Laboratory Evaluation of the Platelet Component of Hemostasis in acute Coronary Syndrome With ST Segment Elevation

RELEVANCE. Acute coronary syndrome (ACS) is one of the most common cardiovascular diseases associated with increased mortality and disability of patients. Regarding the factor of genetic resistance to antiplatelet therapy, and we get an even more serious problem faced by cardiologists around the world. The study of antiplatelet therapy and resistance to it is a pressing issue in modern cardiology. This is important not only for determining the effectiveness of treatment for each patient, but also for personalizing therapy based on genetic characteristics. This allows improving the effectiveness of treatment and preventing recurrent cardiovascular complications. As a result, the study of antiplatelet therapy and resistance to it is an important aspect in the treatment of ACS. This helps prevent recurrent cardiovascular complications, improve the effectiveness of treatment and develop new methods of therapy.

AIM OF THE STUDY. ST-segment elevation ACS (STEMI) based on a personalized approach to antiplatelet therapy and modification of the program to predict the course and outcome. To study the possibilities of various laboratory diagnostic methods for assessing the platelet component of hemostasis in patients with STEMI depending on (1) the combination of antiplatelet drugs used (aspirin + clopidogrel; aspirin + ticagrelor); (2) the presence of factors of genetic resistance to antiplatelet agents.

MATERIAL AND METHODS. The study included patients with STEMI who underwent percutaneous coronary intervention in the infarct-related artery territory , a total of 46 patients (13 women, 33 men) aged 35 to 83 years, average age 61.7 years. Patients were divided into groups according to the received combination of dual antiplatelet therapy (DAPT) aspirin + clopidogrel (23 patients), aspirin + ticagrelor (23 patients), groups with and without genetic determination (GD ) were assessed. The platelet component of hemostasis was assessed in three different ways: standard coagulogram, aggregometry, rotation thromboelasthometry. The following pharmacogenetic markers were determined in all patients: CYP2C19*17, CYP2C19*2, CYP2C19*3, SLCO1B1 , CYP3A5*3 . LOF alleles were detected in 32 patients (67%). Among them, in the group taking aspirin in combination with clopidogrel, three subgroups of patients were distinguished: 7 patients in the slow metabolizer (SM) subgroup, 8 patients in the general rapid metabolizer subgroup , and 8 patients without LOF alleles were designated as normal metabolizers. In the group taking aspirin in combination with ticagrelor, 9 patients with intermediate metabolism were identified. Seven patients in the SM group. Seven patients without LOF alleles were classified as NM group. The course of the disease and its outcomes were assessed.

RESULTS. Against the background of the use of antiplatelet agents, at research points 2 and 3, the values of the CT-EXTEM parameter statistically significantly increased compared to research point 1 and went beyond the reference values, reflecting drug-induced hypocoagulation of the platelet hemostasis link (66.1±2 and 96.3±14.3 s, respectively, p=0.02). It was especially important that in the group with GR, the CT-EXTEM parameter did not change either by research point 2 or by research point 3, reflecting platelet normal or hypercoagulation.

CONCLUSION. Aggregometry parameters do not allow adequate assessment of the state of the platelet hemostasis link and its response to antiplatelet therapy in patients with acute coronary syndrome with ST segment elevation. Among the studied traditional and viscoelastic hemostatic parameters, the only parameter that should be used to assess the state of the platelet hemostasis link and its response to antiplatelet therapy is the CT-EXTEM test.

1. Kiselevich MM, Efremova OA, Petrova GD. Clinical Current and Outcomes of the Acute Coronary Syndrome. Challenges in Modern Medicine. 2018;41(4):547–557. (In Russ.)

2. Fastakovskiy VV, Kireev KA, Fokin AA, Fastakovskaya KS. Formation and Evolution of Surgical Methods for Treatment of Stable Coronary Heart Disease and Acute Myocardial Infarction (Review of Literature). Regional Blood Circulation and Microcirculation. 2023;22(2):4–10. (In Russ.) https://doi.org/10.24884/1682-6655-2023-22-2-4-10

3. Ribichini F, Wijns W. Acute myocardial infarction: reperfusion treatment. Heart. 2002;88(3):298–305. PMID: 12181231 https://doi.org/10.1136/heart.88.3.298

4. Kamran H, Jneid H, Kayani WT, Virani SS, Levine GN, Nambi V, et al. Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review. JAMA. 2021;325(15):1545–1555. PMID: 33877270 https://doi.org/10.1001/jama.2021.0716

5. Varenhorst C, Jensevik K, Jernberg T, Sundström A, Hasvold P, Held C, et al. Duration of dual antiplatelet treatment with clopidogrel and aspirin in patients with acute coronary syndrome. Eur Heart J. 2014;35(15):969–978. PMID: 24122961 https://doi.org/10.1093/eurheartj/eht438

6. Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Grüntzig Lecture ESC 2014. Eur Heart J. 2015;36(47):3320–3331. PMID: 26417060 https://doi.org/10.1093/eurheartj/ehv511

7. Ulehlova J, Slavik L, Kucerova J, Krcova V, Vaclavik J, Indrak K. Genetic Polymorphisms of Platelet Receptors in Patients with Acute Myocardial Infarction and Resistance to Antiplatelet Therapy. Genet Test Mol Biomarkers. 2014;18(9):599–604. PMID: 25093390 http://doi.org/10.1089/gtmb.2014.0077

8. Bokarev IN, Popova LV. Rezistentnost’ k antitrombotsitarnym preparatam. Serdtse: zhurnal dlya praktikuyushchikh vrachey. 2012;11(2):103–107. (In Russ.)

9. Lippi G, Favaloro EJ. Laboratory hemostasis: from biology to the bench. Clin Chem Lab Med. 2018;56(7):1035–1045. PMID: 29455188 https://doi.org/10.1515/cclm-2017-1205

10. Rahe-Meyer N, Winterhalter M, Boden A, Froemke C, Piepenbrock S, Calatzis A, et al. Platelet concentrates transfusion in cardiac surgery and platelet function assessment by multiple electrode aggregometry. Acta Anaesthesiol Scand. 2009;53(2):168–175. PMID: 19175576 http://doi.org/10.1111/j.1399-6576.2008.01845.x

11. Schultz-Lebahn A, Nissen PH, Pedersen TF, Tang M, Hvas AM. Platelet function assessed by ROTEM® platelet in patients receiving antiplatelet therapy during cardiac and vascular surgery. Scand J Clin Lab Invest. 2022;82(1):18–27. PMID: 34890293 http://doi.org/10.1080/00365513.2021.2012820

12. Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962;194:927–929. PMID: 13871375 http://doi.org/10.1038/194927b0

13. Samoš M, Stančiaková L, Duraj L, Kovář F, Fedor M, Šimonová R, Monitoring the hemostasis with rotation thromboelastometry in patients with acute STEMI on dual antiplatelet therapy: First experiences. Medicine (Baltimore). 2017;96(6):e6045. PMID: 28178148 http://doi.org/10.1097/MD.0000000000006045

14. Ise H, Kitahara H, Oyama K, Takahashi K, Kanda H, Fujii S, et al. Hypothermic circulatory arrest induced coagulopathy: rotational thromboelastometry analysis. Gen Thorac Cardiovasc Surg. 2020;68(8):754–761. PMID: 32507998 https://doi.org/10.1007/s11748-020-01399-y

15. Laurent D, Dodd WS, Small C, Gooch MR, Ghosh R, Goutnik M, et al. Ticagrelor resistance: a case series and algorithm for management of non-responders. J Neurointerv Surg. 2022;14(2):179–183. PMID: 34215660 https://doi.org/10.1136/neurintsurg-2021-017638

16. Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J. Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmacol. 2010;69(3):222–230. PMID: 20233192 https://doi.org/10.1111/j.1365-2125.2009.03578.x

17. Hasan MS, Basri HB, Hin LP, Stanslas J. Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention. Int J Neurosci. 2013;123(3):143–154. PMID: 23110469 https://doi.org/10.3109/00207454.2012.744308

18. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update. Clin Pharmacol Ther. 2013;94(3):317–323. PMID: 23698643 https://doi.org/10.1038/clpt.2013.105

19. Dean L, Kane M. (eds.) Clopidogrel Therapy and CYP2C19 Genotype. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US);2012. PMID:28520346 Available at: https://www.ncbi.nlm.nih.gov/books/NBK84114/ [Accessed Nov 22, 2023]

20. Russian Society of Cardiology. 2020 Clinical practice guidelines for Acute ST-segment elevation myocardial infarction. Russian Journal of Cardiology. 2020;25(11):251–310. (In Russ.) https://doi.org/10.15829/29/1560-4071-2020-4103

21. Passacquale G, Sharma P, Perera D, Ferro A. Antiplatelet therapy in cardiovascular disease: Current status and future directions. Br J Clin Pharmacol. 2022;88(6):2686–2699. PMID: 35001413 https://doi.org/10.1111/bcp.15221

22. Hackam DG, Spence JD. Antiplatelet Therapy in Ischemic Stroke and Transient Ischemic Attack: An Overview of Major Trials and Meta-Analyses. Stroke. 2019;50(3):773–778. PMID: 30626286 https://doi.org/10.1161/STROKEAHA.118.023954

23. Gachet Ch, Aleil B. Testing antiplatelet therapy. Eur Heart J Suppl. 2008;10(Issue Suppl_A):A28–A34. https://doi.org/10.1093/eurheartj/sum081

24. Gremmel T, Koppensteiner R, Panzer S. Comparison of Aggregometry with Flow Cytometry for the Assessment of Agonists´-Induced Platelet Reactivity in Patients on Dual Antiplatelet Therapy. PLoS One. 2015;10(6):e0129666. PMID: 26058047 https://doi.org/10.1371/journal.pone.0129666

25. Pakala R, Waksman R. Currently available methods for platelet function analysis: advantages and disadvantages. Cardiovasc Revasc Med. 2011;12(5):312–322. PMID: 21036109 https://doi.org/10.1016/j.carrev.2010.09.005

26. Podda G, Scavone M, Femia EA, Cattaneo M. Aggregometry in the settings of thrombocytopenia, thrombocytosis and antiplatelet therapy. Platelets. 2018;29(7):644–649. PMID: 29537938 https://doi.org/10.1080/09537104.2018.1445843

27. Smyth SS, McEver RP, Weyrich AS, Morrell CN, Hoffman MR, Arepally GM, et al. Platelet functions beyond hemostasis. J Thromb Haemost. 2009;7(11):1759–1766. PMID: 19691483 https://doi.org/10.1111/j.1538-7836.2009.03586.x

28. Tanaka KA, Bolliger D, Vadlamudi R, Nimmo A. Rotational Thromboelastometry (ROTEM)-Based Coagulation Management in Cardiac Surgery and Major Trauma. J Cardiothorac Vasc Anesth. 2012;26(6):1083–1093. PMID: 22863406 https://doi.org/10.1053/j.jvca.2012.06.015

29. Görlinger K, Dirkmann D, Hanke AA. Rotational Thromboelastometry (ROTEM®). In: Trauma Induced Coagulopathy. Springer, Cham; 2016. p. 267–298. https://doi.org/10.1007/978-3-319-28308-1_18

30. Feher G, Feher A, Pusch G, Lupkovics G, Szapary L, Papp E. The genetics of antiplatelet drug resistance. Clin Genet. 2009;75(1):1–18. PMID: 19067731 https://doi.org/10.1111/j.1399-0004.2008.01105.x