Маркеры тромботической опасности: комплекс тканевой активатор плазминогена/ингибитор тканевого активатора плазминогена 1-го типа (часть 1)

Система фибринолиза является одним из важнейших регуляторов гомеостаза и принимает участие в поддержании стабильного тока крови. Ключевым элементом данной системы является баланс активаторов и ингибиторов плазминогена, которые могут рассматриваться как маркеры нормальных физиологических и патологических реакций. Использование лабораторного определения уровня комплекса тканевого активатора плазминогена/ингибитора тканевого активатора плазминогена-1 (tissue plasminogen activator/ plasminogen activator inhibitor-1, t-PA/PAI-1) в клинической практике является перспективным в диагностическом и прогностическом отношении – в качестве биомаркера повышенного тромботического риска на ранних этапах развития осложнения заболевания. В данном обзоре представлена актуальная информация, посвященная структуре, функциям, диагностическим возможностям и применению в медицинской практике такого маркера тромботической опасности, как комплекс t-PA/PAI-1 при венозных тромбоэмболических осложнениях, сепсисе, синдроме диссеминированного внутрисосудистого свертывания и на фоне онкологического процесса.

1. Жалялов А. С. Исследование пространственной динамики роста и лизиса фибринового сгустка в условиях тромболитической терапии: Автореф. дис… канд. мед. наук. М., 2019. 24 с.

2. Жалялов А. С., Баландина А. Н., Купраш А. Д. и др. Современные представления о системе фибринолиза и методах диагностики ее нарушений // Вопросы гематологии/онкологии и иммунопатологии в педиатрии. – 2017. – Т. 16, № 1. – С. 69–82. http://doi.org/10.24287/1726-1708-2017-16-1-69-82.

3. Момот А. П., Лебедева Е. И., Николаева М. Г. и др. Клинические эффекты применения дозированной перемежающейся вазокомпрессии // Проблемы репродукции. – 2019. – Т. 25, № 4. – С. 35–42. http://doi.org/10.17116/repro20192504135.

4. Рябинкина Ю. В., Пирадов М. А., Танашян М. М. и др. Венозное тромбообразование и функциональное состояние системы гемореологии и гемостаза у пациентов с инсультом // Анналы клинической и экспериментальной неврологии. – 2016. – Т. 10, № 1. – С. 6–13. http://doi.org/10.17816/psaic76.

5. Танашян М. М., Раскуражев А. А., Шабалина А. А. и др. Биомаркеры церебрального атеросклероза: возможности ранней диагностики и прогнозирования индивидуального риска // Анналы клинической и экспериментальной неврологии. – 2015. – T. 9, № 3. – С. 20–25.

6. Танашян М. М., Шабалина А. А., Ройтман Е. В. и др. Тромбогенность у больных ишемическим инсультом на фоне истинной полицитемии // Вестник Российского государственного медицинского университета. – 2020. – № 4. – C. 49–55. http://doi.org/10.24075/vrgmu.2020.052.

7. Asakura H., Jokaji H., Saito M. et al. Changes in plasma levels of tissue-plasminogen activator/inhibitor complex and active plasminogen activator inhibitor in patients with disseminated intravascular coagulation // Am J Hematol. – 1991. – Vol. 36, № 3. – P. 176–183. http://doi.org/10.1002/ajh.2830360304.

8. Bai H., Shen L., Zhang H. et al. Clinical value of TAT, PIC and t-PAIC as predictive markers for severe sepsis in pediatric patients // Front Pediatr. – 2024. – Vol. 12. – 1336583. http://doi.org/10.3389/fped.2024.1336583.

9. Bollen L., Peetermans M., Peeters M. et al. Active PAI-1 as marker for venous thromboembolism: case-control study using a comprehensive panel of PAI-1 and TAFI assays // Thromb Res. – 2014. – Vol. 134, № 5. – P. 1097–1102. http://doi.org/10.1016/j.thromres.2014.08.007.

10. Bourrienne M.-C., Loyau S., Faille D. et al. Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms // J Thromb Haemost. – 2024. – Vol. 22, № 11. – P. 3199–3208. http://doi.org/10.1016/j.jtha.2024.07.031.

11. Chan O. T. M., Furuya H., Pagano I. et al. Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients // Oncotarget. – 2017. – Vol. 8, № 59. – P. 99707–99721. http://doi.org/10.18632/oncotarget.20686.

12. Chen R., Petrazzini B. O., Malick W. A. et al. Prediction of venous thromboembolism in diverse populations using machine learning and structured electronic health records // Arterioscler Thromb Vasc Biol. – 2024. – Vol. 44, № 2. – P. 491–504. http://doi.org/10.1161/ATVBAHA.123.320331.

13. Chen Q., Shou W., Wu W. et al. Performance evaluation of thrombomodulin, thrombin-antithrombin complex, plasmin-α2-antiplasmin complex, and t-PA: PAI-1 complex // J Clin Lab Anal. – 2019. – Vol. 33, № 6. – e22913. http://doi.org/10.1002/jcla.22913.

14. Frischmuth T., Hindberg K., Aukrust P. et al. Elevated plasma levels of plasminogen activator inhibitor-1 are associated with risk of future incident venous thromboembolism // J Thromb Haemost. – 2022. – Vol. 20, № 7. – P. 1618–1626. http://doi.org/10.1111/jth.15701.

15. Fu Y., Liu Y., Jin Y. et al. Value of coagulation and fibrinolysis biomarker in lung cancer patients with thromboembolism // Zhongguo Fei Ai Za Zhi. – 2018. – Vol. 21, № 8. – P. 583–587. http://doi.org/10.3779/j.issn.1009-3419.2018.08.03.

16. Gehlot P., Brünnert D., Kaushik V. et al. Unconventional localization of PAI-1 in PML bodies: A possible link with cellular growth of endothelial cells // Biochem Biophys Rep. – 2024. – Vol. 39. – 101793. http://doi.org/10.1016/j.bbrep.2024.101793.

17. Guo Q. Y., Peng J., Shan T. C. et al. Risk factors for mortality in critically ill patients with coagulation abnormalities: a retrospective cohort study // Curr Med Sci. – 2024. – Vol. 44, № 5. – P. 912–922. http://doi.org/10.1007/s11596-024-2920-0.

18. Hayashi M., Ohmori S., Kawai Y. Endothelial GATA3 is involved in coagulofibrinolytic homeostasis during endotoxin sepsis // Exp Anim. – 2025. – Vol. 74, № 1. – P. 104–113. http://doi.org/10.1538/expanim.24-0079.

19. Hong L. R., Chen Y. J., Jiang Q. L. et al. Predictive value of four items of new thrombus markers combined with conventional coagulation tests for thrombosis in antiphospholipid syndrome // Beijing Da Xue Xue Bao Yi Xue Ban. – 2023. – Vol. 55, № 6. – P. 1033–1038. http://doi.org/10.19723/j.issn.1671-167X.2023.06.012.

20. Hoshino K., Kitamura T., Nakamura Y. et al. Usefulness of plasminogen activator inhibitor-1 as a predictive marker of mortality in sepsis // J Intensive Care. – 2017. – Vol. 5, № 1. – P. 42. http://doi.org/10.1186/s40560-017-0238-8.

21. Hoshino K., Nakashio M., Maruyama J. et al. Validating plasminogen activator inhibitor-1 as a poor prognostic factor in sepsis // Acute Med Surg. – 2020. – Vol. 7, № 1. – e581. http://doi.org/10.1002/ams2.581.

22. Huang K., Mo Q., Liao C. et al. The clinical significance of TAT, PIC, TM, and t-PAIC in vascular events of BCR/ABL-negative myeloproliferative neoplasms // Clin Exp Med. – 2024. – Vol. 24, № 1. – P. 107. http://doi.org/10.1007/s10238-024-01371-7.

23. Huang L., Deng X., Fan R.-Z. et al. Coagulation and fibrinolytic markers offer utility when distinguishing between benign and malignant gallbladder tumors: A cross-sectional study // Clin Chim Acta. – 2024. – Vol. 560. – P. 119751. http://doi.org/10.1016/j.cca.2024.119751.

24. Jee J., Brannon A.R., Singh R. et al. DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism // Nat Med. – 2024. – Vol. 30, № 9. – P. 2499–2507. http://doi.org/10.1038/s41591-024-03195-0.

25. Jevrić M., Matić I. Z., Krivokuća A. et al. Association of uPA and PAI-1 tumor levels and 4G/5G variants of PAI-1 gene with disease outcome in luminal HER2-negative node-negative breast cancer patients treated with adjuvant endocrine therapy // BMC Cancer. – 2019. – Vol. 19, № 1. – P. 71. http://doi.org/10.1186/s12885-018-5255-z.

26. Ji Y., Qin Y., Tan Q. et al. Development of a chemiluminescence assay for tissue plasminogen activator inhibitor complex and its applicability to gastric cancer // BMC Biotechnol. – 2024. – Vol. 24, № 1. – P. 30. http://doi.org/10.1186/s12896-024-00850-9.

27. Johansson L., Jansson J. H., Boman K. et al. Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke // Stroke. – 2000. – Vol. 31, № 1. – P. 26–32. http://doi.org/10.1161/01.str.31.1.26.

28. Li H., Shinohara E. T., Cai Q. Plasminogen activator inhibitor-1 promoter polymorphism is not associated with the aggressiveness of disease in prostate cancer // Clin Oncol (R Coll Radiol) . – 2006. – Vol. 18, № 4. – P. 333–337. http://doi.org/10.1016/j.clon.2006.02.005.

29. Li Y., Li H., Wang Y. et al. Potential biomarkers for early diagnosis, evaluation, and prognosis of sepsis-induced coagulopathy // Clin Appl Thromb Hemost. – 2023. – Vol. 29. – 10760296231195089. http://doi.org/10.1177/10760296231195089.

30. Ling L., Huang X., Liu C. et al. Monitoring coagulation-fibrinolysis activation prompted timely diagnosis of hemophagocytic lymphohistiocytosis-related disseminated intravascular coagulation // Thrombosis J. – 2021. – Vol. 19, № 1. – P. 82. http://doi.org/10.1186/s12959-021-00338-y.

31. López-Núñez J. J., Trujillo-Santos J., Monreal M. Management of venous thromboembolism in patients with cancer // J Thromb Haemost. – 2018. – Vol. 16, № 12. – P. 2391–2396. http://doi.org/10.1111/jth.14305.

32. Mathews S. G., Krishna R. B. D., Lavanya M. et al. The role of the plasminogen activator inhibitor 1 (pai1) in ovarian cancer: mechanisms and therapeutic implications // Glob Med Genet. – 2024. – Vol. 11, № 4. – P. 358–365. http://doi.org/10.1055/s-0044-1791734.

33. Mei H., Jiang Y., Luo L. et al. Evaluation the combined diagnostic value of TAT, PIC, tPAIC, and sTM in disseminated intravascular coagulation: A multi-center prospective observational study // Thromb Res. – 2019. – Vol. 173. – P. 20–26. http://doi.org/10.1016/j.thromres.2018.11.010.

34. Nakatsuka E., Sawada K., Nakamura K. et al. Plasminogen activator inhibitor-1 is an independent prognostic factor of ovarian cancer and IMD-4482, a novel plasminogen activator inhibitor-1 inhibitor, inhibits ovarian cancer peritoneal dissemination // Oncotarget. – 2017. – Vol. 8, № 52. – P. 89887–89902. http://doi.org/10.18632/oncotarget.20834.

35. Nicolaides A. N., Fareed J., Spyropoulos A. C. et al. Prevention and management of venous thromboembolism. International Consensus Statement. Guidelines according to scientific evidence // Int Angiol. – 2024. – Vol. 43, № 1. – P. 1–222. http://doi.org/10.23736/S0392-9590.23.05177-5.

36. Nordenhem A., Wiman B. Tissue plasminogen activator (tPA) antigen in plasma: correlation with different tPA/inhibitor complexes // Scand J Clin Lab Invest. – 1998. – Vol. 58, № 6. – P. 475–483. http://doi.org/10.1080/00365519850186274.

37. Nosaka M., Ishida Y., Kuninaka Y. et al. Immunohistochemical detection of uPA, tPA, and PAI-1 in a stasis-induced deep vein thrombosis model and its application to thrombus age estimation // Int J Legal Med. – 2012. – Vol. 126. – P. 421–425. http://doi.org/10.1007/s00414-012-0680-z.

38. Qiu Y., Han S., Ji Y. Development of a thrombin-antithrombin complex detection kit and study in venous thromboembolism complicated by cervical cancer // BMC Biotechnol. – 2024. – Vol. 24, № 1. – P. 103. http://doi.org/10.1186/s12896-024-00930-w.

39. Ren W., Zhang J., Chen Y. Evaluation of coagulation, fibrinolysis and endothelial biomarkers in cirrhotic patients with or without portal venous thrombosis // Clin Appl Thromb Hemost. – 2020. – Vol. 26. – 1076029620982666. http://doi.org/10.1177/1076029620982666.

40. Sotiropoulos G. P., Kotopouli M., Karampela I. et al. Circulating plasminogen activator inhibitor-1 activity: a biomarker for resectable non-small cell lung cancer? // J BUON. – 2019. – Vol. 24, № 3. – P. 943–954. PMID: 31424646.

41. Sternlicht M. D., Dunning A. M., Moore D. H. et al. Prognostic value of PAI1 in invasive breast cancer: evidence that tumor-specific factors are more important than genetic variation in regulating PAI1 expression // Cancer Epidemiol Biomarkers Prev. – 2006. – Vol. 15, № 11. – P. 2107–2114. http://doi.org/10.1158/1055-9965.EPI-06-0351.

42. Swarbreck S. B., Secor D., Ellis C. G. et al. Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis // Blood Coagul Fibrinolysis. – 2015. – Vol. 26, № 4. – P. 436–442. http://doi.org/10.1097/MBC.0000000000000273.

43. Tjärnlund-Wolf A., Brogren H., Lo E.H. et al. Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases // Stroke. – 2012. – Vol. 43, № 10. – P. 2833–2839. http://doi.org/10.1161/STROKEAHA.111.622217.

44. Urano T., Castellino F. J., Suzuki Y. Regulation of plasminogen activation on cell surfaces and fibrin // J Thromb Haemost. – 2018. – Vol. 16, № 8. – P. 1487–1497. http://doi.org/10.1111/jth.14157.

45. Watanabe R., Wada H., Miura Y. et al. Plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tPA/PAI-1 complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura // Clin Appl Thromb Hemost. – 2001. – Vol. 7, № 3. – P. 229–233. http://doi.org/10.1177/107602960100700309.

46. de Witte J. H., Sweep C. G., Klijn J. G. et al. Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer // Br J Cancer. – 1999. – Vol. 80, № 1–2. – P. 286–294. http://doi.org/10.1038/sj.bjc.6690353.

47. Wrzeszcz K., Słomka A., Zarychta E. et al. Tissue plasminogen activator as a possible indicator of breast cancer relapse: a preliminary, prospective study // J Clin Med. – 2022. – Vol. 11, № 9. – P. 2398. http://doi.org/10.3390/jcm11092398.

48. Wu Z., Du Y., Cai X., Xu Q. Caprini score combined with thrombotic molecular markers for predicting DVT in patients with traumatic fractures // Sci Rep. – 2025. – Vol. 15, № 1. – P. 1847. http://doi.org/10.1038/s41598-025-85941-z.

49. Yang Y., Feng G., Yan J. et al. Plasminogen activator inhibitor-1, thrombin-antithrombin, and prothrombin fragment F1+2 have higher diagnostic values than D-dimer for venous thromboembolism after TKA // Clin Appl Thromb Hemost. – 2022. – Vol. 28. – 10760296221097383. http://doi.org/10.1177/10760296221097383.

50. Zhang J., Xue M., Chen Y. et al. Identification of soluble thrombomodulin and tissue plasminogen activator-inhibitor complex as biomarkers for prognosis and early evaluation of septic shock and sepsis-induced disseminated intravascular coagulation // Ann Palliat Med. – 2021. – Vol. 10, № 10. – P. 10170–10184. http://doi.org/10.21037/apm-21-2222.

51. Zhang Q., Jin Y., Li X. et al. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphisms and risk of venous thromboembolism – a meta-analysis and systematic review // Vasa. – 2020. – Vol. 49, № 2. – P. 141–146. http://doi.org/10.1024/0301-1526/a000839.

52. Zhong L., Dou J., Lin Q. et al. Tissue-type plasminogen activator-inhibitor complex as an early predictor of septic shock: a retrospective, single-center study // Dis Markers. – 2022. – 9364037. http://doi.org/10.1155/2022/9364037.

53. Zhou Y., He L.-P., Qi Y.-H. et al. Diagnostic value of tissue plasminogen activator-inhibitor complex in sepsis-induced liver injury: A single-center retrospective case-control study // World J Hepatol. – 2024. – Vol. 16, № 11. – P. 1255–1264. http://doi.org/10.4254/wjh.v16.i11.1255.

54. Zubac D. P., Wentzel-Larsen T., Seidal T. et al. Type 1 plasminogen activator inhibitor (PAI-1) in clear cell renal cell carcinoma (CCRCC) and its impact on angiogenesis, progression and patient survival after radical nephrectomy // BMC Urol. – 2010. – Vol. 10. – P. 20. http://doi.org/10.1186/1471-2490-10-20.