Haematology

Hodgkin's lymphoma is a malignant proliferation of lymphocytes characterised by the presence

of the Reed-Sternberg cell. It has a bimodal age distributions being most common in the third
and seventh decades
o 'B' symptoms also imply a poor prognosis
weight loss > 10% in last 6 months
fever > 38C
night sweats
o Other factors associated with a poor prognosis identified in a 1998 NEJM paper
included:
age > 45 years
stage IV disease
haemoglobin < 10.5 g/dl
lymphocyte count < 600/l or < 8%
male
albumin < 40 g/l
white blood count > 15,000/l
o *Reed-Sternberg cells with nuclei surrounded by a clear space

Burkitts Lymphoma
o Burkitt's lymphoma is a high-grade B-cell neoplasm. There are two major forms:
endemic (African) form: typically involves maxilla or mandible
sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form.
More common in patients with HIV
o Burkitt's lymphoma is associated with the c-myc gene translocation, usually t(8:14). The
Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of
Burkitt's lymphoma and to a lesser extent the sporadic form.
o Microscopy findings
'starry sky' appearance: lymphocyte sheets interspersed with macrophages
containing dead apoptotic tumour cells
 o Management is with chemotherapy. This tends to produce a rapid response which may
cause 'tumour lysis syndrome'. Rasburicase (a recombinant version of urate oxidase, an
enzyme which catalyses the conversion of uric acid to allantoin*) is often given before
the chemotherapy to reduce the risk of this occurring. Complications of tumour lysis
syndrome include:
hyperkalaemia
hyperphosphataemia
hypocalcaemia
hyperuricaemia
acute renal failure
o *allantoin is 5-10 times more soluble than uric acid, so renal excretion is more effective
RA
o A wide variety of extra-articular complications occur in patients with rheumatoid
arthritis (RA):
respiratory: pulmonary fibrosis, pleural effusion, pulmonary nodules,
bronchiolitis obliterans, methotrexate pneumonitis, pleurisy
ocular: keratoconjunctivitis sicca (most common), episcleritis, scleritis, corneal
ulceration, keratitis, steroid-induced cataracts, chloroquine retinopathy
osteoporosis
ischaemic heart disease: RA carries a similar risk to type 2 diabetes mellitus
increased risk of infections
depression
o Less common
Felty's syndrome (RA + splenomegaly + low white cell count)
Amyloidosis
Myeloma
o Multiple myeloma is a neoplasm of the bone marrow plasma cells. The peak incidence is
patients aged 60-70 years.
o Clinical features
bone disease: bone pain, osteoporosis + pathological fractures (typically
vertebral), osteolytic lesions
lethargy
infection
hypercalcaemia (see below)
renal failure
other features: amyloidosis e.g. Macroglossia, carpal tunnel syndrome;
neuropathy; hyperviscosity
o Investigations
monoclonal proteins (usually IgG or IgA) in the serum and urine (Bence Jones
proteins)
increased plasma cells in the bone marrow
bone lesions on the skeletal survey
o The diagnostic criteria for multiple myeloma requires one major and one minor criteria
or three minor criteria in an individual who has signs or symptoms of multiple myeloma.
 o Major criteria
Plasmacytoma (as demonstrated on evaluation of biopsy specimen)
A plasmacytoma is a discrete, solitary mass of neoplastic monoclonal
plasma cells in either bone or soft tissue (extramedullary)
30% plasma cells in a bone marrow sample
Elevated levels of M protein in the blood or urine
o Minor criteria
10% to 30% plasma cells in a bone marrow sample.
Minor elevations in the level of M protein in the blood or urine.
Osteolytic lesions (as demonstrated on imaging studies).
Low levels of antibodies (not produced by the cancer cells) in the blood.
o Hypercalcaemia in myeloma
primary factor: due primarily to increased osteoclastic bone
resorption caused by local cytokines (e.g. IL-1, tumour
necrosis factor) released by the myeloma cells
much less common contributing factors: impaired renal function, increased
renal tubular calcium reabsorption and elevated PTH-rP levels
Blood Films
o Hyposplenism e.g. post-splenectomy
target cells
Howell-Jolly bodies
Pappenheimer bodies
siderotic granules
acanthocytes
o Iron-deficiency anaemia
target cells
'pencil' poikilocytes
if combined with B12/folate deficiency a 'dimorphic' film occurs with mixed
microcytic and macrocytic cells
o Myelofibrosis
'tear-drop' poikilocytes
o Intravascular haemolysis
schistocytes
o Megaloblastic anaemia
hypersegmented neutrophils
Schistocyte Fragmented RBC
Von Willebrands Disease
o Von Willebrand's disease is the most common inherited bleeding disorder. The majority
of cases are inherited in an autosomal dominant fashion* and characteristically behaves
like a platelet disorder i.e. epistaxis and menorrhagia are common whilst
haemoarthroses and muscle haematomas are rare
o Role of von Willebrand factor
large glycoprotein which forms massive multimers up to 1,000,000 Da in size
promotes platelet adhesion to damaged endothelium
carrier molecule for factor VIII
 o Types
type 1: partial reduction in vWF (80% of patients)
type 2: abnormal form of vWF
type 3: total lack of vWF (autosomal recessive)
o Investigation
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
o Management
tranexamic acid for mild bleeding
desmopressin (DDAVP): raises levels of vWF by inducing release of vWF
from Weibel-Palade bodies in endothelial cells
factor VIII concentrate
o *type 3 von Willebrand's disease (most severe form) is inherited as an autosomal
recessive trait. Around 80% of patients have type 1 disease
Sickle-Cell Crises
o Four main types of crises are recognised:
thrombotic, 'painful crises'
sequestration
aplastic
haemolytic
o Thrombotic crises
also known as painful crises or vaso-occlusive crises
precipitated by infection, dehydration, deoxygenation
infarcts occur in various organs including the bones
(e.g. avascular necrosis of hip, hand-foot syndrome in
children, lungs, spleen and brain
o 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
o Aplastic crises
caused by infection with parvovirus
sudden fall in haemoglobin
 The aplastic crisis is temporary cessation of red
cell production. Because of the markedly
shortened red cell survival time in patients with
sickle cell disease, a precipitous drop in
hemoglobin occurs in the absence of adequate
reticulocytosis.
o Haemolytic crises
rare
fall in haemoglobin due an increased rate of
haemolysis
B cell chronic lymphocytic leukaemia (B-CLL) is the most common leukaemia in adults in the
Western world. It is characterised by peripheral blood lymphocytosis (many of which are
precursors, but not blasts), and an uncontrolled proliferation of small, mature lymphocytes in
the bone marrow, lymph nodes (resulting in lymphadenopathy) and spleen (resulting in
splenomegaly). Patients with CLL are often asymptomatic and when symptoms do develop they
tend to be non specific. Generalised lymphadenopathy, and hepatosplenomegaly are seen in 50-
60% of cases. Although lymphoma is a possibility, the question asks for the 'most likely' diagnosis
which would be CLL as it is more common in this age group. In reality further investigation would
be involved to confirm the diagnosis.

Chronic Lymphocytic Leukemia

o Chronic lymphocytic leukaemia (CLL) is caused by a monoclonal proliferation of well-
differentiated lymphocytes which are almost always B-cells (99%)
o Features
often none
constitutional: anorexia, weight loss
bleeding, infections
lymphadenopathy more marked than CML
o Complications
hypogammaglobulinaemia leading to recurrent infections
Autoimmune?
warm autoimmune haemolytic anaemia in 10-15% of patients
transformation to high-grade lymphoma (Richter's transformation)
o Investigations
blood film: smudge cells (also known as smear cells)
immunophenotyping
Heparin
o There are two main types of heparin - unfractionated, 'standard' heparin or low
molecular weight heparin (LMWH). Heparins generally act by activating antithrombin III.
Unfractionated heparin forms a complex which
inhibits thrombin, factors Xa, IXa, XIa and XIIa.
 LMWH however only increases the action of
antithrombin III on factor Xa
o Heparin-induced thrombocytopaenia (HIT)
Abnormally low thrombocytes (platelets)
immune mediated - antibodies form against complexes of
platelet factor 4 (PF4) and heparin
these antibodies bind to the PF4-heparin complexes on the platelet
surface and induce platelet activation by cross-linking FcIIA receptors
usually does not develop until after 5-10 days of treatment
despite being associated with low platelets HIT is actually a
prothrombotic condition
features include a greater than 50% reduction in platelets,
thrombosis and skin allergy
treatment options include alternative anticoagulants such as lepirudin
and danaparoid
o Both unfractionated and low-molecular weight heparin can cause hyperkalaemia.
This is thought to be caused by inhibition of aldosterone secretion.
o Heparin overdose may be reversed by protamine sulphate, although this only
partially reverses the effect of LMWH.
 Disseminated intravascular Coagulation
o Under homeostatic conditions, coagulation and fibrinolysis are coupled. The
activation of the coagulation cascade yields thrombin that converts fibrinogen
to fibrin; the stable fibrin clot being the final product of hemostasis. The
fibrinolytic system breaks down fibrinogen and fibrin. Activation of the
fibrinolytic system generates plasmin (in the presence of thrombin), which is
responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin
results in polypeptides (fibrin degradation products). In a state of homeostasis,
the presence of plasmin is critical, as it is the central proteolytic enzyme of
coagulation and is also necessary for fibrinolysis.
o In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the
result is widespread clotting with resultant bleeding. Regardless of the
triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all
conditions. One critical mediator of DIC is the release of a transmembrane
glycoprotein (tissue factor =TF). TF is present on the surface of many cell types
(including endothelial cells, macrophages, and monocytes) and is not normally in
contact with the general circulation, but is exposed to the circulation after
vascular damage. For example, TF is released in response to exposure to
cytokines (particularly interleukin 1), tumour necrosis factor, and endotoxin. This
plays a major role in the development of DIC in septic conditions. TF is also
abundant in tissues of the lungs, brain, and placenta. This helps to explain why
DIC readily develops in patients with extensive trauma. Upon activation, TF binds
with coagulation factors that then triggers the extrinsic pathway (via Factor VII)
which subsequently triggers the intrinsic pathway (XII to XI to IX) of coagulation.
o Diagnosis
Fibrin degradation products are often raised
 DVT
o NICE published guidelines in 2012 relating to the investigation and
management of deep vein thrombosis (DVT).
o If a patient is suspected of having a DVT a two-level DVT Wells score should be
performed:

Clinical probability simplified score

o DVT likely: 2 points or more
o DVT unlikely: 1 point or less
If a DVT is 'likely' (2 points or more)
o a proximal leg vein ultrasound scan should be carried out within 4 hours and,
if the result is negative, a D-dimer test
o 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)
o perform a D-dimer test and if it is positive arrange:
o a proximal leg vein ultrasound scan within 4 hours
o 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)

Venous thromoboembolism - length of warfarin treatment

o provoked (e.g. recent surgery): 3 months
o unprovoked: 6 months
ITP
o Idiopathic Thrombocytopenic Purpura (ITP)
o Idiopathic thrombocytopenic purpura (ITP) is an immune mediated reduction in
the platelet count. Antibodies are directed against the glycoprotein IIb/IIIa or Ib-
V-IX complex.
o ITP can be divided into acute and chronic forms:
Acute ITP
more commonly seen in children
equal sex incidence
may follow an infection or vaccination
usually runs a self-limiting course over 1-2 weeks
Chronic ITP
more common in young/middle-aged women
tends to run a relapsing-remitting course
Evan's syndrome
 ITP in association with autoimmune haemolytic anaemia (AIHA)
o The isolated thrombocytopenia in a well patient points to a diagnosis of ITP.
The combined oral contraceptive pill does not commonly cause blood dyscrasias
In order of Frequency (Histological Classification of Hodgkins Lymphoma)
o Nodular sclerosing (~70%)
o Mixed cellularity (~20%)
o Lymphocyte predominant (~5%)
o Lymphocyte depleted (rare)
Hodgkins Symptoms / signs
o 'B' symptoms also imply a poor prognosis
weight loss > 10% in last 6 months
fever > 38C
night sweats
o Other factors associated with a poor prognosis identified in a 1998
NEJM paper included:
age > 45 years
stage IV disease
haemoglobin < 10.5 g/dl
lymphocyte count < 600/l or < 8%
male
albumin < 40 g/l
white blood count > 15,000/l
Chronic Myeloid Leukemia
o The Philadelphia chromosome is present in more than 95% of patients with chronic
myeloid leukaemia (CML). It is due to a translocation between the long arm of
chromosome 9 and 22 - t(9:22)(q34; q11). This results in part of the ABL proto-oncogene
from chromosome 9 being fused with the BCR gene from chromosome 22. The resulting
BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of
normal
o Presentation (40-50 years)
middle-age
anaemia, weight loss, abdo discomfort
splenomegaly may be marked
spectrum of myeloid cells seen in peripheral blood
decreased leukocyte alkaline phosphatase
may undergo blast transformation (AML in 80%, ALL in 20%)
o Management
imatinib is now considered first-line treatment
hydroxyurea
interferon-alpha
allogenic bone marrow transplant
o Imatinib
 inhibitor of the tyrosine kinase associated with the BCR-ABL defect
very high response rate in chronic phase CML

Chronic Lymphocytic Leukemia

o Chronic lymphocytic leukaemia (CLL) is caused by a monoclonal proliferation of well-
differentiated lymphocytes which are almost always B-cells (99%)
o Features
often none
constitutional: anorexia, weight loss
bleeding, infections
lymphadenopathy more marked than CML
o Complications
hypogammaglobulinaemia leading to recurrent infections
warm autoimmune haemolytic anaemia in 10-15% of patients
transformation to high-grade lymphoma (Richter's transformation)
o Investigations
blood film: smudge cells (also known as smear cells)
immunophenotyping
Antibody Mediated Hemolysis. In autoimmune hemolytic anemia (AIHA)
RBCs are destroyed by antibodies made by a person against their own
RBCs. AIHA is divided into two types: an IgG or "warm" type (optimally
active at 37oC) and an IgM or "cold" type (optimally active at 4oC).
Factor V Leiden
o Factor V Leiden (activated protein C resistance) is the most common inherited
thrombophilia, being present in around 5% of the UK population. It is due to a mutation
in the Factor V Leiden mutation. Heterozygotes have a 4-5 fold risk of venous
thrombosis.
o Protein C deficiency is a disorder that increases the risk of developing abnormal blood
clots; the condition can be mild or severe. Individuals with mild protein C deficiency
are at risk of a type of blood clot known as a deep vein thrombosis (DVT).
 It is important to remember that most abnormal blood results are reactive. It is first essential to
differentiate between a true and relative polycythaemia. A true polycythaemia can be primary
(e.g. myeloproliferative disorder) or secondary (reactive). Dehydration and diuretics can cause a
relative polycythaemia (pseudopolcythaemia) where there is relatively low plasma volume to
red cell mass ratio. Red cell mass and plasma volume studies are helpful to demonstrate a
relative polycythaemia.
The patient in this example has risk factors for secondary polycythaemia including COPD and
smoking. Impaired oxygen exchange in the lungs can result in a low PaO2 which results in
stimulation of EPO release from the kidneys. EPO stimulates erythropoiesis and increases red
cell mass, thereby resulting in polycythaemia. The low SpO2 is highly suggestive of a hypoxic
driven polycythaemia. Therefore the most likely answer is COPD.
Polycythaemia
o Polycythaemia may be relative, primary (polycythaemia rubra vera) or secondary
o Relative causes
dehydration
stress: Gaisbock syndrome
Gaisbock syndrome is characterised by secondary polycythemia. It
occurs mainly in male sedentary individuals, on a high-calorie diet.
Prevalence is unknown. The clinical picture includes mild obesity,
hypertension and decrease in plasma volume with relative increase in
hematocrit, blood viscosity, serum cholesterol, triglycerides and uric
acid. The reduction in plasma volume seems related to the elevation of
the diastolic blood pressure. Prognosis is impaired by the development
of cardiovascular complications.
o Primary
polycythaemia rubra vera
o Secondary causes
COPD
altitude
obstructive sleep apnoea
excessive erythropoietin: cerebellar haemangioma, hypernephroma, hepatoma,
uterine fibroids*
o To differentiate between true (primary or secondary) polycythaemia and relative
polycythaemia red cell mass studies are sometimes used. In true polycythaemia the total
red cell mass in males > 35 ml/kg and in women > 32 ml/kg
o *uterine fibroids may cause menorrhagia which in turn leads to blood loss -
polycythaemia is rarely a clinical problem
o Polycythaemia vera (PV) is a myeloproliferative disorder, which means the bone marrow
makes too many blood cells.
This patient has a macrocytic anaemia. Hypersegmented neutrophils on the blood film indicate a
megaloblastic anaemia. The haematinics blood test detects levels of serum B12 and folate - a
deficiency of which produces megaloblastic anaemia, therefore this is the best test to confirm
the findings on the blood film.
A 15-year-old girl presents with abdominal pain. She is normally fit and well and currently takes
a combined oral contraceptive pill. The patient is accompanied by her mother, who is known to
have hereditary spherocytosis. The pain is located in the upper abdomen and is episodic in
 nature, but has become severe today. There has been no change to her bowel habit and no
nausea or vomiting. What is the most likely diagnosis?
o This patient has hereditary spherocytosis resulting in chronic haemolysis and gallstone
formation. An important differential in a poorly patient with hereditary spherocytosis
would be splenic rupture
o Basics
most common hereditary haemolytic anaemia in people of northern European
descent
autosomal dominant defect of red blood cell cytoskeleton
the normal biconcave disc shape is replaced by a sphere-shaped red blood cell
red blood cell survival reduced as destroyed by the spleen
o Presentation
failure to thrive
jaundice, gallstones
splenomegaly
aplastic crisis precipitated by parvovirus infection
degree of haemolysis variable
MCHC elevated
Which one of the following types of Hodgkin's lymphoma carries the worst prognosis?
o Lymphocyte depleted
Warfarin
o Indications
venous thromboembolism: target INR = 2.5, if recurrent 3.5
atrial fibrillation, target INR = 2.5
mechanical heart valves, target INR depends on the valve type and location.
Mitral valves generally require a higher INR than aortic valves.
A microcytic anaemia in a female should raise the possibility of either gastrointestinal blood loss
or menorrhagia. However, there is no history to suggest this and the microcytosis is
disproportionately low for the haemoglobin level. This combined with a raised HbA2 points to a
diagnosis of beta-thalassaemia trait
o MICROCYTIC ANAEMIA
A single sudden loss of blood produces a posthemorrhagic anemia that is
normocytic. The bone marrow is stimulated to increase production of
hemoglobin, thereby depleting iron in body stores. Once they are depleted,
hemoglobin synthesis is impaired and microcytic hypochromic erythrocytes are
produced.
The thalassaemias are a group of genetic disorders characterised by a reduced production rate
of either alpha or beta chains. Beta-thalassaemia trait is an autosomal recessive condition
characterised by a mild hypochromic, microcytic anaemia. It is usually asymptomatic
o Features
mild hypochromic, microcytic anaemia - microcytosis is characteristically
disproportionate to the anaemia
HbA2 raised (> 3.5%)

Genital warts - 90% are caused by HPV 6 & 11

It is important to remember that strokes can be caused
by hypercoagulable states and hyperviscosity.
 The blood results demonstrate polycythaemia, which is a hyperviscous state. It is
important to remember that most abnormal blood results are reactive. It is first
essential to differentiate between a true and relative polycythaemia. A true
polycythaemia can be primary (e.g. myeloproliferative disorder) or secondary (reactive).
Dehydration and diuretics can cause a relative polycythaemia (pseudopolycythaemia)
where there is relatively low plasma volume to red cell mass ratio. Red cell mass and
plasma volume studies are helpful to demonstrate a relative polycythaemia.
The patient in this example has a normal SpO2 and EPO which suggest that the
polycythaemia is not secondary in nature. Therefore the most likely explanation is is
polycythaemia vera.
Novel Oral Anticoagulants (NOACs)
o An anticoagulant medicine makes the blood take longer to clot. It plays a vital
part in helping to prevent strokes specifically caused by atrial fibrillation (AF),
which is the most common abnormal heart rhythm in the UK.
o AF increases the risk of stroke as it can lead to blood pooling in the heart, which
increases the risk of clots forming. If these clots are ejected by the heart, they
can block a blood vessel in the brain and cause a stroke.
o Warfarin is the most commonly prescribed anticoagulant and, when used
appropriately, its an effective way of significantly reducing the risk of AF-related
strokes. But it requires frequent blood tests and careful monitoring.
o What are NOACs and who are they recommended for?
The novel oral anticoagulants (NOACs) are a new class of anticoagulant
drug. They
can be used in the prevention of stroke for
people with non-valvular AF, which is when AF is not
associated with a problem in a heart valve. They can also
be used in the management of venous thromboembolism, which is when
a blood clot forms in a vein. Non-valvular AF is the type of AF that most
people in the UK have and, like warfarin, NOACs can help to prevent clots
from forming in the first place and help protect you from certain types of
stroke.
o Novel oral anticoagulants (NOACs) are relatively new medications that offer
many of these potential benefits. The 2 classes of NOACs are direct thrombin
inhibitors and direct factor Xa inhibitors. Dabigatran (Pradaxa) is currently the
only direct thrombin inhibitor and was the first NOAC approved in 2010.
 Haemophilia is a X-linked recessive disorder of coagulation. Up to 30% of patients have
no family history of the condition
o Haemophilia, also spelled hemophilia, is a mostly inherited genetic disorder that
impairs the body's ability to make blood clots, a process needed to stop bleeding
o Haemophilia A is due to a deficiency of factor VIII
o Haemophilia B (Christmas disease) there is a lack of factor IX
Both are essential coagulation proteins
o
o Features
haemoarthroses, haematomas
prolonged bleeding after surgery or trauma
o Blood tests
prolonged APTT
bleeding time, thrombin time, prothrombin time normal
o Up to 10-15% of patients with haemophilia A develop antibodies to factor VIII
treatment
DVT
o 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
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 with
unprovoked 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
o As both malignancy and thrombophilia (APS) are obvious
risk factors for deep vein thrombosis NICE make
recommendations on how to investigate patients with
unprovoked clots.
o 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.
o 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
o 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
In patients with liver cirrhosis, most coagulation factors
and inhibitors of the coagulation and fibrinolytic systems
 are markedly reduced because of impaired protein
synthesis, except for factor VIII and fibrinogen levels,
which may be nor- mal or increased.
Blood Product Transfusion Complications
o Complications
haemolytic: immediate or delayed
febrile reactions
transmission of viruses, bacteria, parasites, vCJD
hyperkalaemia
iron overload
ARDS (Acute Respiratory Distress
clotting abnormalities
o Immediate haemolytic reaction
e.g. ABO mismatch
massive intravascular haemolysis
o Febrile reactions
due to white blood cell HLA antibodies
often the result of sensitization by previous pregnancies or transfusions
o Causes a degree of immunosuppression
e.g. patients with colorectal cancer who have blood transfusions have a
worse outcome than those who do not
Severe sepsis
o sepsis with end organ dysfunction or hypoperfusion (indicated by hypotension,
lactic acidosis or decreased urine output or others)
Septic shock
o severe sepsis with persistently low blood pressure which has failed to respond to
the administration of intravenous fluids.
Waldenstrom's macroglobulinaemia
o Waldenstrom's macroglobulinaemia is an uncommon condition seen in older
men. It is a lymphoplasmacytoid malignancy characterised by the secretion of a
monoclonal IgM paraprotein
o Features
monoclonal IgM paraproteinaemia
systemic upset: weight loss, lethargy
hyperviscosity syndrome e.g. visual disturbance
The symptoms of a raised blood viscosity result from sluggish flow
of blood through the blood vessels.
When occurring in the cerebral system, this may result in fuzzy-
headedness, headaches, blurred vision,
 double vision, poor concentration and thinking, and, in severe
cases, even reduced levels of consciousness.
The risk of stroke is also higher under these circumstances.
hepatosplenomegaly
lymphadenopathy
cryoglobulinaemia e.g. Raynaud's
cryoglobulins proteins (mostly immunoglobulins themselves)
that become insoluble at reduced temperature
Symptoms of high blood viscosity include spontaneous bleeding from mucous
membranes, visual disturbances due to retinopathy, and neurologic symptoms ranging
from headache and vertigo to seizures and coma.
Tear-drop poikilocytes = myelofibrosis
o Myelofibrosis (MF) is a rare condition affecting the bone marrow. Bone marrow
is where our blood cells are made. In MF, scar tissue builds up inside the bone
marrow and blood cells aren't made properly. Other parts of the body, usually
the spleen and liver, begin to make blood cells
Nodular Sclerosing Hodgkins Lymphoma
o Night sweats are a 'B' symptom and imply a poor prognosis
Burkitts Lymphoma
o Burkitt's lymphoma is a high-grade B-cell neoplasm. There are two major forms:
endemic (African) form: typically involves maxilla or mandible
sporadic form: abdominal (e.g. ileo-caecal) tumours are the most
common form. More common in patients with HIV
o Burkitt's lymphoma is associated with the c-myc gene translocation, usually
t(8:14). The Epstein-Barr virus (EBV) is strongly implicated in the development of
the African form of Burkitt's lymphoma and to a lesser extent the sporadic form.
o Microscopy findings
'starry sky' appearance: lymphocyte sheets interspersed with
macrophages containing dead apoptotic tumour cells
o Management is with chemotherapy. This tends to produce a rapid response
which may cause 'tumour lysis syndrome'. Rasburicase (a recombinant version of
urate oxidase, an enzyme which catalyses the conversion of uric acid to
allantoin*) is often given before the chemotherapy to reduce the risk of this
occurring. Complications of tumour lysis syndrome include:
hyperkalaemia
hyperphosphataemia
hyperuricaemia
hypocalcaemia
acute renal failure
o *allantoin is 5-10 times more soluble than uric acid, so renal excretion is more
effective
Factor V Leiden is the most common inherited thrombophilia
 Thrombophilia
o Inherited
Gain of function polymorphisms
factor V Leiden (activated protein C resistance): most common
cause of thrombophilia
prothrombin gene mutation: second most common cause
Deficiencies of naturally occurring anticoagulants
antithrombin III deficiency
protein C deficiency
protein S deficiency
o Acquired
APS
It's thought that one or more environmental triggers may be
needed to trigger APS in some people.
Environmental factors that may be responsible include:
o viral infections, such as the cytomegalovirus (CMV) or
parvovirus B19
o bacterial infections, such as E. coli (a bacteria often
associated with food poisoning) or leptospirosis (an
infection usually spread by certain animals)
o certain medications, such as anti-epileptic medicine or the
oral contraceptive pill
Another theory is that many people with abnormal
antiphospholipid antibodies only go on to develop APS if they
have a higher risk of developing blood clots. For example, if they:
o eat an unhealthy diet, leading to high cholesterol levels in
the blood
o don't do enough exercise
o take the contraceptive pill or hormone replacement
therapy (HRT)
o smoke
o are obese
Drugs COC pill
Activated protein C resistance is due a point mutation in the Factor V gene, encoding for
the Leiden allele. Heterozygotes have a 5-fold risk of venous thrombosis whilst
homozygotes have a 50-fold increased risk
Von Willebrand's disease is the most common inherited bleeding disorder
Polycythaemia vera is a neoplasm of the bone marrow which results in the production
of excessive red blood cells. The classic symptom of this condition is intense itching
which usually occurs after exposure to hot water or hot and humid weather. Is is believe
that this due to abnormal histamine or prostaglandin production.
Due to the excess of red cells, patients who suffer from polycythaemia vera are
predisposed to blood clots which could explain the deep vein thrombosis this patient
 had. Also in polycythaemia vera, roughly 20% of patients will also suffer from gouty
arthritis.
Sewage workers are at risk of leptospirosis which is transmitted through rat urine. It
typically presents as above and can progress to renal failure. Cysticercosis would not
cause jaundice or renal failure. Glomerulonephritis should not cause jaundice or
subconjunctival haemorrhage and acute viral hepatitis would not normally cause renal
failure and would be unlikely without any travel history.
Antiphospholipid syndrome leads to a raised APTT and normal PT and can result in
thrombocytopenia. AITP would cause solely low platelets whilst vWD and haemophilia
A would only affect the APTT. Unfractionated heparin could lead to prolonged APTT
however low platelets would only potentially occur as a long term side effect and is an
unlikely cause of her recurrent miscarriages.
Hereditary Spherocytosis
o The disorder is caused by mutations in genes relating to membrane proteins that
allow for the erythrocytes to change shape. The abnormal erythrocytes are
sphere-shaped (spherocytosis) rather than the normal biconcave disk shaped.
Dysfunctional membrane proteins interfere with the cell's ability to be flexible to
travel from the arteries to the smaller capillaries. This difference in shape also
makes the red blood cells more prone to rupture.[1] Cells with these
dysfunctional proteins are taken for degradation at the spleen. This shortage of
erythrocytes results in hemolytic anemia.
o Basics
most common hereditary haemolytic anaemia in people of northern
European descent
autosomal dominant defect of red blood cell cytoskeleton
the normal biconcave disc shape is replaced by a sphere-shaped red
blood cell
red blood cell survival reduced as destroyed by the spleen
o Presentation
failure to thrive
jaundice, gallstones
splenomegaly
aplastic crisis precipitated by parvovirus infection
degree of haemolysis variable
MCHC elevated
o Diagnosis
osmotic fragility test
The osmotic fragility test (OFT) is used to measure erythrocyte
resistance to hemolysis while being exposed to varying levels of
dilution of a saline solution. When erythrocytes are exposed to a
hypotonic environment, water enters the cell and causes swelling
and eventual lysis.
o Management
folate replacement
 splenectomy
A raised ESR and osteoporosis represents multiple myeloma
unless proven otherwise. The addition of anaemia and renal
impairment would also lean towards myeloma. Monoclonal gammopathy in a
benign condition which would not cause bone lesions. Breast cancer is a common
cause of bone metastasis and if she had been previously given hormone treatment
for this condition this may have led to osteoporosis, but as she has no history of the
condition an acute presentation of myeloma is more likely. Lymphoma can cause
pathological fractures but the combination of a raised ESR, a possible fracture
and renal impairment would lean towards myeloma as the most likely
diagnosis.
Myeloma Features
bone disease: bone pain, osteoporosis + pathological fractures (typically
vertebral), osteolytic lesions
lethargy
infection
hypercalcaemia (see below)
renal failure
other features: amyloidosis e.g. Macroglossia, carpal tunnel syndrome;
neuropathy; hyperviscosity
o Investigations
monoclonal proteins (usually IgG or IgA) in the serum and
urine (Bence Jones proteins)
A Bence Jones protein is a monoclonal globulin protein or
immunoglobulin light chain found in the urine, with a molecular
weight of 22-24 kDa. Detection of Bence Jones protein may be
suggestive of multiple myeloma or Waldenstrm's
macroglobulinemia.
increased plasma cells in the bone marrow
bone lesions on the skeletal survey
o Major criteria
Plasmacytoma (as demonstrated on evaluation of biopsy specimen)
A plasmacytoma is a discrete, solitary mass of neoplastic
monoclonal plasma cells in either bone or soft tissue
(extramedullary).
30% plasma cells in a bone marrow sample
Elevated levels of M protein in the blood or urine
A myeloma protein is an abnormal immunoglobulin fragment or
immunoglobulin light chain that is produced in excess by an
abnormal monoclonal proliferation of plasma cells, typically in
 multiple myeloma. Other terms for such a protein are M protein,
M component, spike protein, or paraprotein.

o Minor criteria
10% to 30% plasma cells in a bone marrow sample.
Minor elevations in the level of M protein in the blood or urine.
Osteolytic lesions (as demonstrated on imaging studies).
Low levels of antibodies (not produced by the cancer cells) in the blood.
It is important in a patient who is also deficient in both vitamin B12 and folic acid to
treat the B12 deficiency first to avoid precipitating subacute combined degeneration of
the cord. Consideration in this case should also be given to secondary care referral to
identify the underlying cause

Myelodysplastic syndromes are a group of cancers in which immature blood cells in the bone
marrow do not mature or become healthy blood cells.
A 48-year-old male is seen on the post take ward round on the acute assessment unit. He has
been found to have a confirmed unprovoked left thigh deep vein thrombosis. He has no prior
personal or family history of venous thromboembolisms (VTE). What are the most appropriate
investigations, if any, to organise?
o Routine bloods (including FBC, Calcium, LFT), Antiphospholipid
antibodies, urinalysis, chest x-ray, CT abdomen / pelvis
o NICE guidelines recommend that all patients with an unprovoked DVT should be
investigated for cancer. As well as a physical examination, this includes routine bloods
(including FBC, Calcium, LFT), Antiphospholipid antibiodies, urinalysis and a chest x-ray.
For those over 40, a CT of the abdomen and pelvis is also recommended. A hereditary
thrombophilia screen is only necessary if there is a significant family history of venous
thromboembolisms.