The influence of clinical characteristics, laboratory and inflammatory markers on ‘high on-treatment platelet reactivity’ as measured with different platelet function tests

Ellen H. A. M. Elsenberg; Jochem W. van Werkum; Ruud M. A. van de Wal; Carla A. Zomer; Heleen J. Bouman; Freek W. A. Verheugt; Jurriën M. ten Berg; Christian M. Hackeng

doi:10.1160/TH09-05-0285

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2009; 102(04): 719-727
DOI: 10.1160/TH09-05-0285

Platelets and Blood Cells

Schattauer GmbH

The influence of clinical characteristics, laboratory and inflammatory markers on ‘high on-treatment platelet reactivity’ as measured with different platelet function tests

Authors

Ellen H. A. M. Elsenberg

¹Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, the Netherlands
Jochem W. van Werkum

²Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands

³Department of Cardiology, UMC St. Radboud, Nijmegen, the Netherlands
Ruud M. A. van de Wal

²Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands
Carla A. Zomer

²Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands
Heleen J. Bouman

²Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands
Freek W. A. Verheugt

³Department of Cardiology, UMC St. Radboud, Nijmegen, the Netherlands
Jurriën M. ten Berg

²Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands
Christian M. Hackeng

¹Department of Clinical Chemistry, St. Antonius Hospital, Nieuwegein, the Netherlands

Abstract

Summary

High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are independently associated with an increased risk of atherothrombotic events. However, despite this positive correlation, the definitions of both HCPR and HAPR vary largely throughout studies and between different platelet function assays.The aim of the present study was to explore clinical and laboratory parameters that are associated with HCPR and HAPR as measured with different platelet function tests. 530 clopidogrel and aspirin pre-treated patients undergoing elective PCI (percutaneous coronary intervention) were enrolled. Platelet function measurements were performed with: optical aggregometry, the VerifyNow device and PFA-100 cartridges (including the novel INNOVANCE® P2Y assay). HCPR as measured with Adenosin-Di-Phospate-induced (ADP) aggregation based tests was associated with clinical factors such as older age, female gender and Diabetes mellitus (DM).TheVerifyNow P2Y12 assay was significantly influenced by haemoglobin and haematocrit levels. HAPR as measured with aggregation based tests was significantly influenced by the presence of malignancy, BMI (Body-Mass Index), older age and increased levels of hsCRP (high sensitivity c-reactive proteine).The PFA-100 COL/ EPI (collagen-epinephrine) and COL/ADP (collagen-ADP) cartridges were significantly influenced by monocyte count,hs-CRP, MPV (mean platelet volume), vWF-antigen (von Willebrand factor) and vWF-activity. HCPR as measured with the novel INNOVANCE® P2Y cartridge was associated with clinical determinants such as BMI,female gender,impaired LVEF (left ventricular ejection fraction), renal failure and dosing of clopidogrel. Laboratory markers that were associated with HCPR as measured with INNOVANCE® P2Y were platelet count, white blood cells (WBC), hsCRP and fibrinogen.

Both HCPR and HAPR are highly dependent on the type of platelet function assay. Each platelet function assay, in turn, is significantly influenced by distinct clinical and laboratory variables.

Keywords

High on-treatment platelet reactivity - clopidogrel - aspirin - platelet function testing

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Referenzen

References
1 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: 527-533.
2 Steinhubl SR, Berger PB, Mann JT. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 2411-2420.
3 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.
4 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.
5 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.
6 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: a multicenter randomized prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
7 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.
8 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.
9 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; 29: 992-1000.
10 Gianetti J, Parri MS, Sbrana S. et al. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty: A 6 months prospective study. Thromb Res 2006; 118: 487-493.
11 Frossard M, Fuchs I, Leitner JM. et al. Platelet function predicts myocardial damage in patients with acute myocardial infarction. Circulation 2004; 110: 1392-1397.
12 Fuchs I, Frossard M, Spiel A. et al. Platelet function in patients with acute coronary syndrome (ACS) predicts recurrent ACS. J Thromb Haemost 2006; 04: 2547-2552.
13 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 Card 2003; 41: 961-965.
14 Chen WH, Cheng X, Lee PY. et al. Aspirin resistance and adverse clinical events in patients with coronary artery disease. Am J Med 2007; 120: 631-563.
15 van Werkum JW, Hackeng CM, Smit JJ. et al. Monitoring antiplatelet therapy with point-of-care platelet function assays: a review of the evidence. Future Cardiology 2008; 08: 33-55.
16 Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539-553.
17 van Werkum JW, Kleibeuker M, Mieremet N. et al. Evaluation of the platelet response to clopidogrel with light transmittance aggregometry: peak aggregation or late aggregation?. J Thromb Haemost 2007; 05: 884-886.
18 Trip MD, Cats VM, van Capelle FJ. et al. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990; 322: 1549-1554.
19 Paniccia R, Antonucci E, Gori AM. et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 2007; 05: 1839-1847.
20 Lordkipanidze M, Pharand C, Schampaert E. et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702-1708.
21 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.
22 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115-1126.
23 Steinhubl SR, Badimon JJ, Bhatt DL. et al. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 2007; 12: 113-122.
24 Weyrich AS, Lindemann S, Zimmerman GA. The evolving role of platelets in inflammation. J Thromb Haemost 2003; 01: 1897-1905.
25 Esmon CT. Inflammation and thrombosis. J Thromb Haemost 2003; 01: 1343-1348.
26 Esmon CT. The impact of the inflammatory response on coagulation. Thromb Res 2004; 114: 321-327.
27 Franchini M, Veneri D, Lippi G. Inflammation and hemostasis: a bidirectional interaction. Clin Lab 2007; 53: 63-67.
28 Yeh ET, Khan BV. The potential role of antiplatelet agents in modulating inflammatory markers in atherothrombosis. J Thromb Haemost 2006; 04: 2308-2016.
29 Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet 1997; 349: 462-466.
30 Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-362.
31 Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, Schömig A, Kastrati A, von Beckerath N. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101: 714-719.

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