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(Received for publication, July 6,
1995) Inactivation of membrane-bound factor Va by activated protein C
(APC) proceeds via a biphasic reaction that consists of a rapid and a
slow phase, which are associated with cleavages at Arg
Volume 270,
Number 46,
Issue of November 17, 1995 pp. 27852-27858
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
by Activated Protein C
and Arg
of the heavy chain of factor Va,
respectively. We have investigated the effects of protein S and factor
Xa on APC-catalyzed factor Va inactivation. Protein S accelerates
factor Va inactivation by selectively promoting the slow cleavage at
Arg
(20-fold). Factor Xa protects factor Va from
inactivation by APC by selectively blocking cleavage at
Arg
. Inactivation of factor Va
, which was
isolated from the plasma of a homozygous APC-resistant patient and
which lacks the Arg
cleavage site, was also stimulated by
protein S but was not affected by factor Xa. This confirms that the
target sites of protein S and factor Xa involve Arg
and
Arg
, respectively. Factor Xa completely blocked
APC-catalyzed cleavage at Arg
in normal factor Va (1
nM) with a half-maximal effect (K
) at 1.9 nM factor Xa.
Expression of cofactor activity of factor Va in prothrombin activation
required much lower factor Xa concentrations (K
= 0.08 nM). When
the ability of factor Xa to protect factor Va from inactivation by APC
was determined at low factor Va concentrations during prothrombin
activation much lower amounts of factor Xa were required (K
= 0.03 nM). This
indicates 1) that factor Va is optimally protected from inactivation by
APC by incorporation into the prothrombinase complex during ongoing
prothrombin activation, and 2) that the formation of a catalytically
active prothrombinase complex and protection of factor Va from
inactivation by APC likely involves the same interaction of factor Xa
with factor Va. In accordance with the proposed mechanisms of action of
protein S and factor Xa, we observed that the large differences between
the rates of APC-catalyzed inactivation of normal factor Va and factor
Va
were almost annihilated in the presence of factor Xa
and protein S. This observation may explain why, in the absence of
other risk factors, APC resistance only results in a weak prothrombotic
condition.
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