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

K. Karnicki, Robert D. McBane, R. S. Miller, R. J. Leadley, J. Morser, W. G. Owen, J. H. Chesebro

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2162-2169
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume2
Issue number12
DOIs
StatePublished - Dec 2004

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Factor Xa
Enoxaparin
Thrombosis
Blood Platelets
Prothrombin Time
Swine
Fidexaban
Wounds and Injuries
Carotid Arteries
Pharmaceutical Preparations
Arteries

Keywords

  • Anticoagulants
  • Factor Xa
  • Low-molecular-weight heparin
  • Platelets
  • Thrombosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Karnicki, K., McBane, R. D., Miller, R. S., Leadley, R. J., Morser, J., Owen, W. G., & Chesebro, J. H. (2004). Inhibition and reversal of platelet-rich arterial thrombus in vivo: Direct vs. indirect factor Xa inhibition. Journal of Thrombosis and Haemostasis, 2(12), 2162-2169. https://doi.org/10.1111/j.1538-7836.2004.01040.x

Inhibition and reversal of platelet-rich arterial thrombus in vivo : Direct vs. indirect factor Xa inhibition. / Karnicki, K.; McBane, Robert D.; Miller, R. S.; Leadley, R. J.; Morser, J.; Owen, W. G.; Chesebro, J. H.

In: Journal of Thrombosis and Haemostasis, Vol. 2, No. 12, 12.2004, p. 2162-2169.

Research output: Contribution to journalArticle

Karnicki, K. ; McBane, Robert D. ; Miller, R. S. ; Leadley, R. J. ; Morser, J. ; Owen, W. G. ; Chesebro, J. H. / Inhibition and reversal of platelet-rich arterial thrombus in vivo : Direct vs. indirect factor Xa inhibition. In: Journal of Thrombosis and Haemostasis. 2004 ; Vol. 2, No. 12. pp. 2162-2169.
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T2 - Direct vs. indirect factor Xa inhibition

AU - Karnicki, K.

AU - McBane, Robert D.

AU - Miller, R. S.

AU - Leadley, R. J.

AU - Morser, J.

AU - Owen, W. G.

AU - Chesebro, J. H.

PY - 2004/12

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N2 - 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.

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KW - Factor Xa

KW - Low-molecular-weight heparin

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