РЕЗИСТЕНТНОСТЬ К ТЕРАПИИ ПРЕПАРАТАМИ АЦЕТИЛСАЛИЦИЛОВОЙ КИСЛОТЫ: ФАКТОРЫ РИСКА, МЕХАНИЗМЫ, МЕТОДЫ ДИАГНОСТИКИ


Авторы

DOI:

https://doi.org/10.32415/jscientia_2020_6_2_16-34

Ключевые слова:

ацетилсалициловая кислота, аспирин, резистентность к аспирину, тромбоциты, антиагреганты, 11-дегидротромбоксан В2

Аннотация

Ацетилсалициловая кислота (аспирин) является самым распространённым препаратом, используемым для вторичной профилактики атеротромботических событий при сердечно-сосудистых заболеваниях. Соответственно, проблему эффективности терапии аспирином следует считать одной из центральных в кардиологии. Остаётся актуальным вопрос персонализации антиагрегантной терапии, поскольку убедительные данные в пользу применения аспирина с целью первичной профилактики в общей популяции отсутствуют. В настоящем обзоре проанализированы данные последних лет о проблеме резистентности к аспирину. Обсуждаются потенциальные механизмы невосприимчивости к аспирину, возможное влияние генетических факторов на клиническую эффективность антиагрегантной терапии, вопросы стандартизации методов и критериев диагностики резистентности к аспирину, а также возможности её преодоления. Проанализированы данные о клиническом и прогностическом значении 11-дегидротромбоксана В2 как одного из наиболее перспективных маркеров тромбоксан-зависимой активации тромбоцитов.

Библиографические ссылки

Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-1860. DOI: 10.1016/S0140-6736(09)60503-1.

Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018;392(10152):1036-1046. DOI: 10.1016/S0140-6736(18)31924-X.

Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. DOI: 10.1136/bmj.324.7329.71.

Christiansen M, Grove EL, Hvas AM. Primary Prevention of Cardiovascular Events with Aspirin: Toward More Harm than Benefit-A Systematic Review and Meta-Analysis. Semin Thromb Hemost. 2019;45(5):478-489. DOI: 10.1055/s-0039-1687905.

Eikelboom JW, Hirsh J, Weitz JI, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;105(14):1650-1655. DOI: 10.1161/01.CIR.0000013777.21160.07.

Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101(10):1206-1218. DOI: 10.1161/01.cir.101.10.1206.

Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet. 2006;367(9510):606-617. DOI: 10.1016/s0140-6736(06)68040-9.

Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat. Rev. Drug Discov. 2003; 2:15-28. DOI: 10.1038/nrd985.

Weber AA, Przytulski B, Schanz A, et al. Towards a definition of aspirin resistance: a typological approach. Platelets. 2002;13(1):37-40. DOI: 10.1080/09537100120104890.

Floyd CN, Ferro A. Mechanisms of aspirin resistance. Pharmacol Ther. 2014;141(1):69-78. DOI: 10.1016/j.pharmthera.2013.08.005.

Schwartz KA. Aspirin resistance: a clinical review focused on the most common cause, noncompliance. Neurohospitalist. 2011;1(2):94-103. DOI: 10.1177/1941875210395776.

Hally KE, La Flamme AC, Larsen PD, Harding SA. Platelet Toll-like receptor (TLR) expression and TLR-mediated platelet activation in acute myocardial infarction. Thromb Res. 2017;158:8-15. DOI: 10.1016/j.thromres.2017.07.031.

Cambria-Kiely JA, Gandhi PJ. Aspirin resistance and genetic polymorphisms. J Thromb Thrombolysis. 2002;14(1):51-58. DOI: 10.1023/a:1022066305399.

O’Donnell CJ, Larson MG, Feng D, et al. Genetic and environmental contributions to platelet aggregation: the Framingham heart study. Circulation. 2001;103(25):3051-3056. DOI: 10.1161/01.cir.103.25.3051.

Li Q, Chen BL, Ozdemir V, et al. Frequency of genetic polymorphisms of COX1, GPIIIa and P2Y1 in a Chinese population and association with attenuated response to aspirin. Pharmacogenomics. 2007;8(6):577-586. DOI: 10.2217/14622416.8.6.577.

Goodman T, Ferro A, Sharma P. Pharmacogenetics of aspirin resistance: a comprehensive systematic review. Br J Clin Pharmacol. 2008;66(2):222-232. DOI: 10.1111/j.1365-2125.2008.03183.x

Würtz M, Kristensen SD, Hvas AM, et al. Pharmacogenetics of the antiplatelet effect of aspirin. Curr Pharm Des. 2012;18(33):5294-5308. DOI: 10.2174/138161212803251907.

Weng Z, Li X, Li Y, et al. The association of four common polymorphisms from four candidate genes (COX-1, COX-2, ITGA2B, ITGA2) with aspirin insensitivity: a meta-analysis. PLoS One. 2013;8(11):e78093. DOI: 10.1371/journal.pone.0078093.

Patrignani P, Tacconelli S, Bruno A, et al. Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol. 2011;4(5):605-621. DOI: 10.1586/ecp.11.36.

Gengo FM, Rubin L, Robson M, et al. Effects of Ibuprofen on the Magnitude and Duration of Aspirin’s Inhibition of Platelet Aggregation: Clinical Consequences in Stroke Prophylaxis. J Clin Pharmacol. 2008;48: 117-122. DOI: 10.1177/0091270007310379.

Greig GM, Francis DA, Falgueyret JP, et al. The interaction of arginine 106 of human prostaglandin G/H synthase-2 with inhibitors is not a universal component of inhibition mediated by nonsteroidal anti-inflammatory drugs. Mol Pharmacol. 1997;52(5):829-838. DOI: 10.1124/mol.52.5.829.

Angiolillo DJ, Weisman SM. Clinical Pharmacology and Cardiovascular Safety of Naproxen. Am J Cardiovasc Drugs. 2017;17(2):97-107. DOI: 10.1007/s40256-016-0200-5.

Elliott MA. The Aspirin-NSAID Interaction: More Data, But a Lack of Clarity Remains. J Am Coll Cardiol. 2018; 71(16):1752-1754 DOI: 10.1016/j.jacc.2018.02.034.

Rainsford KD. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacol. 2009;17:275-342. DOI: 10.1007/s10787-009-0016-x.

MacDonald TM, Wei L. Is there an Interaction between the Cardiovascular Protective Effects of Low‐Dose Aspirin and Ibuprofen? Basic Clin Pharmacol Toxicol. 2006;98:275-280. DOI: 10.1111/j.1742-7843.2006.pto_371.x.

Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345:1809-17. DOI: 10.1056/NEJMoa003199.

Poorani R, Bhatt AN, Dwarakanath BS, et al. COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance. Eur J Pharmacol. 2016;785:116-132. DOI: 10.1016/j.ejphar.2015.08.049.

Charlot M, Grove EL, Hansen PR, et al. Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study. BMJ. 2011;342:d2690. DOI: 10.1136/bmj.d2690.

Giraud MN, Sanduja SK, Felder TB, et al. Effect of omeprazole on the bioavailability of unmodified and phospholipid-complexed aspirin in rats. Aliment Pharmacol Ther. 1997;11:899-906. DOI: 10.1046/j.1365-2036.1997.00216.x.

Bhatt DL, Grosser T, Dong JF, et al. Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol. 2017;69(6):603-612. DOI: 10.1016/j.jacc.2016.11.050.

Haastrup PF, Grønlykke T, Jarbøl DE. Enteric coating can lead to reduced antiplatelet effect of low-dose acetylsalicylic acid. Basic Clin Pharmacol Toxicol. 2015;116(3):212-215. DOI: 10.1111/bcpt.12362.

Cox D, Fitzgerald DJ. Lack of Bioequivalence Among Low-dose, Enteric-coated Aspirin Preparations. Clin. Pharmacol Ther. 2018;103(6):1047-1051. DOI: 10.1002/cpt.874.

Kaur R, Kaur M, Singh J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc Diabetol. 2018;17(1):121. DOI: 10.1186/s12933-018-0763-3.

Ferretti G, Rabini RA, Bacchetti T, et al. Glycated low-density lipoproteins modify platelet properties: a compositional and functional study. J Clin Endocrinol Metab. 2002;87:2180-4. DOI: 10.1210/jcem.87.5.8466.

Simeone P, Boccatonda A, Liani R, Santilli F. Significance of urinary 11-dehydro-thromboxane B2 in age-related diseases: Focus on atherothrombosis. Ageing Res Rev. 2018;48:51-78. DOI: 10.1016/j.arr.2018.09.004.

Knebel SM, Sprague RS, Stephenson AH. Prostacyclin receptor expression on platelets of humans with type 2 diabetes is inversely correlated with hemoglobin A1c levels. Prostaglandins Other Lipid Mediat. 2015;116-117:131-135. DOI: 10.1016/j.prostaglandins.2014.12.002.

Koch KL, Calles-Escandón J. Diabetic Gastroparesis. Gastroenterol Clin North Am. 2015;44(1):39-57. DOI: 10.1016/j.gtc.2014.11.005.

Vanormelingen C, Tack J, Andrews CN. Diabetic gastroparesis. Br Med Bull. 2013;105:213-230. DOI: 10.1093/bmb/ldt003

Patrono C, Rocca B. Measurement of Thromboxane Biosynthesis in Health and Disease. Front Pharmacol. 2019;10:1244. DOI: 10.3389/fphar.2019.01244.

Rocca B, Fox KAA, Ajjan RA, et al. Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur Heart J. 2018;39(19):1672-1686f. DOI: 10.1093/eurheartj/ehy066.

Rothwell PM, Cook NR, Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet. 2018;392(10145):387-399. DOI: 10.1016/S0140-6736(18)31133-4.

Patrono C, Rocca B, De Stefano V. Platelet activation and inhibition in polycythemia vera and essential thrombocythemia. Blood. 2013;121 (10):1701-1711. DOI: 10.1182/blood-2012-10-429134.

Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC, et al. Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: relationship with thrombosis occurrence and JAK2 V617F allele burden. Am J Hematol. 2009;84(2):102-108. DOI: 10.1002/ajh.21338.

Pascale S, Petrucci G, Dragani A, et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood. 2012;119(15):3595-3603. DOI: 10.1182/blood-2011-06-359224.

Lordkipanidzé M. Platelet Function Tests. Semin Thromb Hemost. 2016;42(03):258-267. DOI: 10.1055/s-0035-1564834.

Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost. 2011;105 Suppl 1:S13-S33 DOI: 10.1160/THS10-11-0720.

McFadyen JD, Kaplan ZS. Platelets are not just for clots. Transfus Med Rev. 2015;29(2):110-119 DOI: 10.1016/j.tmrv.2014.11.006.

Hvas AM, Grove EL. Platelet Function Tests: Preanalytical Variables, Clinical Utility, Advantages, and Disadvantages. Methods Mol Biol. 2017;1646:305-320 DOI: 10.1007/978-1-4939-7196-1_24.

Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115(12):3378-3384 DOI: 10.1172/JCI27196.

Roberts LJ 2nd, Sweetman BJ, Oates JA. Metabolism of thromboxane B2 in man. Identification of twenty urinary metabolites. J Biol Chem. 1981;256(16):8384-93. PMID: 7263660.

Olson MT, Kickler TS, Lawson JA, et al. Effect of assay specificity on the association of urine 11-dehydro thromboxane B2 determination with cardiovascular risk. J Thromb Haemost. 2012;10(12):2462-2469. DOI: 10.1111/jth.12026.

Geske FJ, Guyer KE, Ens G. AspirinWorks: a new immunologic diagnostic test for monitoring aspirin effect. Mol Diagn Ther. 2008;12(1):51-54. DOI: 10.1007/BF03256268.

Eikelboom JW, Hankey GJ, Thom J, et al. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation. 2008;118(17):1705-1712. DOI: 10.1161/CIRCULATIONAHA.108.768283.

Becker DM, Segal J, Vaidya D, et al. Sex Differences in Platelet Reactivity and Response to Low-Dose Aspirin Therapy. JAMA. 2006;295(12):1420-1427. DOI: 10.1001/jama.295.12.1420.

Davì G, Guagnano MT, Ciabattoni G, et al. Platelet activation in obese women: role of inflammation and oxidant stress. JAMA. 2002;288(16):2008-2014. DOI: 10.1001/jama.288.16.2008.

Basili S, Pacini G, Guagnano MT, et al. Insulin resistance as a determinant of platelet activation in obese women. J Am Coll Cardiol. 2006;48(12):2531-2538. DOI: 10.1016/j.jacc.2006.08.040.

Ferroni P, Basili S, Santilli F, Davì G. Low-density lipoprotein-lowering medication and platelet function. Pathophysiol Haemost Thromb. 2006;35(3-4):346-354. DOI: 10.1159/000093226.

Notarbartolo A, Davì G, Averna M, et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995;15(2):247-251. DOI: 10.1161/01.atv.15.2.247.

Dragani A, Falco A, Santilli F, et al. Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C→T polymorphism. Thromb. Haemost 2012;108(09):533-542. DOI: 10.1160/th11-12-0899.

Di Minno MN, Pezzullo S, Palmieri V, et al. Genotype-independent in vivo oxidative stress following a methionine loading test: maximal platelet activation in subjects with early-onset thrombosis. Thromb Res. 2011;128(4):e43-e48. DOI: 10.1016/j.thromres.2011.05.017.

Abhinand PA, Manikandan M, Mahalakshmi R, Ragunath PK. Meta-analysis study to evaluate the association of MTHFR C677T polymorphism with risk of ischemic stroke. Bioinformation. 2017;13(6):214-219. DOI: 10.6026/97320630013214.

De Franchis R, Fermo I, Mazzola G, et al. Contribution of the cystathionine beta-synthase gene (844ins68) polymorphism to the risk of early-onset venous and arterial occlusive disease and of fasting hyperhomocysteinemia. Thromb Haemost. 2000;84(4):576-82. PMID: 11057853.

Klerk M, Verhoef P, Clarke R, et al. MTHFR 677C→T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis. JAMA. 2002;288(16):2023-2031. DOI: 10.1001/jama.288.16.2023.

Ferroni P, Basili S, Falco A, Davì G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost. 2004;2(8):1282-1291. DOI: 10.1111/j.1538-7836.2004.00836.x.

Ha H, Lee HB. Oxidative stress in diabetic nephropathy: basic and clinical information. Curr Diab Rep. 2001;1(3):282-287. DOI: 10.1007/s11892-001-0047-1.

Davì G, Ciabattoni G, Consoli A, et al. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation. 1999;99(2):224-229. DOI: 10.1161/01.cir.99.2.224.

De Ferranti SD, de Boer IH, Fonseca V, et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation. 2014;130(13):1110-1130. DOI: 10.1161/CIR.0000000000000034.

Zaccardi F, Rizzi A, Petrucci G, et al. In Vivo Platelet Activation and Aspirin Responsiveness in Type 1 Diabetes. Diabetes. 2016;65(2):503-509. DOI: 10.2337/db15-0936.

Santilli F, Zaccardi F, Liani R, et al. In vivo thromboxane-dependent platelet activation is persistently enhanced in subjects with impaired glucose tolerance. Diabetes Metab Res Rev. 2020;36(2):e3232. DOI: 10.1002/dmrr.3232.

Dołegowska B, Błogowski W, Kedzierska K, et al. Platelets arachidonic acid metabolism in patients with essential hypertension. Platelets. 2009;20(4):242-249. DOI: 10.1080/09537100902849836.

Minuz P, Patrignani P, Gaino S, et al. Determinants of platelet activation in human essential hypertension. Hypertension. 2004;43(1):64-70. DOI: 10.1161/01.HYP.0000105109.44620.1B.

Guagnano MT, Ferroni P, Santilli F, et al. Determinants of platelet activation in hypertensives with microalbuminuria. Free Radic Biol Med. 2009;46(7):922-927. DOI: 10.1016/j.freeradbiomed.2009.01.005.

Barua RS, Sharma M, Dileepan KN. Cigarette Smoke Amplifies Inflammatory Response and Atherosclerosis Progression Through Activation of the H1R-TLR2/4-COX2 Axis. Front Immunol. 2015;6:572. DOI: 10.3389/fimmu.2015.00572.

Barbieri SS, Zacchi E, Amadio P, et al. Cytokines present in smokers’ serum interact with smoke components to enhance endothelial dysfunction. Cardiovascular Research. 2011;90(3),475-483. DOI: 10.1093/cvr/cvr032.

Barbieri SS, Weksler BB. Tobacco smoke cooperates with interleukin-1beta to alter beta-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo. FASEB J. 2007;21(8):1831-1843. DOI: 10.1096/fj.06-7557com.

Lowe FJ, Gregg EO, McEwan M. Evaluation of biomarkers of exposure and potential harm in smokers, former smokers and never-smokers. Clin Chem Lab Med. 2009;47(3):311-320. DOI: 10.1515/cclm.2009.069.

Oliveri D, Liang Q, Sarkar M. Real-World Evidence of Differences in Biomarkers of Exposure to Select Harmful and Potentially Harmful Constituents and Biomarkers of Potential Harm between Adult E-Vapor Users and Adult Cigarette Smokers. Nicotine Tob Res. 2019;ntz185. DOI: 10.1093/ntr/ntz185.

Cerquozzi S, Barraco D, Lasho T, et al. Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer J. 2017;7(12):662. DOI: 10.1038/s41408-017-0035-6.

Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117(10):755-761. DOI: 10.1016/j.amjmed.2004.06.032.

Carobbio A, Thiele J, Passamonti F, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117(22):5857-5859. DOI: 10.1182/blood-2011-02-339002.

Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23(10):2224-2232. DOI: 10.1200/JCO.2005.07.062.

Ferrante E, Vazzana N, Santilli F, et al. Determinants of thromboxane biosynthesis in rheumatoid arthritis: Role of RAGE and oxidant stress. Free Radic Biol Med. 2010;49(5):857-864. DOI: 10.1016/j.freeradbiomed.2010.06.009.

Ferro D, Basili S, Roccaforte S, et al. Determinants of enhanced thromboxane biosynthesis in patients with systemic lupus erythematosus. Arthritis Rheum. 1999;42(12):2689-2697. DOI: 10.1002/1529-0131(199912)42:12<2689::AID-ANR27>3.0.CO;2-X.

Di Sabatino A, Santilli F, Guerci M, et al. Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment. Thromb Haemost. 2016;116(3):486-495. DOI: 10.1160/TH16-02-0167.

Maclouf J, Folco G, Patrono C. Eicosanoids and iso-eicosanoids: constitutive, inducible and transcellular biosynthesis in vascular disease. Thromb Haemost. 1998;79:691-705. PMID: 9569176.

Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286(8):954-959. DOI: 10.1001/jama.286.8.954.

McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006; 296(13):1633-1644. DOI: 10.1001/jama.296.13.jrv60011.

Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006;332(7553):1302-1308. DOI: 10.1136/bmj.332.7553.1302.

Bhatt DL. NSAIDS and the risk of myocardial infarction: do they help or harm? Eur Heart J. 2006; 27(14):1635-1636. DOI: 10.1093/eurheartj/ehl090.

Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin Dose for the Prevention of Cardiovascular Disease: A Systematic Review. JAMA. 2007;297(18):2018-2024. DOI: 10.1001/jama.297.18.2018.

Santilli F, Guagnano MT, Innocenti P, et al. Pentraxin 3 and Platelet Activation in Obese Patients After Gastric Banding. Circ J. 2016;80(2):502-511. DOI: 10.1253/circj.CJ-15-0721.

McCullough PA, Vasudevan A, Sathyamoorthy M, et al. Urinary 11-Dehydro-Thromboxane B2 and Mortality in Patients With Stable Coronary Artery Disease. Am J Cardiol. 2017;119(7):972-977. DOI: 10.1016/j.amjcard.2016.12.004.

Szczeklik W, Stodółkiewicz E, Rzeszutko M, et al. Urinary 11-Dehydro-Thromboxane B2 as a Predictor of Acute Myocardial Infarction Outcomes: Results of Leukotrienes and Thromboxane In Myocardial Infarction (LTIMI) Study. J Am Heart Assoc. 2016;5(8):e003702. DOI: 10.1161/JAHA.116.003702.

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30.04.2020

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Лукьянец К.Ю., Пчелин И.Ю. РЕЗИСТЕНТНОСТЬ К ТЕРАПИИ ПРЕПАРАТАМИ АЦЕТИЛСАЛИЦИЛОВОЙ КИСЛОТЫ: ФАКТОРЫ РИСКА, МЕХАНИЗМЫ, МЕТОДЫ ДИАГНОСТИКИ // Juvenis Scientia. 2020. т. 6, № 2. сс. 16-34.

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