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Role of free protein S and C4b binding protein in regulating the coagulant
response to Escherichia coli
FB Taylor , B Dahlback, AC Chang, MS Lockhart, K Hatanaka, G Peer and CT Esmon
Oklahoma Medical Research Foundation, Program of Cardiovascular Biology,
Oklahoma City 73104, USA.
Previous studies showed that infusion of C4b-binding protein with sublethal
Escherichia coli (E. coli) in the primate produced a consumptive
coagulopathy followed by microvascular thrombosis and renal failure. The
first objective of this study was to characterize the pathophysiology and
mechanism of this phenomena following infusion of both these agents with
emphasis on defining the role of free protein S. The second objective was
to examine the relevance of this model to the hemolytic uremic syndrome.
Infusion of C4b-binding protein alone reduced free protein S and decreased
platelet concentration to 20% of baseline, whereas infusion of the
C4b-binding protein/protein S complex did not. There was no activation of
other inflammatory or coagulant factors. Infusion of sublethal E coli alone
produced a transient inflammatory response with no reduction of free
protein S. However, coinfusion of C4b-binding protein with sublethal E coli
reduced free protein S and produced a thrombocytopenia, anemia, and a
microvascular thrombotic response, whereas infusion of the C4b-binding
protein/protein S complex with sublethal E coli did not. Studies comparing
the effects of neutralizing (S-163) and nonneutralizing (S- 145) antibodies
with protein S coinfused with sublethal E coli produced similar contrasting
results. Therefore, we concluded that neutralization of free protein S, and
not some other property of C4b- binding protein influenced by protein S,
accounted for this microvascular thrombotic response. This response is
similar to the hemolytic uremic syndrome characterized by thrombocytopenia,
anemia, shistocytosis, and renal glomerular thrombosis with uremia.
Comparison of the respective renal histopathologic appearance supports this
conclusion. This raises the possibility that inhibition of protein S
activity (possibly by one of the forms of C4b-binding proteins) might be
one of the factors contributing to microvascular thrombotic disorder, such
as the hemolytic uremic syndrome.
Volume 86,
Issue 7,
pp. 2642-2652,
10/01/1995
Copyright © 1995 by The American Society of Hematology
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