ANTITHROMBOTIC EFFECT OF GYKI-14766 IN A CANINE MODEL OF ARTERIAL ANDVENOUS RETHROMBOSIS - A COMPARISON WITH HEPARIN

We compared the antithrombotic effects of the thrombin inhibitor, D-me thyl-phenylalanyl-prolyl-arginal (GYKI-14766) with those of heparin in a canine model of arterial and venous rethrombosis. Thrombogenesis wa s induced by electrolytic injury to the endothelial surface of the car otid artery and jugular vein. Either heparin (300 U/kg, n = 7), GYKI-1 4766 (0.5 mg/kg/h, n = 7), or saline (n = 10) was administered intrave nously (i.v.) immediately after the local administration of anisoylate d plasminogen streptokinase activator complex (APSAC 0.1 U/kg). Supple mental doses of heparin (100 U/kg) were administered at 1-h intervals. Infusion of GYKI-14766 was maintained for 5 h throughout the experime nt. Ex vivo platelet aggregation in response to ADP or arachidonic aci d (AA) was not changed in any of the experimental groups. Both GYKI-14 766 and heparin increased the activated partial thromboplastin time (a PTT) over their respective baseline values. Heparin, but not GYKI-1476 6, increased the bleeding time. After successful thrombolysis, arteria l and venous rethrombosis occurred in all saline-treated dogs. GYKI-14 766 prevented cyclic flow variations and reocclusion in the artery and the vein (p < 0.01). Heparin had only minimal effects on the artery a nd no effect on the vein. Arterial thrombus weights were reduced by GY KI-14766 [saline control = 24 +/- 4 mg, GYKI-14766 = 9 +/- 3 mg, (p < 0.05); heparin = 14 +/- 2 mg, p = NS]. The venous thrombus weights wer e reduced slightly by GYKI-14766 and were unchanged by heparin (saline = 25 +/- 5 mg, GYKI-14766 = 13 +/- 4 mg, heparin = 26 +/- 3 mg). The data suggest that GYKI-14766 is effective in preventing occlusive reth rombosis in both the arterial and venous circulation after thrombolysi s without augmenting bleeding time. GYKI-14766 may represent an altern ative to heparin as an adjunctive agent during thrombolytic therapy.