436
Chapter 12
plasma protein,
protein C
(distinguish this from protein
kinase C, Chapter 5). The binding to thrombin activates
protein C, which, in combination with yet another plasma
protein, then inactivates factors VIIIa and Va. Thus, we saw
earlier that thrombin directly activates factors VIII and V, and
now we see that it indirectly inactivates them via protein C.
Table 12–14
summarizes the effects—both stimulatory and
inhibitory—of thrombin on the clotting pathways.
A third naturally occurring anticoagulant mechanism is
a plasma protein called
antithrombin III,
which inactivates
thrombin and several other clotting factors. To do so, circulat-
ing antithrombin III must itself be activated, and this occurs
when it binds to
heparin,
a substance present on the surface
of endothelial cells. Antithrombin III prevents the spread of
a clot by rapidly inactivating clotting factors that are carried
away from the immediate site of the clot by the fl owing blood.
The Fibrinolytic System
TFPI, protein C, and antithrombin III all function to
limit
clot formation. The system to be described now, however, dis-
solves a clot
after
it is formed.
A fi brin clot is not designed to last forever. It is a tempo-
rary fi x until permanent repair of the vessel occurs. The
bri-
nolytic
(or thrombolytic)
system
is the principal effector of
clot removal. The physiology of this system (
Figure 12–79
)
is analogous to that of the clotting system: It constitutes a
plasma proenzyme,
plasminogen,
which can be activated to
the active enzyme
plasmin
by protein
plasminogen activa-
tors.
Once formed, plasmin digests fi brin, thereby dissolving
the clot.
The fi brinolytic system is proving to be every bit as com-
plicated as the clotting system, with multiple types of plasmin-
ogen activators and pathways for generating them, as well as
several inhibitors of these plasminogen activators. In describ-
ing how this system can be set into motion, we restrict our
discussion to one example—the particular plasminogen acti-
vator known as
tissue plasminogen activator (t-PA),
which
is secreted by endothelial cells. During clotting, both plas-
minogen and t-PA bind to fi
brin and become incorporated
throughout the clot. The binding of t-PA to fi brin is crucial
because t-PA is a very weak enzyme in the absence of fi brin.
The presence of fi brin profoundly increases the ability of
t-PA to catalyze the generation of plasmin from plasminogen.
Thus, fi brin is an important initiator of the fi brinolytic process
that leads to its own dissolution.
The secretion of t-PA is the last of the various anticlot-
ting functions exerted by endothelial cells that we have men-
tioned in this chapter. They are summarized in
Table 12–15
.
Anticlotting Drugs
Various drugs are used clinically to prevent or reverse clotting,
and a brief description of their actions serves as a review of key
clotting mechanisms. One of the most common uses of these
drugs is in the prevention and treatment of myocardial infarc-
tion (heart attack), which, as described in Section E, is often
the result of damage to endothelial cells. Such damage not only
triggers clotting but interferes with the endothelial cells’ nor-
mal
anticlotting
functions. For example, atherosclerosis inter-
feres with the ability of endothelial cells to secrete nitric oxide.
Aspirin
inhibits the cyclooxygenase enzyme in the eico-
sanoid pathways that generate prostaglandins and thrombox-
anes (Chapter 5). Because thromboxane A
2
, produced by
the platelets, is important for platelet aggregation, aspirin
Activated
protein C
Factor VIIIa
Factor Va
Thrombin
Endothelial cell
Protein C
Thrombomodulin
Figure 12–78
Thrombin indirectly inactivates factors VIIIa and Va via protein C.
To activate protein C, thrombin must fi rst bind to a thrombin
receptor, thrombomodulin, on endothelial cells; this binding also
eliminates thrombin’s procoagulant effects. The
E
symbol indicates
inactivation of factors Va and VIIIa.
Table 12–14
Actions of Thrombin
Procoagulant
Cleaves fi brinogen to fi brin
Activates clotting factors XI, VIII, V, and XIII
Stimulates platelet activation
Anticoagulant
Activates protein C, which inactivates
clotting factors VIIIa and Va
Soluble fibrin fragments
Fibrin
Plasmin
Plasminogen
Plasminogen activators
Figure 12–79
Basic fi brinolytic system. There are many different plasminogen
activators and many different pathways for initiating their activity.
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