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Mechanism of protein C-dependent clot lysis: role of plasminogen activator
inhibitor
Y Sakata, DJ Loskutoff, CL Gladson, CM Hekman and JH Griffin
The mechanism by which activated protein C stimulates fibrinolysis was
studied in a simple radiolabeled clot lysis assay system containing
purified tissue-type plasminogen activator, bovine endothelial plasminogen
activator inhibitor (PAI), plasminogen, 125I-fibrinogen and thrombin.
Fibrinolysis was greatly enhanced by the addition of purified bovine
activated protein C; however, in the absence of PAI, activated protein C
did not stimulate clot lysis, thus implicating this inhibitor in the
mechanism. In clot lysis assay systems containing washed human platelets as
a source of PAI, bovine-activated protein C-dependent fibrinolysis was
associated with a marked decrease in PAI activity as detected using reverse
fibrin autography. Bovine-activated protein C also decreased PAI activity
of whole blood and of serum. In contrast to the bovine molecule,
human-activated protein C was much less profibrinolytic in these clot lysis
assay systems and much less potent in causing the neutralization of PAI.
This species specificity of activated protein C in clot lysis assays
reflect the known in vivo profibrinolytic species specificity. When
purified bovine-activated protein C was mixed with purified PAI, complex
formation was demonstrated using immunoblotting techniques after
polyacrylamide gel electrophoresis in the presence of sodium dodecyl
sulfate. These observations suggest that a major mechanism for bovine
protein C- dependent fibrinolysis in in vitro clot lysis assays involves a
direct neutralization of PAI by activated protein C.
Volume 68,
Issue 6,
pp. 1218-1223,
12/01/1986
Copyright © 1986 by The American Society of Hematology
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