patients with platelet functional abnormalities
that will be suppressed. Now let us look at
some of the clinical disorders that can lead
to bleeding problems and I want to start with
the vessel itself before we move on to consider
the platelet and then the coagulation factors.
Now let us look at the vessels vascular disorder.
Now sometimes these can be inherited probably
the most important one is represented with
the clinical picture on the left.
This is called hereditary hemorrhagic telangiectasia.
It has an autosomal dominant inheritance and
involves proteins which involved in collagen
formation and strength. Endoglin is one of
these molecules as often mutated and these
telangiectasia developed in the skin, the
mucous membranes you can see them on the tongue
and also in internal organs. It can be a challenging
condition to treat that we will use local
factors sometimes and . . . perhaps even the
hormonal treatment. There are several acquired
disorders that can affect ability of vessels
to stop blood clotting. Probably the most
common is aging as our skin gets older, it
gets thinner and you often see bruises in
older people. Steroids as well thin in the
skin and that is one reason you should not
keep putting high dose steroids onto areas
of skin. On the right is the hand of an elderly
person, you can see some of that bruising
on the skin, which become very thin. But two
other conditions on that slide which are themselves
have interest. One is a relatively rare condition,
but very interesting, HenochSchonlein purpura.
This is often see in young people after a
recent infection and it is a vasculitis mediated
through IgA and it leads to a purpura on the
extensor part of the limbs and on the buttocks
and finally the bottom a classic disease scurvy,
which I am sure you know used to . . . many
sailors who went around the world on long
trips and did not get sufficient vitamin C.
Vitamin C is quite important for maintaining
collagen in its most active form and so bleeding
was a major problem with scurvy. We rarely
see it now, but sometimes if people on a very
poor diet, you may see perifollicular hemorrhages
in vitamin C deficiency.
Now let us look at some platelet disorders
and we will stop the disorders where they
are low numbers of platelets so called thrombocytopenia
and as you will see on the left, this can
be due to increased destruction where the
bottom decreased production. Let us look at
some of the ways by which platelets can be
destroyed. The most common is the immune disorder,
immune mediated thrombocytopenia and here
the body produces IgG antibodies against the
platelets and that leads to their destruction.
Sometimes it is triggered by the recent infection
or sometimes it can occur out of the blue
and it can be seen in young people or older
people. They can be treated in a number of
ways. Some of them are represented on the
slide. Steroids we may remove the spleen perhaps
or we can use drugs, which stimulate thrombopoietin-receptor
activity. Other disorders, which reduced the
platelet count, severe infections, there is
a modest reduction in the platelet count during
pregnancy, which is not clinically important
and sometimes drugs can cause this effect.
The cause that I will put up there thrombotic
thrombocytopenic purpura, an important disorder
I want to discuss it on the next slide.
Platelets can also be reduced because of decreased production.
The bone marrow simply not making enough platelets
and we see that in patients who have bone
marrow failure due to aplastic anemia or chemotherapy.
If your platelet count is reduced, you tend
to get bruising or mucous membrane bleeds
and you will see on the right the patient
with quite severe bruising and purpura on
the skin due to thrombocytopenia. I will just
talk a little bit more about that disorder
that has a very long name thrombotic thrombocytopenic
purpura. The name is quite interesting in
itself because we are suggesting that it is
low platelets here. It is from the cytopenic
and you got purpura, bruising or thrombotic
as well. So we are getting blood clots.
So it is a paradox of clotting and bruising.
How can this happen? Fortunately, it is a
rare disorder, but it is fascinating pathophysiology.
In this disorder, patients have a deficiency
of the metalloprotease and enzyme. It is called
ADAMTS13 as you can see on the slide.
Sometimes it is congenital and we see this disorder
in children. But in adults, it is autoimmune
disorder and these patients have developed
an antibody against that protein. One of the
important functions of that protein is to
break down von Willebrand factor into smaller
components. It is VWF is made in very large
aggregates and it needs to be broken down.
If you are deficient in this enzyme, you have
very large circulating multimers as we call
them of VWF and they adhere the platelets
very strongly to your vessels. That is why
thrombocytopenic purpura because the platelets
stick to the vessel. Those platelets plugs
also damage red cells that are trying to get
through and as you will see on the right that
is a blood film NTTP and you will see all
those damaged and sheared red cells and that
produces them as you see hemolytic anemia
and this can reduce blood flow to organs like
the brain, the kidney and also cause of fever
producing that classic spectrum of symptoms
that I have put there. This can be a very
serious disorder if it is not recognised with
the high fatality rate and so it is important
if it is treated and the best way to treat
this with plasma exchange taking off the patient's
plasma and infusing it from a donor.
As well as the abnormalities in platelets number,
we can also get disorders of platelet function.
I have represented some here. They are all
rare inherited disorders that we see in children
and that is two of the classic types, Glanzmann's
disorder and Bernard Souller disease and you
can see that they are fat to the protein that
we have learned about in this lecture, IIb/IIa
and Ib and you now understand how that can
lead to bleeding disorders. But at the bottom
of course acquired disorders of platelet function,
which is the most common of the use of antiplatelet
drugs very widely used on millions of people
around the world, aspirin, clopidogrel and
so far. On the right, we have got a nice example
of platelet aggregometry, platelet testing.
Here we take blood platelets into a tube and
we put light through that tube and if you
put in various molecules such as ADP, collagen,
adrenaline as you can see at the top, agonist
that will cause the platelets to adhere and
aggregate and more light can go through the
system as you will see on the left, increasing
light transmission and in green, you will
see what happens when you add the agonist.
The platelets adhere more light can shine
through, but in the top in pink there are
platelets from somebody with Glanzmann's disease,
Glanzmann's thrombasthenia and you can see
there is no platelet addition or aggregation
at all. That is a commonly used test to assess
Now let us finish by talking about the coagulation
disorders and will stop with the inherited
types. Haemophilia A is the classic condition
in this area, huge deficiency of factor VIII.
It is X-linked and therefore only seen in
boys with a frequency you can see around 30-100
per million. Now the gene may run in families
passed on from the mother or it may result
from a new mutation. So it sometimes spontaneously
arises in the family. Now if this is untreated,
it is a very serious disease. Tends to stop
with bruising in babies, but throughout life
you can get serious bleeds particularly in
joints and muscles, very characteristic feature
of this disease. You will see on the right
what can happen to the joints after frequent
bleeds into them and it can lead to a lot
of disabling . . . Fortunately, factor VIII
concentrates are now available. They can prevent
this bleeding and also stop it once it is
started. What we have seen in the treatment
of haemophilia. It is a move away from waiting
until patients have a bleed and then treating
them to giving factor VIII prophylactically
stop the bleeding and that is because if you
look on the right on the top is a chart there
showing that the amount of factor VIII in
the blood determines the severity of the disease.
You can see values that suggest severe, moderate
or mild disease and with prophylactic therapy,
only a modest increase, in fact, can dramatically
reduce the number of bleeds of the patient
gets and so that is the approach that we need
to aspire to in the management of haemophilia.
The bottom is haemophilia B, a rarest of type
and that is due to deficiency factor IX.
Other inherited disorders of coagulation are von
Willebrand disease. This is due to a deficiency
or inactivity of that factor VWF that we have
mentioned so much during this talk and the
prevalence of this is actually not that low
1 in 10,000 individuals and I put at the top
right there reminder of the activity of the
VWF linking the platelet through GPIb to the
damaged cell on the collagen. VWF also carries
factor VIII. That is one of its important
functions. Now the bottom I have shown you
electrophoresis diagram, which represents
some of the subtypes of von Willebrand disease
and you can see that there are several from
type 1 whereas modest reduction of VWF to
type III where there is really none at all.
That is a very serious bleeding disorder.
We can treat this disorder by local factors,
drugs such as DDAVP, which release VWF and
sometimes we need VWF infusions, which we
can generate.Finally acquired disorders
of the coagulation
system and top here is disseminated intravascular
coagulation. You will see on the right gangrene
in the toes of this patient who has disseminated
intravascular coagulation. Now this is a paradoxical
disorder because in fact there is excessive
coagulation. What that does is it depletes
coagulation factors and leads the patient
very prone to bleeding and it usually triggered
by extreme events, severe infections perhaps
severe problems in childbirth and the classic
clinical feature of DIC is the patients bruise
and bleed spontaneously. There may have blood
taken a day or two ago and suddenly the venopuncture
site starts to ooze. The whole-blood system
fails to clot and that needs to be treated
by infusion of things like fresh frozen plasma
and platelets, perhaps fibrinogen through
. . . A second disorder vitamin K deficiency.
Sometimes it is seen in the newborn and those
with liver disease. Vitamin K is needed to
activate several clotting factors. Again that
is why warfarin works as an antithrombotic
agent by inhibiting vitamin K and finally
a rare disorder acquired haemophilia.
This is seen in adults and they have a clinical
picture that resembles inherited haemophilia.
This is developed not due to congenital deficiency,
but due to an autoimmune disease against the
factor VIII. They can be very challenging to treat.
So In summary, haemostasis depends on the
interaction of the blood vessel. the platelets
and the coagulation system. Vessels and platelet
disorders lead to bleeding into the skin and
mucous membranes. Immune thrombocytopenia
is the most common cause of thrombocytopenia.
Haemophilia is the most important inherited
coagulation disorder or can now be managed
by the use of prophylactic factor VIII. I
hope you have enjoyed this lecture on bleeding.