Lab Med Online.  2015 Jul;5(3):137-142. 10.3343/lmo.2015.5.3.137.

Platelet Activation Markers (beta-thromboglobulin and platelet factor 4) and Clopidogrel Drug Response in Patients with Myocardiac Infarction

Affiliations
  • 1Department of Laboratory Medicine, Chungnam National University, Daejeon, Korea. jmkim@cnuh.co.kr
  • 2Department of Cardiology, Chungnam National University, Daejeon, Korea.

Abstract

BACKGROUND
Dual antiplatelet therapy (aspirin and clopidogrel) is used to prevent adverse cardiac events in patients undergoing percutaneous coronary intervention (PCI). Some patients do not respond adequately to clopidogrel. Beta-thromboglobulin (beta-TG) and platelet factor 4 (PF-4) can act as markers to detect platelet activation. We investigated the relationship between clopidogrel response and the dynamics of beta-TG and PF4 concentrations.
METHODS
This study included 36 myocardial infarction (MI) patients, who underwent PCI and was indicated for dual antiplatelet therapy. Platelet reactivity, using the VerifyNow P2Y12 assay, was measured on the 3rd day of PCI. At the time of admission, and on the 3rd and 10th day of PCI, the plasma beta-TG and PF4 concentrations were quantified.
RESULTS
Ten patients (27.8%) were clopidogrel non-responders displaying >208 P2Y12 reaction units. At the time of admission, levels of beta-TG in patients were elevated than that in the healthy controls (P<0.001). A similar trend was observed on the 3rd and 10th day of PCI (P<0.001). The beta-TG levels on the 10th day were reduced than those at the time of admission and on the 3rd day of PCI. PF4 levels were not different between patients and controls, and were not significantly reduced after PCI. Higher beta-TG levels were observed in clopidogrel non-responders on the 10th day, but not significant.
CONCLUSIONS
Clopidogrel therapy in MI reduce beta-TG concentration, but the beta-TG and PF4 levels before and after therapy are not associated with the response to clopidogrel. Platelet-derived markers may not be suitable for distinguishing clopidogrel non-responders.

Keyword

Beta-thromboglobulin; Clopidogrel; Myocardial infarction; Platelet factor 4

MeSH Terms

beta-Thromboglobulin
Blood Platelets*
Humans
Infarction*
Myocardial Infarction
Percutaneous Coronary Intervention
Plasma
Platelet Activation*
Platelet Factor 4
Platelet Factor 4
beta-Thromboglobulin

Figure

  • Fig. 1 Comparison of β-thromboglobulin and platelet factor 4 at each time point of measurement in 36 patients with myocardial infarction. The central box and middle line represent 25 to 75 percentile and the median. A line extends from the minimum to the maximum value.


Reference

1. Persantine and aspirin in coronary heart disease. Persantine-Aspirin Reinfarction Study Research Group. Circulation. 1980; 62:449–461.
2. Caro JJ, Migliaccio-Walle K. Generalizing the results of clinical trials to actual practice: the example of clopidogrel therapy for the prevention of vascular events. CAPRA (CAPRIE Actual Practice Rate Analysis) Study Group. Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events. Am J Med. 1999; 107:568–572.
Article
3. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, 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.
Article
4. Angiolillo DJ. Variability in responsiveness to oral antiplatelet therapy. Am J Cardiol. 2009; 103:3 suppl. 27A–34A.
Article
5. Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010; 303:754–762.
Article
6. Godino C, Mendolicchio L, Figini F, Latib A, Sharp ASP, Cosgrave J, et al. Comparison of VerifyNow-P2Y12 test and Flow Cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy? Thromb J. 2009; 7:4.
Article
7. Kaplan KL, Owen J. Plasma levels of beta-thromboglobulin and platelet factor 4 as indices of platelet activation in vivo. Blood. 1981; 57:199–202.
Article
8. Levine SP, Lindenfeld J, Ellis JB, Raymond NM, Krentz LS. Increased plasma concentrations of platelet factor 4 in coronary artery disease: a measure of in vivo platelet activation and secretion. Circulation. 1981; 64:626–632.
Article
9. Smitherman TC, Milam M, Woo J, Willerson JT, Frenkel EP. Elevated beta-thromboglobulin in peripheral venous blood of patients with acute myocardial ischemia: direct evidence for enhanced platelet reactivity in vivo. Am J Cardiol. 1981; 48:395–402.
Article
10. Gavaghan TP, Hickie JB, Krilis SA, Baron DW, Gebski V, Low J, et al. Increased plasma beta-thromboglobulin in patients with coronary artery vein graft occlusion: response to low dose aspirin. J Am Coll Cardiol. 1990; 15:1250–1258.
Article
11. Minar E, Ehringer H. Influence of acetylsalicylic acid (1.0 g/day) on platelet survival time, beta-thromboglobulin and platelet factor 4 in patients with peripheral arterial occlusive disease. Thromb Res. 1987; 45:791–802.
Article
12. Klovaite J, Benn M, Yazdanyar S, Nordestgaard BG. High platelet volume and increased risk of myocardial infarction: 39,531 participants from the general population. J Thromb Haemost. 2011; 9:49–56.
Article
13. Asher E, Fefer P, Shechter M, Beigel R, Varon D, Shenkman B, et al. Increased mean platelet volume is associated with non-responsiveness to clopidogrel. Thromb Haemost. 2014; 112:137–141.
Article
14. Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, Müller U, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol. 2012; 59:2159–2164.
Article
15. Maruyama H, Takeda H, Dembo T, Nagoya H, Kato T, Fukuoka T, et al. Clopidogrel resistance and the effect of combination cilostazol in patients with ischemic stroke or carotid artery stenting using the VerifyNow P2Y12 Assay. Intern Med. 2011; 50:695–698.
Article
16. Kim MH, Huo SH, Kim KS, Kim MS, Song JS. Study on the platelet factor and beta-thromboglobulin in the patients with ischemic heart disease. Korean J Intern Med. 1986; 1:1–6.
Article
17. Diop S, Ka-Cisse M, Toure-Fall AO, Diagne Fall-Sarr F, Diop SN, Thiam D, et al. Evaluation of thrombotic risk in type 2 diabetes: determination of platelet factor 4 and beta thromboglobulin. Dakar Med. 2002; 47:247–251.
18. Buyukasýk NS, Ileri M, Alper A, Senen K, Atak R, Hisar I, et al. Increased blood coagulation and platelet activation in patients with infective endocarditis and embolic events. Clin Cardiol. 2004; 27:154–158.
Article
19. Jaffe AS, Lee RG, Perez JE, Geltman EM, Wilner GD, Sobel BE. Lack of elevation of platelet factor IV in plasma from patients with myocardial infarction. J Am Coll Cardiol. 1984; 4:653–659.
Article
20. Minar E, Ehringer H, Jung M, Koppensteiner R, Stümpflen A. Lack of influence of low-dose acetylsalicylic acid (100 mg daily) on platelet survival time, beta-thromboglobulin and platelet factor 4 in patients with peripheral arterial occlusive disease. Thromb Res. 1988; 52:219–226.
Article
21. Weltermann A, Fritsch P, Kyrle PA, Schoenauer V, Heinze G, Wojta J, et al. Effects of pretreatment with clopidogrel on platelet and coagulation activation in patients undergoing elective coronary stenting. Thromb Res. 2003; 112:19–24.
Article
22. Kamath S, Blann AD, Chin BS, Lip GY. A prospective randomized trial of aspirin-clopidogrel combination therapy and dose-adjusted warfarin on indices of thrombogenesis and platelet activation in atrial fibrillation. J Am Coll Cardiol. 2002; 40:484–490.
Article
23. Garcia AE, Mada SR, Rico MC, Dela Cadena RA, Kunapuli SP. Clopidogrel, a P2Y12 receptor antagonist, potentiates the inflammatory response in a rat model of peptidoglycan polysaccharide-induced arthritis. PLoS One. 2011; 6:e26035.
Article
24. Krajewski S, Kurz J, Neumann B, Greiner TO, Stolz A, Balkau B, et al. Short-acting P2Y12 blockade to reduce platelet dysfunction and coagulopathy during experimental extracorporeal circulation and hypothermia. Br J Anaesth. 2012; 108:912–921.
Article
25. McCabe DJ, Harrison P, Sidhu PS, Brown MM, Machin SJ. Circulating reticulated platelets in the early and late phases after ischemic stroke and transient ischemic attack. Br J Haematol. 2004; 126:861–869.
Article
26. Park KW, Jeon KH, Kang SH, Oh IY, Cho HJ, Lee HY, et al. Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study). Am J Cardiol. 2011; 108:1556–1563.
Article
Full Text Links
  • LMO
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr