Summary
Current therapeutic use of heparin as an adjunct to thrombolytic therapy for myocardial
infarction is suboptimal with respect to efficacy and bleeding risk. In a rat carotid
arterial thrombolysis model (FeCl3- induced injury) we evaluated the combined effect of tPA (2.0 mg/kg/ 30 min) with our
potent injectable direct thrombin inhibitor, BCH-2763 (Ki 0.11 nM; MW 1.5 kDa), which,
unlike heparin, inhibits bound and free thrombin; comparisons were with standard heparin
(SH), other direct thrombin inhibitors, r-hirudin (MW 6.5 kDa) and hirulog (MW 2.3
kDa), or tPA alone. Time to lysis (TL), patency time (PT), aPTT (fold increase) and
bleeding time (BT) were determined. ED100 (100% of rats reperfused) for BCH-2763, hirulog or r-hirudin was 1, 3 or 2 mg/kg/60
min, respectively; 67% of rats reperfused with SH at the highest dose tested (220
U/kg/60 min) and 43% with tPA alone. At these doses, TL (min) was shorter (p <0.01)
with BCH-2763 (0.5 ± 0.1), hirulog (3.3 ± 2.3) or r-hirudin (2.3 ± 1.0) than SH (66.3
± 30.8) or tPA alone (93.4 ± 21.4). The aPTT fold increase after 15 min infusion was
markedly greater (p <0.001) for SH (32.0 ± 0.8) than BCH-2763 (3.7 ± 0.5), hirulog
(5.2 ± 0.3) or r-hirudin (4.5 ± 0.8) in combination with tPA or tPA alone (1.1 ± 0.1).
In addition, the BT (min) for BCH-2763 (3.0 ± 0.4) was similar to tPA alone (1.6 ±
0.3), but prolonged (p <0.05) for hirulog (7.5 ± 2.7), r-hirudin (6.6 ± 0.8) or SH
(7.3 ± 1.8). Comparisons at same aPTT fold increase revealed that in combination with
tPA, BCH-2763 required a lower anticoagulant level to shorten the TL and prolong the
PT than hirulog, r-hirudin or SH. Thus, in this rat arterial thrombolysis model direct
thrombin inhibitors are more effective than SH as antithrombotic adjuncts to tPA.
BCH-2763 is effective at a lower gravimetric dose and more modest aPTT fold increase
than hirulog or r-hirudin with less alteration in haemostasis, which may confer an
improved safety index.
