New aspects on efficient anticoagulation and antiplatelet strategies in sheep

BMC Veterinary Research

Justus P Beier⁴  Raymund E Horch⁴  Dorothee Klumpp³  Oliver Bleiziffer⁴  Andreas Arkudas⁴  Ulrich Kneser³  Maren Mieth¹  Jürgen Ringwald²  Anja M Boos⁴  Annika Weigand⁴ 

[1] Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany;Department of Transfusion Medicine and Hemostaseology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany;Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center, Ludwigshafen, Germany;Department of Plastic and Hand Surgery, University Hospital of Erlangen Friedrich-Alexander University of Erlangen-Nürnberg, Krankenhausstr. 12, Erlangen D-91054, Germany

关键词: Ticagrelor;    Sodium enoxaparin;    Sheep model;    Platelet aggregation inhibitor;    Factor Xa inhibitor;    Dabigatran etexilate;    Clopidogrel;    Anticoagulation therapy;    Aggregometry;    Acetylsalicylic acid;   

Others  :  1119446
DOI  :  10.1186/1746-6148-9-192

 received in 2012-10-23, accepted in 2013-09-26,  发布年份 2013

【 摘 要 】

Background

After addressing fundamental questions in preclinical models in vitro or in small animals in vivo, the translation into large animal models has become a prerequisite before transferring new findings to human medicine. Especially in cardiovascular, orthopaedic and reconstructive surgery, the sheep is an important in vivo model for testing innovative therapies or medical devices prior to clinical application. For a wide variety of sheep model based research projects, an optimal anticoagulation and antiplatelet therapy is mandatory. However, no standardised scheme for this model has been developed so far. Thus the efficacy of antiplatelet (acetylsalicylic acid, clopidogrel, ticagrelor) and anticoagulant (sodium enoxaparin, dabigatran etexilate) strategies was evaluated through aggregometry, anti-factor Xa activity and plasma thrombin inhibitor levels in sheep of different ages.

Results

Responses to antiplatelet and anticoagulant drugs in different concentrations were studied in the sheep. First, a baseline for the measurement of platelet aggregation was assessed in 20 sheep. The effectiveness of 225 mg clopidogrel twice daily (bid) in 2/5 sheep and 150 mg bid in 3/5 lambs could be demonstrated, while clopidogrel and its metabolite carboxylic acid were detected in every plasma sample. High dose ticagrelor (375 mg bid) resulted in sufficient inhibition of platelet aggregation in 1/5 sheep, while acetylsalicylic acid did not show any antiplatelet effect. Therapeutic anti-factor Xa levels were achieved with age-dependent dosages of sodium enoxaparin (sheep 3 mg/kg bid, lambs 5 mg/kg bid). Administration of dabigatran etexilate resulted in plasma concentrations similar to human ranges in 2/5 sheep, despite receiving quadruple dosages (600 mg bid).

Conclusion

High dosages of clopidogrel inhibited platelet aggregation merely in a low number of sheep despite sufficient absorption. Ticagrelor and acetylsalicylic acid cannot be recommended for platelet inhibition in sheep. Efficient anticoagulation can be ensured using sodium enoxaparin rather than dabigatran etexilate in age-dependent dosages. The findings of this study significantly contribute to the improvement of a safe and reliable prophylaxis for thromboembolic events in sheep. Applying these results in future translational experimental studies may help to avoid early dropouts due to thromboembolic events and associated unnecessary high animal numbers.

【 授权许可】

   
2013 Weigand et al.; licensee BioMed Central Ltd.

【 图 表 】

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