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Inhibition of factor XIIIa in a canine model of coronary thrombosis: effect
on reperfusion and acute reocclusion after recombinant tissue- type
plasminogen activator
RJ Shebuski, GR Sitko, DA Claremon, JJ Baldwin, DC Remy and AM Stern
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories,
West Point, PA 19486.
The effect of inhibition of factor XIIIa with 2-(l-acetonylthio)-5-
methylthiazolo[2,3-b]1,3,4-thiadiazo lium perchlorate (L-722,151) on
coronary thrombolysis and reocclusion was studied in an acute dog model of
electrically induced coronary thrombosis. L-722,151 (0.1 mg/kg/min
intravenously [IV] or placebo was administered 15 minutes before current
initiation (150 microA) and for the duration of the experiment (270
minutes). Fifteen minutes after thrombus formation, heparin (300 U/kg, IV)
was administered, followed 45 minutes later by recombinant tissue-type
plasminogen activator (tPA) (10 micrograms/kg/min, IV for 90 minutes).
Placebo-treated animals thrombosed at 48.9 +/- 8.1 minutes (mean +/- SEM)
and reperfused in response to tPA at 49.1 +/- 9.3 minutes. L-722,151
pretreated animals thrombosed at 44.4 +/- 9.7 minutes and reperfused in
response to tPA at 16.4 +/- 2.8 minutes (P less than .05 v vehicle).
Furthermore, residual thrombus mass was reduced by L-722,151 from 6.9 +/-
1.9 mg in placebo-treated animals to 1.7 +/- 0.6 mg (P less than .05 v
vehicle). Acute reocclusion occurred in 86% of placebo and in 75% of
L-722,151-treated animals. The incidence of tPA-induced reperfusion in
L-722,151-treated dogs was 100% (8 of 8), whereas only 70% (7 of 10) of
placebo-treated dogs reperfused. These results demonstrate that
pretreatment with L-722,151 hastens reperfusion time threefold and reduces
residual thrombus mass. These effects occurred with no change in systemic
blood pressure in response to L-722,151. When L-722,151 was administered 15
minutes after thrombus formation in a separate group of dogs (n = 5), no
beneficial effect on thrombolysis time or thrombus mass was observed. Thus,
the specific factor XIIIa catalyzed crosslinking reaction(s), which may
determine(s) resistance to plasmin-mediated fibrin degradation, occur(s)
rapidly. Inhibition of this crosslinking by pretreatment with L-722,151
promotes tPA-induced thrombolysis.
Volume 75,
Issue 7,
pp. 1455-1459,
04/01/1990
Copyright © 1990 by The American Society of Hematology
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