Clinical and Genetic Characteristics of Antiplatelet Therapy Resistance After Ischemic Stroke (Literature Review)
https://doi.org/10.52420/umj.24.3.139
EDN: OHCAOU
Abstract
Every year, 20 % of all ischemic strokes are recurrent, characterized by severe course and high mortality and disability rates. Secondary prevention measures are aimed at preventing repeated brain catastrophes, which leads to a 20–30 % reduction in the risk of recurrent stroke. One of the directions of therapy is the appointment of antiplatelet drugs. Currently, acetylsalicylic acid and clopidogrel are widely used in the Russia. Effective platelet inhibition by prescribing these antiplatelet agents is one of the priorities in the treatment of atherothrombotic ischemic stroke. At the same time, a number of patients develop resistance to antiplatelet agents, which is associated with a variety of factors, such as drug interactions, concomitant diseases, and genetic predisposition. In order to control the formation of laboratory resistance, several methods for assessing platelet function have been developed. For example, optical Born aggregatometry, thromboelastogram, flow cytometry. Currently, there is no “golden method” for determining the high residual activity of platelets, since none of them has achieved a significant advantage. This article discusses methods for detecting laboratory resistance and factors influencing its development, depending on the prescribed antiplatelet drug.
About the Authors
T. Yu. BatenkovaRussian Federation
Tatiana Yu. Batenkova — Neurologist of the Neurological Unit, Consultative and Diagnostic Polyclinic, Sverdlovsk Regional Clinical Hospital No. 1.
Ekaterinburg
Competing Interests:
None
L. I. Volkova
Russian Federation
Larisa I. Volkova — Doctor of Sciences (Medicine), Professor, Professor of the Department of Neurology and Neurosurgery, Institute of Clinical Medicine, Ural State Medical University; Neurologist, Scientific Supervisor of the Neurological Clinic, Sverdlovsk Regional Clinical Hospital No. 1.
Ekaterinburg
Competing Interests:
None
E. V. Kudryavtseva
Russian Federation
Elena V. Kudryavtseva — Doctor of Sciences (Medicine), Associate Professor, Geneticist of the Medical and Genetic Counseling Unit, Clinical and Diagnostic Center “Health Care of Mother and Child”; Professor of the Department of Obstetrics and Gynecology, Ural Institute of Public Health Management named after A.B. Blokhin.
Ekaterinburg
Competing Interests:
None
References
1. Ignatieva VI, Voznyuk IA, Reznik AV, Vinitsky AA, Derkach EV. Socio-economic burden of stroke in the Russian Federation. S.S. Korsakov Journal of Neurology and Psychiatry. 2023;123(8–2):5–15. (In Russ.). DOI: https://doi.org/10.17116/jnevro20231230825.
2. Bhutto AM, Raza RA, Abbasi MB, Jauhar I, Arbani N, Mubashir M, et al. Comparative efficacy of clopidogrel-aspirin combination therapy versus aspirin monotherapy in preventing recurrent events in transient ischemic attack and minor stroke: A systematic review and meta-analysis. The Egyptian Journal of Internal Medicine. 2025;37(1):20. DOI: https://doi.org/10.1186/s43162-025-00408-x.
3. Liu Y, Lu K, Zhang R, Hu D, Yang Z, Zeng J, et al. Advancements in the treatment of atherosclerosis: From conventional therapies to cutting-edge innovations. ACS Pharmacology & Translational Science. 2024;7(12): 3804–3826. DOI: https://doi.org/10.1021/acsptsci.4c00574.
4. Roy H, Bhardwaj S, Yla-Herttuala S. Molecular genetics of atherosclerosis. Human Genetics. 2009;125 (5–6):467–491. DOI: https://doi.org/10.1007/s00439-009-0654-5.
5. Vasiliev AP, Streltsova NN. Cholesterol, atherosclerosis, lipid-lowering therapy. Is it completely clear? Ural Medical Journal. 2024;23(2):131–147. (In Russ.). DOI: https://doi.org/10.52420/umj.23.2.131.
6. Ricotta JJ, AbuRahma A, Ascher E, Eskandari M, Faries P, Lal BK. Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease. Journal of Vascular Surgery. 2011;54(3):E1–E31. DOI: https://doi.org/10.1016/j.jvs.2011.07.031.
7. Society for Vascular Surgery Lower Extremity Guidelines Writing Group; Conte MS, Pomposelli FB, Clair DG, Geraghty PJ, McKinsey JF, Mills JL, et al. Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: Management of asymptomatic disease and claudication. Journal of Vascular Surgery. 2015;61(3 Suppl):2S–41S.E1. DOI: https://doi.org/10.1016/j.jvs.2014.12.009.
8. Wiśniewski A. Multifactorial background for a low biological response to antiplatelet agents used in stroke prevention. Medicina. 2021;57(1):59. DOI: https://doi.org/10.3390/medicina57010059.
9. Spectre G, Varon D. New antiplatelet agents. Current Opinion in Hematology. 2009;16(5):365–370. DOI: https://doi.org/10.1097/MOH.0b013e32832ec222.
10. Zhang J, Chen Z, Wang H, Wang M, Li C, He S, et al. Prognostic analysis and an appropriate antiplatelet strategy for patients with percutaneous coronary intervention and high bleeding risk: Rationale and protocol for a multi-center cohort study. Cardiology Discovery. 2024;4(3):213–220. DOI: https://doi.org/10.1097/CD9.0000000000000121.
11. Tsoupras A, Gkika DA, Siadimas I, Christodoulopoulos I, Efthymiopoulos P, Kyzas GZ. The multifaceted effects of non-steroidal and non-opioid anti-inflammatory and analgesic drugs on platelets: Current knowledge, limitations, and future perspectives. Pharmaceuticals. 2024;17(5):627. DOI: https://doi.org/10.3390/ph17050627.
12. Kamarova M, Baig S, Patel H, Monks K, Wasay M, Ali A, et al. Antiplatelet use in ischemic stroke. Annals of Pharmacotherapy. 2022;56(10):1159–1173. DOI: https://doi.org/10.1177/10600280211073009.
13. Floyd CN, Ferro A. Mechanisms of aspirin resistance. Pharmacology & Therapeutics. 2014;141(1):69–78. DOI: https://doi.org/10.1016/j.pharmthera.2013.08.005.
14. Grosser T, Fries S, Lawson JA, Kapoor SC, Grant GR, FitzGerald GA. Drug resistance and pseudoresistance: An unintended consequence of enteric coating aspirin. Circulation. 2013;127(3):377–385. DOI: https://doi.org/10.1161/CIRCULATIONAHA.112.117283.
15. Ibrahim HK, Mohammed AM, Abdalaziz AM, Alside RA, Masoud HM. Anticoagulant medications: A comparative review of aspirin, warfarin, heparin, and apixaban. International Journal of Multidisciplinary Sciences and Arts. 2024;3(2):298–306. DOI: https://doi.org/10.47709/ijmdsa.v3i1.3755.
16. Kulikov A, Konovalov A, Pugnaloni PP, Bilotta F. Aspirin interruption before neurosurgical interventions: A controversial problem. World Journal of Cardiology. 2024;16(4):191–198. DOI: http://dx.doi.org/10.4330/wjc.v16.i4.191.
17. Wiśniewski A, Filipska K. The phenomenon of clopidogrel high on-treatment platelet reactivity in ischemic stroke subjects: A comprehensive review. International Journal of Molecular Sciences. 2020;21(17):6408. DOI: https://doi.org/10.3390/ijms21176408.
18. Amin AM, Sheau ChL, Azri MND, Abdul MA, Kah HY, Ibrahim B. The personalization of clopidogrel antiplatelet therapy: The role of integrative pharmacogenetics and pharmacometabolomics. Cardiology Research and Practice. 2017;2017:8062796. DOI: https://doi.org/10.1155/2017/8062796.
19. Krishnan K, Nguyen TN, Appleton JP, Law ZK, Caulfied M, Cabrera CP, et al. Antiplatelet resistance: A review of concepts, mechanisms, and implications for management in acute ischemic stroke and transient ischemic attack. Stroke: Vascular and Interventional Neurology. 2023;3(3):1–15. DOI: https://doi.org/10.1161/SVIN.122.000576.
20. Kim J, Shin BS, Kim DH, Shin DI, Ahn SH, Kim JG, et al. Molecular genomic and epigenomic characteristics related to aspirin and clopidogrel resistance. BMC Medical Genomics. 2024;17(1):166. DOI: https://doi.org/10.1186/s12920-024-01936-1.
21. Parsa M, Mansouritorghabeh H. Aspirin and clopidogrel resistance; A neglected gap in stroke and cardiovascular practice in Iran: A systematic review and meta-analysis. Thrombothis Journal. 2023;21(1):79. DOI: https://doi.org/10.1186/s12959-023-00522-2.
22. Kang HG, Lee SJ, Heo SH, Chang D, Kim BJ. Clopidogrel resistance in patients with stroke recurrence under single or dual antiplatelet treatment. Frontiers in Neurology. 2021;12:652416. DOI: https://doi.org/10.3389/fneur.2021.652416.
23. Lim ST, Thijs V, Murphy SJX, Fernandez-Cadenas I, Montaner J, Offiah C, et al. Platelet function/reactivity testing and prediction of risk of recurrent vascular events and outcomes after TIA or ischaemic stroke: Systematic review and meta-analysis. Journal of Neurology. 2020;267(10):3021–3037. DOI: https://doi.org/10.1007/s00415-020-09932-y.
24. Subramanian A, Delaney S, Murphy SJX, Smith DR, Offiah C, McMahon J, et al. Platelet biomarkers in patients with atherosclerotic extracranial carotid artery stenosis: A systematic review. European Journal of Vascular and Endovascular Surgery. 2022;63(3):379–389. DOI: https://doi.org/10.1016/j.ejvs.2021.10.045.
25. Lim ST, Murphy SJX, Murphy SM, Coughlan T, O’Neill D, Tierney S, et al. Assessment of on-treatment platelet reactivity at high and low shear stress and platelet activation status after the addition of dipyridamole to aspirin in the early and late phases after TIA and ischaemic stroke. Journal of the Neurological Sciences. 2022;441:120334. DOI: https://doi.org/10.1016/j.jns.2022.120334.
26. Kantemirova B, Zhidovinov A, Abdullaev M, Orlova E, Chernysheva E, Sultanova O. Factors influencing the effectiveness of antiplatelet therapy. Archiv Euromedica. 2022;12(1):19–25. DOI: https://doi.org/10.35630/2199-885X/2022/12/1.5.
27. Pradhan A, Bhandari M, Vishwakarma P, Sethi R. Clopidogrel resistance and its relevance: Current concepts. Journal of Family Medicine and Primary Care. 2024;13(6):2187–2199. DOI: https://doi.org/10.4103/jfmpc.jfmpc_1473_23.
28. Van DH, Van E, Koudstaal PJ, Van DL, Bos D. Sex differences in carotid atherosclerosis: A systematic review and meta-analysis. Stroke. 2023;54(2):315–326. DOI: https://doi.org/10.1161/STROKEAHA.122.041046.
29. Friede KA, Infeld MM, Tan RS, Knickerbocker HJ, Myers RA, Dubois LG, et al. Influence of sex on platelet reactivity in response to aspirin. Journal of the American Heart Association. 2020;9(14):e014726. DOI: https://doi.org/10.1161/JAHA.119.014726.
30. Lavanya S, Babu D, Dheepthi D, Dhinakar E, Vivekanandh G. Clopidogrel resistance in ischemic stroke patients. Annals of Indian Academy of Neurology. 2024; 27(5):493–497. DOI: https://doi.org/10.4103/aian.aian_79_24.
31. Yi X, Lin J, Wang C, Huang R, Han Z, Li J. Platelet function-guided modification in antiplatelet therapy after acute ischemic stroke is associated with clinical outcomes in patients with aspirin nonresponse. Oncotarget. 2017;8:106258–106269. DOI: https://doi.org/10.18632/oncotarget.22293.
32. DiChiara J, Bliden KP, Tantry US, Hamed MS, Antonino MJ, Suarez TA, et al. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients. Diabetes. 2007;56(12):3014–3019. DOI: https://doi.org/10.2337/db07-0707.
33. Hung J, Lam JYT, Lacoste L, Letchacovski G. Cigarette smoking acutely increases platelet thrombus formation in patients with coronary artery disease taking aspirin. Circulation. 1995;92(9):2432–2436. DOI: https://doi.org/10.1161/01.CIR.92.9.2432.
34. Mao Y, Lei L, Su J, Yu Y, Liu Z, Huo Y. Regulators of G protein signaling are up-regulated in aspirin-resistant platelets from patients with metabolic syndrome. Pharmazie. 2014;69(5):371–373. DOI: https://doi.org/10.1691/ph.2014.3833.
35. Pankert M, Quilici J, Loundou AD, Verdier V, Lambert M, Deharo P, et al. Impact of obesity and the metabolic syndrome on response to clopidogrel or prasugrel and bleeding risk in patients treated after coronary stenting. American Journal of Cardiology. 2014;113(1):54–59. DOI: https://doi.org/10.1016/j.amjcard.2013.09.011.
36. Santilli F, Vazzana N, Liani R, Guagnano MT, Davì G. Platelet activation in obesity and metabolic syndrome. Obesity Reviews. 2012;13(1):27–42. DOI: https://doi.org/10.1111/j.1467-789X.2011.00930.x.
37. Huang X, Song J, Zhang X, Wang M, Ding Y, Ji X, et al. Understanding drug interactions in antiplatelet therapy for atherosclerotic vascular disease: A systematic review. CNS Neuroscience & Therapeutics. 2025;31(2): e70258. DOI: https://doi.org/10.1111/cns.70258.
38. Ohbuchi M, Noguchi K, Kawamura A, Usui T. Different effects of proton pump inhibitors and famotidine on the clopidogrel metabolic activation by recombinant CYP2B6, CYP2C19 and CYP3A4. Xenobiotica. 2012; 42(7):633–640. DOI: https://doi.org/10.3109/00498254.2011.653655.
39. Feher G, Feher A, Pusch G, Koltai K, Tibold A, Gasztonyi B, et al. Clinical importance of aspirin and clopidogrel resistance. World Journal of Cardiology. 2010;2(7):171–186. DOI: https://doi.org/10.4330/wjc.v2.i7.171.
40. Gorelick PB, Farooq MU. Advances in our understanding of “resistance” to antiplatelet agents for prevention of ischemic stroke. Stroke Research and Treatment. 2013;2013:727842. DOI: https://doi.org/10.1155/2013/727842.
41. Topçuoglu MA, Arsava EM, Ay H. Antiplatelet resistance in stroke. Expert Review of Neurotherapeutics. 2011;11(2):251–263. DOI: https://doi.org/10.1586/ern.10.203.
42. Strisciuglio T, Franco D, Di Gioia G, De Biase C, Morisco C, Trimarco B, et al. Impact of genetic polymorphisms on platelet function and response to anti platelet drugs. Cardiovascular Diagnosis and Therapy. 2018;8(5):610–620. DOI: https://doi.org/10.21037/cdt.2018.05.06.
43. Ellithi M, Baye J, Wilke RA. CYP2C19 genotype-guided antiplatelet therapy: Promises and pitfalls. Pharmacogenomics. 2020;21(12):889–897. DOI: https://doi.org/10.2217/pgs-2020-0046.
44. Lee SJ, Kim WY, Kim H, Shon JH, Lee SS, Shin JG. Identification of new CYP2C19 variants exhibiting decreased enzyme activity in the metabolism of S-mephenytoin and omeprazole. Drug Metabolism and Disposition. 2009;37(11):2262–2269. DOI: https://doi.org/10.1124/dmd.109.028175.
45. De Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. The Journal of Biological Chemistry. 1994;269(22):15419–15422. DOI: https://doi.org/10.1016/s0021-9258(17)40694-6.
46. De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Molecular Pharmacology. 1994;46(4):594–598. DOI: https://doi.org/10.1016/s0026-895x(25)09788-3.
47. Sim S, Risinger C, Dahl M, Aklillu E, Christensen M, Bertilsson L, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clinical Pharmacology & Therapeutics. 2006;79(1):103–113. DOI: https://doi.org/10.1016/j.clpt.2005.10.002.
48. Pan Y, Chen W, Xu Y, Yi X, Han Y, Yang Q, et al. Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack: A systematic review and meta-analysis. Circulation. 2017; 135(1):21–33. DOI: https://doi.org/10.1161/CIRCULATIONAHA.116.024913.
49. Kittipanprayoon S, Vorasayan P, Chutinet A, Chariyavilaskul P, Suwanwela NC. The prevalence of CYP2C19 polymorphism in patients with symptomatic intracranial atherosclerosis. Cerebrovascular Diseases Extra. 2025;15(1):68–72. DOI: https://doi.org/10.1159/000543331.
50. Lee CR, Luzum JA, Sangkuhl K, Gammal RS, Sabatine MS, Stein CM, et al. Clinical pharmacogenetics implementation consortium guideline for CYP2C19 genotype and clopidogrel therapy: 2022 update. Clinical Pharmacology & Therapeutics. 2022;112(5):959–967. DOI: https://doi.org/10.1002/cpt.2526.
51. Klein MD, Williams AK, Lee CR, Stouffer GA. Clinical utility of CYP2C19 genotyping to guide antiplatelet therapy in patients with an acute coronary syndrome or undergoing percutaneous coronary intervention. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39(4):647–652. DOI: https://doi.org/10.1161/ATVBAHA.118.311963.
52. Ikonnikova A, Anisimova A, Galkin S, Gunchenko A, Abdukhalikova Z, Filippova M, et al. Genetic association study and machine learning to investigate differences in platelet reactivity in patients with acute ischemic stroke treated with aspirin. Biomedicines. 2022;10(10):2564. DOI: https://doi.org/10.3390/biomedicines10102564.
53. Antúnez-Rodríguez A, García-Rodríguez S, Pozo-Agundo A, Sánchez-Ramos JG, Moreno-Escobar E, Triviño-Juárez JM, et al. Targeted next-generation sequencing panel to investigate antiplatelet adverse reactions in acute coronary syndrome patients undergoing percutaneous coronary intervention with stenting. Thrombosis Research. 2024;240:109060. DOI: https://doi.org/10.1016/j.thromres.2024.109060.
54. Gremmel T, Frelinger AL 3rd, Michelson AD. Platelet Physiology. Seminars in Thrombosis and Hemostasis. 2016;42(03):191–204. DOI: https://doi.org/10.1055/s-0035-1564835.
55. Hou X. Epoxidase inhibitor-aspirin resistance and the relationship with genetic polymorphisms: A review. Journal of International Medical Research. 2024;52(2). DOI: https://doi.org/10.1177/03000605241230429.
56. Cambria-Kiely JA, Gandhi PJ. Aspirin resistance and genetic polymorphisms. Journal of Thrombosis and Thrombolysis. 2002;14(1):51–58. DOI: https://doi.org/10.1023/A:1022066305399.
57. Liu H, Wang Y, Zheng J, Li G, Chen T, Lei J, et al. Platelet glycoprotein gene Ia C807T, HPA-3, and Ibα VNTR polymorphisms are associated with increased ischemic stroke risk: Evidence from a comprehensive meta-analysis. International Journal of Stroke. 2017;12(1):46–70. DOI: https://doi.org/10.1177/1747493016672085.
58. Kunicki TJ, Kritzik M, Annis DS, Nugent DJ. Hereditary variation in platelet integrin alpha 2 beta 1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence. Blood. 1997;89(6):1939–1943. DOI: https://doi.org/10.1182/blood.V89.6.1939.
59. Patrignani P, Tacconelli S, Piazuelo E, Di Francesco L, Dovizio M, Sostres C, et al. Reappraisal of the clinical pharmacology of low‐dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action. Journal of Thrombosis and Haemostasis. 2014;12(8):1320–1330. DOI: https://doi.org/10.1111/jth.12637.
60. Mei L, Shen Z, Wu C. The association between thromboxane A2 receptor gene polymorphisms and the risk of cerebral infarction. Clinical Neurology and Neurosurgery. 2020;198:106134. DOI: https://doi.org/10.1016/j.clineuro.2020.106134.
61. Albert F, Christopher NF. The platelet fibrinogen receptor: From megakaryocyte to the mortuary. JRSM Cardiovascular Disease. 2012;1(2):1–13. DOI: https://doi.org/10.1258/cvd.2012.012007.
62. Kadnikov LI, Izmozherova NV, Popov AA, Antropova IP, Kudryavtseva EV. Assessment of multimorbidity in patients with COVID-19 and polymorphisms C807T of the ITGA2 Gene and T1565C of the ITGB3 Gene. Ural Medical Journal. 2024;23(6):45–57. DOI: https://doi.org/10.52420/umj.23.6.45.
63. Yi X, Lin J, Zhou Q, Huang R, Chai Z. The TXA2R rs1131882, P2Y1 rs1371097 and GPIIIa rs2317676 three-loci interactions may increase the risk of carotid stenosis in patients with ischemic stroke. BMC Neurology. 2019;19(1):44. DOI: https://doi.org/10.1186/s12883-019-1271-0.
64. Zeng W, Chu T, Chow E, Hu M, Fok B, Chan J, et al. Genetic factors related to aspirin resistance using the Multiplate® device in Hong Kong Chinese patients with stable coronary heart disease. Heliyon. 2024;10(14): e34552. DOI: https://doi.org/10.1016/j.heliyon.2024.e34552.
65. Oros MM, Lutz VV, Pavlo AH, Sitkar AD. Investigation of the influence of thrombophilicgenes polimorpfism, including serpin 1 (PAI-1), FII, protrombin and ITGB3 integrin, on the frequency of stroke in association with controllable risk factor for its occurrence. Wiadomosci lekarskie. 2020;73(3):471–477. DOI: https://doi.org/10.36740/WLek202003112.
66. Mutch NJ, Thomas L, Moore NR, Lisiak KM, Booth NA. TAFIa, PAI‐1 and α2‐antiplasmin: Complementary roles in regulating lysis of thrombi and plasma clots. Journal of Thrombosis and Haemostasis. 2007; 5(4):812–817. DOI: https://doi.org/10.1111/j.1538-7836.2007.02430.x.
67. Liu Y, Cheng J, Guo X, Mo J, Gao B, Zhou H, et al. The roles of PAI-1 gene polymorphisms in atherosclerotic diseases: A systematic review and meta-analysis involving 149,908 subjects. Gene. 2018;673:167–173. DOI: https://doi.org/10.1016/j.gene.2018.06.040.
68. Sikora J, Karczmarska-Wódzka A, Bugieda J, Sobczak P. The importance of platelets response during antiplatelet treatment after ischemic stroke — between benefit and risk: A systematic review. International Journal of Molecular Sciences. 2022;23(3):1043. DOI: https://doi.org/10.3390/ijms23031043.
69. Khan H, Kanny O, Syed MH, Qadura M. Aspirin resistance in vascular disease: A review highlighting the critical need for improved point-of-care testing and personalized therapy. International Journal of Molecular Sciences. 2022;23(19):11317. DOI: https://doi.org/10.3390/ijms231911317.
Review
For citations:
Batenkova TY, Volkova LI, Kudryavtseva EV. Clinical and Genetic Characteristics of Antiplatelet Therapy Resistance After Ischemic Stroke (Literature Review). Ural Medical Journal. 2025;24(3):139–156. (In Russ.) https://doi.org/10.52420/umj.24.3.139. EDN: OHCAOU