Hello, Welcome to this lecture on thrombosis and
antithrombotic therapy. We will see in this
lecture thrombosis is one of the most important
problems in medicine at the current time.
Some people carry an inherited predisposition
to venous thrombosis and environmental risk
factors include bed rest or surgery. Arterial
thrombosis is primarily the result
of atherosclerosis and heparin and warfarin
have been mainstays of anti-thrombotic therapy,
but a range of new oral agents are now available.
Let us introduce thrombosis. Thrombi are plugs
consisting primarily of platelets and fibrin
and, of course, the main clinical problem
that arises from this is ischemia, lack of
blood supply that happens beyond the clot.
Now thrombi may occur in either the arterial
or the venous circulation and an important
is thrombophilia that refers to the inherited
predisposition to thrombosis. On the right,
you will see a very large thrombus in the
Let us start by discussing arterial thrombosis. These
arise on areas of atherosclerosis particularly
when there is plaque rupture. When the plaques
formed enough respiratory break and platelet
adhere to that site. A platelet adhesion,
aggregation and release may actually serve
to promote the development of atherosclerotic
lesions and that might be one reason why aspirin
is so effective in reducing the risk of atherosclerotic
events. But as well as ischemia, thrombosis
may also lead to the release of emboli, the
flow to downstream vessels sometimes seen
from atherosclerotic plaques in the neck leading
to emboli into the brain.
Atherosclerosis is being one of the major problems
in human health over the last few decades and we know
a lots about the risk factors cholesterol,
hypertension and smoking. There is some good
news here because the incidence and also the
mortality from atherosclerotic disorders has
increased markedly in recent years as we served
to reduce those risk factors and control them.
Venous thrombosis has three classic risk factors
used to be known as Virchow's triad.
One is when the blood slows down. Secondly the blood
may be hypercoagulable sometimes see perhaps
in pregnancy after surgery or trauma and finally
when the vessel wall is damaged, which can
trigger adhesion of platelets to that damage
and you can see those three factors often
occur in patients in hospital beds after surgery.
Let us discuss inherited thrombophilia because
it has been shown that after 30 percent of
people who develop a venous thrombosis do
have a genetic predisposition of thrombosis.
Now to understand these disorders, we need
to discuss the natural physiological activity
of something called protein C. Look at that
diagram on the right. On the top left, we
can see thrombin. Thrombin is a key molecule
in the coagulation cascade and it activates
fibrinogen to release the fibrin, but as well
as promoting coagulation at also leads to
inactivation of coagulation factors through
a negative feedback pathway and the mechanism is
represented there. It happens by a fascinating
route. Thrombin binds together molecule on the
surface of the endothelium called thrombomodulin.
Once it is found, it can then activate protein
C, which can see in red. Now protein C needs
protein S as a cofactor, but those two together
can then inactivate the active forms of factor
V and factor VIII, which are critical cofactors
for coagulation. So you can see the C and
S very important in limiting the amount of active
coagulation factors . . . of thrombosis.
An important inherited thrombophilia is factor
V Leiden, which we can now start to understand.
This is an inherited allele in the factor
V genes very common in many populations after
3 percent of the population perhaps it has
been selected in evolution because it does
provide a little bit more protection against
bleeding problems. But this allele at factor
V makes factor V slightly more difficult to
cleave by the activated protein C.
Heterozygotes have a 5-8 fold risk of thrombophilia
from this disorder whereas homozygotes have a huge
30-140 fold risk of thrombosis if they have
a factor V Leiden from both the mother and
the father. Protein C or S can be also deficient.
These are rare disorders and usually seen
an autosomal recessive inheritance from the
mother or the father. Sometimes babies are
born with protein C or S deficiency from both
mother and the father. That is a very devastating
disorder, which leads to very severe thrombosis
in early life. Antithrombin can also deficient
and that is another thing, which can be checked
in tests of thrombophilia.
Now let us look at some of the risk factors
in life that can put a risk of developing
thrombus. This can be seen in a range of states.
Some are listed there on the left. Postoperatively
because of rest or increased coagulability
of the blood or indeed vessel damage, immobility.
Many malignant disorders trigger excess blood
coagulation. Oestrogen therapy and the use
of the contraceptive pill can increase the
risk of thrombosis. Ageing is a very important
risk factor and that is actually shown on
the right where you can see new episodes of
venous thromboembolism plotted in terms of
incidence on the Y-axis against age on the
X-axis and you can see that very steep increase
after the age of 60. Antiphospholipid syndrome
and myeloproliferative disorders also lead
to an increased risk of thrombophilia.
How do we make the diagnosis of a thrombosis?
Well, to investigate thrombophilia we can
look at the blood count to check the platelets,
we can do clotting tests and we can also do
genetic tests to look for the presence of
factor V abnormalities in protein C or protein
S. A deep vein thrombosis is usually diagnosed
by the clinical picture very commonly in the
lower leg. The calf may be swollen and warm
and may be tendouness but that is noy at a
very reliable picture and we will need other
tests before we could commit a patient to
anti thrombotic therapy. D-dimers or fragments
are released after blood clotting and they
are raised in patients with deep vein thrombosis
and imaging in the form of an ultrasound or
perhaps MRI scan is also needed.