Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function

Anna Maria Gori; Rossella Marcucci; Rita Paniccia; Betti Giusti; Sandra Fedi; Emilia Antonucci; Piergiovanni Buonamici; David Antoniucci; Gian Franco Gensini; Rosanna Abbate

doi:10.1160/TH08-06-0374

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(06): 1136-1145
DOI: 10.1160/TH08-06-0374

Platelets and Blood Cells

Schattauer GmbH

Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function

Anna Maria Gori

¹Department of Medical and Surgical Critical Care, University of Florence; Centre for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, Florence, Italy

,

Rossella Marcucci

¹Department of Medical and Surgical Critical Care, University of Florence; Centre for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, Florence, Italy

,

Rita Paniccia

¹Department of Medical and Surgical Critical Care, University of Florence; Centre for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, Florence, Italy

,

Betti Giusti

¹Department of Medical and Surgical Critical Care, University of Florence; Centre for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, Florence, Italy

,

Sandra Fedi

¹Department of Medical and Surgical Critical Care, University of Florence; Centre for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, Florence, Italy

,

Emilia Antonucci

¹Department of Medical and Surgical Critical Care, University of Florence; Centre for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, Florence, Italy

,

Piergiovanni Buonamici

²Department of Heart and Vessels, Azienda Ospedaliero-Universitaria, Florence, Italy

,

David Antoniucci

²Department of Heart and Vessels, Azienda Ospedaliero-Universitaria, Florence, Italy

,

Gian Franco Gensini

¹Department of Medical and Surgical Critical Care, University of Florence; Centre for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, Florence, Italy

,

Rosanna Abbate

¹Department of Medical and Surgical Critical Care, University of Florence; Centre for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, Florence, Italy

› Author Affiliations

Abstract

Summary

A higher rate of clinical events in poor clopidogrel and/or aspirin responders was documented by using different methods to measure platelet function, but no conclusive data about the appropriate methodology to explore platelet reactivity are available.A total of 746 patients included in the cohort of the RECLOSE trial who had successful drug-eluting stent implantation were assessed for post-treatment residual platelet reactivity (RPR) in platelet-rich plasma by 10 µM adenosine 5’-diphosphate (ADP),1 mM arachidonic acid (AA) and 2 µg/ml collageninduced platelet aggregation and in whole blood by the PFA-100 system. At six-month follow-up, RPR by two stimuli (ADP and AA or ADP and collagen) and by three stimuli (ADP,AA and collagen) is significantly associated with higher percentage of primary (definite or probable stent thrombosis) and secondary cardiac mortality and stent thrombosis) end-points than RPR by ADP,AA, collagen and PFA-100 system.According to the primary and secondary end points, the specificity values for RPR identified by two (ADP and AA: 94%;ADP and collagen: 97%) and three stimuli were higher with respect to RPR by ADP (88%), or RPR by AA (83%) or RPR by collagen (90%).The positive likelihood ratio values of RPR by three stimuli (9.55) or of RPR by ADP and collagen (8.08) were higher than those of RPR by ADP (2.59), byAA (2.05), by collagen (4.73), or by PFA-100 (2.63).This prospective study documents that the evaluation of platelet reactivity addressed to identify patients at risk of thrombotic events on dual antiplatelet treatment has to be carried out by methods able to explore different pathways.

Keywords

Residual platelet reactivity - stent thrombosis - cardiac mortality - platelet function tests - aspirin - clopidogrel

Full Text

References

References
1 Willerson JT, Golino P, Eidt J. et al. Specific platelet mediators and unstable coronary artery lesions. Experimental evidence and potential clinical implications. Circulation 1989; 80: 198-205.
2 Fitzgerald DJ, Roy L, Catella F. et al. Platelet activation in unstable coronary disease. New Engl J Med 1986; 315: 983-989.
3 Ault KA, Cannon CP, Mitchell J. et al. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1999; 33: 634-639.
4 Mehta SR, Yusuf S, Peters RJ. et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
5 Steinhubl SR, Berger PB, Mann 3rd JT. et al. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
6 Bhatt DL, Bertrand ME, Berger PB. et al. Metaanalysis of randomized and registry comparison of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 2002; 39: 9-14.
7 Steinberg DH, Pinto Slottow TL, Buch AN. et al. Impact of in-stent restenosis on death and myocardial infarction. Am J Cardiol 2007; 100: 1109-1113.
8 Lemos PA, Lee CH, Degertekin M. et al. Early outcome after sirolimus-eluting stent implantation in patients with acute coronary syndromes: insights from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. J Am Coll Cardiol 2003; 41: 2093-2099.
9 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
10 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
11 Gurbel PA, Bliden KP, Guyer K. et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46: 1820-1826.
12 Ajzenberg N, Aubry P, Huisse MG. et al. Enhanced shear-induced platelet aggregation in patients who experienced stent thrombosis. J Am Coll Cardiol 2005; 45: 1753-1756.
13 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; 04: 542-549.
14 Buonamici P, Marcucci R, Migliorini A. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
15 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation|. Eur Heart J. 2008 prepub online doi:10.1093/eurheartj/ehn046.
16 Crescente M, Di Castelnuovo A, Iacoviello L. et al. Response variability to aspirin as assessed by the platelet function analyzer (PFA)-100. A systematic review. Thromb Haemost 2008; 99: 14-26.
17 Gum PA, Kottke-Marchant K, Welsh PA. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-965.
18 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
19 Paniccia R, Antonucci E, Gori AM. et al. Comparison of different methods to evaluate the effect of aspirin on platelet function in high-risk patients with ischemic heart disease receiving dual antiplatelet treatment. Am J Clin Pathol 2007; 128: 143-149.
20 Shankar H, Garcia A, Prabhakar J. et al. P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation. J Thromb Haemost 2006; 04: 638-647.
21 André P, LaRocca T, Delaney SM. et al. Anticoagulants (thrombin inhibitors) and aspirin synergize with P2Y12 receptor antagonism in thrombosis. Circulation 2003; 108: 2697-2703.
22 Lecut C, Schoolmeester A, Kuijpers MJ. et al. Principal role of glycoprotein VI in alpha2beta1 and alphaIIbbeta3 activation during collagen-induced thrombus formation. Arterioscler Thromb Vasc Biol 2004; 24: 1727-1733.
23 Mannini L, Marcucci R, Paniccia R. et al. Erythrocyte deformability and white blood cell count are associated with aspirin resistance in high-risk vascular patients. Clin Hemorheol Microcirc 2006; 35: 175-181.
24 Marcucci R, Gori AM, Paniccia R. et al. Residual platelet reactivity is associated with clinical and laboratory characteristics in patients with ischemic heart disease undergoing PCI on dual antiplatelet therapy. Atherosclerosis 2007; 195: e217-223.
25 Lepäntalo A, Beer JH, Siljander P. et al. Variability in platelet responses to collagen--comparison between whole blood perfusions, traditional platelet function tests and PFA-100. Thromb Res 2001; 103: 123-133.
26 Marcucci R, Paniccia R, Antonucci E. et al. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events. Am J Cardiol 2006; 98: 1156-1159.
27 Wiviott SD, Braunwald E, McCabe CH. et al. TRITON-TIMI 38 Investigators TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
28 Gurbel PA, Becker RC, Mann KG. et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007; 50: 1822-1834.
29 Bonello L, Camoin-Jau L, Arques S. et al. Adjusted clopidogrel loading doses according to vasodilatorstimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance. J Am Coll Cardiol 2008; 51: 1404-1411.