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Cleavage of human high-molecular weight kininogen by purified kallikreins
and upon contact activation of plasma
S Reddigari and AP Kaplan
Department of Medicine, State University of New York, Stony Brook 11794.
To study the digestion pattern of human high-molecular weight (mol wt)
kininogen (HMWK) in plasma during contact activation we have prepared
monoclonal antibodies (MoAbs) to the light-chain (LC) and the heavy- chain
moiety of HMWK. One MoAb from each set was purified, and neither MoAb
inhibited the clotting activity of HMWK. In enzyme-linked immunosorbent
assay and immunoblotting experiments neither antibody bound to
kininogen-deficient plasma. Digestion of purified HMWK with plasma
kallikrein yielded, on reduced sodium dodecyl sulfate gels, two LC forms,
at 62 and 49 kd, respectively. Digestion of HMWK with tissue kallikrein
(TK) yielded mainly the 62-kd form. In immunoblot analyses of these
digests, the anti-LC MoAb detected products at 62 and 49 kd respectively.
With plasma kallikrein, the 62-kd species slowly shifted to 49 kd, and with
TK, the 62-kd species accumulated with time. Anti-LC MoAb was also used as
a probe in immunoblotting experiments to study the digestion pattern of
HMWK in whole plasma activated with kaolin or dextran sulfate. In activated
normal pooled plasma (NHP) and factor XI- deficient plasma, native HMWK
(mol wt, 115 kd) was cleaved within five to ten minutes, and two LC forms
at 62 and 49 kd were detected. In kaolin-activated prekallikrein
(PK)-deficient plasma, the disappearance of the 115-kd form was relatively
slow, and only the 62-kd form of LC was seen. HMWK was not cleaved when
factor XII-deficient plasma was incubated with kaolin. LC-dependent
coagulant activity paralleled the presence of LC bands seen in the
immunoblots, and lower-mol wt fragments of LC were not identified. These
data indicate that in activated NHP two forms of LC of HMWK (62 and 49 kd)
are formed sequentially. Further, the LC-dependent coagulant activity
remains detectable long enough to suggest that proteolytic inactivation of
LC is too slow to be an important control mechanism.
Volume 71,
Issue 5,
pp. 1334-1340,
05/01/1988
Copyright © 1988 by The American Society of Hematology
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