Arterial antithrombotic effects of aspirin, heparin, enoxaparin and clopidogrel alone, or in combination, in the rat

Daykin, Heather; Sturgeon, Sharelle Anne; Jones, Catherine; Wright, Christine E.

doi:10.1016/j.thromres.2005.11.015

Cited by 25 publications

(15 citation statements)

References 21 publications

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“…This result is consistent with our previous study, which demonstrated that coadministration of low doses of aspirin and the direct FXa inhibitor DPC423 enhanced antithrombotic efficacy but did not prolong bleeding time [13]. Other investigators have also reported that aspirin enhances the antithrombotic effect of anticoagulants such as heparin, low molecular weight heparin, FIX antibody and a direct thrombin inhibitor in animals [21][22][23]. Clopidogrel at 1 mg/kg/h IPV was marginally effective in preventing arterial thrombosis in the rabbit ECAT model.…”

Section: Discussionsupporting

confidence: 93%

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Wong

Crain

Watson

et al. 2007

J Thromb Thrombolysis

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Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial thrombosis. Combination therapy with antiplatelet and anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial thrombosis. Few studies have thoroughly investigated the combined antithrombotic and bleeding effects of these antithrombotic agents. We, therefore, evaluated the antithrombotic and bleeding profiles of dual and triple therapy with razaxaban, a direct factor Xa inhibitor, plus aspirin and/or clopidogrel in rabbit models of electrolytic injury-induced carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED(50) of razaxaban averaged 0.22 +/- 0.05 mg/kg/h (n = 6). Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 +/- 0.1- and 2.3 +/- 0.1-fold, respectively, and inhibited ex vivo factor Xa activity significantly by 91 +/- 5% (n = 6, P < 0.05) without affecting ex vivo thrombin activity. Razaxaban at concentrations up to 10 muM did not alter in vitro platelet aggregation responses to ADP, gamma-thrombin or collagen. To identify additive or synergistic antithrombotic effects of the various combination therapies, we purposefully used marginally effective doses of razaxaban at 0.1 mg/kg/h, aspirin at 0.3 mg/kg/h and clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of razaxaban and aspirin or clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual therapy with aspirin and clopidogrel (38 +/- 5% increase in blood flow), addition of razaxaban increased blood flow to 75 +/- 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary, razaxaban was an effective antithrombotic agent in a rabbit model of arterial thrombosis. Low-dose razaxaban was useful in combination with sub-optimal doses of aspirin and/or clopidogrel for the prevention of occlusive arterial thrombosis without excessive bleeding.

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Section: Discussionsupporting

confidence: 93%

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Wong

Crain

Watson

et al. 2007

J Thromb Thrombolysis

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“…Together, these results support the suggestion that apixaban has a wide therapeutic index. The findings from the current study are consistent with previous observations demonstrating that the addition of aspirin to anticoagulants, such as heparin, low molecular weight heparin, FIX antibody, and direct thrombin and FXa inhibitors, enhances antithrombotic effects in animals [16][17][18][19][20]. Further, the additional antithrombotic efficacy was also demonstrated with the oral direct thrombin inhibitor ximelagatran in combination with aspirin during six months of treatment in patients with ACS [21].…”

Section: Discussionsupporting

confidence: 91%

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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“…Two sets of sham (4 rats) and exposed (5 rats) groups, which had 4 h urine collection followed by euthanasia, were used to assess the influence of two common clinical drugs on the GCH clotting. Heparin was administered IV 1 hour before exposure at a dose of 500 units/kg, which was expected to reduce clotting (Daykin et al 2006). Aminocaproic acid (ACA) was administered IV at a dose of 300 mg/kg at 18 h and 6 h pre exposure and at the time of exposure, which was expected to enhance clotting (Hruby et al 1996).…”

Section: Methodsmentioning

confidence: 99%

Glomerular Capillary Hemorrhage Induced in Rats by Diagnostic Ultrasound with Gas–Body Contrast Agent Produces Intratubular Obstruction

Miller

Dou

Wiggins

2009

Ultrasound in Medicine & Biology

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Glomerular capillary hemorrhage (GCH) induced by ultrasonic cavitation during diagnostic imaging represents a unique contrast-agent related nephron injury. Consequences of GCH during 1.5 MHz diagnostic ultrasound with contrast agent were examined by histological methods in rats. Definity was infused at 10 μl/kg/min for 5 min at the start of 8 min of intermittent image-exposure with 2.3 MPa in situ peak rarefactional pressure amplitude. Kidney samples were taken for histology at 5 min, 30 min, 4 h, 2 d, 1 wk and 4 wks post exposure. In addition, samples were taken at 4 h from groups treated with heparin or aminocaproic acid. GCH was found in 61% of glomeruli in the center of the scan plane 5 min after exposure, which declined (P<0.05) to 36.3 % after 4 hr. The width of Bowman's space was significantly increased for glomeruli with GCH relative to glomeruli without GCH (P<0.05), consistent with tubular obstruction. Antibody staining revealed fibrin clotting in Bowman's space in 4 hr samples and this persisted in the 2 d samples. Heparin reduced and aminocaproic acid increased the GCH seen in 4 h samples. Tubular dilatation was evident with injury to the epithelium after 2d. After 1 week, areas of inflammatory cell infiltration were present. After 4 weeks, areas of interstitial fibrosis were revealed by Masson's trichrome stain. The consequences of GCH induced by diagnostic ultrasound with contrast agents include rupture of glomerular capillaries, procoagulant activity resulting in intra-tubular obstruction, and the potential for progression of the resulting tubular injury toward interstitial fibrosis.

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Arterial antithrombotic effects of aspirin, heparin, enoxaparin and clopidogrel alone, or in combination, in the rat

Cited by 25 publications

References 21 publications

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

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

Glomerular Capillary Hemorrhage Induced in Rats by Diagnostic Ultrasound with Gas–Body Contrast Agent Produces Intratubular Obstruction

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