Massive blood transfusion

Although all of the given options are causes of thrombocytopenia, the
most likely cause in this patient is massive blood transfusion without
replacement of platelets (C). Massive blood loss may be defined as losing
one’s entire circulating blood volume in 24 hours. Other definitions
include losing 50 per cent of one’s blood volume in 3 hours or a rate
of loss of greater than or equal to 150 mL/min. This patient has been
transfused 20 units of blood in the space of 24 hours, thus fulfilling the
criteria for massive haemorrhage. Massive transfusion has its own particular
complications, including thrombocytopenia. This is because this
patient was only given packed red cells and fresh frozen plasma. These
two blood products contain very few platelets and in general, a platelet
count of around 50 × 109/L is to be expected when approximately
two blood volumes have been replaced, as is the case in this patient. In
this situation, the expert consensus is to keep the platelet level above
50 × 109/L, but there is marked interindividual variation therefore some
consider using 75 × 109/L as the trigger value for platelet transfusion.

Question 24

Which of the following is not often associated with a very high (>100 mm/hour)
erythrocyte sedimentation rate (ESR)?

A Myeloma

B Anaemia

C Leukaemia

D Aortic aneurysm

E Malignant prostatic cancer

Answer 24

B Anaemia

ESR is a commonly used laboratory test to detect the presence of inflammation
in general. It is performed by adding a sample of anticoagulant
to a blood sample and adding this mixture to a calibrated vertical tube
(Westergren tube). As the red cells fall with gravity and accumulate, they
lie in the bottom of the tube, and are called sediment. The rate at which
they accumulate is therefore the erythrocyte sedimentation rate. Factors which influence the ESR include age, sex and pathological
processes which increase plasma proteins or the number of red cells.
Women generally have a higher ESR than men and it also increases
with age. Depending on the exact reference range for your particular
lab, women and men over 50 can have an ESR of up to 30 and 20 mm/
hour, respectively, and still be normal. Conditions which increase
plasma proteins such as fibrinogen, acute phase proteins and immunoglobulins
can increase the ESR as these proteins reduce the ionic resistance
between erythrocytes leading to an increased fall rate. They also
promote rouleaux formation of erythrocytes which is the characteristic
stacking of erythrocytes seen under the microscope. The most important
protein to promote rouleaux formation is fibrinogen. The number of red
cells in a given volume also influences ESR; in severe anaemia ESR is
falsely raised as the reduced ionic repulsion between erythrocytes allow
faster sedimentation. However, this rarely leads to an ESR of >100 mm/
hour, making anaemia (B) the correct answer.

Question 25

A 62-year-old man presents with shortness of breath. This has been gradually
getting worse for the last few years and is associated with chronic productive
cough. He is a heavy smoker. His chest X-ray reveals a hyperexpanded chest
with no other abnormalities. His bloods tests are normal except for a raised haemoglobin
and raised haematocrit. What is the most likely cause for this?

A Polycythaemia rubra vera

B Idiopathic erythrocytosis

C Secondary polycythaemia

D Gaisbock’s disease

E Combined polycythaemia

Answer 25

E Combined polycythaemia

Combined polycythaemia (E), also known as smoker’s polycythaemia,
has multiple aetiological factors. Cigarettes contain high concentrations
of carbon monoxide gas which bind avidly to haemoglobin, thus
displacing oxygen. This leads to increased erythropoietin (EPO) secretion
from the hypoxic renal interstitium. EPO promotes erythrocyte proliferation
and differentiation and prevents their apoptosis in the bone
marrow, thus increasing red cell mass. Smoking is also a significant risk
factor for chronic obstructive pulmonary disease, which is what this
man suffers from. The obstructed airways reduce oxygen delivery to
the alveoli and pulmonary vessels they supply thus causing a reduction
of oxygen supply furthering the hypoxia. Finally, smokers also have
an associated reduced plasma volume, thus increasing the relative concentration
of haemoglobin. This is therefore ‘combined’ because of the
presence of both increased red cell mass and reduced plasma volume.

Question 26

A 25-year-old black man develops jaundice and dark red urine 2 days after
starting primaquine, an anti-malarial. His blood tests reveal a macrocytic anaemia
with raised bilirubin and urine dipstick is positive for blood. A peripheral
blood film reveals ‘bite cells’ and Heinz bodies. The most likely diagnosis is:

A Hereditary spherocytosis

B Glucose-6-phosphate dehydrogenase deficiency

C Paroxysmal nocturnal haemoglobinuria

D Microangiopathic haemolytic anaemia

E Autoimmune haemolytic anaemia

Answer 26

B Glucose-6-phosphate dehydrogenase deficiency

G6PD deficiency (B) (also known as favism) is an X-linked condition
where the lack of this enzyme increases the oxidative damage sustained
by red blood cells. It is part of the pentose phosphate pathway which
maintains levels of reduced glutathione – an important erythrocyte antioxidant.
People with this condition have erythrocytes with less reduced glutathione and are thus more sensitive to oxidative stress resulting in
haemolysis. There are many variants of G6PD of differing severity. It is
unlike some X-linked conditions where women can also be affected if
they are homozygous. Precipitating factors include anti-malarials, primaquine,
nitrofurantoin, dapsone, sulphonylureas and sulphonamides.
Its alternate name, favism, relates to the fact that fava beans (broad
beans) can trigger a haemolytic attack. The haemolysis released intracellular
haemoglobin causing jaundice in this patient and haemoglobinuria,
which caused a positive dipstick result. It is important to note that
the differential for a positive dipstick for blood includes haemoglobinuria
and myoglobinuria. Macrocytosis occurs from the raised reticulocyte
production from increased bone marrow activity. Heinz bodies are seen
due to the denatured haemoglobin which gets removed by macrophages
in the spleen leaving ‘bite’ cells. A G6PD assay is useful in this patient
but less so in the acute setting as the new reticulocytes can contain
normal G6PD levels, thus giving a false negative result.

Question 27

What are the likely laboratory findings for a patient with renal cell carcinoma
with secondary polycythaemia who is not dehydrated?

A Normal red cell count, normal red cell mass, increased erythropoietin concentration

B Increased red cell count, increased red cell mass, increased erythropoietin
concentration

C Decreased red cell count, decreased red cell mass, normal erythropoietin
concentration

D Increased red cell count, decreased red cell mass, increased erythropoietin
concentration

E Decreased red cell count, increased red cell mass, decreased erythropoietin
concentration

Answer 27

B Increased red cell count, increased red cell mass, increased erythropoietin
concentration

This question tests your understanding of erythropoeisis physiology
and your understanding of laboratory measurements in a standard
full blood count analysis. Red cell count is measured as the number of
erythrocytes in a quantum of plasma, whereas red cell mass is determined
by isotope studies quoted as mL/kg. It is a measure of absolute
red cell mass and is therefore not affected if someone is dehydrated, for
example, where the relative plasma volume is reduced giving a falsely
high red cell concentration. There are many situations where the red cell
concentration and red cell mass do not parallel each other, e.g. vomiting,
diarrhoea or overuse of diuretics. If a patient has increased red cell
concentration this may therefore be absolute or relative – the latter
being secondary to reduced plasma volume thus making the polycythaemia
secondary to haemoconcentration. Absolute polycythaemia may
be primary or secondary. In this case there is secondary polycythaemia
where the renal cell carcinoma is inappropriately producing too much
EPO, thus overstimulating bone marrow erythropoeisis. Secondary polycythaemia
is not always inappropriate – people with cyanotic heart
disease, lung disease, haemoglobinopathies with high oxygen affinity or
those living at altitude can get appropriate secondary polycythaemia as
a physiological response to chronic hypoxaemia.

Question 28

von Willebrand’s disease is characterized by abnormal platelet aggregation when
they are exposed to:

A Streptomycin

B Aspirin

C Fibrinogen

D Collagen

E Ristocetin

Answer 28

E Ristocetin

von Willebrand’s disease (vWD) is characterized by a quantitive or
qualititative defect in von Willebrand factor (vWF). Ristocetin, an antibiotic
no longer used clinically, causes vWF to bind the platelet receptor
glycoprotein Ib (GlpIb) through an unknown mechanism. If ristocetin
is added to platelets with defective vWF or defective GlpIb (called
Bernard–Soulier syndrome) then platelet aggregation does not occur. It
will occur, however, with other pro-aggregative factors including collagen
(D) and fibrinogen (C). If vWF or GlpIb is absent, aggregation does
not occur with collagen as there is no molecular link between collagen
and the platelet. However, this is the case with all patients with vWF. Furthermore, cryoprecipitate which contains vWF will correct defects in
vWD but not in Bernard–Soulier syndrome.

Question 29

An 18-month-old child with Down syndrome presents with recurrent infections
and petechial bleeding. A blood film was analyzed showing a particular distinctive
feature of haematological malignancy. What is the most likely diagnostically
helpful finding seen in this patient?

A Smudge cell

B Reed Sternberg cell

C Auer rod

D Pelger Huet anomaly

E Hairy cell

Answer 29

C Auer rod

The Auer rod (C) is pathognomonic of acute myeloblastic leukaemia
(AML). Children with Down syndrome are at higher risk of this disease
due to chromosome 21 duplication where a ‘dosage’ effect is
theorized to increase the expression of proto-oncogenes. This may
also explain the increased risk of AML in Warkany syndrome type 2
(trisomy 8). Another dosage effect example, also in Down syndrome,
is the increased risk of Alzheimer’s disease with beta amyloid, which
accumulates in Alzheimer’s disease and is coded for on chromosome
21. Epidemiologically, children with Down syndrome are more likely
to get AML than ALL in the first 3 years of their life, but thereafter are
more likely to get ALL, similar to those without Down syndrome. Auer
rod’s are pathognomonic for AML and are found in the cytoplasm. They
represent stacked granules in myeloblasts and are azurophilic. They
are particularly common in the M3 subtype of AML (according to the
French American British classification).

Question 30

An 8-year-old African boy presents with a large jaw mass which has been growing
rapidly over the last few weeks. A histological sample was taken and a classical
‘starry sky’ appearance was observed. The most likely diagnosis is:

A Follicular lymphoma

B Marginal zone lymphoma

C Burkitt’s lymphoma

D Diffuse large B cell lymphoma

E Mantle cell lymphoma

Answer 30

C Burkitt’s lymphoma

Burkitt’s lymphoma (C) is one of the most aggressive malignancies
known to man. It is a type of non-Hodgkin’s lymphoma (NHL)
which arises from lymph node germinal centres. It is associated with
Epstein–Barr virus and there are three subtypes – endemic, sporadic
and immunodeficiency
related. It is associated with translocation and
dysregulation of the c-myc gene on chromosome 8 including t(8;14),
t(2;8) and t(8;22). Histologically, there is profound proliferation. The
starry sky appearance reflects islands of macrophages ingesting necrotic
tumour cells as they have outgrown their own blood supply. Clinically,
the endemic form affects younger men and classically presents with a
jaw mass which spreads to extranodal sites including mesentery, ovary,
testis, bone marrow and meninges.

Question 31

A 35-year-old Afro-American man presents with painless lymphadenopathy
which he noticed after shaving. He denies any recent infections, fevers, weight
loss or night sweats. A biopsy is performed which shows lymphocytic and histiocytic
cells. A haematologist calls to confirm the diagnosis of non-classical
Hodgkin’s lymphoma. Which subtype is this?

A Nodular sclerosis

B Mixed cellularity

C Nodular lymphocytic

D Lymphocytic rich

E Lymphocytic depleted

Answer 31

C Nodular lymphocytic

Nodular lymphocytic (C) Hodgkin’s lymphoma is often called the nonclassical
subtype of Hodgkin’s lymphoma. It is so called due to the atypical
nature of the Reed–Sternberg cell which characterizes all Hodgkin’s
lymphomas. This cell is known as the lymphocytic and histiocytic cell
or L&H variant. Sometimes these cells are referred to as ‘popcorn’ cells
because their nucleus resembles an exploded popcorn kernel. This subtype
of HL accounts for 5 per cent of cases and has a bimodal age distribution
– children and adults between the ages of 30 and 40. Unlike common
HL, this type is more common in African American men compared with
Caucasians in the US. Clinically, patients often present with peripheral
lymphadenopathy without B symptoms (namely fever, night sweats and
weight loss). It is generally thought of as a more indolent form of HL.

Question 32

A 17-year-old boy with glucose-6-phosphate dehydrogenase (G6PD) deficiency
presents with tiredness and is noticed to be jaundiced. These features have developed
since he was diagnosed with a chest infection 1 week ago. What is the most
likely haematological finding?

A Positive direct antiglobulin test

B Low mean cell volume

C Reduced reticulocyte count

D Haemoglobinuria

E Increased haptoglobin concentration

Answer 32

D Haemoglobinuria

This patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency;
a common X-linked condition where the reduction of G6PD function
leads to haemolysis when erythrocytes are exposed to oxidative stress.
Less commonly there is a chronic haemolysis when enzymatic activity is
less than 10 per cent of normal. Unlike some other X-linked conditions,
women can be affected due to the random nature of X chromosome
inactivation (lyonization) which leads to some cells being vulnerable
to oxidative stress. G6PD is important in the pentose phosphate shunt
which critically regenerates NADPH, a cofactor important in glutathione
metabolism. Reduced glutathione is the primary buffer against oxidative
stress. Haemoglobinuria (D) occurs due to intravascular haemolysis in
the face of oxidative stress in a susceptible patient. Red cells undergo
intravascular and extravascular haemolysis leading to haemoglobinaemia
and haemoglobinuria. Common precipitants include intercurrent
infection but also drugs, the most notorious of which are dapsone, primaquine
and nitrofurantoin. Classically, haemolysis can be triggered by
fava beans (hence its alternate name ‘Favism’) as well as naphthalene
(found in moth balls and henna).

Question 33

A 35-year-old Asian woman presents with tiredness. The full blood count shows:
Haemoglobin: 10.1 g/dL (11.5–16.5)
Platelet count: 160 × 109 (150–400 × 109)
White cell count: 6.6 × 109 (4–11 × 109)
Mean cell volume: 62 fL (80–96 fL)
Hb A2: 6.3 per cent (2–3 per cent)
Which of the following is the most likely diagnosis?

A Sickle cell disease

B Acute myeloid leukaemia

C b-Thalassaemia major

D b-Thalassaemia trait

E Hereditary spherocytosis

Answer 33

D b-Thalassaemia trait

This woman presents with microcytic anaemia, the most common cause
of which is iron deficiency. However, the mean cell volume is disproportionally
reduced compared with the degree of anaemia indicating there
might be a haemoglobinopathy present. The presence of increased Hb A2
confirms the diagnosis of b-thalassaemia trait. Unfortunately the nomenclature
surrounding b-thalassaemia is relatively confusing but an attempt
to clarify it will be made here. Firstly, thalassaemia is the reduction or
absence of a type of globin gene. Normal haemoglobin is a tetramer of
two alpha and two beta globin proteins. The ratio of alpha to non-alpha
globin production is tightly controlled. There are two alpha genes located
on chromosome 16, whereas only one beta gene on chromosome 11.
b-Thalassaemia implies a reduction or absence of the beta chain. Beta (0)
thalassaemia refers to an absence of beta globin production. This encompasses
over 40 genetic mutations. Patients with this are often described
as having b-thalassaemia major (C), however, confusingly some patients
can produce beta globin genes but to such a poor extent they behave
very similar clinically, as if they had no production. Within the first year
of life they have profound life-long transfusion dependent anaemia. This
is therefore not compatible in this patient’s case.

Question 34

A 62-year-old man presents with bruising and tiredness. Examination reveals
moderate splenomegly and his a reveal a normocytic anaemia with blood tests
platelet count of 900 × 109/L, neutrophilia, basophilia, numerous myelocytes and
4 per cent myeloblasts. The neutrophils have low leukocyte alkaline phosphatase
levels. Which of the following is likely to be present in this patient?

A t(9;22)

B t (8;14)

C BCR-Abl fusion gene only

D V617F point mutation in JAK2

E 5q-Syndrome

Answer 34

A t(9;22)

This patient exhibits features of chronic myeloid leukaemia as evidenced
by raised myeloid lineage cells including neutrophils, myelocytes
and basophils. The neutrophils are morphologically normal but
cytochemically different – a laboratory test sometimes used to differentiate
between reactive or leukaemoid neutrophilia and CML is the
leukocyte alkaline phosphatase. It is normal or high in the former, but
characteristically low in CML. Absolute basophilia is a universal finding
in CML, with absolute eosinophilia found in 90 per cent of cases.
A raised platelet count is also common in CML; a low platelet count,
however, should make one reconsider the diagnosis, e.g. myelodysplastic
syndromes.
Up to 95 per cent of patients with chronic myeloid leukaemia have the
Philadelphia chromosome – a fusion chromosome between the long
arms of chromosomes 9 and 22 (A). The formation of the BCR-
Abl
fusion gene acts as a constitutively active tyrosine kinase, but the induction of leukaemogenesis is complicated and mediated through
both tyrosine dependent and independent pathways. It is known, however,
that the tyrosine kinase activity of the BCR-Abl gene is absolutely
required for transformation. BCR-Abl fusion genes alone (C) can occur
without the t(9;22) translocation but this is much less common. This
Robertsonian translocation is worth remembering as it is frequently
asked about in examinations.
The t(8;14) translocation occurs in Burkitt’s lymphoma: a highly aggressive
lymphoma where cmyc, an oncogene, is under the influence of
an immunoglobulin promoter, which is highly expressed. The V617F
point mutation in JAK2 (D) is found in up to 99 per cent of cases of
polycythaemia rubra vera. JAK2 is involved in downstream processing
of the erythropoietin receptor signalling

Question 35

Which of the following patients has the worse prognosis?

A 25-year-old man with inguinal lymphadenopathy

B 25-year-old woman with mediastinal and inguinal lymphadenopathy

C 25-year-old woman with mediastinal and inguinal lymphadenopathy and
night sweats

D 25-year-old woman with mediastinal and inguinal lymphadenopathy with
5 per cent weight loss in last 6 months

E 25-year-old man with cervical and mediastinal lymphadenopathy

Answer 35

C 25-year-old woman with mediastinal and inguinal lymphadenopathy and
night sweats

This question relies on the candidate’s knowledge and understanding of
the Ann Arbor staging system. This clinical staging system is relatively
intuitive – stages are between I and IV either in the absence or presence
of ‘B symptoms’. A simplified version of the classification is as follows:
• Stage I: involvement of a single lymph node region
• Stage II: involvement of two or more lymph node regions on the
same side of the diaphragm
• Stage III: involvement of lymph nodes on both sides of the
diaphragm
• Stage IV: extranodal spread (not spleen however, this is taken as a
lymph node)
The definition of B symptoms includes significant unexplained fever,
night sweats or unexplained weight loss of over 10 per cent during
6 months prior to diagnosis. The presence of B symptoms is denoted
by a B subscript after the stage number, the absence is denoted by an
A subscript. Patient A would therefore be classified as Ia, patient B as
IIa, patient C as IIIb, patient D as IIIa, technically as she does not quite
fulfil the 10 per cent loss in 6 months and finally patient E as stage
IIa. Note that in Hodgkin’s lymphoma, the disease always spreads contiguously
whereas in non-Hodgkin’s lymphoma this is not always the
case. Further investigations for clinical staging include an upright chest X-ray, integrated positron emission tomography/computer tomography
of the chest/abdomen/pelvis and sometimes a unilateral bone marrow
aspirate and biopsy for those with stage III or IV with B symptoms.

Question 36

A patient presents with acute promyelocytic leukaemia. What is the most likely
mechanism of underlying leukaemogenesis?

A Telomere shortening

B Aberrant fusion of two genes

C Impaired protein degredation

D Over-expression of cellular oncogene

E Post-translational modification

Answer 36

B Aberrant fusion of two genes

Acute promyelocytic leukaemia is interesting for a number of reasons.
There is a reciprocal translocation between the long arms of chromosomes
15 and 17 giving the PML-RARA fusion gene (B). This links the
retinoic acid receptor alpha (RARA) gene on chromosome 17 with the
promyelocytic leukaemia (PML) gene on chromosome 15. RARA is a
member of a family of retinoin-binding transcription factors that regulate
gene expression. It heterodimerizes with retinoid X receptor (RXR)
and binds to retinoic acid response elements to influence gene transcription.
In the absence of retinoic acid, the RARA/RXR dimer interacts
with another protein (nuclear corepressor) to repress gene transcription.
Therefore, addition of retinoic acid stimulates gene transcription. In
the setting of promyelocytic leukaemia, retinoic acid induces myeloid
differentiation
which is abnormally halted thus providing remission
by encouraging cell differentiation rather than cell death. The second
reason
this type of leukaemia is interesting is its association with disseminated
intravascular coagulopathy. The pathogenesis is not completely
understood but recognizing it early is important as treatment
with retinoic acid plus supportive therapy can lead to rapid improvement
in the coagulopathy.

Question 37

A 64-year-old man presents with lethargy, weight loss and abdominal fullness.
He is found to have chronic myeloid leukaemia. He is started on imatinib as part
of the initial treatment to control his disease. What is the mechanism of action
of imatinib?

A Proteosome inhibitor

B Tyrosine kinase inhibitor

C IL-6 inhibitor

D p53 inhibitor

E Human epidermal growth factor receptor 2 protein inhibitor

Answer 37

B Tyrosine kinase inhibitor

Imatinib is a tyrosine kinase inhibitor (B) and is used in the treatment of
chronic myeloid leukaemia. It is a rational therapy which acts to inhibit
the BCR-Abl tyrosine kinase thus blocking proliferation and inducing
apoptosis in BCR-Abl positive cell lines. The BCR-Abl fusion is most
commonly secondary to a balanced Robertsonian translocation between
chromosomes 9 and 22. Imatinib is also used for gastrointestinal stromal
tumour (GIST). Other tyrosine kinase inbitors include dasatinib and
nilotinib. They do not cure CML but provide long-term control in the
majority of patients, thus they are the initial treatment of choice for
almost all newly diagnosed patients with CML.

Question 38

A 16-year-old girl with mild von Willebrand’s disease is scheduled for a dental
extraction. She has had one previously where she required two units of blood
transfused. What is the most appropriate treatment for this patient prior to
surgery?

A Cryoprecipitate

B Desmopressin

C Fresh frozen plasma

D Vitamin K

E Recombinant factor VIII concentrate

Answer 38

B Desmopressin

This woman has mild von Willebrand’s disease (vWD) which can be
treated with desmopressin (B). There are three types of vWD – type I is
a quantitative deficiency of von Willebrand Factor (vWF), type II is a
qualitative defect in vWF whereas type III results in profound deficiency
in vWF. There are four subtypes of type II vWF (2A, 2B, 2M and 2N).
vWF is important in two ways; first it acts as a bridge between platelets
and between platelets and subendothelial structures at the site of
injury; and second it carries factor VIII which is a key molecule in the
clotting cascade. Desmopressin acts to increase vWF and factor VIII
concentration by encouraging its release from endothelial cell storage
sites. Desmopressin is efficacious in type I and most type II disease but not in type III. This woman is known to have ‘mild’ disease thus making
desmopressin a viable option. Interestingly, desmopressin in patients
with type 2B will lead to a transient worsening of their thrombocytopenia.
Patients with type 2B vWD have increased binding of the abnormal
vWF to platelets causing sequestration and clearance of platelets.
This is worsened for desmopressin, if only for a few hours. Despite this,
there have been reports of patients benefiting from desmopressin.

Question 39

An 80-year-old man presents with tiredness and lethargy. After initial work-up,
a diagnosis of myelodysplastic syndrome is suspected. Which of the following is
true about this condition?

A A blood film will typically show neutrophil toxic granulation

B If there are 1 per cent blasts of the total white cell count, this represents
leukaemic transformation

C Cytotoxic chemotherapy is first line treatment

D Mortality is more likely to be from infection than leukaemic transformation

E Absence of the short arm of chromosome 5 is a subtype

Answer 39

D Mortality is more likely to be from infection than leukaemic transformation

The myelodysplastic syndromes are a heterogeneous group of conditions
characterized by an abnormal clone of stem cells with impaired proliferation
and differentiation. The result is a peripheral cytopenia, qualitative
abnormalities in erythroid, myeloid and megakaryocyte maturation,
as well as increased risk of leukaemic transformation. The abnormalities,
both quantitative and qualitative, in neutrophils mean susceptibility to
bacterial infection is high and thus a corresponding increased likelihood
of mortality (D). Skin infections are particularly common and resistant
to treatment.

Question 40

A middle-aged woman comes to the dermatology clinic with a suspicious mole
on her back. You decide excision is required and during the history she says ‘I
have Factor V Leiden’. Which of the following best describes the pathophysiology
of Factor V Leiden mutation?

A Prothrombin mutation

B Activated protein C resistance

C Antithrombin III deficiency

D Protein C deficiency

E Protein S deficiency

Answer 40

B Activated protein C resistance

Factor V Leiden is an autosomal dominantly inherited point mutation
where arginine is replaced by glutamine in the 506th position. Factor V
normally circulates in plasma as an inactivated factor and is activated
by thrombin which then acts as a co-factor, with factor Xa, to convert
prothrombin to thrombin. Factor Va is inactivated by cleavage of its
heavy chain; firstly at position Arg506, which causes conformational
change to reveal a further two cleavage sites (Arg306 and Arg 679).
This inactivation is performed by the activated protein C complex, and
thus the Leiden mutation confers resistance (B). The prothrombotic
consequence of Factor V Leiden is actually two-fold – first Factor V is
degraded more slowly thus there is more generation of thrombin in the
prothrombinase complex and second, once factor V is cleaved at the
first Arg506 site, it is thought to play a role, with protein S, to support
activated protein C in Factor VIIIa degradation too.