Biomedical Engineering Reference
In-Depth Information
a blood vessel, and it initiates the extrinsic coagulation cascade at the site of damage as described
below.
Factor VII contains a number of
-carboxyglutamate residues (as do factors II, IX and X),
which play an essential role in facilitating their binding of Ca
2
ions. The initial events initiat-
ing the extrinsic pathway entail the interaction of factor VII with Ca
2
and tissue factor. In this
associated form, factor VII becomes proteolytically active. It displays both binding affi nity for,
and catalytic activity against, factor X. It thus activates factor X by proteolytic processing, and
factor Xa, which initiates the terminal stages of clot formation, remains attached to the tissue fac-
tor-Ca
2
complex at the site of damage. This ensures that clot formation only occurs at the point
where it is needed (Figure 12.1).
The initial steps of the intrinsic pathway are somewhat more complicated. This system requires
the presence of clotting factors VIII, IX, XI and XII, all of which, except for factor VIII, are
endo-acting proteases. As in the case of the extrinsic pathway, the intrinsic pathway is triggered
upon exposure of the clotting factors to proteins present on the surface of body tissue exposed by
vascular injury. These protein binding/activation sites probably include collagen.
Additional protein constituents of the intrinsic cascade include prekallikrein, an 88 kDa protein
zymogen of the protease kallikrein, and high molecular mass kininogen, a 150 kDa plasma glyco-
protein that serves as an accessory factor.
The intrinsic pathway appears to be initiated when factor XII is activated by contact with sur-
face proteins exposed at the site of damage. High molecular mass kininogen also appears to form
part of this initial activating complex (Figure 12.2).
Factor XIIa can proteolytically cleave and, hence, activate two substrates:
γ
Figure 12.1
Schematic diagram of the initial steps of the extrinsic blood coagulation pathway. See text for
details (TF: tissue factor)
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