54
7.12 C1-INH is the Primary Inhibitor of
the Kallikrein-Kinin System (KKS)
In addition to regulating vascular permeability and angio-
genesis, the KKS has counteradhesive, profibrinolytic,
inflammatory, and antithrombotic properties.
107
Acting as a serpin, C1-INH is the primary inhibitor of:
•
Factor XIIa in the KKS and intrinsic coagulation
cascade
5-8,12,25,28,102,103,108
•
Kallikrein in the KKS.
5-8,12,25,28,102-104
In the KKS, C1-INH is responsible for about 90% of the in-
hibition of both FXIIa (alpha-FXIIa) and FXIIf (beta-FXIIa),
and it accounts for 42% to 84% of the inhibition of active
plasma kallikrein.
106
The C1-INH molecule forms a 1:1 co-
valent bond as it inactivates the target protease.
Since the conversion of prekallikrein to kallikrein is
activated by FXIIa on the contact surface or by FXIIf
in plasma, the irreversible binding of C1-INH to FXIIa
results in decreased activation of kallikrein. Consequently,
since kallikrein is the enzyme that releases bradykinin from
high molecular weight kininogen (HMWK), C1-INH inhibi-
tion occurs early in the KKS, preventing the downstream
formation of bradykinin.
Without adequate C1-INH, uninhibited activation of the
KKS during an HAE attack produces excessive kinins,
especially bradykinin.
25
It was shown that, in patients with
HAE, the mean plasma bradykinin concentration is eleva-
ted during acute attacks and can be immediately lowered
by infusion of C1-INH concentrate (Figure 27).
109
Current
research suggests that bradykinin is a potent – although
not exclusive – end mediator of vascular permeability
during an HAE attack.
5,6,12,27
Among the most important
activities of the kinins are enhancing vascular permeability
and, in the GI tract, intensifying smoothmuscle contraction.
24
Reciprocal activation and interactions occur between
coagulation factor XII (FXII or Hageman factor) and pre-
kallikrein, which both gain protease activity when they
themselves are cleaved.
One theory is that prekallikrein is first activated to kallikrein
by intracellular proteases and that kallikrein then activates
FXII to FXIIa and subsequently to FXIIf. As a potentiating
mechanism, FXIIa and FXIIf then, in turn, cleave more pre-
kallikrein to generate kallikrein. Thus, a positive feedback
loop would be established if activation is not inhibited.
Another theory, which is not necessarily exclusive, is that
negatively charged surfaces lead to FXII activation (FXIIa)
and then FXIIa cleaves more FXII to FXIIa by autoactivation.
Only in the second step is prekallikrein then cleaved to
kallikrein.
106,107
No matter which of the mechanisms is
present or dominant in HAE, both lead, through kallikrein,
to the liberation of bradykinin from HMWK.
107
Plasma Bradykinin Concentration After Infusion of
C1-INH Concentrate During an Attack
0 1
12
Time After C1-INH Infusion (hours)
HAE
Attack
C1-INH Infusion (2,000 IU/10 min)
24
36
42
15
5
10
20
0
Plasma Bradykinin (fmol/mL)
Figure 27 – Decrease of Plasma Bradykinin Concen-
tration After Infusion of C1-INH Concentrate During
an HAE Attack
109
