Download PDF
Thromb Haemost 2011; 105(04): 663-669
DOI: 10.1160/TH10-08-0550
Platelets and Blood Cells
Schattauer GmbH

Residual cyclooxygenase-1 activity and epinephrine reduce the antiplatelet effect of aspirin in patients with acute myocardial infarction

Antonio Moscardó
1   Research Center, University Hospital La Fe, Valencia, Spain
,
María Teresa Santos   *
1   Research Center, University Hospital La Fe, Valencia, Spain
,
María Paz Fuset
2   Intensive Care Unit, University Hospital La Fe, Valencia, Spain
,
Miguel Ruano
2   Intensive Care Unit, University Hospital La Fe, Valencia, Spain
,
Juana Vallés   *
1   Research Center, University Hospital La Fe, Valencia, Spain
› Author Affiliations Financial support: This work was supported in part by grants from the Spanish Fondo de Investigaciones Sanitarias del Ministerio de Sanidad y Consumo (FIS) [FIS07/0463] to [AM, MTS, JV]; Fundación Mutua Madrileña to [MTS, JV] and Fundación de Investigación Hospital La Fe to [MPF].
Further Information

Publication History

Received: 25 August 2010

Accepted after major revision: 19 January 2011

Publication Date:
28 November 2017 (online)

    Permissions and Reprints

Summary

Aspirin treatment is essential in patients with acute myocardial infarction (AMI) to block platelet thromboxane (TXA)2 synthesis. Epinephrine is known to enhance platelet reactivity induced by other agonists and to be elevated in patients with AMI due to stress. Our objective was to study the influence of epinephrine on platelet TXA2 synthesis in patients treated with aspirin for AMI at early onset (within 48 hours) and the potential biochemical mechanisms involved in the functional response. Washed platelets from 45 patients with AMI and 10 aspirin-free controls were stimulated with arachidonic acid (AA) or AA + epinephrine, and aggregation and TXA2 synthesis were evaluated. Full platelet aggregation was recorded in 8/45 patients (18%) with a partial TXA2 inhibition (86%) vs. the aspirin-free controls. Platelets from the remaining 37 patients did not aggregate to AA and had TXA2 inhibition >95%. However, when platelets were simultaneously stimulated with AA + epinephrine, in 25/37 patients a large intensity of aggregation (73%) was observed and a 5.5-fold increase in TXA2 synthesis, although this remained residual (<5% of aspirin-free controls). This residual-TXA2 was critical in the functional response, as demonstrated by the complete inhibition by TXA2 receptor blockade or additional aspirin in vitro. The phosphatidylinositol-3-kinase activity and the cytosolic calcium levels participated in this platelet response elicited by a receptor cooperation mechanism, while the Rho/p160ROCK pathway or the blockade of the ADP receptors (P2Y1, P2Y12) were without effect. Residual-cyclooxygenase –1 activity and epinephrine enhance TXA2-dependent platelet function, which may reduce the clinical benefit of aspirin in patients with AMI.

Keywords

Platelets - aspirin - thromboxane A2 - epinephrine - acute myocardial infarction

* MTS and JV contributed equally to this study.


 

  • References

  • 1 RISC.. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet 1990; 336: 827-830.
    CrossrefPubMedGoogle Scholar
  • 2 ISIS-2.. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. J Am Coll Cardiol 1988; 12: 3A-13A.
    CrossrefPubMedGoogle Scholar
  • 3 Valles J, Santos MT, Fuset MP. et al. Partial inhibition of platelet thromboxane A2 synthesis by aspirin is associated with myonecrosis in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2007; 99: 19-25.
    CrossrefPubMedGoogle Scholar
  • 4 Santos MT, Fuset MP, Ruano M. et al. Effect of atorvastatin on platelet thromboxane A(2) synthesis in aspirin-treated patients with acute myocardial infarction. Am J Cardiol 2009; 104: 1618-1623.
    CrossrefPubMedGoogle Scholar
  • 5 Pulcinelli FM, Biasucci LM, Riondino S. et al. COX-1 sensitivity and thromboxane A2 production in type 1 and type 2 diabetic patients under chronic aspirin treatment. Eur Heart J 2009; 30: 1279-1286.
    CrossrefPubMedGoogle Scholar
  • 6 Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and clopidogrel in atherothrombotic disease. Circulation 2007; 115: 2196-2207.
    CrossrefPubMedGoogle Scholar
  • 7 Santos MT, Valles J, Lago A. et al. Residual platelet thromboxane A2 and prothrombotic effects of erythrocytes are important determinants of aspirin resistance in patients with vascular disease. J Thromb Haemost 2008; 6: 615-621.
    CrossrefPubMedGoogle Scholar
  • 8 Yang J, Wu J, Jiang H. et al. Signaling through Gi family members in platelets. Redundancy and specificity in the regulation of adenylyl cyclase and other effectors. J Biol Chem 2002; 277: 46035-46042.
    CrossrefPubMedGoogle Scholar
  • 9 Stubbs PJ, Laycock J, Alaghband-Zadeh J. et al. Circulating stress hormone and insulin concentrations in acute coronary syndromes: identification of insulin resistance on admission. Clin Sci (Lond) 1999; 96: 589-595.
    CrossrefPubMedGoogle Scholar
  • 10 Dorn 2nd GW, Liel N, Trask JL. et al. Increased platelet thromboxane A2/prostaglandin H2 receptors in patients with acute myocardial infarction. Circulation 1990; 81: 212-218.
    CrossrefPubMedGoogle Scholar
  • 11 Wallen NH, Held C, Rehnqvist N. et al. Impact of treatment with acetylsalicylic acid on the proaggregatory effects of adrenaline in vitro in patients with stable an-gina pectoris: influence of the anticoagulant. Clin Sci (Lond) 1993; 85: 577-583.
    CrossrefPubMedGoogle Scholar
  • 12 Lanza F, Beretz A, Stierle A. et al. Epinephrine potentiates human platelet activation but is not an aggregating agent. Am J Physiol 1988; 255: H1276-1288.
    PubMedGoogle Scholar
  • 13 Santos MT, Moscardo A, Valles J. et al. Participation of tyrosine phosphorylation in cytoskeletal reorganization, alpha(IIb)beta(3) integrin receptor activation, and aspirin-insensitive mechanisms of thrombin-stimulated human platelets. Circulation 2000; 102: 1924-1930.
    CrossrefPubMedGoogle Scholar
  • 14 Brash AR. Arachidonic acid as a bioactive molecule. J Clin Invest 2001; 107: 1339-1345.
    CrossrefPubMedGoogle Scholar
  • 15 Jackson SP, Schoenwaelder SM, Goncalves I. et al. PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 2005; 11: 507-514.
    CrossrefPubMedGoogle Scholar
  • 16 Klages B, Brandt U, Simon MI. et al. Activation of G12/G13 results in shape change and Rho/Rho-kinase-mediated myosin light chain phosphorylation in mouse platelets. J Cell Biol 1999; 144: 745-754.
    CrossrefPubMedGoogle Scholar
  • 17 Moers A, Nieswandt B, Massberg S. et al. G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat Med 2003; 9: 1418-1422.
    CrossrefPubMedGoogle Scholar
  • 18 Yazaki A, Tamaru S, Sasaki Y. et al. Inhibition by Rho-kinase and protein kinase C of myosin phosphatase is involved in thrombin-induced shape change of megakaryocytic leukemia cell line UT-7/TPO. Cell Signal 2005; 17: 321-330.
    CrossrefPubMedGoogle Scholar
  • 19 Dorsam RT, Kim S, Jin J. et al. Coordinated signaling through both G12/13 and G(i) pathways is sufficient to activate GPIIb/IIIa in human platelets. J Biol Chem 2002; 277: 47588-47595.
    CrossrefPubMedGoogle Scholar
  • 20 Rocca B, Secchiero P, Ciabattoni G. et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002; 99: 7634-7639.
    CrossrefPubMedGoogle Scholar
  • 21 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: 1182-1191.
    CrossrefPubMedGoogle Scholar
  • 22 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: 507-516.
    CrossrefPubMedGoogle Scholar
  • 23 Patrono C, Coller B, FitzGerald GA. et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 234S-264S.
    CrossrefPubMedGoogle Scholar
  • 24 Marcucci R, Gori AM, Paniccia R. et al. High on-treatment platelet reactivity by more than one agonist predicts 12-month follow-up cardiovascular death and non-fatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting. Thromb Haemost 2010; 104: 279-286.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Crescente M, Di Castelnuovo A, Iacoviello L. et al. PFA-100 closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a meta-analysis of 19 studies comprising 3,003 patients. Thromb Haemost 2008; 99: 1129-1131.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Zimmermann N, Hohlfeld T. Clinical implications of aspirin resistance. Thromb Haemost 2008; 100: 379-390.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006; 4: 542-549.
    CrossrefPubMedGoogle Scholar
  • 28 Banga HS, Simons ER, Brass LF. et al. Activation of phospholipases A and C in human platelets exposed to epinephrine: role of glycoproteins IIb/IIIa and dual role of epinephrine. Proc Natl Acad Sci USA 1986; 83: 9197-9201.
    CrossrefPubMedGoogle Scholar
  • 29 Mustonen P, van Willigen G, Lassila R. Epinephrine--via activation of p38-MAPK--abolishes the effect of aspirin on platelet deposition to collagen. Thromb Res 2001; 104: 439-449.
    CrossrefPubMedGoogle Scholar
  • 30 Altman R, Scazziota A, Funes JC. Why single daily dose of aspirin may not prevent platelet aggregation. Thromb Res 1988; 51: 259-266.
    CrossrefPubMedGoogle Scholar
  • 31 Walsh M, Foley JF, Kinsella BT. Investigation of the role of the carboxyl-terminal tails of the alpha and beta isoforms of the human thromboxane A(2) receptor (TP) in mediating receptor:effector coupling. Biochim Biophys Acta 2000; 1496: 164-182.
    CrossrefPubMedGoogle Scholar
  • 32 Li Z, Zhang G, Le Breton GC. et al. Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases. J Biol Chem 2003; 278: 30725-30731.
    CrossrefPubMedGoogle Scholar
  • 33 Goel R, Phillips-Mason PJ, Gardner A. et al. Alpha-thrombin-mediated phosphatidylinositol 3-kinase activation through release of Gbetagamma dimers from Galphaq and Galphai2. J Biol Chem 2004; 279: 6701-6710.
    CrossrefPubMedGoogle Scholar
  • 34 Nieswandt B, Schulte V, Zywietz A. et al. Costimulation of Gi- and G12/G13-mediated signaling pathways induces integrin alpha IIbbeta 3 activation in platelets. J Biol Chem 2002; 277: 39493-39498.
    CrossrefPubMedGoogle Scholar