Inhibition and reversal of platelet-rich arterial thrombus in vivo: direct vs. indirect factor Xa inhibition.
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 microg kg(-1) bolus + 1.5 microg kg(-1) min(-1) infusion, n=6); ZK-807834-Dose 2 (20 microg kg(-1) bolus + 0.75 microg 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 x 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.
Karnicki
K
K
Division of Cardiology, May Clinic, Rochester, MN 55905, USA.
McBane
R D
RD
Miller
R S
RS
Leadley
R J
RJ
Morser
J
J
Owen
W G
WG
Chesebro
J H
JH
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D002339:Carotid Arteries / Q000473:pathology*; D002341:Carotid Artery Thrombosis / Q000188:drug therapy* / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005260:Female; D006493:Heparin / Q000378:metabolism; D020128:Inhibitory Concentration 50; D010477:Perfusion; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology; D013552:Swine; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control; D013997:Time Factors
D000578:Amidines; D000925:Anticoagulants; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D011725:Pyridines; C114592:Fidexaban; D006493:Heparin