Platelet Aggregometry and Receptor Binding to Predict the Magnitude of Antithrombotic and Bleeding Time Effects of Clopidogrel in Rabbits

Wong, Pancras C.; Crain, Earl J.; Watson, Carol A.; Jiang, Xiaosui; Hua, Jinping; Bostwick, Jeffrey S.; Ogletree, Martin L.; Schumacher, William A.; Rehfuss, Robert

doi:10.1097/fjc.0b013e31803e8772

Cited by 18 publications

(31 citation statements)

References 26 publications

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“…For example, studies performed in rabbits suggest that unexplained bleeding occurs at levels of clopidogrel greater than those required to provide complete inhibition of platelet aggregation (Wong et al, 2009). In particular, high doses of clopidogrel providing limited incremental benefits in preventing arterial thrombosis have been associated with disproportionate levels of bleeding in both rabbits and rats Wong et al, 2007). Similar discrepancies have been reported in humans, with CYP2C19*2 carriers having a higher rate of thrombotic events but a rate of bleeding similar to those of noncarriers (Mega et al, 2009).…”

Section: Introductionmentioning

confidence: 53%

Thienopyridines, but Not Elinogrel, Result in Off-Target Effects at the Vessel Wall That Contribute to Bleeding

André¹,

DeGuzman²,

Haberstock-Debić³

et al. 2011

J Pharmacol Exp Ther

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Clinical studies with clopidogrel or prasugrel show that although increased inhibition of P2Y 12 and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested a greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We used multiple in vivo (FeCl 3 -induced arterial thrombosis in mesenteric arteries, blood loss after tail transsection, and platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, prothrombin time, and activated partial thromboplastin time) mouse models to 1) compare the TI of clopidogrel, prasugrel, and elinogrel, a reversible, competitive antagonist, with that in P2Y 12 (Ϫ/Ϫ) mice and 2) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y 12 . Data indicated greater (elinogrel) and decreased (thienopyridines) TI compared with that in P2Y 12 (Ϫ/Ϫ) mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y 12 activities on platelet function or coagulation but was related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that the prasugrel off-target effect was dose-and time-dependent and of a reversible nature. In conclusion, the TI of thienopyridines in the mouse may be decreased by P2Y 12 -independent off-target effects at the vessel wall, whereas that of elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.

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Section: Introductionmentioning

confidence: 53%

Thienopyridines, but Not Elinogrel, Result in Off-Target Effects at the Vessel Wall That Contribute to Bleeding

André¹,

DeGuzman²,

Haberstock-Debić³

et al. 2011

J Pharmacol Exp Ther

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“…We adopted the doses of cilostazol (100 mg/kg), aspirin (10 mg/kg), and clopidogrel (3 mg/kg) for our MCA occlusion study because this dose of cilostazol showed greatest inhibition, and these were the minimal effective doses for aspirin and clopidogrel. Higher dosages of aspirin and clopidogrel were not used to avoid an unnecessary risk of bleeding during the experiments (Clark et al, 1991;Wong et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Cilostazol, a Phosphodiesterase Inhibitor, Attenuates Photothrombotic Focal Ischemic Brain Injury in Hypertensive Rats

Ito

Hashimoto

Matsumoto

et al. 2009

J Cereb Blood Flow Metab

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The aim of this study was to evaluate and compare the effects of anti-platelet agents with different modes of action (cilostazol, aspirin, and clopidogrel) on brain infarction produced by photothrombotic middle-cerebral-artery (MCA) occlusion in male, spontaneously hypertensive rats. Cerebral blood flow (CBF) was measured with laser-Doppler flowmetry in the penumbral cortex. Infarct size was evaluated 24 h after MCA occlusion. The effects of these drugs on infarct size were examined by pretreatment of rats undergoing MCA occlusion. Pretreatment with cilostazol (100 mg/kg) significantly reduced infarct size. In contrast, aspirin (10 mg/kg) and clopidogrel (3 mg/kg) failed to mitigate infarct size, regardless of their apparent inhibitory effects on platelet aggregation. Post-treatment with cilostazol also significantly attenuated the infarct size, associated with improved CBF in the penumbral region. In support of this effect, cilostazol increased nitric oxide (NO) production and prostaglandin-I 2 (PGI 2 ) release in cultured human brain microvascular endothelial cells. Cilostazol-induced NO production and PGI 2 release were completely abolished by an NO synthase inhibitor and aspirin, respectively. These findings show that cilostazol reduced brain infarct size due to an improvement in penumbral CBF possibly in association with increased endothelial NO and PGI 2 production.

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“…the threshold dose that completely blocks ex vivo platelet aggregation response to arachidonic acid and serum production of thromboxane B 2 [12], and is thus comparable to the 81 mg clinical dose of aspirin [13]. We studied clopidogrel at 3 mg kg )1 day )1 per oral (p.o.…”

Section: Arterial Thrombosis Studiesmentioning

confidence: 99%

“…) was dosed orally once daily for three days as described previously [12]. Following the third oral dose of clopidogrel or vehicle, rabbits were anesthetized 0.5 h post-dose, i.v.…”

Section: Arterial Thrombosis Studiesmentioning

confidence: 99%

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Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

Wong

Watson

Crain

2008

Journal of Thrombosis and Haemostasis

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To cite this article: Wong PC, Watson CA, Crain EJ. Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J Thromb Haemost 2008; 6: 1736-41.Summary. Background: Optimal treatment of arterial thrombosis may include a combination of antiplatelet and anticoagulant drugs. We evaluated apixaban, a direct and highly selective factor Xa inhibitor, in combination with clinically relevant doses of aspirin and/or clopidogrel for prevention of arterial thrombosis in rabbits. Methods: Studies were conducted in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding time (BT). Apixaban 0.04 and 0.3 mg kg )1 h )1 or aspirin 1 mg kg )1 h )1 was infused intravenous (i.v.) continuously from 1 h before artery injury or cuticle bleed until the end of the experiment. Clopidogrel at 3 mg kgwas dosed orally once daily for three days, with the last dose given 2 h before injury. Results: Control thrombus weight and BT averaged 8.6 ± 0.9 mg and 181 ± 12 s, respectively (n = 6 per group). Effective doses of apixaban that reduced thrombus weight by 20 and 50% (ED 20 and ED 50 ) were 0.04 and 0.3 mg kg )1 h )1 i.v., respectively. Addition of aspirin to apixaban ED 20 and ED 50 significantly reduced the thrombus weight from 7.4 ± 0.5 to 5.3 ± 0.3 and 3.6 ± 0.3 mg, respectively, with no significant increases in BT (190 ± 7 s vs.181 ± 9 and 225 ± 11 s, respectively). Addition of aspirin and apixaban (ED 20 dose) to clopidogrel produced a further significant reduction in thrombus weight from 5.3 ± 0.3 to 0.7 ± 0.1 mg. This combination of clopidogrel and aspirin with apixaban (ED 20 dose) produced a significant but moderate BT increase of 2.1 times control. Conclusions: The combination of apixaban and aspirin or apixaban, aspirin and clopidogrel can reduce formation of occlusive arterial thrombosis without excessive increases in BT in rabbits.

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Platelet Aggregometry and Receptor Binding to Predict the Magnitude of Antithrombotic and Bleeding Time Effects of Clopidogrel in Rabbits

Cited by 18 publications

References 26 publications

Thienopyridines, but Not Elinogrel, Result in Off-Target Effects at the Vessel Wall That Contribute to Bleeding

Thienopyridines, but Not Elinogrel, Result in Off-Target Effects at the Vessel Wall That Contribute to Bleeding

Cilostazol, a Phosphodiesterase Inhibitor, Attenuates Photothrombotic Focal Ischemic Brain Injury in Hypertensive Rats

Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

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