Haem

Question 1

What is favism?

Answer 1

This is caused by the ingestion of fava beans. It can produce an acute
haemolysis in patients with glucose-6-phosphate deficiency (G6PD

Question 2

What is the haemoglobin content of reticulocytes and how can this be
measured or determined?

Answer 2

The reticulocyte is a young erythrocyte without a nucleus. Over
90% of the reticulocyte’s protein is haemoglobin. It is not normally
measured.

Question 3

We are told that an erythrocyte sedimentation rate (ESR) above
100 mm/h has a limited differential diagnosis, mainly vasculitis,
malignancy and granulomatous diseases. Could you explain whether
that applies to an ESR after one hour or two?

Answer 3

It applies to the ESR after 1 hour.

Question 4

What causes a raised erythrocyte sedimentation rate (ESR)?

Answer 4

A raised ESR is due to a rise in the large plasma proteins (e.g. fibrinogen
or immunoglobulins). These proteins cause rouleaux formation when the
cells clump together like a stack of coins and therefore fall more rapidly
in a tube.

Question 5

What are the causes of very raised erythrocyte sedimentation rate (ESR)?
I mean an ESR 100 mm/h. Is this test diagnostic in any disease besides
polymyalgia rheumatica and giant cell arteritis?

Answer 5

A very high ESR occurs with myeloma and sometimes with malignancies
where there is an increase in the plasma concentration of immunoglobulins.
It can also occur in inflammatory conditions, e.g. rheumatoid
arthritis and inflammatory bowel disease (IBD). It is never diagnostic but
sometimes adds strong support to the clinical picture, e.g. polymyalgia,
giant cell arteritis, rheumatic fever. Its main use is in monitoring the
response to treatment, e.g. when using steroids for IBD, a fall in the ESR
indicates a good response.

Question 6

1. Does the erythrocyte sedimentation rate (ESR) rise with age?
2. Can an ESR of 50 mm/h in an 80-year-old female with no evidence of
   systemic disease be considered normal?

Answer 6

1. There is a progressive rise with age. For example, in men aged 61–70
   years the ESR is about 14; over 70, it is about 30. Women have slightly
   higher levels: aged 61–70 years the ESR is 20 and, over 70 it is 35.

An ESR of 50 mm/h is therefore abnormal in an 80-year-old but it is
not usually worth pursuing beyond simple investigation (e.g. blood
count). Do remember the various ways polymyalgia rheumatica
can present, e.g. tiredness, loss of weight and often without the
characteristic pain. It responds dramatically to steroids

Question 7

1. What is a ‘normal’ erythrocyte sedimentation rate (ESR)? Is the
   equation of a normal ESR age 10, correct?
2. Would a normal ESR exclude a vasculitic cause in the case of stroke?

Answer 7

1. Up to 20 mm in 1 hour. The equation is not helpful.

2. This makes it very unlikely but not impossible

Question 8

In which conditions is C-reactive protein (CRP) more informative than
the erythrocyte sedimentation rate (ESR)?

Answer 8

CRP follows the clinical state of the patient much more closely in many
inflammatory conditions, e.g. Crohn’s disease. It is unaffected by anaemia.
The CRP does not rise in systemic lupus erythematosus but the ESR does

Question 9

What is the management of an isolated high ferritin (without any signs,
symptoms or changes in the other blood investigations)?

Answer 9

Ferritin is an acute-phase protein and therefore will go up in
inflammation, malignant disease or with acute liver necrosis. A high
serum ferritin not associated with any of these should be investigated
for possible hereditary haemochromatosis. Sending blood for genetic
analysis of the HFE gene is now the best way to make this diagnosis

Question 10

Is the mean corpuscular volume (MCV) useful? What is the RDW and
when is it used?

Answer 10

The MCV (normal range 80–96 fL) is useful in diagnosing the type of
anaemia. A reading of 80 would suggest microcytic anaemia and 96 fL,
macrocytic anaemia. The RDW (red blood cell distribution width) is the
ratio of the width of the red cell over the MCV. It helps in the diagnosis
of microcytosis but not macrocytosis. In a patient with anaemia, a raised
RDW would favour iron deficiency and a normal RDW, thalassaemia.

Question 11

What is the significance of renal disease with respect to anaemia, if any?

Answer 11

Anaemia is common in chronic kidney disease. The anaemia is often the
normochromic, normocytic anaemia of chronic disease. The major cause
of anaemia is a relative deficiency of erythropoietin. Other causes include
bone marrow toxins, haemolysis, deficiency of haematinic factors (K&C
7e, p. 628).
Recombinant human erythropoietin is effective treatment in these
cases; remember to replenish iron stores to optimize therapy

Question 12

Can anaemia be a differentiating point between muscle wasting and
cachexia owing to another systemic disorder?

Answer 12

Not really; anaemia can occur with cachexia associated with cancer and
can also occur with muscle wasting associated with polymyositis.

Question 13

Anaemia of chronic disease does not respond to iron therapy, but there
are trials studying the use of iron and erythropoietin (EPO). Could you
tell me where to find more detailed information about these trials, and
whether there have since been any further developments?

Answer 13

The statement is correct, the anaemia does not respond to iron therapy
alone. EPO is used in anaemia of chronic disease, e.g. rheumatoid
arthritis, chronic kidney disease. The response can be dramatic so that
iron must be made available, otherwise iron deficiency will occur.

Question 14

Is the deoxyuridine test helpful?

Answer 14

The problem with this test is it needs a bone marrow sample. It is
useful, however, because it gives a rapid result for vitamin B12 and folate status, whereas the blood tests take more time. It is not used very often

Question 15

The Schilling test is very rarely performed. Why is this?

Answer 15

Because radiolabelled vitamin B12 is now unavailable in the UK.

Question 16

There is no extramedullary haematopoiesis in aplastic anaemia, why?

Answer 16

In aplastic anaemia there is damage to the stem cells, due to a number
of causes including viruses and radiation. Damaged stem cells mean no
haematopoiesis of any sort.

Question 17

Why is the anaemia in aplastic anaemia, macrocytic?

Answer 17

In aplastic anaemia there are few red cells and the anaemia is usually
normocytic. It can occasionally be macrocytic as the abnormal red cells
can be big.

Question 18

Is vitamin B12 absorbed passively from the jejunum?

Answer 18

Yes. Patients with pernicious anaemia who have no intrinsic factor can
still be treated with vitamin B12 orally by giving large amounts (2 mg per
day), which are absorbed passively in the jejunum. There is a specific
transport mechanism for vitamin B12 in the ileum, which requires
intrinsic factor as a cofactor.

Question 19

What role does ‘R’ binder play in the absorption of vitamin B12?

Answer 19

Vitamin B12 is liberated from protein complexes in food by gastric
enzymes and then bound to ‘R’ binder (a B12 binding protein) from the
saliva. This is similar to transcobalamin that is found in plasma. The
bound B12 is released by pancreatic enzymes and then becomes bound to
intrinsic factor for absorption.

Question 20

In pernicious anaemia, investigation of the serum shows an elevated
level of gastrin. Why is it so?

Answer 20

In pernicious anaemia, there is atrophy of parietal cells and therefore no
acid is produced. The gastrin level is raised as there is no negative
feedback.

Question 21

1. Please explain the term Coombs’ positive (direct and indirect) and
   negative haemolytic anaemia.
2. What are the principles of the Coombs’ test?

Answer 21

1. In the direct Coombs’ test, the patient’s red cells are sensitized
   in vivo; the test is positive if agglutination occurs on the addition of
   antihuman globulin. In the indirect Coombs’ test, normal red cells are
   sensitized in vitro by incubation with the patient’s serum and again
   will be positive if there is agglutination on the addition of antihuman
   globulin.
2. The Coombs’ test detects autoantibody on the surface of the patient’s
   red cells.

Question 22

How often is Aldomet (alpha methyldopa) associated with autoimmune
haemolytic anaemia or hepatitis? Is a normal person, with a positive Coombs’
test owing to previous treatment with this drug, safe to donate blood?

Answer 22

Twenty per cent of patients develop a positive Coombs’ test with methyldopa
but haemolytic anaemia is rare. Your normal person with previous drug
treatment would not be able to donate blood because of problems with
cross-matching and interference with agglutination tests. Hepatitis is rare.

Question 23

What is the mechanism of priapism in sickle-cell anaemia?

Answer 23

Veno-occlusion

Question 24

Is sickle-cell disease associated with any of the glomerular disorders?

Answer 24

Yes; focal glomerulosclerosis leads to chronic kidney disease.

Question 25

What is the acute chest syndrome?

Answer 25

This describes the pulmonary complications that occur in sickle-cell disease.
These include pneumonia, thrombosis causing infarctions in the chest or
bone marrow and embolism due to fat. It occurs in about 30–50% of patients
with sickle-cell disease and is the commonest acute problem in the chest.

Question 26

Patients with thalassaemia intermedia have recurrent leg ulcers and
recurrent infections. What is the mechanism of this?

Answer 26

The mechanism is unclear but hypoxia due to anaemia has been

suggested. Many are traumatic.

Question 27

What is the mechanism of iron absorption from iron polymaltose
complex and carbonyl iron?

Answer 27

These compounds will be broken down in the intestine. Ferrous iron is
absorbed in the duodenum initially by attaching to a protein divalent
metal transporter, which transports Fe2
into the cell where it is
transported across the cell to reach the plasma or stored as ferritin (see
reference). These compounds are, however, often passed intact beyond
the point of iron absorption, the first part of the duodenum. Always
prescribe simple iron preparations, e.g. ferrous sulphate.

Question 28

Iron overload in patients with thalassaemia major should be checked by
measuring the serum ferritin and hepatic iron stores. How are the hepatic
iron stores measured? By liver biopsy? And does not the measurement of
serum ferritin suffice?

Answer 28

Iron stores have traditionally been assessed on liver biopsy – grams of
iron per dry weight of liver. Magnetic resonance imaging is now the best
technique. Measurement of serum ferritin will, however, suffice when
monitoring treatment.

Question 29

In the investigation for paroxysmal nocturnal haemoglobinuria (PNH),
are the sucrose haemolysis test and Ham’s acid serum test commonly
done? What are the principles behind these tests?

Answer 29

Osmotic damage does not occur when normal red cells are exposed to
isotonic sucrose. The low ionic strength of the solution enhances the binding of the complement components to the red cell membrane. PNH
cells develop membrane defects and sucrose molecules enter the red cell,
producing osmotic lysis; 5% lysis is positive. In the Ham test, PNH red
cells are significantly lysed when exposed to acidified serum (1% is
positive). However, both these tests have now been replaced by flow
cytometric analysis of red cells with anti-CD55 and anti-CD59 antibodies to
the protein involved in the destruction of red cells by activated complement.

Question 30

Why isn’t the blood of polycythaemia vera patients, after repeated
phlebotomies, used for transfusion purposes? Although it is a
premalignant condition, the red cells do not contain a nucleus and thus
transfusion of only pure red blood cells (RBCs) would be a great benefit

Answer 30

Polycythaemia vera is a clonal cell disorder in which 5% of patients develop
acute myeloid leukaemia. It is thus thought to be unwise to use this for
blood transfusion. Red cells do not contain nuclei but even pure red cell
concentrates still contain a few leukocytes that of course do contain nuclei

Question 31

What investigations are necessary to exclude secondary polycythaemia?

Answer 31

The secondary causes can sometimes be excluded with a history and
examination. A renal ultrasound, an arterial PO2 and carboxyhaemoglobin
levels will exclude most causes of secondary polycythaemia.

Question 32

What is the management plan in a patient with secondary polycythaemia
presenting with transient ischaemic attacks (TIA)?

Answer 32

Treatment of the cause if possible; venesection may help. Aspirin 75 mg
daily should be given

Question 33

Why do patients with polycythaemia vera have a tendency to bleed, even
though 50% of them have an elevated platelet count?

Answer 33

Platelets show a functional defect and haemorrhage causes death in 5%
of patients.

Question 34

In hyposplenic patients, what precautions are necessary for patients who
intend to travel to Saudi Arabia for the Haj?

Answer 34

These patients should already have had pneumococcal and
meningococcal group C vaccines. They should receive, in addition, the
meningococcal polysaccharide vaccine (A, C, W, Y types).

Question 35

What is the mechanism of development of splenomegaly in chronic
leukaemia?

Answer 35

The splenomegaly is due to a combination of extramedullary

haemopoiesis and infiltration of the spleen with neutrophils

Question 36

In idiopathic thrombocytopenic purpura (ITP), thrombocytes are mainly
destroyed in the spleen owing to an immune mechanism. Why, therefore,
is there no splenic enlargement as there is with other diseases?

Answer 36

There is no explanation as to why the spleen remains the normal size.
Presumably platelet destruction can occur without enlargement.

Question 37

Where exactly is the Traub’s space? How exact is the percussion of the
Traub’s space as a sign indicating the size of the spleen?

Answer 37

The area of resonance overlying the gas bubble in the left lateral
hemithorax. Its size and localization depend on the contents and position
of the stomach. It is displaced downwards by an enlarged spleen.
Compared with ultrasound scanning in one study, the sign was 62%
sensitive and 72% specific

Question 38

Can you please tell me the indications and complications of blood
transfusion.

Answer 38

The main indication for blood transfusion is hypovolaemia due to loss of
blood. The complications of blood transfusion are several (K&C 7e, p. 425)
and include immunological causes (red cell and leucocyte incompatibility,
anaphylactic reactions, graft versus host) and non-immunological (infection
transmission, volume overload, thrombophlebitis). An avoidable cause is
the transfusion of the wrong unit of blood.

Question 39

‘white blood cells elevated with a

left shift’. I am wondering what ‘left shift’ or ‘left deviation’ stands for.

Answer 39

A blood film shows a shift to the left if there are relatively more young
polymorphonuclear leucocytes present than normal. These young cells
have more band forms within them, and in addition there are sometimes
myelocytes present; for example this occurs in acute infection.

Question 40

What is the clear definition of ‘bleeding time’ and ‘clotting time’? And
what are the applied differences between them?

Answer 40

The bleeding time measures platelet plug formation in vivo. Platelet
function defects and low platelet numbers (80 109 L) result in an
increased bleeding time. Activated whole blood clotting time has been
replaced by activated partial thromboplastin time (APTT), which is
also known as the partial thromboplastin time with kaolin (PTTK) as a
measure of clotting.

Question 41

What is the meaning of the international normalized ratio (INR) blood test?

Answer 41

The INR is the ratio of the patient’s prothrombin time (PT) to a normal
control when using the international reference preparation. PT tests are
therefore standardized, whichever laboratory is used.

Question 42

What is the cause of moderate thrombocytopenia in Bernard–Soulier
syndrome? It is a qualitative defect not a quantitative platelet disorder

Answer 42

The cause of the moderate thrombocytopenia in Bernard–Soulier
syndrome is unclear. It is possibly related to ineffective or decreased
thrombopoiesis

Question 43

What is new about thrombopoietin?

Answer 43

Thrombopoietin is a regulator of platelet function. Its clinical use is in
cancer chemotherapy, both for solid tumours and for acute leukaemia,
hopefully avoiding platelet transfusion. It was also used in idiopathic
autoimmune thrombocytopenia as second line therapy but Romiplostim,
a similar protein, is now used.

Question 44

What is the rationale behind the use of desmopressin in bleeding
disorders?

Answer 44

Desmopressin is used in von Willebrand’s disease to release von
Willebrand factor from the endothelium. In platelet function disorders
it might have an effect on platelet function. In haemophilia A,
desmopressin produces a transient rise in factor VIII and is useful for
treating bleeding episodes in mild haemophilia and as a prophylaxis
before minor surgery.

Question 45

What effect does the contraceptive pill have on the blood fibrinogen level
and on blood coagulability?

Answer 45

Factors V, VIII, X and fibrinogen levels are increased by ethinylestradiol,
which can enhance thrombosis

Question 46

Does standard (unfractionated) heparin in doses of 10 000–15 000
units/day need monitoring?

Answer 46

Unfractionated heparin should always be monitored with activated
partial thromboplastin time (APTT) to ensure adequacy of effect. The
dose of 10 000–15 000 units will not be dangerous but might well be
ineffective.

Question 47

Is there an antidote for low-molecular-weight heparin (LMWH)? Can
Enoxaprin be used?

Answer 47

Antidotes are not usually required for LMWH. Protamine (if used) is less
effective than as an antidote against standard heparin. In patients at risk
of bleeding, give LMWH twice daily instead of once. Enoxaparin is a
LMWH.

Question 48

1. What is the mechanism of the action of aprotinin?
2. What is the therapeutic window for aprotinin?
3. In a case of haemorrhagic stroke, how many days should aprotinin be
   prescribed for and what is the recommended dosage?

Answer 48

1. Aprotinin inhibits the activation of plasminogen to plasmin. It
   also inhibits kallikrein. These actions mean that aprotinin has an
   antifibrinolytic effect as well as inhibiting coagulation.
2. Aprotinin is given intravenously every hour in open heart surgery to
   reduce bleeding.
3. It is not recommended for haemorrhagic stroke.

Question 49

My question is, what are thrombophilia scan tests? Can we use these in
patients on anticoagulant therapy?

Answer 49

You cannot do thrombophilia scan tests on patients on anticoagulants.
The thrombophilia tests are full blood count and coagulation screen,
which will detect erythrocytosis, thrombocytosis and dysfibrinogenaemia
and the possible presence of a lupus anticoagulant. Specific tests include;
assay for antithrombin, protein C and S, molecular testing for factor V
Leiden and for anticardiolipin antibodies

Question 50

In thromboembolic disorders, how is clopidogrel superior to aspirin?

Answer 50

A number of studies have shown some slight benefit of clopidogrel over
aspirin but with more bleeding, and it is more expensive. The question
asks how is it superior? This is unclear, but is possibly due to a different
site of action. Aspirin inhibits the enzyme cyclo-oxygenase (COX), resulting in reduced action of thromboxane A2 (TXA2). Clopidogrel
affects the adenosine diphosphate (ADP) activation of the glycoprotein
11b/111a complex.

Question 51

What are the definitions for prothrombin time (PT) and partial
thromboplastin time (PTT), and how are they different?

Answer 51

The prothrombin time is prolonged with abnormalities of coagulation
factors VII, X, V, II or I, liver disease or if the patient is on warfarin.
The activated partial thromboplastin time (APTT) is prolonged with
abnormalities of factors XII, XI, IX, X, V, II or I (not factor VII).

Question 52

1. Why, in chronic disease anaemia, are serum iron and the total ironbinding
   capacity (TIBC) low?
2. Why, in sideroblastic anaemia with increased levels of serum iron, is
   the TIBC normal?

Answer 52

1. The bone marrow contains iron but this is not released into the serum.
   The TIBC is low, as are levels of many circulating proteins. The
   mechanisms of these effects are unclear but are probably mediated by
   inflammatory cytokines.
2. In sideroblastic anaemia the TIBC might be high or normal, but not
   low.

Question 53

What is the red cell distribution width (RDW) value above which
anisocytosis can be diagnosed?

Answer 53

15%

Question 54

Is anisocytosis diagnostic of iron deficiency anaemia?

Answer 54

No; anisocytosis just means that the red cells are of different size on a
blood film. This can occur with iron deficiency but also, for example,
with thalassaemia

Question 55

In the case of a patient who has been treated with streptokinase and has
bleeding complications in the form of haematemesis, haemoptysis or
similar, how can the effect of streptokinase on the coagulation system be
reversed, and can tranexamic acid help?

Answer 55

Stop the streptokinase immediately. Fresh frozen plasma and
cryoprecipitate should also be given. Antiproteolytic agents such as
tranexamic acid can be tried. No treatment is, however, very effective
and if the bleeding is significant, the mortality is high

Question 56

We know that salmonella infection is a common complication in patients
with sickle cell anaemia. Is this true for patients with thalassaemia major
and, if so, why?

Answer 56

Salmonella infection does occur but much less commonly than in sickle
disease. The explanation is probably splenic dysfunction.