Inhibition and reversal of platelet-rich arterial thrombus in vivo: Direct vs. indirect factor Xa inhibition

Background/objective: The efficacy of a direct factor (F)Xa inhibitor, ZK-807834, was compared with indirect inhibition by enoxaparin for inhibition and deaggregation of acute platelet-rich thrombi in a well-characterized porcine carotid injury model. Methods: A crush injury was performed on a randomly chosen carotid artery and the thrombus allowed to propagate for 30 min. Pigs then received intravenous drug for 35 min: ZK-807834-Dose 1 (40 μg kg^-1 bolus + 1.5 μg kg^-1 min^-1 infusion, n = 6); ZK-807834-Dose 2 (20 μg kg^-1 bolus + 0.75 μg kg^-1 min^-1 infusion; n = 6); enoxaparin (1 mg kg^-1 bolus; n = 6); or saline (n = 6). Five minutes after drug initiation, the contralateral artery was injured. Thrombus size was monitored by scintillation detection of autologous ¹¹¹In-platelets. Results: The prothrombin time ratio was 2.2 ± 0.1; 1.4 ± 0.3; 1.2 ± 0.9 and 1.1 ± 0.2, respectively. ZK-807834-Dose 1 significantly inhibited carotid platelet deposition (525 ± 226 × 10⁶ cm^-2; P = 0.008), whereas ZK-807834-Dose 2 (2325 ± 768) and enoxaparin (1236 ± 383) were not different from saline (2776 ± 642). Thrombus deaggregation was greatest for animals receiving ZK-807834-Dose 1 (473 ± 185). Neither ZK-807834-Dose 2 (1588 ± 480) nor enoxaparin (1618 ± 686) was different from saline control (2222 ± 598). Conclusions: Direct FXa inhibition with ZK-807834, at a prothrombin time ratio of 2.2, effectively inhibits thrombosis and promptly deaggregates thrombi induced by arterial injury. In contrast, indirect FXa inhibition with enoxaparin was ineffective.