MAINTENANCE OF CANINE CORONARY-ARTERY PATENCY FOLLOWING THROMBOLYSIS WITH FRONT LOADED PLUS LOW-DOSE MAINTENANCE CONJUNCTIVE THERAPY - A COMPARISON OF FACTOR XA VERSUS THROMBIN INHIBITION

Objective: The aim was to examine the abilities of the direct thrombin inhibitor, recombinant hirudin (rHIR), and the coagulation factor Xa inhibitor, recombinant tick anticoagulant peptide (rTAP), given in com bination with rt-PA as high dose front loading plus low dose maintenan ce infusions, to enhance reperfusion and maintain vessel patency in a canine model of left circumflex coronary artery stenosis and electroly tic lesion. Methods: Occlusive coronary artery thrombosis was induced in anaesthetised dogs by electrical injury (150 muA) of the intimal su rface of the vessel. Thirty minutes after occlusive thrombosis, high d ose front loading infusions (45 min) of rTAP (200 mug-kg-1.min-1) and rHIR (300 mug.kg-1.min-1) were initiated concomitant with the start of a 90 min infusion of recombinant tissue-type plasminogen activator (r t-PA). Following the termination of front loading infusions, maintenan ce infusions of rTAP (10 or 20 mug.kg-1.min-1) or rHIR (20 mug.kg-1.mi n-1) were initiated and continued for the duration of the protocol (18 0 min after rt-PA termination). Results: Reperfusion was incomplete in the rHIR group (7/9; 78%), whereas all rTAP-treated preparations repe rfused (8/8 per group, aggregate 16/16; 100%). Following thrombolysis, the rHIR group had a high incidence of reocclusion, ranging from inte rmittent to long periods of occlusion, with only 2/7(29%) of the prepa rations which initially recanalised remaining patent during the 180 mi n period following rt-PA termination. In contrast, 5/8 preparations in each of the two rTAP groups [aggregate 10/16; 63%] remained patent du ring the same period. The greater efficacy of rTAP v rHIR in maintaini ng vessel patency was also reflected in integrated coronary artery blo od flows [91.0(SEM 5.8)% and 84.9(6.1)% of preocclusion flow in rTAP g roups v 57.5(12.2)% of preocclusion flow in rHIR group], times to reoc clusion [123.3(22.8) and 128.0(6.7) min in rTAP groups v 36.6(23.2) mi n in rHIR group; p < 0.05], and residual thrombus masses [1.8(0.3) and 2.0(0.3) mg in rTAP groups v 10.4(3.8) mg in rHIR group; p < 0.05]. C onclusions: With the present front loading plus low dose maintenance i nfusions designed to limit the duration of ''high dose'' conjunctive t herapy, rTAP was more effective than rHIR at equimolar plasma concentr ations in maintaining post-thrombolysis vessel patency, preserving cor onary artery blood flow, and reducing residual thrombus mass. These fi ndings further support the therapeutic potential of inhibiting factor Xa in the setting of coronary artery thrombolysis.