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0:00
My
name is Geoff Kemball-Cook
and I work in the hemostasis and
thrombosis group of the Clinical
Sciences Center in London.
My talk is on Factor
VIII and hemophilia A.
0:10
I'd like to touch
on three main areas.
First is to review the normal
coagulant function of factor VIII.
The second is to move on to describe
the molecular pathology that we
find in patients with
hemophilia A. And lastly,
to briefly mention a
rare bleeding disorder,
combined factor V-
factor VIII deficiency.
0:31
So a brief review of factor
VIII function in coagulation.
The cartoon in this slide shows
blood flowing from left to right
in the upper part within a vessel.
This is demarcated by the
endothelial cell layer, marked
as ECs in the slide, which
presents an anticoagulant surface
to flowing blood, including the
soluble coagulation factors shown.
For example, factor
VIII, VII, X, et cetera.
And the various blood cells,
which are also immersed in plasma.
Outside the endothelial cell
layer, in the vascular tissue,
are found cells
bearing tissue factor,
or TF, which is a potent
initiator of coagulation.
1:10
In the event to vascular damage,
blood flows out under pressure
through a breach in
the endothelial cell
layer and contacts the
extravascular tissues.
In particular, coagulation
factor VII forms a tight complex
with tissue factor,
and this constitutes
the initiates of coagulation.
1:29
What part does FVIII play in
amplifying this initial stimulus?
Well, tissue factor VIIa complex is
capable of producing small amounts
of factor Xa and factor IXa, which
are activated serine proteases,
from their zymogen forms.
However, the levels of factor
Xa produced by this direct route
are inadequate to produce the
amount of thrombin needed to produce
a solid clot from
fibrinogen. Hence, factor
VIII and the related
molecule, factor V,
are activated by trace
amounts of thrombin
to their active cofactor forms,
factor VIIIa and factor Va.
In the case of factor VIIIa,
this assembles with trace amounts
of factor IXa to
produce an extremely
potent complex for increasing the
rate of cleavage of factor X to Xa.
This enormously increased
amount of factor Xa
is then able to produce the
large amounts of thrombin which
are necessary to make a solid clot.
