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Inhibition of the intrinsic factor X activating complex by protein S:
evidence for a specific binding of protein S to factor VIII
SJ Koppelman, TM Hackeng, JJ Sixma and BN Bouma
Department of Haematology, University Hospital Utrecht, The Netherlands.
Protein S is a vitamin K-dependent nonenzymatic anticoagulant protein that
acts as a cofactor to activated protein C. Recently it was shown that
protein S inhibits the prothrombinase reaction independent of activated
protein C. In this study, we show that protein S can also inhibit the
intrinsic factor X activation via a specific interaction with factor VIII.
In the presence of endothelial cells, the intrinsic activation of factor X
was inhibited by protein S with an IC50 value of 0.28 +/- 0.04 mumol/L
corresponding to the plasma concentration of protein S. This inhibitory
effect was even more pronounced when the intrinsic factor X activation was
studied in the presence of activated platelets (IC50 = 0.15 +/- 0.02
mumol/L). When a nonlimiting concentration of phospholipid vesicles was
used, the plasma concentration of protein S (300 nmol/L) inhibited the
intrinsic factor X activation by 40%. Thrombin-cleaved protein S inhibited
the endothelial cell-mediated factor X activation with an IC50 similar to
that of native protein S (0.26 +/- 0.02 mumol/L). Protein S in complex with
C4b-binding protein inhibited the endothelial cell-mediated factor X
activation more potently than protein S alone (IC50 = 0.19 +/- 0.03
mumol/L). Using thrombin activated factor VIII, IC50 values of 0.53 +/-
0.09 mumol/L and 0.46 +/- 0.10 mumol/L were found for native protein S and
thrombin-cleaved protein S, respectively. The possible interactions of
protein S with factor IXa, phospholipids, and factor VIII were
investigated. The enzymatic activity of factor IXa was not affected by
protein S, and interaction of protein S with the phospholipid surface could
not fully explain the inhibitory effect of protein S on the factor X
activation. Using a solid-phase binding assay, we showed a specific,
saturable, and reversible binding of protein S to factor VIII with a high
affinity. The concentration of protein S where half-maximal binding was
reached (B1/2max) was 0.41 +/- 0.06 mumol/L. A similar affinity was found
for the interaction of thrombin-cleaved protein S with factor VIII (B1/2max
= 0.40 +/- 0.04 mumol/L). The affinity of the complex protein S with
C4B-binding protein appeared to be five times higher (B1/2max = 0.07 +/-
0.03 mumol/L). Because the affinities of the interaction of the different
forms of protein S with factor VIII correspond to the IC50 values observed
for the intrinsic factor X activating complex, the interaction of protein S
with factor VIII may explain the inhibitory effect of protein S on the
intrinsic factor X activating complex.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 86,
Issue 3,
pp. 1062-1071,
08/01/1995
Copyright © 1995 by The American Society of Hematology
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