Antithrombotic efficacy of single subcutaneous administration of a recombinant nematode anticoagulant peptide (rNAP5) in a canine model of coronary artery thrombolysis

We examined the adjunctive benefit of recombinant nematode anticoagulant pe ptide (rNAP5), a factor Xa inhibitor, in a canine model of recombinant (rt) -PA-induced thrombolysis, In anesthetized dogs, a stable occlusive thrombus was formed by electrolytic injury of the vessel wall, after which the anim als were administered rt-PA (1.44 mg/kg, i.v.) and rNAP5 (0.1 mg/kg, s.c,; n = 13), or rt-PA plus vehicle (1-2 ml, s.c,; n = 13), Hemodynamic and coag ulation parameters were monitored for 360 minutes. Single subcutaneous admi nistration of rNAP5 resulted in a prolonged and sustained increase in the a ctivated partial thromboplastin time (>10-fold), whereas prothrombin time w as unchanged. The template bleeding time was not altered significantly thro ughout the protocol (maximum 1.4-fold). The incidence of reperfusion was si milar in the two groups with a trend toward faster reperfusion in the rNAP5 group (34+/-4 minutes) compared to the vehicle group (63+/-15 minutes; p = 0.07). After reperfusion, 80% of the vessels in the vehicle group reocclud ed, whereas only 14% of vessels reoccluded in the rNAP5-treated group. Time s to reocclusion were 65+/-21 minutes and 221 +/- 28 minutes, respectively (p<0.05). Single subcutaneous administration of rNAP5 sustained the coronar y artery blood flow after reperfusion, such that at the end of protocol the flow was 47% of the preocclusion value as compared to the vehicle group in which the flow was 11% (p<0.05). Cyclic flow reductions were most prominen t during rt-PA-induced reperfusion and were similar in both groups. The res ults indicate that a single subcutaneous administration of rNAP5 provides a sustained antithrombotic effect in maintaining the coronary artery patency during rt-PA-induced thrombolysis, (C) 2000 Elsevier Science Ltd. All righ ts reserved.