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Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to
endotoxin-induced intravascular coagulation and the generalized Shwartzman
reaction
PM Sandset, BJ Warn-Cramer, SL Maki and SI Rapaport
Department of Medicine, University of California at San Diego, La Jolla.
We have reported earlier that immunodepletion of extrinsic pathway
inhibitor (EPI) sensitizes rabbits to disseminated intravascular
coagulation (DIC) induced by infusing a low concentration of tissue factor
(TF). We now describe the effect of immunodepletion of EPI in rabbits
administered endotoxin. Cortisone-treated rabbits were administered
anti-rabbit EPI immunoglobulin (IgG) or Fab fragments or were administered
control nonimmune material before an injection of endotoxin. In four of
seven rabbits administered anti-EPI, plasma EPI activity levels were
reduced by 70% to 80% of initial levels for 6 to 8 hours. In these rabbits
the endotoxin induced extensive DIC, as evidenced by substantial decreases
in fibrinogen, factor V, factor VIII, and platelets, and gross hemorrhagic
necrosis of the kidneys due to massive deposition of fibrin in the
glomerular microcirculation (the generalized Shwartzman reaction). In three
rabbits administered anti- EPI, plasma EPI levels were only transiently
reduced. In these rabbits and in four rabbits administered nonimmune IgG or
Fab, endotoxin induced minimal to moderate intravascular clotting and
deposits of fibrin were not found in the glomerular capillaries. Because it
is believed that TF expressed on monocytes triggers endotoxin-induced
coagulation, these data are taken as evidence that EPI functions as a
natural anticoagulant that can regulate factor VIIa/TF activity expressed
on cell surfaces in vivo. They support a hypothesis that EPI prevents
thrombotic complications that might otherwise result from exposure of blood
to cytokine-induced generation of small amounts of TF on cell surfaces in
many inflammatory and infectious disease states.
Volume 78,
Issue 6,
pp. 1496-1502,
09/15/1991
Copyright © 1991 by The American Society of Hematology
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