55
Since kallikrein, FXIIa, and FXIIf are all active serine prote-
ases themselves, they can also initiate activation of other
enzyme cascades, such as those of the classical comple-
ment pathway, the intrinsic plasma coagulation system,
and the fibrinolytic system. Thus, the activation of all of
these systems frequently occurs in concert and they are
all regulated by C1-INH. For example, kallikrein and FXIIa
(from the KKS) can activate C1r and C1s in the classical
complement system to form C1 esterase. This intercon-
nectivity of activation/inhibition in the enzyme cascades is
illustrated in Figure 28.
7.13 C1-INH Inhibits the Coagulation Cascade
During HAE attacks, the coagulation cascade is also
activated.
5,106
C1-INH is known to help regulate the
coagulation cascade through its inhibition of:
•
Factor XIa (FXIa) in the intrinsic coagulation
cascade
5-8,12,25,28,102
•
Thrombin.
5,102
C1-INH is an important inhibitor of FXIa, responsible for
nearly half of its plasma inhibition.
103,106
However, the role
of C1-INH in inhibiting thrombin
in vivo
is likely inconse-
quential.
5,103
Figure 28 also shows the interconnectivity between the
KKS and the coagulation cascade. By inhibiting FXIIa,
C1-INH blocks the activation of the coagulation cascade.
7.14 C1-INH Inhibits the Fibrinolytic System
The fibrinolytic system, like the coagulation system, is
activated during an HAE attack.
5,106
It is also known that
kallikrein, produced in the contact system, activates the
fibrinolytic system. In turn, the fibrinolytic system activates
the complement system.
These interactions are also illustrated in Figure 28.
In vitro
, C1-INH is an inhibitor of:
•
Plasmin
5-8,28,102,103
•
Tissue plasminogen activator.
5-7,102,103
Under normal circumstances, this inhibitory effect on
plasmin
in vivo
is inconsequential compared to that of
another serpin, alpha2-antiplasmin. However, under some
conditions, such as during attacks of angioedema, in
endotoxic shock, or during exhaustive exercise, the inhibi-
tory role of C1-INH seems to be more significant.
5,106
MOA
Figure 28 – Simplified Diagram of Inhibition of
the Interrelated Serine Protease Cascades of the
Complement, Kallikrein-Kinin, Coagulation,
and Fibrinolytic Systems
Complement
Coagulation
Kallikrein-kinin System
FXIIf
Prekallikrein
Kallikrein
Action site of C1-INH
FXIIa
FXII
Bradykinin
HMWK
C4
C2
C1
C1 esterase
FXI
scuPA
uPA
Plasmin Plasminogen
FXIa
Fibrinolysis
