Влияние системы фибринолиза на исходы применения тромболитической терапии при острой сосудистой патологии

Тромболизис является одним из эффективно применяемых методов лечения пациентов с острой сосудистой патологией. Несмотря на высокий технический успех применения данной терапии, некоторые проблемы фибринолитического лечения все еще остаются нерешенными. Наиболее важной из них является резистентность к тромболитическим агентам с последующей неудовлетворительной реперфузией сосудистого русла. В настоящее время, несмотря на достижения в фармакотерапии препаратов, используемых при тромболизисе, усовершенствование технической базы его проведения, до сих пор четко не определены предикторы, влияющие на его исход. Применение фибринолитических препаратов во время тромболизиса индуцирует активацию прокоагуляционного звена гемостаза в виде увеличения активности тромбина, фрагментов протромбина 1.2 и комплекса тромбин–антитромбин III в ответ на избыточный фибринолиз, вызванный данным методом лечения.

Данная парадоксальная прокоагулянтная активация системы гемостаза может в 15–25% случаев быть причиной отсутствия начальной реперфузии сосудистого русла и от 5 до 15% случаев ранней тромботической реокклюзии после изначально успешного тромболизиса. Параллельно с активацией коагуляционного звена гемостаза на фоне данного вида лечения происходят изменения в функционировании системы фибринолиза, что непосредственно оказывает влияние на исходы применения тромболизиса. В данной работе представлен всесторонний обзор спектра основных маркеров системы фибринолиза, которые были изучены в контексте результатов тромболизиса у пациентов с острой сосудистой патологией. Сделан вывод о необходимости расширения лабораторных исследований показателей крови за счет непосредственного определения значений ингибитор активатора плазминогена-1, активируемого тромбином ингибитор фибринолиза, ингибитор α2-плазмина с целью прогнозирования исходов проведения тромболизиса.

1. Narula N, Olin JW, Narula N. Pathologic Disparities Between Peripheral Artery Disease and Coronary Artery Disease. Arterioscler Thromb Vasc Biol. 2020;40(9):1982–1989. PMID: 32673526 https://doi.org/10.1161/ATVBAHA.119.312864

2. Udaya R, Sivakanesan R. Synopsis of Biomarkers of Atheromatous Plaque Formation, Rupture and Thrombosis in the Diagnosis of Acute Coronary Syndromes. Curr Cardiol Rev. 2022;18(5):53–62. PMID: 35410616 https://doi.org/10.2174/1573403X18666220411113450

3. de Athayde Soares R, Matielo MF, Brochado Neto FC, Cury MVM, Duque de Almeida R, et al. Analysis of the results of endovascular and open surgical treatment of acute limb ischemia. J Vasc Surg. 2019;69(3):843– 849. PMID: 30679009 https://doi.org/10.1016/j.jvs.2018.07.056

4. Khandkar C, Madhavan MV, Weaver JC, Celermajer DS, Karimi Galougahi K. Atherothrombosis in Acute Coronary Syndromes-From Mechanistic Insights to Targeted Therapies. Cells. 2021;10(4):865. PMID: 33920201 https://doi.org/10.3390/cells10040865

5. Güneş Y, Sincer I, Erdal E. Catheter-directed intra-arterial thrombolysis for lower extremity arterial occlusions. Anatol J Cardiol. 2019;22(2):54–59. PMID: 31375648 https://doi.org/10.14744/AnatolJCardiol.2019.63296

6. Fluck F, Augustin AM, Bley T, Kickuth R. Current Treatment Options in Acute Limb Ischemia. Rofo. 2020;192(4):319–326. PMID: 31461761 https://doi.org/10.1055/a-0998-4204

7. Brinjikji W, Madalina Mereuta O, Dai D, Kallmes DF, Savastano L, Liu Y, et al. Mechanisms of fibrinolysis resistance and potential targets for thrombolysis in acute ischaemic stroke: lessons from retrieved stroke emboli. Stroke Vasc Neurol. 2021;6(4):658–667. PMID: 34312319 https://doi.org/10.1136/svn-2021-001032

8. Zeng J, Chen F, Chen Y, Peng M, Chen X, Yang Q, et al. Predictors of hemorrhagic complications after intravenous thrombolysis in acute cerebral infarction patients: A single-center study of 391 cases. Medicine (Baltimore). 2021;100(37):e27053. PMID: 34664830 https://doi.org/10.1097/MD.0000000000027053

9. Broderick C, Patel JV. Infusion techniques for peripheral arterial thrombolysis. Cochrane Database Syst Rev. 2021;11(11):CD000985. PMID: 34786692 https://doi.org/10.1002/14651858.CD000985.pub3

10. Vakhitov D, Hakovirta H, Saarinen E, Oksala N, Suominen V. Prognostic risk factors for recurrent acute lower limb ischemia in patients treated with intra-arterial thrombolysis. J Vasc Surg. 2020;71(4):1268–1275. PMID: 31495677 https://doi.org/10.1016/j.jvs.2019.07.061

11. Abendschein DR, Baum PK, Verhallen P, Eisenberg PR, Sullivan ME, Light DR. A novel synthetic inhibitor of factor Xa decreases early reocclusion and improves 24-h patency after coronary fibrinolysis in dogs. J Pharmacol Exp Ther. 2001;296(2):567–572. PMID: 11160645

12. Ammollo CT, Semeraro F, Incampo F, Semeraro N, Colucci M. Dabigatran enhances clot susceptibility to fibrinolysis by mechanisms dependent on and independent of thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost. 2010;8(4):790–798. PMID: 20088944 https://doi.org/10.1111/j.1538-7836.2010.03739.x

13. Gram J, Munkvad S, Leebeek FW, Kluft C, Jespersen J. Reactive coagulation induced by plasmin in patients treated with recombinant tissue-type plasminogen activator. Coron Artery Dis. 1993;4(4):371–377. PMID: 8261210 https://doi.org/10.1097/00019501-199304000-00009

14. Letunica N, Van Den Helm S, McCafferty C, Swaney E, Cai T, Attard C, et al. Proteomics in Thrombosis and Hemostasis. Thromb Haemost. 2022;122(7):1076–1084. PMID: 34753192 https://doi.org/10.1055/a-1690-8897

15. Miles LA, Ny L, Wilczynska M, Shen Y, Ny T, Parmer RJ. Plasminogen Receptors and Fibrinolysis. Int J Mol Sci. 2021;22(4):1712. PMID: 33567773 https://doi.org/10.3390/ijms22041712

16. Kietsiriroje N, Ariëns RAS, Ajjan RA. Fibrinolysis in Acute and Chronic Cardiovascular Disease. Semin Thromb Hemost. 2021;47(5):490–505. PMID: 33878782 https://doi.org/10.1055/s-0040-1718923

17. Hvas CL, Larsen JB. The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment. Int J Mol Sci. 2023;24(18):14179. PMID: 37762481 https://doi.org/10.3390/ijms241814179

18. Калинин Р.Е., Сучков И.А., Мжаванадзе Н.Д., Журина О.Н., Климентова Э.А., Поваров В.О. Фактор фон виллебранда при выполнении инвазивных вмешательств у больных с периферическим атеросклерозом. Российский медико-биологический вестник имени академика И. П. Павлова. 2021;29(3):389–396. https://doi.org/10.17816/PAVLOVJ79099

19. Калинин Р.Е., Сучков И.А., Мжаванадзе Н.Д., Короткова Н.В. Климентова Э.А., Поваров В.О.Метаболиты оксида азота при развитии осложнений после открытых реконструктивных вмешательств у пациентов с периферическим атеросклерозом. Наука молодых. 2021;9(3):407–414. https://doi.org/10.23888/HMJ202193407-414

20. Puy C, Ngo ATP, Pang J, Keshari RS, Hagen MW, Hinds MT, et al. Endothelial PAI-1 (Plasminogen Activator Inhibitor-1) Blocks the Intrinsic Pathway of Coagulation, Inducing the Clearance and Degradation of FXIa (Activated Factor XI). Arterioscler Thromb Vasc Biol. 2019;39(7):1390–1401. PMID: 31242030 https://doi.org/10.1161/ATVBAHA.119.312619

21. Lin PY, Shen HC, Chen CJ, Wu SE, Kao HL, Huang JH, et al. The inhibition in tumor necrosis factor-alpha-induced attenuation in endothelial thrombomodulin expression by carvedilol is mediated by nuclear factor-kappaB and reactive oxygen species. J Thromb Thrombolysis. 2010;29(1):52-59. PMID: 19333555 https://doi.org/10.1007/s11239-009-0318-2

22. Stepanova TV, Ivanov AN, Tereshkina NE, Popyhova EB, Lagutina DD. Markers of endothelial dysfunction: pathogenetic role and diagnostic significance. Klin Lab Diagn. 2019;64(1):34–41. PMID: 30912882 https://doi.org/10.18821/0869-2084-2018-63-34-41

23. Scharfstein JS, Abendschein DR, Eisenberg PR, George D, Cannon CP, Becker RC, et al. Usefulness of fibrinogenolytic and procoagulant markers during thrombolytic therapy in predicting clinical outcomes in acute myocardial infarction. TIMI-5 Investigators. Thrombolysis in Myocardial Infarction. Am J Cardiol. 1996;78(5):503–510. PMID: 8806332 https://doi.org/10.1016/s0002-9149(96)00353-0

24. Ueda T, Hatakeyama T, Sakaki S, Ohta S, Kumon Y, Uraoka T. Changes in coagulation and fibrinolytic system after local intra-arterial thrombolysis for acute ischemic stroke. Neurol Med Chir (Tokyo). 1995;35(3):136–143. PMID: 7770106 https://doi.org/10.2176/nmc.35.136

25. Urano T, Suzuki Y, Iwaki T, Sano H, Honkura N, Castellino FJ. Recognition of Plasminogen Activator Inhibitor Type 1 as the Primary Regulator of Fibrinolysis. Curr Drug Targets. 2019;20(16):1695–1701. PMID: 31309890 https://doi.org/10.2174/1389450120666190715102510

26. Park SY, Kim J, Kim OJ, Kim JK, Song J, Shin DA, et al. Predictive value of circulating interleukin-6 and heart-type fatty acid binding protein for three months clinical outcome in acute cerebral infarction: multiple blood markers profiling study. Crit Care. 2013;17(2):R45. PMID: 23497639 https://doi.org/10.1186/cc12564

27. Zeng L, Liu J, Wang Y, Wang L, Weng S, Chen S, et al. Cocktail blood biomarkers: prediction of clinical outcomes in patients with acute ischemic stroke. Eur Neurol. 2013;69(2):68–75. PMID: 23154383 https://doi.org/10.1159/000342896

28. Sillen M, Declerck PJ. Thrombin Activatable Fibrinolysis Inhibitor (TAFI): An Updated Narrative Review. Int J Mol Sci. 2021;22(7):3670. PMID: 33916027 https://doi.org/10.3390/ijms22073670

29. Martí-Fàbregas J, Borrell M, Cocho D, Martínez-Ramírez S, MartínezCorral M, Fontcuberta J, Martí-Vilalta JL. Change in hemostatic markers after recombinant tissue-type plasminogen activator is not associated with the chance of recanalization. Stroke. 2008;39(1):234–236. PMID: 18048863 https://doi.org/10.1161/STROKEAHA.107.493767

30. Brouns R, Heylen E, Sheorajpanday R, Willemse JL, Kunnen J, De Surgeloose D, et al. Carboxypeptidase U (TAFIa) decreases the efficacy of thrombolytic therapy in ischemic stroke patients. Clin Neurol Neurosurg. 2009;111(2):165–170. PMID: 18980797 https://doi.org/10.1016/j.clineuro.2008.09.002

31. Colucci M, Semeraro N. Thrombin activatable fibrinolysis inhibitor: at the nexus of fibrinolysis and inflammation. Thromb Res. 2012;129(3):314–319. PMID: 22113149 https://doi.org/10.1016/j.thromres.2011.10.031

32. Alessi MC, Gaudin C, Grosjean P, Martin V, Timsit S, Mahagne MH, et al. Changes in Activated Thrombin-Activatable Fibrinolysis Inhibitor Levels Following Thrombolytic Therapy in Ischemic Stroke Patients Correlate with Clinical Outcome. Cerebrovasc Dis. 2016;42(5–6):404–414. PMID: 27387478 https://doi.org/10.1159/000447722

33. Fernandez-Cadenas I, Alvarez-Sabin J, Ribo M, Rubiera M, Mendioroz M, Molina CA, et al. Influence of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 gene polymorphisms on tissue-type plasminogen activator-induced recanalization in ischemic stroke patients. J Thromb Haemost. 2007;5(9):1862–1868. PMID: 17723126 https://doi.org/10.1111/j.1538-7836.2007.02665.x

34. Szegedi I, Nagy A, Székely EG, Czuriga-Kovács KR, Sarkady F, Lánczi LI, et al. PAI-1 5G/5G genotype is an independent risk of intracranial hemorrhage in post-lysis stroke patients. Ann Clin Transl Neurol. 2019;6(11):2240–2250. PMID: 31637872 https://doi.org/10.1002/acn3.50923

35. Cruden NL, Graham C, Harding SA, Ludlam CA, Fox KA, et al. Plasma TAFI and soluble CD40 ligand do not predict reperfusion following thrombolysis for acute myocardial infarction. Thromb Res. 2006;118(2):189–197. PMID: 16055173 https://doi.org/10.1016/j.thromres.2005.06.014

36. Kim SH, Han SW, Kim EH, Kim DJ, Lee KY, Kim DI, et al. Plasma fibrinolysis inhibitor levels in acute stroke patients with thrombolysis failure. J Clin Neurol. 2005;1(2):142–147. PMID: 20396461 https://doi.org/10.3988/jcn.2005.1.2.142

37. Sinkovic A. Pretreatment plasminogen activator inhibitor-1 (PAI-1) levels and the outcome of thrombolysis with streptokinase in patients with acute myocardial infarction. Am Heart J. 1998;136(3):406–411. PMID: 9736130 https://doi.org/10.1016/s0002-8703(98)70213-3

38. Paganelli F, Alessi MC, Morange P, Maixent JM, Lévy S, Vague IJ. Relationship of plasminogen activator inhibitor-1 levels following thrombolytic therapy with rt-PA as compared to streptokinase and patency of infarct related coronary artery. Thromb Haemost. 1999;82(1):104–108. PMID: 10456462

39. Ribo M, Montaner J, Molina CA, Arenillas JF, Santamarina E, Quintana M, et al. Admission fibrinolytic profile is associated with symptomatic hemorrhagic transformation in stroke patients treated with tissue plasminogen activator. Stroke. 2004;35(9):2123–2127. PMID: 10456462 https://doi.org/10.1161/01.STR.0000137608.73660.4c

40. Ribo M, Montaner J, Molina CA, Arenillas JF, Santamarina E, AlvarezSabín J. Admission fibrinolytic profile predicts clot lysis resistance in stroke patients treated with tissue plasminogen activator. Thromb Haemost. 2004;91(6):1146–1151. PMID: 15175801 https://doi.org/10.1160/TH04-02-0097

41. Takazoe K, Ogawa H, Yasue H, Sakamoto T, Oshima S, Arai H, et al. Association of plasma levels of activated protein C with recanalization of the infarct-related coronary artery after thrombolytic therapy in acute myocardial infarction. Thromb Res. 1999;95(1):37–47. PMID: 10403685 https://doi.org/10.1016/s0049-3848(99)00020-1

42. Cocho D, Borrell M, Martí-Fàbregas J, Montaner J, Castellanos M, Bravo Y, et al. Pretreatment hemostatic markers of symptomatic intracerebral hemorrhage in patients treated with tissue plasminogen activator. Stroke. 2006;37(4):996–999. PMID: 16497981 https://doi.org/10.1161/01.STR.0000206461.71624.50

43. Rupin A, Martin F, Vallez MO, Bonhomme E, Verbeuren TJ. Inactivation of plasminogen activator inhibitor-1 accelerates thrombolysis of a platelet-rich thrombus in rat mesenteric arterioles. Thromb Haemost. 2001;86(6):1528–1531. PMID: 11776323

44. Custodio-Chablé SJ, Lezama RA, Reyes-Maldonado E. Platelet activation as a trigger factor for inflammation and atherosclerosis. Cir Cir. 2020;88(2):233–243. PMID: 32116325 https://doi.org/10.24875/CIRU.19000725

45. Farrehi PM, Ozaki CK, Carmeliet P, Fay WP. Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice. Circulation. 1998;97(10):1002–1008. PMID: 9529269 https://doi.org/10.1161/01.cir.97.10.1002

46. Colucci M, Scopece S, Gelato AV, Dimonte D, Semeraro N. In vitro clot lysis as a potential indicator of thrombus resistance to fibrinolysisstudy in healthy subjects and correlation with blood fibrinolytic parameters. Thromb Haemost. 1997;77(4):725–729. PMID: 9134650

47. Vaughan DE, Declerck PJ, Van Houtte E, De Mol M, Collen D. Reactivated recombinant plasminogen activator inhibitor-1 (rPAI-1) effectively prevents thrombolysis in vivo. Thromb Haemost. 1992;68(1):60–63. PMID: 1514173

48. Sakamoto T, Ogawa H, Takazoe K, Yoshimura M, Shimomura H, Moriyama Y, et al. Effect of activated protein C on plasma plasminogen activator inhibitor activity in patients with acute myocardial infarction treated with alteplase: comparison with unfractionated heparin. J Am Coll Cardiol. 2003;42(8):1389–1394. PMID: 14563580 https://doi.org/10.1016/s0735-1097(03)01059-3

49. Zhang S, Cao Y, Du J, Liu H, Chen X, Li M, et al. Neutrophil extracellular traps contribute to tissue plasminogen activator resistance in acute ischemic stroke. FASEB J. 2021;35(9):e21835. PMID: 34449927 https://doi.org/10.1096/fj.202100471RR

50. Martí-Fàbregas J, Borrell M, Cocho D, Belvís R, Castellanos M, Montaner J, et al. Hemostatic markers of recanalization in patients with ischemic stroke treated with rt-PA. Neurology. 2005;65(3):366–370. PMID: 16087899 https://doi.org/10.1212/01.wnl.0000171704.50395.ba

51. Lirong T, Minmin X, Manqiu Y, Yanping L. Performance evaluation of thrombus molecular markers thrombomodulin, thrombin-antithrombin complex, plasmin-α2-plasmin inhibitor complex, and tissue plasminogen activator-inhibitor complex by a chemiluminescence analyzer. Hippokratia. 2022;26(2):78–82. PMID: 37188051

52. Bagoly Z, Baráth B, Orbán-Kálmándi R, Szegedi I, Bogáti R, Sarkady F, et al. Incorporation of α2-Plasmin Inhibitor into Fibrin Clots and Its Association with the Clinical Outcome of Acute Ischemic Stroke Patients. Biomolecules. 2021;11(3):347. PMID: 33669007 https://doi.org/10.3390/biom11030347

53. Reed GL 3rd, Matsueda GR, Haber E. Inhibition of clot-bound alpha 2antiplasmin enhances in vivo thrombolysis. Circulation. 1990;82(1):164–168. PMID: 1694738 https://doi.org/10.1161/01.cir.82.1.164

54. Reed GL, Houng AK, Wang D. Microvascular thrombosis, fibrinolysis, ischemic injury, and death after cerebral thromboembolism are affected by levels of circulating α2-antiplasmin. Arterioscler Thromb Vasc Biol. 2014;34(12):2586–2593. PMID: 25256235 https://doi.org/10.1161/ATVBAHA.114.304530