Platelet inhibition by aspirin is diminished in patients during carotid surgery: a form of transient aspirin resistance?

Summary

The majority of patients who suffer peri-operative thromboembolic complication while undergoing vascular procedures do so despite taking aspirin. This study examined the antiplatelet effect of aspirin during surgery in patients undergoing carotid endarterectomy (CEA). Fifty patients undergoing CEA were standardised to 150 mg aspirin daily for ≥2 weeks. Platelet aggregation in response to arachidonic acid (AA) was measured in platelet rich plasma prepared from blood taken prior to, during, and at the end of surgery. Spontaneous platelet aggregation was also studied, as was the role of physiological agonists (ADP, collagen, thrombin, and epinephrine) in mediating the in vivo and in vitro responses to AA. Eighteen patients undergoing leg angioplasty, also on 150 mg aspirin, without general anaesthesia, served as a control group. In the CEA patients aggregation induced by AA (5 mM) increased significantly from 7.6 ± 5.5% pre-surgery to 50.8 ± 29.5% at the end of surgery (p <0.0001). Aggregation to AA was even greater in samples taken mid-surgery from a sub-set of patients (73.8 ± 7.2%; p = 0.0001), but fell to 45.9 ± 7.4% by the end of surgery. The increased aggregation in response to AA was not due to intra-operative release of physiological platelet agonists since addition of agents that block/neutralise the effects of ADP (apyrase; 4 µg/ml), thrombin (hirudin; 10 units/ml), or epinephrine (yohimbine; 10 µM/l) to the samples taken at the end of surgery did not block the increased aggregation.The patients undergoing angioplasty also showed a significant rise in the response to AA (5 mM), from 5.6 ± 5.5% pre-angioplasty to 32.4 ± 24.9% at the end of the procedure (p <0.0001), which fell significantly to 11.0 ± 8.1% 4 hours later. The antiplatelet activity of aspirin, mediated by blockade of platelet arachidonic acid metabolism, diminished significantly during surgery, but was partially restored by the end of the procedure without additional aspirin treatment.This rapidly inducible and transient effect may explain why some patients undergoing cardiovascular surgery remain at risk of peri-operative stroke and myocardial infarction.

Keywords

Aspirin - platelets - surgery - carotid artery - aspirin resistance

• References

• 1 Antithombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. Br Med J 2002; 321: 71-86.
• 2 Roth GJ, Stanford N, Marjerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci USA 1975; 72: 3073-6.
• 3 Collaborative overview of randomised trials of antiplatelet therapy. II. Maintenance of vascular graft or arterial patency by antiplatelet therapy. Antiplatelet Trialists’ Collaboration. Br Med J 1994; 308: 159-68.
• 4 Barnett HJM, Taylor DW, Eliasziw M. et al. for the North American Symptomatic carotid endarterectomy Trial. The benefit of carotid endarterectomy in symptomatic patients with moderate and severe stenosis. N Engl J Med 1988; 339: 1415-25.
• 5 Taylor DW, Barnett HJ, Haynes RB. et al. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Lancet 1999; 353: 2179-84.
• 6 Boysen G, Sorensen PS, Juhler M. Danish very low-dose aspirin after carotid endarterectomy trial. Stroke 1988; 19: 1211-5.
• 7 MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. European Carotid Surgery Trialists’ Collaborative Group. Lancet 1991; 337: 1235-43.
• 8 Weber AA, Przytulski B, Schanz A. et al. Towards a definition of aspirin resistance: a typological approach. Platelets 2002; 13: 37-40.
• 9 Pappas JM, Westengard JC, Bull BS. Population variability in the effect of aspirin on platelet function: Implications for clinical trials and therapy. Arch Pathol Lab Med 1994; 118: 801-4.
• 10 Eikelboom JW, Hirsh J, Weitz JI. et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650-5.
• 11 Gum PA, Kotte-Marchant K, Poggio ED. et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230-5.
• 12 Helgason CM, Bolin KM, Hoff JA. et al. Development of aspirin resistance in persons with previous ischaemic stroke. Stroke 1994; 25: 2231-6.
• 13 Buchanan RB, Brister SJ. Individual variation in the effects of ASA on platelet function: Implications for the use of ASA clinically. Can J Cardiol 1995; 11: 221-7.
• 14 Zimmermann N, Wenk A, Kim U. et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003; 108: 542-7.
• 15 Payne DA, Jones CI, Hayes PD. et al. Beneficial effects of Clopidogrel combined with aspirin in reducing cerebral emboli in patients undergoing carotid endarterectomy. Circulation 2004; 109: 1476-81.
• 16 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-72.
• 17 FitzGerald GA, Oates JA, Hawiger J. et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest 1983; 71: 678-88.
• 18 Patrono C, Coller B, Dalen JE. et al. Plateletactive drugs; the relationships among dose, effectiveness and side effects. Chest 2001; 119: 39S-63S.
• 19 Robless PA, Tegos TJ, Okonko D. et al. Platelet activation during carotid endarterectomy and the antiplatelet effect of Dextran 40. Platelets 2002; 13: 231-9.
• 20 Wells J, Nicosia S, Wale C. et al. Thrombin generation in patients undergoing carotid endarterectomy: implications in acute vessel wall closure and antithrombotic therapy. Thromb Res 1994; 75: 419-26.
• 21 Kabakibi A, Vamvakas EC, Cannistraro PA. et al Collagen-induced whole blood platelet aggregation in patients undergoing surgical procedures associated with minimal to moderate blood loss. Am J Clin Pathol 1998; 109: 392-8.
• 22 Lanza F, Bertetz A, Stierle A. et al. Epinephrine potentiates human platelet activation but is not an aggregating agent. Am J Physiol 1988; 255: H1276-H1288.
• 23 Hjemdahl P, Chronos NAF, Wilson DJ. et al. Epinephrine sensitises human platelets in vivo and in vitro as studied by fibrinogen binding and P-selectin expression. Arterioscler Thromb 1994; 14: 77-84.
• 24 Larsson PT, Wallen NH, Hjemdahl P. Norepinephrine-induced platelet activation invivo is only partly counteracted by aspirin. Circulation 1994; 89: 1951-7.
• 25 Chong BH, Ismail F. The mechanism of heparin-induced platelet aggregation. Eur J Haematol 1989; 43: 245-51.
• 26 Knight CJ, Panesara M, Wilson DJ. et al. Increased platelet responsiveness following coronary stenting: Heparin as a possible aetiological factor in stent thrombosis. Eur Heart J 1998; 19: 1239-48.
• 27 Horne MK, Chao ES. Heparin binding to resting and activated platelets. Blood 1989; 74: 238-43.
• 28 Olivecrona T, Bengtsson-Olivecrona G, Ostergaard P. et al. New aspects on heparin and lipoprotein metabolism. Haemostasis 1993; 23: 150-60.
• 29 Melin T, Qi C, Bengstsson-Olivecrona G. et al. Hydrolysis of chylomicron polyenoic fatty acid esters with lipoprotein lipase and hepatic lipase. Biochim Biophys Acta 1991; 1075: 259-66.
• 30 Sutherland M, Shankaranaraynan P, Schewe T. et al. Evidence for the presence of phospholipid hydroperoxide glutathione peroxidase in human platelets: implications for its involvement in the regulatory network of 12-lipoxygenase pathway of arachidonic acid metabolism. Biochem J 2001; 353: 91-100.
• 31 Buchanan MR, Butt RW, Hirsh J. et al. Role of lipoxygenase metabolism in platelet function: effect of aspirin and salicylate. Prostagland Leukot Med 1986; 21: 157-68.
• 32 Morita I, Murota SI. Role of 12-lipoxygenase products of arachidonic acid on platelet aggregation. Adv Prostaglandin Thromboxane Leukot Res 1987; 17: 219-23.
• 33 Calzade C, Vericel E, Lagarde M. Low concentrations of lipid hydroperoxides prime human platelet aggregation specifically via cyclo-oxygenase activation. Biochem J 1997; 325: 495-500.
• 34 Johnson EN, Brass LF, Funk CD. Increased platelet sensitivity to ADP in mice lacking platelet-type 12 lipoxygenase. Proc Natl Acad Sci USA 1998; 95: 3100-5.
• 35 Csiszar A, Stef G, Pacher P. et al. Oxidative stress-induced isoprostane formation may contribute to aspirin resistance in platelets. Prostaglandins Leukot Essent Fatty Acids 2002; 66: 557-8.
• 36 Karim S, Habib A, Levy-Toledano S. et al. Cyclo-oxygenase –1 and –2 of endothelial cells utilize exogenous or endogenous arachidonic acid for transcellular production of thromboxane. J Biol Chem 1996; 271: 12042-8.
• 37 Weber AA, Zimmermann N, Meyer-Kirchrath J. et al. Cyclo-oxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999; 353: 900.
• 38 Rocca B, Secchiero P, Ciabattoni G. et al. Cyclo-oxygenase-2 expression is induced during human megakaryopoiesis and characterises newly formed platelets. Proc Natl Acad Sci USA 2002; 99: 7634-9.
• 39 Reiter R, Resc U, Sinzinger H. Do human platelets express COX-2?. Prostaglandins Leukot Essent Fatty Acids 2001; 64: 299-305.