# 045

# Chapter 7

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
Types
•
Sickle cell trait: heterozygous (HbAS)

occurs when a child inherits a sickle gene from one parent and a normal gene from 
the other parent. 
•
Sickle cell disease: homozygous (HbSS)

occurs when a child inherits a sickle gene from each parent.
•
Other, rarer forms of sickle cell disease in which the person has only one copy of the 
mutation that causes Hb S and one copy of another abnormal Hb allele. Examples:
“HbSC”: (sickle –haemoglobin C disease).
“HbS/β+”: (sickle-beta-plus-thalassemia).
“HbS/β0” : (sickle-beta-zero-thalassemia)
Sickling of the erythrocyte
•
A low partial pressure of oxygen (PO2) causes HbS to polymerise and precipitate resulting 
in sickling of the erythrocyte.
HbSS patients sickle at PO2 of 5-6 kPa 
HbAS patients sickle at PO2 of 2.5-4 kPa.
HbSC Sickling occurs at around 4 kPa.
Sickle cell disease and malaria
•
Sickle cell trait (HbAS) is known to protect against falciparum malaria. As a result, the 
frequencies of sickle cell carriers are high in malaria-endemic areas.
•
Patients with HbSS are at higher risk of severe malaria with complications and have a 
higher mortality rate. 
Feature
•
Black pigment gallstones occur in 50 % of patients with sickle cell disease
due to an increase in bilirubin excretion.
Their small size allows migration into the common bile duct causing low-grade 
obstruction. 
Typically leading to hyperbilirubinaemia rather than bile duct dilatation.

cholecystectomy is suggested for patients with sickle cell disease if abdominal 
surgery is being performed for other reasons.
Due to decreased life span of the erythrocyte, average 17 days (normal 120 days), 
there is also a chronic circulating unconjugated hyperbilirubinaemia.
•
There is often an inability to concentrate urine
The inner medulla is hypoxic, hypertonic and acidotic and therefore predisposes to 
sickling of red blood cells, which results in vasoocclusion and reduction in renal 
medullary blood flow.
proximal tubule dysfunction impairs  urinary concentration
distal tubular dysfunction impairs potassium excretion.
•
Functional hyposplenism in SCD also renders sufferers susceptible to infection with 
encapsulated bacteria (pneumococci, meningococci).
Patients with sickle cell disease have a predisposition to develop osteomyelitis due 
to Salmonella species.

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

Sickle-cell crises: Four main types of crises are recognised:
•
thrombotic crises, also known as painful crises or vaso-occlusive crises
precipitated by infection, dehydration, deoxygenation ,acidosis , cold temperatures, 
extreme exercise and stress.
infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, 
hand-foot syndrome in children, lungs, spleen and brain
•
sequestration crises
sickling within organs such as the spleen or lungs causes pooling of blood with 
worsening of the anaemia
acute chest syndrome: dyspnoea, chest pain, pulmonary infiltrates, low pO2 - the 
most common cause of death after childhood
stroke 

5-10% of sickle cell patients will suffer a stroke, usually during childhood. 

The risk can be predicted by transcranial Doppler measurement of middle 
cerebral artery (MCA) flow rate, 

prompt institution of a prophylactic transfusion program to reduce the HbS % 
can prevent further strokes. 

treatment once occurred Exchange transfusion programme
•
aplastic crises
caused by infection with parvovirus
sudden fall in haemoglobin without an appropriate ↑reticulocytosis.
The condition is self-limited, with bone marrow recovery occurring in 7-10 days, 
followed by brisk reticulocytosis.
•
haemolytic crises
rare
The anaemia associated with sickle cell disease is usually only symptomatic below 
70 g/L, as oxygen is released more readily from erythrocytes.

remember, patients with sickle cell tend to run with a Hb between 70-90 g/L 
normally
The anemia of SC is usually a chronic, reasonably well-compensated hemolytic 
anemia with an appropriate reticulocytosis. For example, the mean hemoglobin and 
hematocrit concentrations on average may be 79 g/L and 22.9% respectively, with a
reticulocyte count of between 3-15%.
Diagnosis of sickle cell disease requires the detection of HbS.
•
Sickledex test: addition of reagent to blood turbidity confirming the presence of HbS, 
but it gives no information on other haemoglobins.
•
Haemoglobin electrophoresis is the only investigation that determines the nature of the 
haemoglobinopathy
predominance of HbS. 
Absent HbA.
HbF 2-20%
Treatment
•
General management
analgesia e.g. opiates

NSAIDs do not usually provide effective analgesia on their own in sickle cell 
painful crises.
rehydrate
oxygen

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
consider antibiotics if evidence of infection
blood transfusion
exchange transfusion: e.g. if neurological complications
•
Avoid
iron therapy: There is a tendency to iron overload and therefore iron therapy is not 
usually indicated. 
Intra-articular steroids have been associated with a sickle cell crisis, the mechanism 
of which is not fully understood, but they should be avoided.
•
pharmaceutical interventions to prevent sickle cell crisis and other acute 
complications 
Hydroxyurea

acts by inhibiting ribonucleotide reductase, which inhibits both purine and 
pyrimidine synthesis.

Action: ↑fetal haemoglobin (Hb F) which protects against sickling. 

reduces the incidence of acute chest syndrome and the need for blood 
transfusion

The major side effect is severe myelosuppression.
Malaria chemoprophylaxis in endemic area
•
Acute chest syndrome
defines  as 'an acute illness characterized by fever and/or respiratory symptoms, 
accompanied by a new pulmonary infiltrate on chest X-ray'.
management:

Oxygen therapy to maintain saturations > 95%

Intravenous fluids to ensure euvolaemia

Adequate pain relief

Incentive spirometry in all patients presenting with rib or chest pain

Antibiotics with cover for atypical organisms

Early consultation with the critical care team and haematology

Blood transfusion:
A senior haematologist will make a decision as to whether a simple or 
exchange transfusion is necessary.
guidelines suggest Hb target of 100-110g/L in either instance. 
•
All adults who have hyposplenism, including patients with SCD, need: 
Yearly influenza vaccine. 
Pneumococcal C vaccine, (adults and children over 2 years) repeated every five 
years. 
Haemophilus influenzae type b; if not already given as part of childhood 
immunisation. 
Conjugated meningococcal C vaccine; if not already given as part of childhood 
immunisation. 
Meningococcal ACWY vaccine; if travelling to areas with high risk of meningitis.
•
Patients with sickle cell disease are prone to infections within encapsulated organisms
because of their asplenic state. 
These include:

Streptococcus pneumoniae,

Haemophilus influenzae and

Neisseria meningitidis.
To combat these infections, patients with homozygous sickle cell disease should be 
on lifelong penicillin and be vaccinated against these organisms.
Salmonella osteomyelitis is seen in patients with sickle cell anaemia

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

screening for sickle cell disease in a pregnant women:
•
She will first be screened for sickle cell carrier status. 
•
If that test is positive, her partner will be screened, 
•
If both are found to be carriers this is confirmed by genetic testing before offering chorionic 
villus sampling (CVS) (8-10 weeks) or amniocentesis (14-16 weeks).
Priapism 
•
Priapism is most often due to idiopathic thrombosis of the prostatic venous plexus.
•
Other causes include:

leukaemia, 
sickle-cell anaemia and

carcinomatosis.
•
Priapism occurs fairly frequently which may lead to permanent impotence if it is not 
relieved.
____________________________________________________
Sideroblastic anaemia
Definition
•
Sideroblastic anaemia is a condition where red cells fail to completely form haem, whose 
biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the 
mitochondria that form a ring around the nucleus called a ring sideroblast. 
Causes: It may be congenital or acquired
•
Congenital cause: delta-aminolevulinate synthase-2 deficiency
The enzyme delta aminolevulinic acid (ALA) is essential in the biosynthesis of heme. 

Delta ALA requires pyridoxine (vitamin B6) and copper as cofactors.
Hereditary sideroblastic anemia follows a X-linked genetic inheritance pattern.
•
Acquired causes
myelodysplasia (seen in older age groups)
alcohol

the most common reversible cause
lead
drugs: anti-TB medications, chloramphenicol.

Pyridoxine (vitamin B6) deficiency, caused by isoniazid and oral 
contraceptives, is a reversible cause of sideroblastic anemia.
Investigations
•
hypochromic microcytic anaemia (more so in congenital)
•
Basophilic stippling:
visualization of ribosomes on the surface of red blood cells 
can be seen on a peripheral blood smear of patients with sideroblastic anemia.
•
Ferritin levels are increased
•
bone marrow: 
sideroblasts and increased iron stores
Sideroblasts are red cell precursors with iron-laden mitochondria and are detected 
via Prussian blue staining.
Ringed sideroblasts are pathognomonic for sideroblastic anemia.
Management
•
supportive
•
treat any underlying cause

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
removal of toxic agents such as zinc and lead, and drugs such as penicillamine and 
isoniazid. 
•
pyridoxine may help
•
Deposition of iron in secondary haemochromatosis (haemosiderosis):
Oral iron chelators 

First-line : oral deferasirox

Second-line: Deferiprone
side effect: bloody dyscrasias and liver dysfunction.
Liver function tests are imperative whilst the patient is being 
administered both deferiprone and deferasirox.

Desferrioxamine results in compliance issues due to the subcutaneous route 
and long infusion time.
Whereas phlebotomy is effective at decreasing iron overload, in a patient who is 
anaemic this is not a viable option. 
The figure illustrates sideroblasts, which 
are nucleated (immature) erythrocytes with
granules of iron in their cytoplasm.

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

Haemolytic anaemias: by site
The combination of anaemia and jaundice should always suggest haemolytic anaemia until 
proved otherwise
•
In intravascular haemolysis free haemoglobin is released which binds to haptoglobin. 
The benefit of this  process (Haptoglobin binds with free plasma hemoglobin):

permits degradative enzymes access to the hemoglobin, 

preventing the loss of iron via the kidneys, 

shielding the kidneys from damage by hemoglobin.
•
As haptoglobin becomes saturated haemoglobin binds to albumin forming methaemalbumin 
(detected by Schumm's test). 
•
Free haemoglobin is excreted in the urine as haemoglobinuria, haemosiderinuria
Intravascular haemolysis
Extravascular haemolysis
•
mismatched blood transfusion
•
G6PD deficiency*
•
red cell fragmentation: heart valves, 
TTP, DIC, HUS
•
paroxysmal nocturnal haemoglobinuria
•
cold autoimmune haemolytic anaemia
•
haemoglobinopathies: sickle cell, 
thalassaemia
•
hereditary spherocytosis
•
haemolytic disease of newborn
•
warm autoimmune haemolytic anaemia
*strictly speaking there is an element of extravascular haemolysis in G6PD as well, although it is 
usually classified as a intravascular cause
Haemolytic anaemias: by cause
Hereditary causes
•
can be subdivided into membrane, metabolism or haemoglobin defects 
membrane: hereditary spherocytosis/elliptocytosis
metabolism: G6PD deficiency
haemoglobinopathies: sickle cell, thalassaemia
Acquired causes 
•
can be subdivided into immune and non-immune causes
Acquired: immune causes

autoimmune: warm/cold antibody type

alloimmune: transfusion reaction, haemolytic disease newborn

drug: methyldopa, penicillin
methyldopa Anti-RBC antibodies 
penicillin reaction between penicillin-like drugs and their antibodies
Acquired: non-immune causes

microangiopathic haemolytic anaemia (MAHA): TTP/HUS, DIC, malignancy, 
pre-eclampsia

prosthetic cardiac valves

paroxysmal nocturnal haemoglobinuria

infections: malaria

Direct (non-immune) red cell toxicity may occur after lead exposure.
laboratory tests 
•
Hemoglobin: decreased
•
MCV: normocytic
•
Reticulocyte count and reticulocyte production index: increased
•
Unconjugated bilirubin: increased
•
LDH: increased (esp. in intravascular hemolysis)
•
Haptoglobin: reduced

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
 
Microangiopathic anemia
•
The patient’s newly diagnosed heart murmur along with new anemia and 
schistocytes indicate aortic stenosis as the underlying cause.
•
Aortic stenosis mechanical destruction of RBCs (as they travel through the 
narrowed aortic opening) microangiopathic anemia
•
Schistocytes are fragmented RBCs. Also called helmet cells, they are pathognomic of 
microagiopathic hemolytic anemias.
Zieve syndrome
•
triad of jaundice, hemolytic anemia, and hyperlipidemia. 
•
Hepatic dysfunction is usually evident in all cases. 
•
Hemolytic anemia is reversible. 
•
Hyperlipidemia due to excess alcohol intake causes metabolic and osmotic abnormalities in 
(RBCs), making them very susceptible to hemolysis. 
•
Peripheral blood smear reveals:
normocytic normochromic anemia
acanthocytes

Acanthocytes are also called spur cells. 

They have multiple projections on their surface caused by hyperlipidemia.
•
Definitive treatment alcohol cessation.
Zieve's syndrome should be suspected whenever there is anemia and elevation of unconjugated 
bilirubin in the setting of acute alcohol intake with no obvious sign of gastrointestinal bleeding.
____________________________________________________
Autoimmune haemolytic anaemia (AIHA)
•
Autoimmune haemolytic anaemia (AIHA) may be divided in to 'warm' and 'cold' types, 
according to at what temperature the antibodies best cause haemolysis. 
•
It is most commonly idiopathic but may be secondary to a lymphoproliferative disorder, 
infection or drugs. 
•
AIHA is characterised by a positive direct antiglobulin test (Coombs' test)
Warm AIHA
•
In warm AIHA the antibody (usually IgG) causes haemolysis best at body temperature and 
haemolysis tends to occur in extravascular sites, for example the spleen. Management 
options include steroids, immunosuppression and splenectomy. 
•
Causes of warm AIHA
autoimmune disease: e.g. systemic lupus erythematosus*

SLE can rarely be associated with a mixed-type AIHA
neoplasia: e.g. lymphoma, CLL
drugs: e.g. methyldopa, Penicillins, Cephalosporins, levodopa, NSAIDs and 
Quinidine

treated by stopping the drug ± short course of oral prednisolone.
•
The bone marrow respond by increasing RBCs production, which will be evident in 
peripheral blood by increase in the reticulocytes, immature RBCs, which will have high 
MCV.  
•
Management options include steroids, immunosuppression and splenectomy.

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

•
Blood transfusion can be life-saving until immunosuppression can take effect. 
•
All patients with active haemolysis are at risk of acquiring folate deficiency due to increased 
metabolic demands and all should receive folic acid replacement therapy.
Cold AIHA
•
The antibody in cold AIHA is usually IgM and causes haemolysis best at 4 deg C. 
•
Haemolysis is mediated by complement and is more commonly intravascular.
•
Causes of cold AIHA
neoplasia: e.g. lymphoma
infections: e.g. mycoplasma, EBV
Secondary cold agglutinin disease typically presents with anaemia and 
haemoglobinuria due to intravascular haemolysis two to three weeks following 
infection such as with:

Mycoplasma pneumoniae

Viruses (EBV, CMV, etc)

Legionnaires' disease

Malaria The best diagnostic test Cold agglutinin titre
Cold agglutinins occur normally but at very low titres.
•
Features may include symptoms of Raynaud's and acrocyanosis
•
Patients respond less well to steroids
Warm AIHA
Cold AIHA
Definition
haemolysis best at body temperature
haemolysis best at 4 deg C
Antibody
IgG
IgM
Site of haemolysis
extravascular (e.g :spleen)
intravascular
Causes 
•
autoimmune disease: e.g. systemic 
lupus erythematosus
•
neoplasia: e.g. lymphoma, CLL
•
drugs: e.g. methyldopa
•
neoplasia: e.g. lymphoma
•
infections: e.g. 
mycoplasma, EBV
Treatment
steroids, immunosuppression and 
splenectomy.
respond less well to steroids
Paroxysmal cold haemoglobinuria (PCH)
•
a rare type of autoimmune haemolytic anaemia (AIHA) occurring primarily in 
children/adolescent. 
•
The classic symptom is a sudden onset of haemoglobinuria following exposure to cold, 
even for a few minutes.  
•
Symptoms may occur minutes to hours following exposure to cold. 
•
Haemoglobinuria is not always present because in some persons with PCH the
autoantibody level is not high enough to cause intravascular haemolysis.
•
The direct agglutination test (DAT) (Coomb’s test) is usually negative.

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
Cold agglutinin disease 
•
caused by autoantibodies that react at temperatures < 37 °C, 
•
typical causes are:
lymphoproliferative disorders,

infections such as mycoplasma or Epstein–Barr virus. 
Around 50% of cases are idiopathic. 
Non-Hodgkin’s lymphoma is more typically associated with cold agglutinins 
than Hodgkin’s.
Hook effect
•
Also called or the prozone effect
•
In agglutination test, a person's serum (which contains antibodies) is added to a test tube, 
which contains a particular antigen. 
•
If the antibodies agglutinate with the antigen to form immune complexes, then the test is 
interpreted as positive. 
•
However, if too many antibodies are present that can bind to the antigen, then the antigenic 
sites are coated by antibodies, and few or no antibodies directed toward the pathogen are 
able to bind more than one antigenic particle. Since the antibodies do not bridge between 
antigens, no agglutination occurs. Because no agglutination occurs, the test is interpreted 
as negative. In this case, the result is a false negative. 
•
The range of relatively high antibody concentrations within which no reaction occurs is
called the prozone.
•
The effect can also occur because of antigen excess, when both the capture and detection 
antibodies become saturated by the high analyte concentration. In this case, no sandwich 
can be formed by the capturing antibody, the antigen and the detection antibody. In this 
case, free antigen is in competition with captured antigen for detection antibody binding.
•
Examples include:
•
high levels of syphilis antibodies in HIV patients or high levels of cryptococcal antigen 
leading to false negative tests in undiluted samples.
•
This phenomenon is also seen in serological tests for Brucellosis. 
•
when the serum is diluted, the blocking antibody is as well and its concentration decreases 
enough for the proper precipitation reaction to occur.
____________________________________________________
Hereditary spherocytosis
Epidemiology
•
most common hereditary haemolytic anaemia in people of northern European descent
Aetiology
•
autosomal dominant defect of red blood cell cytoskeleton
•
the most frequent cause is a mutation in the spectrin gene; 
spectrin is a component of the red cell membrane. 
•
The most common mutation in a Northern European population is a combined 
spectrin and ankyrin mutation, which is found in 40–65% of patients.
•
the normal biconcave disc shape is replaced by a sphere-shaped red blood cell
•
red blood cell survival reduced as destroyed by the spleen
Pathophysiology
•
Genetic mutation → Defects in RBC membrane proteins (especially spectrin and/or ankyrin) 
responsible for tying the inner membrane skeleton with the outer lipid bilayer → Continuous 
loss of lipid bilayer components → Decreased surface area of RBCs in relation to volume 
→ Sphere-shaped RBCs with decreased membrane stability → Inability to change form 
while going through narrowed vessels:

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

→ Entrapment within splenic vasculature → Splenomegaly
→ Destruction via splenic macrophages → Extravascular hemolysis
Features
Patient with hereditary spherocytosis + acute abdomen think of: Biliary colic or rupture 
spleen.
normocytic anaemia, gallstones and family history hereditary spherocytosis
•
failure to thrive
•
Congenital skeletal abnormalities (eg, tower-shaped skull, polydactylism) occasionally 
occur.
•
Anemia and pallor
•
jaundice  (↑unconjugated bilirubin)
•
gallstones (pigment stones) 
common and may be the presenting symptom
(made of calcium bilirubinate)
may lead to cholecystitis
•
Splenomegaly with left upper quadrant pain
•
aplastic crisis precipitated by parvovirus infection
Complications
•
Aplastic crisis
can be triggered by parvovirus B19 infection.
Investigations
•
Normocytic anemia (normal MCV) 
•
increase in both RDW and MCHC ( the high MCHC, indicating hyperdense cells)
•
Findings of hemolytic anemia
↑ Unconjugated bilirubin
↑ LDH
↓ Haptoglobin
Reticulocytosis
•
Direct antiglobulin (direct Coombs) test
to exclude autoimmune hemolytic anemia (positive Coombs test), since 
spherocytosis is seen in both clinical presentations
Direct Coombs' test is negative in Hereditary spherocytosis, as it is not an immune 
haemolysis
•
Eosin-5-maleimide binding test (EMA): test of choice, as results are readily available 
(within two hours)
•
Osmotic fragility test (Rupture of Spherocytes in mildly hypotonic solution), 
unreliable and is no longer recommended in routine clinical practice. 
this has now been replaced by the eosin-5-maleimide binding to red cells and
then being detected by flow cytometry.
•
Osmotic gradient ektacytometry
used to differentiate hereditary spherocytosis from hereditary stomatocytosis, but is 
only available in specialised laboratories. 
•
If the diagnosis is equivocal, the cryohaemolysis test and EMA binding can be used. 
•
In atypical cases, gel electrophoresis analysis of erythrocyte membranes is the test of 
choice.
•
Blood smear
Characteristic spherocytes (absent central pallor) 
Potentially anisocytosis
•
Ultrasound: 
to evaluate gallbladder complications

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
Diagnosis
1. The first step in analysis of a spherocytic hemolytic anaemia is direct antiglobulin 
test (to determine whether the process is hemolytic or not). 
2. If negative confirm HS with other tests.
3. The osmotic fragility test is unreliable and is no longer recommended in routine 
clinical practice.
4. Osmotic gradient ektacytometry is used to differentiate hereditary spherocytosis 
from hereditary stomatocytosis
Management
•
supportive for most patients: folate replacement
•
splenectomy
best avoided until at least 6 years of age to reduce the risk of post-splenectomy 
sepsis.
It is important to rule out stomatocytosis where splenectomy is contraindicated 
because of the thrombotic risk.
____________________________________________________
Hereditary elliptocytosis (HE)
•
autosomal dominant condition.
•
Elliptocytosis is usually caused by spectrin and spectrin-protein 4.1 defects.
•
Horizontal membrane protein defects (for example, spectrin ankyrin interaction defect) 
results in HE whereas vertical defects result in hereditary spherocytosis.
•
Features
Clinical manifestations range from an asymptomatic carriage to severe haemolytic 
anaemia. 
Most patients with HE or its variants lead healthy lives.
The degree of haemolysis does not correlate with the percentage of elliptocytes seen 
in the blood.
presence of cigar-shaped elliptocytes on the peripheral blood smear (The hallmark of 
HE)
Elliptocytes are normochromic and normocytic and range from few to 100% of 
erythrocytes.
•
Complication 
Aplastic crisis
•
Treatment 
Heterozygotes are asymptomatic but show elliptocytes on blood film; they do 
not have haemolysis and do not require any particular treatment
The treatment for symptomatic hereditary elliptocytosis is splenectomy.
Hereditary elliptocytosis

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

____________________________________________________
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Basics
•
(G6PD) plays a vital role in the hexose monophosphate pathway
•
It is involved in the oxidation of glucose 6-phosphate to 6-phosphoglycerate.This 
oxidation reaction is needed in RBCs as it provides the only source of NADPH
•
NADPH maintains the level of glutathione protect the RBCs 
against oxidative damage from compounds like hydrogen peroxide 
Prevalence
•
G6PD deficiency is the commonest red blood cell enzyme defect. 
•
It is more common in people from the Mediterranean, Africa and Chinese
Aetiology
•
inherited in a X-linked recessive fashion. 
•
Homozygotes and heterozygotes can be symptomatic, although the disease typically is 
more severe in persons who are homozygous for the deficiency.
Factors which Precipitates crisis:
•
infections (the most common cause)
•
drugs 
•
broad (fava) beans
Favism is most common in persons with G6PD class II variants, but rarely it can 
occur in patients with the G6PD A–variant (Class III African descent).
•
henna
Pathophysiology
•
↓ G6PD → ↓ glutathione → increased red cell susceptibility to oxidative stress
•
The haemolytic anaemia is non-immune (direct antiglobulin test [DAT] negative).
Features
•
usually asymptomatic
•
neonatal jaundice is often seen
•
intravascular haemolysis 
Decreased haptoglobin levels, hematuria, and presence of urinary hemosiderin
indicate severe intravascular hemolysis.
•
acute hemolysis can cause back or abdominal pain and jaundice secondary to a rise in 
unconjugated bilirubin
Jaundice, in the setting of normal liver function, typically does not occur until > 50% 
of the erythrocytes have been hemolyzed.
•
gallstones are common
•
splenomegaly may be present
•
Heinz bodies (denatured hemoglobin) on blood films
Diagnosis:
•
made by using a G6PD enzyme assay
•
usually done by fluorescent spot test detecting the generation of NADPH from NADP.
The test is positive if the blood spot fails to fluoresce under ultraviolet light.
•
In patients with acute hemolysis, testing for G6PD deficiency may be falsely negative 
because older erythrocytes with a higher enzyme deficiency have been hemolyzed. Young 
erythrocytes and reticulocytes have normal or near-normal enzyme activity. 
•
Female heterozygotes may be hard to diagnose because of X-chromosome mosaicism 
leading to a partial deficiency that will not be detected reliably with screening tests.
•
Acute haemolytic reaction
Blood count is normal between attacks of haemolysis
During an attack the blood film may show:

irregularly contracted cells

bite cells

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology

blister cells

Heinz bodies

Reticulocytosis
•
Peripheral blood smear Heinz bodies (rarely seen in clinical practice)
•
Reticulocyte count: Increases four to seven days after hemolysis
•
Haptoglobin Decreased
Treatment
•
avoidance exposure to an oxidative stressor in the form of an infection, oxidative drug, or 
fava beans
•
Acute hemolysis is self-limited, but in rare instances it can be severe enough to warrant a 
blood transfusion

Hemolysis typically occurs 24 to 72 hours after ingestion, with resolution within 4 to 
7 days.
•
Methaemoglobinaemia in G6PD-deficient patients is best treated with exchange
transfusion.
Some drugs causing haemolysis
•
anti-malarials: primaquine
•
Quinine/quinidine.
•
Ciprofloxacin
•
Nitrofurantoin
•
chloramphenicol
•
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
•
vitamin K, probenecid 
•
aspirin and (NSAIDs)
Some drugs thought to be safe
•
penicillins
•
cephalosporins
•
macrolides
•
tetracyclines
•
trimethoprim
In “Co-trimoxazole”: the sulfamethoxazole causes haemolysis in G6PD, not the 
trimethoprim.
Comparing G6PD deficiency to hereditary spherocytosis:
G6PD deficiency
Hereditary spherocytosis
Gender
Male (X-linked recessive)
Male + female (autosomal dominant)
Ethnicity
African + Mediterranean descent
Northern European descent
Typical 
history
• Neonatal jaundice
• Infection/drugs precipitate 
haemolysis
• Gallstones
• Neonatal jaundice
• Chronic symptoms although haemolytic 
crises may be precipitated by infection
• Gallstones
• Splenomegaly is common
Blood film
Heinz bodies
Spherocytes (round, lack of central pallor)
Diagnostic 
test
Measure enzyme activity of G6PD
Osmotic fragility test

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

Other notes
•
G6PD deficiency confers partial protection against malaria
•
Hemolysis begins 24 to 72 hours after exposure to oxidant stress.
•
Hemolysis due to oxidant stresses are usually self-limiting within 8 to 14 days due to the 
compensatory production of young red blood cells with high levels of G6PD.
•
Young RBCs are not vulnerable to oxidative damage and hence limit the duration of 
hemolysis.
•
G6PD deficiency is an X-linked inherited disease that primarily affects men. 
•
Women may be affected if:

they are homozygous, which occurs in populations in which the frequency of G6PD 
deficiency is quite high.
Heterozygous women (carriers) can experience clinical disease as a result of:
1. X chromosome inactivation, 
2. gene mosaicism, or 
3. hemizygosity
•
Severe hemolysis due to G6PD deficiency may manifest as methemoglobinemia
____________________________________________________
_Paroxysmal nocturnal haemoglobinuria (PNH)
The triad of hemolytic anemia, pancytopenia, and thrombosis PNH 
•
(PNH) is an acquired disorder leading to haemolysis (mainly intravascular) of 
haematological cells. 
•
Caused by increased sensitivity of cell membranes to complement due to a lack of 
glycoprotein glycosyl-phosphatidyl-inositol (GPI). 
•
Patients are more prone to venous thrombosis
•
50% of PNH affected individuals are died due to thrombotic complications
Pathophysiology
•
GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
•
complement-regulating surface proteins, e.g. decay-accelerating factor CD 55 (DAF) and
Membrane Inhibitor of Reactive Lysis CD 59 (MIRL)., are not properly bound to the cell 
membrane due a lack of GPI
•
Hemolysis occurs when patients develop a mild acidosis at night, due to a relative 
hypoventilation, resulting in the passage of dark urine in the early morning.
•
thrombosis is thought to be caused by a lack of CD59 on platelet membranes
predisposing to platelet aggregation
•
Intrinsic hemolytic anemia with intravascular hemolysis
Features
•
symptoms of anemia (Pallor, fatigue, weakness)
•
Intermittent jaundice
•
haemoglobinuria
classically dark-coloured urine in the morning (although has been shown to occur 
throughout the day)
•
Abdominal pain 
may be due to small mesenteric vein thrombi.
Complications
•
thrombosis e.g. Budd-Chiari syndrome
•
Vasoconstriction: headache, pulmonary hypertension
•
aplastic anaemia may develop in some patients
•
↑ Risk of acute leukemias
Investigations
•
CBC
haemolytic anaemia
pancytopaenia 
•
Dipstick analysis of the urine:

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology

will be positive for 'blood', but the microscopy will show no red blood cells. 

This because there is intravascular haemolysis, with intravascular release of 
haemoglobin. This then passes through the renal tubules, ending up in the 
urine, and turning the dipstick analysis positive. However, because there are 
no actual red blood cells in the urine, the microscopy will be negative.
•
Flow cytometry (immunophenotyping) of blood 
absence of CD55 and CD59 on the surface of RBCs
now replaced Ham's test as the gold standard investigation in PNH
•
Ham's test: 
acid-induced haemolysis (normal red cells would not)
acidified serum (pH 6.2) is added to blood: PNH cells, but not normal cells, will be 
lysed.
•
Coombs test: negative
Management
•
blood product replacement
•
anticoagulation
•
eculizumab, a monoclonal antibody directed against terminal protein C5 (C5 
inhibitor), is reducing intravascular haemolysis
•
stem cell transplantation
The gold standard curative treatment
____________________________________________________
Splenectomy
•
Following a splenectomy patients are particularly at risk of infections from:
pneumococcus, 
Haemophilus, 
meningococcus and 
Capnocytophaga canimorsus*(*usually from dog bites) 
•
Vaccination
if elective, should be done 2 weeks prior to operation
Hib, meningitis A & C
annual influenza vaccination
pneumococcal vaccine every 5 years
•
Antibiotic prophylaxis
penicillin V: unfortunately clear guidelines do not exist of how long antibiotic 
prophylaxis should be continued. It is generally accepted though that penicillin 
should be continued for at least 2 years and at least until the patient is 16 years of 
age, although the majority of patients are usually put on antibiotic prophylaxis for life

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

Blood products
Whole blood fractions
Fraction
Key points
Packed red 
cells
•
Used for transfusion in chronic anaemia and cases where infusion of large 
volumes of fluid may result in cardiovascular compromise. 
•
Product obtained by centrifugation of whole blood.
•
In a stable patient, red cell packs may be transfused over 90-120 
minutes
Rapid infusion of red cells or fresh frozen plasma may be required 
in an acutely bleeding patient but not in patient who is stable.
Platelet rich 
plasma
•
Usually administered to patients who are thrombocytopaenic and are 
bleeding or require surgery. 
•
It is obtained by low speed centrifugation.
Platelet 
concentrate
•
Prepared by high speed centrifugation 
•
administered to patients with thrombocytopaenia.
•
the life span of transfused platelets is only 3-7 days.
•
platelet transfusion should not take more than 20-30 minutes.
•
Patients who are refractory to platelet transfusions: 
should be first investigated to check for adequate platelet 
rises. This is best done on a one or two-hour post platelet 
transfusion sample.
Further test would include checking for HLA antibodies
Fresh frozen 
plasma
•
Prepared from single units of blood.
•
Contains clotting factors, albumin and immunoglobulin.
•
Unit is usually 200 to 250ml.
•
Usually used in correcting clotting deficiencies in patients with hepatic 
synthetic failure who are due to undergo surgery.
•
Usual dose is 12-15ml/Kg-1.
•
It should not be used as first line therapy for hypovolaemia.
Cryoprecipitate
•
Formed from supernatant of FFP.
•
Rich source of Factor VIII and fibrinogen.
•
Allows large concentration of factor VIII to be administered in small 
volume.
SAG-Mannitol 
Blood
Removal of all plasma from a blood unit and substitution with:
•
Sodium chloride
•
Adenine
•
Anhydrous glucose
•
Mannitol
Up to 4 units of SAG M Blood may be administered. Thereafter whole blood is 
preferred. After 8 units, clotting factors and platelets should be considered.
Plasma derivatives 
•
plasma derivatives (such as factor VIII) are prepared from several thousand plasma 
donations, typically 20,000, or 5,000 kg of plasma at a time.
•
Pooled plasma has been sourced from outside the UK since 1999 to avoid vCJD risks.

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
 
The process involves several chemical steps including:

ethanol extraction, 

chromatography, and 

viral inactivation steps which results in a freeze-dried product.
•
These products have a long shelf life of several months to years.
Cell saver devices
These collect patients own blood lost during surgery and then re-infuse it. There are two main 
types:
•
Those which wash the blood cells prior to re-infusion. These are more expensive to 
purchase and more complicated to operate. However, they reduce the risk of re-infusing 
contaminated blood back into the patient.
•
Those which do not wash the blood prior to re-infusion.
Their main advantage is that they avoid the use of infusion of blood from donors into patients and 
this may reduce risk of blood borne infection. It may be acceptable to Jehovah's witnesses. It is 
contraindicated in malignant disease for risk of facilitating disease dissemination.
Blood products used in warfarin reversal
Immediate or urgent surgery in patients taking warfarin:
1. Stop warfarin
2. Vitamin K (reversal within 4-24 hours)

IV takes 4-6h to work (at least 5mg)

Oral can take 24 hours to be clinically effective
3. Fresh frozen plasma 

Used less commonly now as 1st line warfarin reversal

30ml/kg-1

Need to give at least 1L fluid in 70kg person (therefore not appropriate in fluid 
overload)

Need blood group

Only use if human prothrombin complex is not available
4. Human Prothrombin Complex (reversal within 1 hour)

Bereplex 50 u/kg

Rapid action but factor 6 short half life, therefore give with vitamin K
Neonatal exchange transfusion
•
An exchange transfusion requires blood which is plasma reduced whole blood in 
CPD (citrate phosphate dextrose/anticoagulant), irradiated and less than five days 
old.
•
The Rh group should either be Rh negative or identical to the neonate, to avoid haemolytic 
transfusion reaction in the neonate.
Blood Transfusion Thresholds
■ Sepsis: 7 g/dL
■ Upper or lower GI bleeds: 7 g/dL
■ Acute neurologic injury or TBI : 7 g/dL
■ Stable CV disease: 8 g/dL
■ ACS: 10 g/dL

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

____________________________________________________
Blood product transfusion complications
Complications
•
haemolytic: immediate or delayed
•
febrile reactions
•
transmission of viruses, bacteria, parasites, vCJD
•
hyperkalaemia
•
iron overload
•
ARDS
•
clotting abnormalities
Immediate haemolytic reaction
•
occur during the transfusion.
•
e.g. ABO mismatch
•
massive intravascular haemolysis
Delayed haemolytic transfusion reaction
•
occurs 24 hours after the transfusion.
•
This happens in a patient who has been previously immunised by transfusions or 
pregnancy. The antibodies are not detectable initially but become obvious as a secondary 
immune response to the antigen exposure during the transfusion occurs.
Febrile reactions
•
due to anti HLA antibodies in recipient serum or granulocyte specific antibodies (for 
example, sensitisation during previous pregnancy or previous blood transfusion). 
•
Febrile non-haemolytic reactions are very common and are due to the presence of 
pyrogenic cytokines released from leucocytes during storage of the blood units.
apart from a mild fever, the patient is very well.
rapid rise in temperature may be  due to ABO incompatibility, but With ABO 
incompatibility patients become shocked very quickly.
Rhesus D mismatch
•
It is very often necessary to give D positive platelets to D negative people due to platelet 
shortage.
•
If the recipient of this mismatch is a female of child bearing age, then prophylactic anti- D
should be administered with the platelets to prevent production of immune anti- D. 
•
If anti-D does not administered, the immune anti-D she has made can cross the placenta 
when she become pregnant in the future and cause haemolytic disease of the 
fetus/newborn, if the baby is D positive, and this can be life threatening to the baby.
Advise patient that this is only likely to be of consequence should she become 
pregnant in the future.
Causes a degree of immunosuppression
•
e.g. patients with colorectal cancer who have blood transfusions have a worse outcome 
than those who do not
The risk of viral transmission 
•
A broad knowledge of the risks may be required while consenting a patient for blood 
transfusion. 
•
in the United Kingdom, the risks;
For hepatitis B are 1 per 1.3 million donations
For HIV are 1 in 6.5 million and
For hepatitis C 1 in 28 million donations.
Transmission of vCJD
•
although the absolute risk is very small, vCJD may be transmitted via blood transfusion
•
a number of steps have been taken to minimise this risk, including:
•
→ from late 1999 onward, all donations have undergone removal of white cells 
(leucodepletion) in order to reduce any vCJD infectivity present

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
•
→from 1999, plasma derivatives have been fractionated from imported plasma rather than 
being sourced from UK donors. Fresh Frozen Plasma (FFP) used for children and certain 
groups of adults needing frequent transfusions is also imported
•
→ from 2004 onward, recipients of blood components have been excluded from donating 
blood
iron overload
•
secondary to chronic blood transfusion (eg : in myelodysplastic syndrome) 
•
early signs:
grey skin 
early hear failure 
diabetes 
•
treatment:
iron chelation with desferrioxamine subcutaneously 
bind iron 
needs to be given for 8 – 12 hours a day for 5 – 7 days per week 
common side effects of desferrioxamine: 
high frequency deafness
retinopathy 
Yersinia infection
irradiated blood products 
•
the advantage of irradiated red cells
Inactivates donor lymphocytes
•
Indications for irradiated blood products
Those at risk of transfusion associated with graft versus host disease such as 
neonates
Those receiving purine analogues-based chemotherapy 
Hodgkin's lymphoma 
Immunodeficiency states
Post bone marrow transplants 
Pre-operative request for the blood bank for elective surgeries
•
Group and save only
A 'group and save' is adequate for elective surgeries and is standard practice in most 
modern blood banks. This will involve blood grouping and its confirmation as well as 
an antibody screen.
Other options include cross match and a direct Coombs' test are not routinely done 
for elective surgery 
Transfusion errors
•
Mislabelling of samples, requests, or wrongly identifying recipients are the commonest 
transfusion errors.
January 2016 exam: What is the risk of variant Creutzfeldt-Jakob Disease (vCJD) 
transmission via blood transfusion?
Measures are taken to reduce the risk of vCJD transmission but there remains a 
very small risk of transmission

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

____________________________________________________
Transfusion Related Acute Lung Injury (TRALI)
Definition
•
(TRALI) is a rare but serious syndrome characterized by sudden acute respiratory distress 
within six hours after blood product administration
Risk factors
•
Caused by anti-HLA, Human Neutrophil Antigens (HNA) or anti-granulocytes antibody in 
donor blood.
•
Donor’s blood sensitization occurs in:
Multiparous ♀ develop these antibodies through exposure to fetal blood
Previous transfusion
Transplantation patient
•
When blood is obtained from above mentioned donors, it carries higher risk for recipient to 
develop TRALI; those who have lung pathology are more susceptible. TRALI symptoms 
resemble ARDS.
Pathophysiology
•
transfused human leukocyte or neutrophil antigen (HLA or HNA) antibodies activation of 
donor neutrophils Neutrophils adhere to pulmonary endothelium to increase permeability 
and cause pulmonary edema.
•
Patients with certain clinical conditions (eg, infection, inflammation, surgery) have primed 
neutrophils that are susceptible to activation by transfused bioactive substances.
•
TRALI has two proposed pathophysiologic mechanisms: 
1. the antibody hypothesis. (antigen-antibody interactions)
The human leukocyte antigen (HLA class I, HLA class II) or human neutrophil 
antigen (HNA) antibody in the transfused component reacts with neutrophil antigens 
in the recipient The recipient's neutrophils lodge in the pulmonary capillaries and 
release mediators that cause pulmonary capillary leakage. 
As a consequence, many patients with TRALI will develop transient leukopenia.
However, transfusions of blood components containing neutrophil antibodies may 
cause leukopenia, that do not meet the definition of TRALI. 
2. The neutrophil priming hypothesis:
does not require antigen-antibody interactions 
occurs in patients with clinical conditions that predispose to neutrophil priming and 
endothelial activation such as infection, surgery, or inflammation. 
Bioactive substances in the transfused component activate the primed, sequestered 
neutrophils, and pulmonary endothelial damage occurs.
•
Both mechanisms lead to pulmonary edema in the absence of circulatory overload.
Feature
•
Occurring within 1 to 6 hours of transfusion of plasma-containing blood components. 
•
Patients present with the rapid onset of dyspnea and tachypnea. 
•
There may be associated fever, cyanosis, and hypotension. 
•
Clinical examination reveals hypoxic respiratory distress, and pulmonary crackles may be 
present without signs of congestive heart failure or volume overload. 
•
Chest x-ray (CXR) shows evidence of bilateral pulmonary edema unassociated with heart 
failure (non-cardiogenic pulmonary edema), with bilateral patchy infiltrates, which may 
rapidly progress to complete "white out" indistinguishable from acute respiratory distress 
syndrome (ARDS). 
•
Physiologic findings include acute hypoxemia with PaO2/FiO2 less than 300 mmHg and 
normal cardiac function on echocardiogram.

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
Diagnosis: 
•
confirmed by finding of anti-HLA or anti-Neutrophil antibody in donors’ or recipient blood.
Treatment
•
Early and intensive pulmonary support reduces the risk of a fatal outcome.
•
Since the pulmonary edema in TRALI is not related to fluid overload or cardiac dysfunction, 
but to altered vascular permeability in the lungs with exudation of fluid and protein into the 
alveoli, it is logical that:

maintenance of adequate circulating volume is the most beneficial and appropriate 
therapy.

Corticosteroids, 
epinephrine 
and also ventilatory support are treatment options. 
How to distinguish TRALI and ARDS from Pulmonary oedema?
•
In the exam take into account the clinical findings and scenario to distinguish.
•
The hallmark of ARDS is refractory hypoxia with non-cardiogenic pulmonary edema
•
Normal pulmonary capillary wedge pressure is between 5 - 15 mmHg. A PCWP 
exceeding 15 mmHg suggests mitral stenosis, mitral insufficiency, severe aortic stenosis, 
aortic regurgitation, ventricular failure, or other cardiac defects or pathologies. 
•
When the PCWP exceeds 20 mmHg, the transmission of this pressure back into the 
pulmonary vasculature increases pulmonary capillary hydrostatic pressure which can lead 
to pulmonary oedema.
____________________________________________________
Graft versus host disease (GVHD) See transplant topic in renal system
____________________________________________________
Plasma exchange
Indications for plasma exchange (also known as plasmapheresis)
•
Guillain-Barre syndrome
•
myasthenia gravis
•
Goodpasture's syndrome
•
ANCA positive vasculitis e.g. Wegener's, Churg-Strauss
•
TTP/HUS
•
cryoglobulinaemia
•
hyperviscosity syndrome e.g. 
secondary to myeloma
____________________________________________________
Deep vein thrombosis (DVT)
DVT Risk Factors:
•
Hematological
Thrombophilia: e.g. Activated protein C resistance, protein C and S deficiency
Polycythemia
Paroxysmal nocturnal hemoglobinuria
Hyperviscosity syndrome
•
Autoimmune
Antiphospholipid syndrome
Behcet's

•
Drugs
Combined oral contraceptive pill: 3rd generation more than 2nd generation
Antipsychotics (especially olanzapine) have recently been shown to be a risk factor
•
Other conditions
Homocystinuria
Diagnosis
If a patient is suspected of having a DVT a two-level DVT Wells score should be performed:
Two-level DVT Wells score
Clinical feature
Points
Active cancer (treatment ongoing, within 6 months, or palliative)

Paralysis, paresis or recent plaster immobilisation of the lower 
extremities
Recently bedridden for 3 days or more or major surgery within 12 
weeks requiring general or regional anaesthesia
Localised tenderness along the distribution of the deep venous 
system
Entire leg swollen

Calf swelling at least 3 cm larger than asymptomatic side

Pitting oedema confined to the symptomatic leg

Collateral superficial veins (non-varicose)

Previously documented DVT

An alternative diagnosis is at least as likely as DVT
-2
Clinical probability simplified score
•
DVT likely: 2 points or more
•
DVT unlikely: 1 point or less
If a DVT is 'likely' (2 points or more)
•
a proximal leg vein ultrasound scan should be carried out within 4 hours and, if the result is 
negative, a D-dimer test
•
if a proximal leg vein ultrasound scan cannot be carried out within 4 hours a D-dimer test 
should be performed and low-molecular weight heparin administered whilst waiting for the 
proximal leg vein ultrasound scan (which should be performed within 24 hours)
If a DVT is 'unlikely' (1 point or less)
•
perform a D-dimer test and if it is positive arrange:
•
a proximal leg vein ultrasound scan within 4 hours
•
if a proximal leg vein ultrasound scan cannot be carried out within 4 hours low-molecular 
weight heparin should be administered whilst waiting for the proximal leg vein ultrasound 
scan (which should be performed within 24 hours)
Management
Low molecular weight heparin (LMWH) or fondaparinux should be given initially after a DVT is 
diagnosed.
•
a vitamin K antagonist (i.e. warfarin) should be given within 24 hours of the diagnosis
Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
•
the LMWH or fondaparinux should be continued for at least 5 days or until the international 
normalised ratio (INR) is 2.0 or above for at least 24 hours, whichever is longer, i.e. LMWH 
or fondaparinux is given at the same time as warfarin until the INR is in the therapeutic 
range
•
warfarin should be continued for at least 3 months. At 3 months, NICE advise that clinicians 
should 'assess the risks and benefits of extending treatment'
•
NICE add 'consider extending warfarin beyond 3 months for patients 
withunprovoked proximal DVT if their risk of VTE recurrence is high and there is no 
additional risk of major bleeding'. This essentially means that if there was no obvious cause 
or provoking factor (surgery, trauma, significant immobility) it may imply the patient has a 
tendency to thrombosis and should be given treatment longer than the norm of 3 months. In 
practice most clinicians give 6 months of warfarin for patients with an unprovoked DVT/PE
•
for patients with active cancer NICE recommend using LMWH for 6 months
•
for patients with active ulcerative colitis who developed DVT :
may require Emergency colectomy, as such warfarinisation would be inappropriate. 
should be heparinised as this would be easily reversible if it needs to be 
discontinued prior to surgery or if severe worsening of bleeding occurs.
Time of starting prophylaxis in elective knee replacement surgery:
•
LMWH or fondaparinux (s/c factor X inhibitor) should be started 6 – 12 hours after 
surgery
•
Dabigatran (oral factor X inhibitor) 1 – 4 hours after surgery 
Unprovoked VTE 
(Malignancy investigations and thrombophilia screening)
•
As both malignancy and thrombophilia are obvious risk factors for deep vein thrombosis 
NICE make recommendations on how to investigate patients with unprovoked clots.
Malignancy investigations
•
Offer all patients diagnosed with unprovoked DVT or PE who are not already known to have 
cancer the following investigations for cancer:
a physical examination (guided by the patient's full history) and
a chest X-ray and
blood tests (full blood count, serum calcium and liver function tests) and urinalysis.
•
Consider further investigations for cancer with an abdomino-pelvic CT scan (and a 
mammogram for women) in all patients aged over 40 years with a first unprovoked DVT or 
PE
Thrombophilia screening
•
not offered if patients will be on lifelong warfarin (i.e. won't alter management)
•
consider testing for antiphospholipid antibodies if unprovoked DVT or PE
•
consider testing for hereditary thrombophilia in patients who have had unprovoked DVT or 
PE and who have a first-degree relative who has had DVT or PE
The next most important investigation:
•
Unprovoked VTE chest X-ray, blood tests and urinalysis
•
Unprovoked VTE + family history of VTE Thrombophilia screening

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad

____________________________________________________
Pregnancy: DVT/PE
Coagulation elements in pregnancy:
•
Increased factors VII, VIII, IX, X, and XII ,fibrinogen, plasminogen, and D-dimer. 
•
Decreased factor XI and protein S. 
•
Not changed Factor II, protein C, and anti-thrombin III.
Overview
•
pregnancy is a hypercoagulable state
•
majority occur in last trimester
Pathophysiology
•
increase in factors VII, VIII, X and fibrinogen
•
decrease in protein S
•
uterus presses on IVC causing venous stasis in legs
Management
•
warfarin contraindicated
•
S/C low-molecular weight heparin preferred to IV heparin (less bleeding and 
thrombocytopenia)
____________________________________________________
Post-thrombotic syndrome
•
It is increasingly recognised that patients may develop complications following a DVT. 
•
Venous outflow obstruction and venous insufficiency result in chronic venous hypertension. 
•
The resulting clinical syndrome is known as post thrombotic syndrome. 
Features 
•
painful, heavy calves
•
pruritus
•
swelling
•
varicose veins
•
venous ulceration
Management
•
Compression stockings should be offered to all patients with deep vein thrombosis to 
help reduce the risk of post-thrombotic syndrome.
•
NICE state the following:
Offer below-knee graduated compression stockings with an ankle pressure greater 
than 23 mmHg to patients with proximal DVT a week after diagnosis or when 
swelling is reduced sufficiently and if there are no contraindications, and:

advise patients to continue wearing the stockings for at least 2 years

ensure that the stockings are replaced two or three times per year or 
according to the manufacturer's instructions

advise patients that the stockings need to be worn only on the affected leg or 
legs.
____________________________________________________
Venous thromboembolism: prophylaxis in patients admitted to
hospital
Venous thromboembolism (VTE) still accounts for a significant proportion of avoidable hospital 
deaths. In an effort to tackle this problem NICE produced guidelines in 2010.
Before admission
•
advise women to consider stopping oestrogen-containing oral contraception or HRT 4 
weeks before surgery.

Notes & Notes for MRCP                          
By Dr. Yousif Abdallah Hamad
Chapter 7

Haematology&Oncology
•
assess the risks and benefits of stopping antiplatelet therapy 1 week before surgery.
The following patients are deemed at risk of VTE
Medical patients
•
if mobility significantly reduced for >= 3 days or
•
if expected to have ongoing reduced mobility relative to normal state plus any VTE risk 
factor (see below)
Surgical patients and patients with trauma
•
if total anaesthetic + surgical time > 90 minutes or
•
if surgery involves pelvis or lower limb and total anaesthetic + surgical time > 60 minutes or
•
if acute surgical admission with inflammatory or intra-abdominal condition or
•
if expected to have significant reduction in mobility or
•
if any VTE risk factor present (see below)
VTE risk factors
•
active cancer or cancer treatment
•
age > 60 years
•
critical care admission
•
dehydration
•
known thrombophilias
•
obesity (BMI > 30 kg/m2)
•
one or more significant medical comorbidities (for example: heart disease; metabolic, 
endocrine or respiratory pathologies; acute infectious diseases; inflammatory conditions)
•
personal history or first-degree relative with a history of VTE
•
use of HRT
•
use of oestrogen-containing contraceptive therapy
•
varicose veins with phlebitis
In-patient VTE prophylaxis
As a general rule pharmacological VTE prophylaxis is used for medical patients unless there is a 
contraindication.
For surgical patients mechanical VTE prophylaxis is offered for patients at risk. Pharmacological 
VTE prophylaxis is also given for if the risk of major bleeding is low.
Pharmacological VTE prophylaxis options:
•
fondaparinux sodium
•
low molecular weight heparin (LMWH)
•
unfractionated heparin (UFH) (for patients with renal failure)
Mechanical VTE prophylaxis options:
•
anti-embolism stockings (thigh or knee length)
•
foot impulse devices
•
intermittent pneumatic compression devices (thigh or knee length)
Post-procedure VTE prophylaxis
For certain procedures pharmacological VTE prophylaxis is recommended for all patients, using 
one of the following:
•
dabigatran, started 14 hours after surgery
•
fondaparinux, started 6 hours after surgery
•
LMWH, started 6-12 hours after surgery
•
rivaroxaban, started 6-10 hours after surgery.
•
Apixaban
Procedure
Length of prophylaxis
Elective hip
28-35 days
Elective knee
10-14 days
Hip fracture
28-35 days