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Thromb Haemost 2014; 111(04): 713-724
DOI: 10.1160/TH13-08-0643
Platelets and Blood Cells
Schattauer GmbH

Thrombin-induced platelet-fibrin clot strength: Relation to high on-clopidogrel platelet reactivity, genotype, and post-percutaneous coronary intervention outcomes

Young-Hoon Jeong
1   Sinai Center for Thrombosis Research, Baltimore, Maryland, USA
2   Department of Internal Medicine, Gyeongsang National University Hospital and Gyeongsang National University, Jinju, Korea
,
Kevin P. Bliden
1   Sinai Center for Thrombosis Research, Baltimore, Maryland, USA
,
Alan R. Shuldiner
3   Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
,
Udaya S. Tantry
1   Sinai Center for Thrombosis Research, Baltimore, Maryland, USA
,
Paul A. Gurbel
1   Sinai Center for Thrombosis Research, Baltimore, Maryland, USA
› Author Affiliations
Further Information

Publication History

Received: 07 August 2013

Accepted after minor revision: 03 November 2013

Publication Date:
29 November 2017 (online)

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Summary

The relationship between thrombin-induced platelet-fibrin clot strength (MATHROMBIN), genotype and high on-treatment platelet reactivity (HPR) is unknown. The aim of this study is to assess the influence of MATHROMBIN measured by thrombelastography on HPR and long-term major adverse cardiovascular events (MACE) in percutaneous coronary intervention (PCI)-treated patients during aspirin and clopidogrel therapy. MATHROMBIN, platelet aggregation, genotype, and two-year MACE were assessed in 197 PCI-treated patients. HPR was defined as 5 µM ADP-induced PR46% measured by conventional aggregometry. Both high MATHROMBIN ( 68 mm) and CYP2C19*2 allele carriage were independently associated with ADP-induced platelet aggregation ([uni03B2] coefficient: 8.3% and 12.0%, respectively). The combination of CYP2C19*2 allele carriage and high MATHROMBIN increased the predictive value for the risk of HPR (odds ratio: 13.89; 95% confidence interval: 3.41 to 55.56; p < 0.001). MACE occurred in 25 patients (12.7%). HPR and high MATHROMBIN were both associated with MACE (hazard ratio: 3.09 and 2.24, respectively), and patients with both HPR and high MATHROMBIN showed an increased risk for MACE (adjusted hazard ratio: 5.56; 95% confidence interval: 1.85 to 16.67; p = 0.002). In conclusion, this is the first study to demonstrate that high platelet-fibrin clot strength is an independent determinant of HPR in PCI-treated patients. Combining the measurements of platelet aggregation and platelet-fibrin clot strength may enhance post-PCI risk stratification and deserves further study.

Keywords

Percutaneous coronary intervention - clot strength - platelet - clopidogrel - cytochrome P450

 

  • References

  • 1 Tantry US, Bonello L, Aradi D. et al. Consensus and update on the definition of on-treatment platelet reactivity to ADP associated with ischemia and bleeding.. J Am Coll Cardiol. 2013 Epub ahead of print.
    PubMedGoogle Scholar
  • 2 Levine GN, Bates ER, Blankenship JC. et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: Executive Summary A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions.. J Am Coll Cardiol 2011; 58: 2550-2583.
    CrossrefPubMedGoogle Scholar
  • 3 Mega JL, Close SL, Wiviott SD. et al. Cytochrome p-450 polymorphisms and response to clopidogrel.. N Engl J Med 2009; 360: 354-362.
    CrossrefPubMedGoogle Scholar
  • 4 Fernando H, Dart AM, Peter K, Shaw JA. Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy.. Thromb Haemost 2011; 105: 933-944.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Lippi G, Franchini M, Targher G. Arterial thrombus formation in cardiovascular disease.. Nat Rev Cardiol 2011; 8: 502-512.
    CrossrefPubMedGoogle Scholar
  • 6 Hobson AR, Agarwala RA, Swallow RA. et al. Thrombelastography: current clinical applications and its potential role in interventional cardiology.. Platelets 2006; 17: 509-518.
    CrossrefPubMedGoogle Scholar
  • 7 Tantry US, Bliden KP, Suarez TA. et al. Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study.. Platelets 2010; 21: 360-367.
    CrossrefPubMedGoogle Scholar
  • 8 Ostrowski SR, Windeløv NA, Ibsen M. et al. Consecutive thrombelastography clot strength profiles in patients with severe sepsis and their association with 28-day mortality: A prospective study.. J Crit Care 2013; 28: 317.e1-317.e11.
    CrossrefPubMedGoogle Scholar
  • 9 Ives C, Inaba K, Branco BC. et al. Hyperfibrinolysis elicited via Thromboelastography predicts mortality in trauma.. J Am Coll Surg 2012; 215: 496-502.
    CrossrefPubMedGoogle Scholar
  • 10 Rafiq S, Johansson PI, Ostrowski SR. et al. Hypercoagulability in patients undergoing coronary artery bypass grafting: prevalence, patient characteristics and postoperative outcome.. Eur J Cardiothorac Surg 2012; 41: 550-555.
    CrossrefPubMedGoogle Scholar
  • 11 Cotton BA, Minei KM, Radwan ZA. et al. Admission rapid thrombelastography predicts development of pulmonary embolism in trauma patients.. J Trauma Acute Care Surg 2012; 72: 1470-1475.
    CrossrefPubMedGoogle Scholar
  • 12 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.
    CrossrefPubMedGoogle Scholar
  • 13 Gurbel PA, Bliden KP, Navickas IA. et al. Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischaemic events.. Am Heart J 2010; 160: 346-354.
    CrossrefPubMedGoogle Scholar
  • 14 Shuldiner AR, O’Connell JR, Bliden KP. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.. J Am Med Assoc 2009; 302: 849-857.
    CrossrefPubMedGoogle Scholar
  • 15 Lewis JP, Fisch AS, Ryan K. et al. Paraoxonase 1 (PON1) gene variants are not associated with clopidogrel response.. Clin Pharmacol Ther 2011; 90: 568-574.
    CrossrefPubMedGoogle Scholar
  • 16 Thygesen K, Alpert JS, Jaffe AS. et al. Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction.. Third universal definition of myocardial infarction.. J Am Coll Cardiol 2012; 60: 1581-1598.
    CrossrefPubMedGoogle Scholar
  • 17 Cutlip DE, Nakazawa G, Krucoff MW. et al. Autopsy validation study of the academic research consortium stent thrombosis definition.. JACC Cardiovasc Interv 2011; 4: 554-559.
    CrossrefPubMedGoogle Scholar
  • 18 Breet NJ, van Werkum JW, Bouman HJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.. J Am Med Assoc 2010; 303: 754-762.
    CrossrefPubMedGoogle Scholar
  • 19 Tantry US, Gurbel PA. Assessment of oral antithrombotic therapy by platelet function testing.. Nat Rev Cardiol 2011; 8: 572-579.
    CrossrefPubMedGoogle Scholar
  • 20 Gurbel PA, Bliden KP, Saucedo JF. et al. Bivalirudin and clopidogrel with and without eptifibatide for elective stenting: effects on platelet function, thrombelastographic indexes, and their relation to periprocedural infarction results of the CLEAR PLATELETS-2 (Clopidogrel with Eptifibatide to Arrest the Reactivity of Platelets) study.. J Am Coll Cardiol 2009; 53: 648-657.
    CrossrefPubMedGoogle Scholar
  • 21 Ahn SG, Lee SH, Yoon JH. et al. Different prognostic significance of high on-treatment platelet reactivity as assessed by the VerifyNow P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction.. JACC Cardiovasc Interv 2012; 5: 259-267.
    CrossrefPubMedGoogle Scholar
  • 22 Mangiacapra F, Patti G, Peace A. et al. Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention.. Am J Cardiol 2010; 106: 619-623.
    CrossrefPubMedGoogle Scholar
  • 23 Müller K, Aichele S, Herkommer M. et al. Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease.. Atherosclerosis 2010; 213: 256-262.
    CrossrefPubMedGoogle Scholar
  • 24 Srinivasa V, Gilbertson LI, Bhavani-Shankar K. Thromboelastography: where is it and where is it heading?. Int Anesthesiol Clin 2001; 39: 35-49.
    CrossrefPubMedGoogle Scholar
  • 25 McCrath DJ, Cerboni E, Frumento RJ. et al. Thromboelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction.. Anesth Analg 2005; 100: 1576-1583.
    CrossrefPubMedGoogle Scholar
  • 26 Chen A, Teruya J. Global haemostasis testing thromboelastography: old technology, new applications.. Clin Lab Med 2009; 29: 391-407.
    CrossrefPubMedGoogle Scholar
  • 27 Jeong YH, Bliden KP, Antonino MJ. et al. Usefulness of thrombelastography platelet mapping assay to measure the antiplatelet effect of P2Y12 receptor inhibitors and high on-treatment platelet reactivity.. Platelets 2013; 24: 166-169.
    CrossrefPubMedGoogle Scholar
  • 28 Mahla E, Suarez TA, Bliden KP. et al. Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study.. Circ Cardiovasc Interv 2012; 5: 261-269.
    CrossrefPubMedGoogle Scholar
  • 29 Kwak YL, Kim JC, Choi YS. et al. Clopidogrel responsiveness regardless of the discontinuation date predicts increased blood loss and transfusion requirement after off-pump coronary artery bypass graft surgery.. J Am Coll Cardiol 2010; 56: 1994-2002.
    CrossrefPubMedGoogle Scholar
  • 30 Ahn SG, Lee SH, Yoon JH. et al. Different prognostic significance of high on-treatment platelet reactivity as assessed by the VerifyNow P2Y12 assay after coronary stenting in patients with and without acute myocardial infarction.. JACC Cardiovasc Interv 2012; 5: 259-267.
    CrossrefPubMedGoogle Scholar
  • 31 Park DW, Ahn JM, Song HG. et al. Differential prognostic impact of high on-treatment platelet reactivity among patients with acute coronary syndromes versus stable coronary artery disease undergoing percutaneous coronary intervention.. Am Heart J 2013; 165: 34-42.e1.
    CrossrefPubMedGoogle Scholar
  • 32 Inoue T, Croce K, Morooka T. et al. Vascular inflammation and repair: implications for re-endothelialisation, restenosis, and stent thrombosis.. JACC Cardiovasc Interv 2011; 4: 1057-1066.
    CrossrefPubMedGoogle Scholar
  • 33 Oikawa Y, Yajima J, Costa MA. et al. Intravascular ultrasound, angioscopic and histopathological characterisation of heterogeneous patterns of restenosis after sirolimus-eluting stent implantation: insights into potential “thromborestenosis” phenomenon.. EuroIntervention 2010; 6: 380-387.
    CrossrefPubMedGoogle Scholar
  • 34 Cvirn G, Hoerl G, Schlagenhauf A. et al. Stent implantation in the superficial fe-moral artery: short thrombelastometry-derived coagulation times identify patients with late in-stent restenosis.. Thromb Res 2012; 130: 485-490.
    CrossrefPubMedGoogle Scholar
  • 35 Motoda C, Ueda H, Hayashi Y. et al. Impact of platelet reactivity to adenosine diphosphate before implantation of drug-eluting stents on subsequent adverse cardiac events in patients with stable angina.. Circ J 2012; 76: 641-649.
    CrossrefPubMedGoogle Scholar
  • 36 Nishio R, Shinke T, Otake H. et al. Effect of cytochrome P450 2C19 polymorphism on target lesion outcome after drug-eluting stent implantation in japanese patients receiving clopidogrel.. Circ J 2012; 76: 2348-2355.
    CrossrefPubMedGoogle Scholar
  • 37 Spiliopoulos S, Pastromas G, Katsanos K. et al. Platelet responsiveness to clopidogrel treatment after peripheral endovascular procedures: the PRECLOP study: clinical impact and optimal cut-off value of on-treatment high platelet reactivity.. J Am Coll Cardiol 2013; 61: 2428-2434.
    CrossrefPubMedGoogle Scholar
  • 38 Mega JL, Braunwald E, Wiviott SD. et al ATLAS ACS 2–TIMI 51 Investigators.. Rivaroxaban in patients with a recent acute coronary syndrome.. N Engl J Med 2012; 366: 9-19.
    CrossrefPubMedGoogle Scholar
  • 39 Davis PK, Musunuru H, Walsh M. et al. The ex vivo reversibility of dabigatran-induced whole-blood coagulopathy as monitored by thromboelastography: mechanistic implications for clinical medicine.. Thromb Haemost 2012; 108: 586-588.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Xu Y, Wu W, Wang L. et al. Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro.. Blood Coagul Fibrinolysis 2013; 24: 332-338.
    CrossrefPubMedGoogle Scholar
  • 41 Samama MM, Martinoli JL, LeFlem L. et al. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor.. Thromb Haemost 2010; 103: 815-825.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Grove EL, Hossain R, Storey RF. Platelet function testing and prediction of procedural bleeding risk.. Thromb Haemost 2013; 109: 817-824.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Alexopoulos D, Galati A, Xanthopoulou I. et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study.. J Am Coll Cardiol 2012; 60: 193-199.
    CrossrefPubMedGoogle Scholar
  • 44 Cattaneo M. High on-treatment platelet reactivity--definition and measurement.. Thromb Haemost 2013; 109: 792-798.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Dahlen JR, Price MJ, Parise H. et al. Evaluating the clinical usefulness of platelet function testing: considerations for the proper application and interpretation of performance measures.. Thromb Haemost 2013; 109: 808-816.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Trenk D, Kristensen SD, Hochholzer W. et al. High on-treatment platelet reactivity and P2Y12 antagonists in clinical trials.. Thromb Haemost 2013; 109: 834-845.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Huber K, Schrör K. High on-treatment platelet reactivity--why should we be concerned?. Thromb Haemost 2013; 109: 789-791.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Brouwer MA, Jaspers Focks J, Verheugt FW. High platelet reactivity—the challenge of prolonged anticoagulation therapy after ACS.. Thromb Haemost 2013; 109: 799-807.
    Article in Thieme ConnectPubMedGoogle Scholar