ENHANCEMENT OF THROMBOLYTIC EFFICACY OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR BY ADJUVANTS IN THE GUINEA-PIG THROMBOSIS MODEL

Reocclusion following thrombolysis is a major limitation of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). We investigated the effects of vapiprost ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-7-(5-((1,1'-biphenyl)-4-yl-methoxy)-3-hydroxy- 2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, a thromboxane A(2) receptor antagonist); argatroban ((2R,4R)-4-methyl-1-[N-2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl)]-2-piperidine-carboxylic acid, a specific thrombin inhibitor) and MK-886 (3-[1-(4-chlorobenzyl)-3-t -butyl-thio-5-isoprapylindol-2-yl]-2,2-dimethylpropanoic acid, a specific leukotriene biosynthesis inhibitor) on the thrombolytic efficacy of rt-PA. The guinea pig femoral artery was thrombotically occluded by photochemical reaction between rose bengal and green light. Thirty min after the occlusion, rt-PA was administered and the time (T-1) for reopening of the vessel and the frequency of reocclusion (F-ro) 24 h after thrombolysis were monitored. With rt-PA alone, T-1 was 28 +/- 7 min (n = 10) and F-ro was 70%. T-1 was reduced to 9 and 20 min by a combination of rt-PA with vapiprost and argatroban respectively. F-ro was reduced by all three adjuvants. Histological observations revealed extensive adherence of polymorphonuclear leucocytes to the damaged endothelium at the site of thrombolysis. It is concluded that thromboxane A(2), thrombin and leucocytes are involved in reocclusion after thrombolysis.