Inhibition of factor XIIIa in a canine model of coronary thrombosis: effect on reperfusion and acute reocclusion after recombinant tissue-type plasminogen activator.
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.
Shebuski
R J
RJ
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Sitko
G R
GR
Claremon
D A
DA
Baldwin
J J
JJ
Remy
D C
DC
Stern
A M
AM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000188:drug therapy*; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D003331:Coronary Vessels / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D008297:Male; D015425:Myocardial Reperfusion; D011994:Recombinant Proteins / Q000627:therapeutic use; D013830:Thiadiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
D011994:Recombinant Proteins; D013830:Thiadiazoles; C063511:L 722151; D011503:Transglutaminases; D010959:Tissue Plasminogen Activator