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Anticoagulant and fibrinolytic activities are promoted, not retarded, in
vivo after thrombin generation in the presence of a monoclonal antibody
that inhibits activation of protein C
FB Taylor , H Hoogendoorn, AC Chang, G Peer, ME Nesheim, R Catlett, DC Stump and AR Giles
Cardiovascular Biology Research Program, Oklahoma Medical Research
Foundation, Oklahoma City 73104.
This study examines the assumption that both the anticoagulant and
fibrinolytic activity that follow the generation of thrombin induced by
infusion of factor Xa/PCPS are due to generation of activated protein C.
Untreated controls or animals given unrelated antibody were compared with
animals pretreated with a specific monoclonal antibody to protein C (HPC4).
Compared with untreated controls excess HPC4 substantially reduced the
level of protein C activation as observed by protein C immunoblotting and
enzyme-linked immunosorbent assay for antitrypsin/activated protein C
complexes. Despite this, the anticoagulant activity as reflected by the
decline of factors Va and VIIIa levels (as observed by coagulation assays
and by factor V immunoblotting) was significantly greater than controls.
The fibrinolytic activity (as observed by assays of tissue plasminogen
activator, D-Dimer, alpha 2-antiplasmin) also was significantly greater
than controls. We conclude that neutralization of the protein C
anticoagulant system while resulting in a significantly more intense
coagulant response to Xa/PCPS does not preclude inactivation of factors Va
and VIIIa and the full expression of the fibrinolytic response. We conclude
further that after thrombin generation in vivo, protein C activation is not
a prerequisite for the promotion of the fibrinolytic response previously
observed, and that the inactivation of factors Va/VIIIa may be mediated by
enzymes other than activated protein C. The reduction in alpha
2-antiplasmin levels in association with increased tissue plasminogen
activator activity suggests that plasmin is a likely candidate.
Volume 79,
Issue 7,
pp. 1720-1728,
04/01/1992
Copyright © 1992 by The American Society of Hematology
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