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Inhibition and reversal of platelet‐rich arterial thrombus in vivo : direct vs. indirect factor Xa inhibition
Author(s) -
KARNICKI K.,
MCBANE R. D.,
MILLER R. S.,
Leadley R. J.,
MORSER J.,
OWEN W. G.,
CHESEBRO J. H.
Publication year - 2004
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2004.01040.x
Subject(s) - thrombus , saline , medicine , bolus (digestion) , platelet , pharmacology , thrombosis , anesthesia
Summary. 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 111 In‐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 × 10 6 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.