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Thromb Haemost 2006; 95(02): 354-361
DOI: 10.1160/TH05-05-0377
Animal Models
Schattauer GmbH

Potent low dose platelet inhibitory effects of clopidogrel and aspirin on coronary thrombus formation in an animal model of acute unstable angina

Benjamin Bierbach   *
1   Deptartment of Cardiothoracic and vascular surgery
,
Georg Horstick   *
2   2nd Medical Clinic, Johannes Gutenberg-University Mainz, Germany
,
Oliver Berg
2   2nd Medical Clinic, Johannes Gutenberg-University Mainz, Germany
,
Axel Heimann
3   Institute for Neurosurgical Pathophysiology, Johannes Gutenberg-University Mainz, Germany
,
Thomas Münzel
2   2nd Medical Clinic, Johannes Gutenberg-University Mainz, Germany
,
Christian-Friedrich Vahl
1   Deptartment of Cardiothoracic and vascular surgery
,
Oliver Kempski
3   Institute for Neurosurgical Pathophysiology, Johannes Gutenberg-University Mainz, Germany
,
Harald Darius
2   2nd Medical Clinic, Johannes Gutenberg-University Mainz, Germany
› InstitutsangabenFinancial support: We gratefully acknowledge Sanofi-Synthelabo and Bristol-Myers Squibb for supplying clopidogrel.
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Publikationsverlauf

Received 30. Mai 2005

Accepted after resubmission 09. Januar 2005

Publikationsdatum:
28. November 2017 (online)

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Summary

Application of clopidogrel before percutaneous coronary intervention in patients with acute coronary syndrome reduces the risk of cardiac events. Clopidogrel administration before surgery increases bleeding complications after CABG. Therefore, the antithrombotic effect of the low-dose combination of clopidogrel and aspirin was investigated in an in vivo pig model of coronary artery thrombus formation with cyclic flow reductions. The platelet inhibitory effect was determined by platelet aggregation and CFR, according to the methodology described by Folts. CFR were initiated by endothelial damage and placement of a constrictor around the LAD. 30 min after CFR were established, clopidogrel (0.1 mg/kg or5 mg/kg), aspirin (1 mg/kg or 7 mg/kg) or LDC (0.1 mg/kg clopidogrel and 1 mg/kg aspirin) were administered orally. CFR-frequency was determined for further 240 min. CFR-frequency (CFR/30 min) was significantly reduced at 60 min in response to aspirin (7 mg/kg, −48%, p<0.05), and at 120 min in response to clopidogrel (5 mg/kg, −65%, p<0.05) but not at low doses of either compound. In contrast, LDC of clopidogrel (0.1 mg/kg) plus aspirin (1 mg/kg) resulted in a complete and rapid abrogation of CFR at 90 min (−70%, p<0.05). Furthermore, LDC led to reduction of platelet aggregation when CFR-frequency was already significantly decreased. In contrast, high dose groups presented a significant reduction of platelet aggregation prior to CFR-frequency decrease. Low dose combination of clopidogrel plus aspirin demonstrates a potent over additive anti-thrombotic effect in vivo with a significant reduction in thrombus formation early after drug application. The effect occurs before inhibition of platelet aggregation is detectable.

Keywords

Aspirin - clopidogrel - platelets - acute coronary syndrome - coronary artery bypass grafting

* Authors contributed equally to this work.


 

  • References

  • 1 Yeghiazarians Y, Braunstein JB, Askari A. et al. Unstable angina pectoris. N Engl J Med 2000; 342: 101-14.
    CrossrefPubMedSuche in Google Scholar
  • 2 Darbhamulla VN, Lewis PS, Maguire M. et al. Is an early invasive approach superior to a conservative strategy in patients with acute coronary syndrome?. Int Cardiovasc Thor Surg 2004; 03: 363-7.
    PubMedSuche in Google Scholar
  • 3 Steinhubl SR, Berger PB, Mann 3rd JT. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 2411-20.
    CrossrefPubMedSuche in Google Scholar
  • 4 Braunwald E. Application of current guidelines to the management of unstable angina and non-ST-elevation myocardial infarction. Circulation 2003; 108: Iii28-37.
    PubMedSuche in Google Scholar
  • 5 Lewis Jr HD, Davis JW, Archibald DG. et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N EnglJ Med 1983; 309: 396-403.
    CrossrefPubMedSuche in Google Scholar
  • 6 Cairns JA, Gent M, Singer J. et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 1985; 313: 1369-75.
    CrossrefPubMedSuche in Google Scholar
  • 7 Theroux P, Ouimet H, McCans J. et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319: 1105-11.
    CrossrefPubMedSuche in Google Scholar
  • 8 Collaboration At. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. BMJ 2002; 324: 71-86.
    CrossrefPubMedSuche in Google Scholar
  • 9 Herbert JM, Dol F, Bernat A. et al. The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost 1998; 80: 512-8.
    Thieme ConnectPubMedSuche in Google Scholar
  • 10 Mehta SR, Yusuf S, Peters RJ. et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-33.
    CrossrefPubMedSuche in Google Scholar
  • 11 Makkar RR, Eigler NL, Kaul S. et al. Effects of clopidogrel, aspirin and combined therapy ina porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J 1998; 19: 1538-46.
    CrossrefPubMedSuche in Google Scholar
  • 12 Bertrand ME, Rupprecht HJ, Urban P. et al. Doubleblind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102: 624-9.
    CrossrefPubMedSuche in Google Scholar
  • 13 Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med 2001; 29: 2271-5.
    CrossrefPubMedSuche in Google Scholar
  • 14 Hongo RH, Ley J, Dick SE. et al. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002; 40: 231-7.
    CrossrefPubMedSuche in Google Scholar
  • 15 Ray JG, Deniz S, Olivieri A. et al. Increased blood product use among coronary artery bypass patients prescribed preoperative aspirin and clopidogrel. BMC Cardiovasc Disord 2003; 03: 3.
    CrossrefPubMedSuche in Google Scholar
  • 16 Fox KA, Mehta SR, Peters R. et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004; 110: 1202-8.
    CrossrefPubMedSuche in Google Scholar
  • 17 Chen L, Bracey AW, Radovancevic R. et al. Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg 2004; 128: 425-31.
    CrossrefPubMedSuche in Google Scholar
  • 18 Chu MW, Wilson SR, Novick RJ. et al. Does clopidogrel increase blood loss following coronary artery bypass surgery?. Ann Thorac Surg 2005; 78: 1536-41.
    PubMedSuche in Google Scholar
  • 19 Horstick G, Heimann A, Gotze O. et al. Intracoronary application of C1 esterase inhibitor improves cardiac function and reduces myocardial necrosis in an experimental model of ischemia and reperfusion. Circulation 1997; 95: 701-8.
    CrossrefPubMedSuche in Google Scholar
  • 20 Folts JD, Crowell Jr EB, Rowe GG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 1976; 54: 365-70.
    CrossrefPubMedSuche in Google Scholar
  • 21 Folts J. An in vivo model of experimental arterial stenosis, intimal damage, and periodic thrombosis. Circulation 1991; 83 (Suppl. 06) IV3-14.
    PubMedSuche in Google Scholar
  • 22 Folts J, Rowe G. Acute thrombus formation in stenosed pig coronary arteries, causing sudden death by ventricular fibrillation. Circulation 1983; 68 Suppl III 264-9.
    PubMedSuche in Google Scholar
  • 23 Samama CM, Bonnin P, Bonneau M. et al. Comparative arterial antithrombotic activity of clopidogrel and acetyl salicylic acid in the pig. Thromb Haemost 1992; 68: 500-5.
    Thieme ConnectPubMedSuche in Google Scholar
  • 24 Just M, Martorana PA. Effect of molsidomine on thrombus formation in stenosed coronary arteries of dogs and pigs. J Cardiovasc Pharmacol 1989; (14) (Suppl. 11) S129-36.
    PubMedSuche in Google Scholar
  • 25 Born G, Cross M. The aggregation of blood platelets. J Physiol 1963; 168: 178-95.
    CrossrefPubMedSuche in Google Scholar
  • 26 Patrono C, Coller B, Dalen JE. et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 1998; 114: 470S-488S.
    CrossrefPubMedSuche in Google Scholar
  • 27 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.
    CrossrefPubMedSuche in Google Scholar
  • 28 Folts JD, Rowe GG. Epinephrine potentiation of in vivo stimuli reverses aspirin inhibition of platelet thrombus formation in stenosed canine coronary arteries. Thromb Res 1988; 50: 507-16.
    CrossrefPubMedSuche in Google Scholar
  • 29 Maalej N, Folts JD. Increased shear stress overcomes the antithrombotic platelet inhibitory effect of aspirin in stenosed dog coronary arteries. Circulation 1996; 93: 1201-5.
    CrossrefPubMedSuche in Google Scholar
  • 30 Owen NE, Feinberg H, Le Breton GC. Epinephrine induces Ca2+ uptake in human blood platelets. Am J Physiol 1980; 239: H483-H488.
    PubMedSuche in Google Scholar
  • 31 Plow EF, Marguerie GA. Induction of the fibrinogen receptor on human platelets by epinephrine and the combination of epinephrine and ADP. J Biol Chem 1980; 255: 10971-7.
    PubMedSuche in Google Scholar
  • 32 Roux SP, Sakariassen KS, Turitto VT. et al. Effect of aspirin and epinephrine on experimentally induced thrombogenesis in dogs. A parallelism between in vivo and ex vivo thrombosis models. Arterioscler Thromb 1991; 11: 1182-91.
    CrossrefPubMedSuche in Google Scholar
  • 33 Lin H, Young DB. Opposing effects of plasma epinephrine and norepinephrine on coronary thrombosis in vivo . Circulation 1995; 91: 1135-42.
    CrossrefPubMedSuche in Google Scholar
  • 34 Roussi J, Berge N, Bal dit Sollier C. et al. Clopidogrel-induced qualitative changes in thrombus formation correlate with stent patency in injured pig cervical arteries. Thromb Res 2002; 105: 209-16.
    CrossrefPubMedSuche in Google Scholar
  • 35 Begent N, Born GV. Growth rate in vivo of platelet thrombi, produced by iontophoresis of ADP, as a function of mean blood flow velocity. Nature 1970; 227: 926-30.
    CrossrefPubMedSuche in Google Scholar
  • 36 Anderson HV, McNatt J, Clubb FJ. et al. Platelet inhibition reduces cyclic flow variations and neointimal proliferation in normal and hypercholesterolemic-atherosclerotic canine coronary arteries. Circulation 2001; 104: 2331-7.
    CrossrefPubMedSuche in Google Scholar
  • 37 Yao SK, Ober JC, McNatt J. et al. ADP plays an important role in mediating platelet aggregation and cyclic flow variations in vivo in stenosed and endotheliuminjured canine coronary arteries. Circ Res 1992; 70: 39-48.
    CrossrefPubMedSuche in Google Scholar