Thrombin infusion in endotoxin-treated rabbits reduces the plasma levels of
plasminogen activator inhibitor: evidence for a protein-C- mediated
mechanism [see comments]
M Colucci, R Triggiani, LG Cavallo and N Semeraro
Istituto di Patologia Generale, Universita di Bari, Italy.
Plasminogen activator inhibitors (PAIs) play a pivotal role in the control
of fibrinolysis. The mechanisms regulating the plasma levels of PAI(s) are
still unknown. We report here that the infusion of bovine thrombin (1
U/kg/min, over 60 minutes) in rabbits treated with 0.5 microgram/kg
endotoxin (to induce an increase in circulating fast- acting PAI) causes a
marked reduction of PAI (50% of preinfusion value), as indicated by
functional assay and reverse fibrin autography. Moreover, blood clots
prepared from samples obtained after thrombin infusion lysed faster than
preinfusion clots when exposed, in vitro, to tissue plasminogen activator.
Donor-receiver transfusion experiments showed that the half-life of
circulating PAI activity was shorter in thrombin-infused rabbits than in
controls (4.1 minutes versus 7.4 minutes), suggesting an accelerated
clearance. As expected, thrombin infusion resulted also in activation of
protein C (PC). The following observations suggest a close relationship
between PC activation and PAI reduction. (1) Infusion of thrombin in
rabbits made deficient in vitamin K-dependent plasma proteins by warfarin
treatment did not result in modification of PAI activity. (2) Treatment of
the latter animals with a barium citrate eluate (PE) of rabbit plasma
restored both the anticoagulant and profibrinolytic response to thrombin.
(3) Short infusion of thrombin-activated PE (containing activated PC, PCa),
but not of unactivated PE, induced both anticoagulation and reduction of
PAI activity. In vitro, incubation of PAI-rich rabbit serum with
thrombin-activated PE and phospholipids resulted in a progressive
disappearance of PAI activity with a t1/2 of 30 minutes. However, this slow
inactivation rate does not fully explain the results obtained in vivo. Our
data suggest that thrombin infusion in rabbits causes a reduction of
circulating PAI activity and that activation of PC is the intermediary
mechanism involved in this phenomenon.
Volume 74,
Issue 6,
pp. 1976-1982,
11/01/1989
Copyright © 1989 by The American Society of Hematology
