Тромбоз, гемостаз и реология

Tromboz, Gemostaz I Reologiya
scientific and practical journal

ISSN 2078–1008 (Print); ISSN 2687-1483 (online)
2026, Review
2026

Thrombotic risk markers: thrombin-antithrombin complex

Review
Marine M. Tanashyan
Russian Center of Neurology and Neurosciences; 80 Volokolamskoe Shosse, Moscow 125367, Russia
Eugene V. Roitman
Russian Center of Neurology and Neurosciences; 80 Volokolamskoe Shosse, Moscow 125367, Russia
Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation; 1 Ostrovityanova Str., Moscow 117513, Russia
Anton A. Raskurazhev
Russian Center of Neurology and Neurosciences; 80 Volokolamskoe Shosse, Moscow 125367, Russia
Polina I. Kuznetsova
Russian Center of Neurology and Neurosciences; 80 Volokolamskoe Shosse, Moscow 125367, Russia
Andrey S. Mazur
Russian Center of Neurology and Neurosciences; 80 Volokolamskoe Shosse, Moscow 125367, Russia

Keywords

thrombin-antithrombin complex
TAT
biomarker
hemostasis
  Full Text

Abstract

Summary. Thrombin-antithrombin complex (TAT) is a relatively stable marker of thrombotic risk with a sufficient degree of sensitivity reflecting thrombin production in the blood. TAT is also a recognized indicator of thrombin generation. The TAT level can provide valuable insight into coagulation system activation associated with a range of conditions in which its significant increase is observed. However, this indicator should be evaluated in conjunction with other markers of thrombotic danger (including in assessing the response to ongoing antithrombotic therapy). This review provides up-to-date information on the TAT structure, functions, diagnostic capabilities, and application in clinical practice.

For citation: Tanashyan M.M., Roitman E.V., Raskurazhev A.A., Kuznetsova P.I., Mazur A.S. Thrombotic risk markers: thrombin-antithrombin complex. Tromboz, gemostaz i reologiya. 2026;(1):29–37. (In Russ.).

References

  1. Levy J.H., Sniecinski R.M., Welsby I.J., Levi M. Antithrombin: antiinflammatory properties and clinical applications. Thromb Haemost. 2016;115(4):712–28. DOI: 10.1160/TH15-08-0687.
  2. Amiral J., Seghatchian J. Revisiting antithrombin in health and disease, congenital deficiencies and genetic variants, and laboratory studies on α and β forms. Transfus Apher Sci. 2018;57(2):291– 7. DOI: 10.1016/j.transci.2018.04.010.
  3. Iba T. Thrombin-Antithrombin System. In: Trauma Induced Coagulopathy. Eds. H.B. Moore, M.D. Neal, E.E. Moore. Springer, Cham, 2021. 43–51. DOI: 10.1007/978-3-030-53606-0_4.
  4. Ishiguro K., Kojima T., Kadomatsu K. et al. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest. 2000;106(7):873–8. DOI: 10.1172/JCI10489.
  5. Li W., Johnson D.J., Esmon C.T., Huntington J.A. Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat Struct Mol Biol. 2004;11(9):857–62. DOI: 10.1038/nsmb811.
  6. Van Cott E.M., Orlando C., Moore G.W. et al. Subcommittee on Plasma Coagulation Inhibitors. Recommendations for clinical laboratory testing for antithrombin deficiency; Communication from the SSC of the ISTH. J Thromb Haemost. 2020;18(1):17–22. DOI: 10.1111/jth.14648.
  7. Khan A.B., Siddiqui U., Fatima S. et al. Protein disulfide isomerase uses thrombin-antithrombin complex as a template to bind its target protein and alter the blood coagulation rates. Biosci Rep. 2024;44(5):BSR20231540. DOI: 10.1042/BSR20231540.
  8. Römisch J., Pâques E.P. Thrombin-hirudin complex stability: a comparison with the thrombin-antithrombin III complex. Blood Coagul Fibrinolysis. 1991;2(5):643–6.
  9. Seitz R., Egbring R., Wagner C., Dati F. Thrombin-antithrombin III complex (TAT): a marker for activation of intravascular coagulation. Internist (Berl). 1990;31(1):69–74. (In German).
  10. Momot A.P., Tsyvkina L.P., Taranenko I.A. et al. Current methods of recognizing the state of thrombotic readiness. Barnaul: Altai State University, 2022. 146 рр. (In Russ.).
  11. Napalkova O.S., Emanuel V.L., Lapin S.V. et al. Thrombin as a key enzyme of hemostasis and its role in atherosclerosis and inflammation. Medicinskij alfavit. 2015;3(11):42–5. (In Russ.).
  12. Lobastov K.V., Dementieva G.I.,Laberko L.A. Modernideasabout the etiology and pathogenesis of venous thrombosis: rethinking the Virchov triad. Flebologiya. 2019;13(3):227–35. (In Russ.). DOI: 10.17116/flebo201913031227.
  13. Ling L., Liu C., Huang X. et al. Anti-Xa activity test is needed but is not enough for monitoring fondaparinux therapy among critically ill patients. Arch Pathol Lab Med. 2025;149(1): e11-e18. DOI: 10.5858/ arpa.2023-0496-OA.
  14. Liu Z., Liu C., Zhong M. et al. Changes in coagulation and fibrinolysis in post-cesarean section parturients treated with low molecular weight heparin. Clin Appl Thromb Hemost. 2020;26:1076029620978809. DOI: 10.1177/1076029620978809.
  15. Rogozina A.S., Vorobyeva N.A. The effect of vitamin K antagonists on thrombinemia and homocysteine levels. Vestnik Severnogo (Arkticheskogo) federal’nogo universiteta. Seriya: mediko-biologicheskie nauki. 2014;(4):66–72. (In Russ.).
  16. Weisshaar S., Litschauer B., Gouya G. et al. Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects. J Thromb Haemost. 2014;12(11):1850–60. DOI: 10.1111/jth.12726.
  17. Berezhnyak I.V., Momot A.P., Merkulov I.V. Comparative assessment of effectiveness of thromboprophylaxis by novel oral anticoagulants at total hip replacement. Tromboz, gemostaz i reologiya. 2017;(3):32–40. (In Russ.).
  18. Schiffer S., Schwers S., Heitmeier S. The effect of rivaroxaban on biomarkers in blood and plasma: a review of preclinical and clinical evidence. J Thromb Thrombolysis. 2023;55(3):449–63. DOI: 10.1007/ s11239-023-02776-z.
  19. Yao Y., Li Y., Jin Q. et al. Perioperative treatment with rivaroxaban and dabigatran on changes of coagulation and platelet activation biomarkers following left atrial appendage closure. Cardiovasc Ther. 2024;2024:4405152. DOI: 10.1155/2024/4405152.
  20. Koretsune Y., Yamashita T., Akao M. et al. Coagulation biomarkers and clinical outcomes in elderly patients with nonvalvular atrial fibrillation: ANAFIE subcohort study. JACC Asia. 2023;3(4):595– 607. DOI: 10.1016/j.jacasi.2023.06.004.
  21. Averkov O.V., Slavina N.N., Graziansky N.A. Acute coronary syndrome without persistent ST segment elevation: changes in some indicators of the blood coagulation system and Willebrand factor with short-term use of ticlopidine or clopidogrel. Kardiologiya. 2003;10(43): 50–9. (In Russ.).
  22. Song P., Xie J., Li W. et al. Effect of plasma thrombin-antithrombin complex on ischemic stroke: a systematic review and meta-analysis. Syst Rev. 2023;12(1):17. DOI:10.1186/s13643-023-02174-9.
  23. Borissoff J.I., Heeneman S., Kilinç E. et al. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation. 2010;122(8):821– 30. DOI: 10.1161/CIRCULATIONAHA.109.907121.
  24. Xi G., Wagner K.R., Keep R.F. et al. Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke. 1998;29(12):2580–6. DOI: 10.1161/01.str.29.12.2580.
  25. Wu C.H., Yang R.L., Huang S.Y. et al. Analysis of thrombinantithrombin complex contents in plasma and hematoma fluid of hypertensive intracerebral hemorrhage patients after clot removal. Eur J Neurol. 2011;18(8):1060–6. DOI: 10.1111/j.1468-1331.2010.03336.x.
  26. Lin Z., Sun H., Li D. et al. Thrombin antithrombin complex concentration as an early predictor of deep vein thrombosis after total hip arthroplasty and total knee arthroplasty. BMC Musculoskelet Disord. 2022;23(1):574. DOI: 10.1186/s12891-022-05532-1.
  27. Siddiqui F., Tafur A., Darki A. et al. Decreased thrombin generation is associated with increased thrombin generation biomarkers and blood cellular indices in pulmonary embolism. Clin Appl Thromb Hemost. 2024;30:10760296241261076. DOI: 10.1177/10760296241261076.
  28. Bitsadze V.O., Slukhanchuk E.V., SolopovaA.G. et al. Von Willebrand factor and ADAMTS13 as predictors of thrombosis in gynecologic cancer patients undergoing chemotherapy. Voprosy ginekologii, akusherstva i perinatologii. 2023;22(4):39–47. (In Russ.). DOI: 10. 20953/1726-1678-2023-4-39-47.
  29. Gyldenholm T., Hvas A.M., Christensen T.D., Larsen J.B. Thrombin generation markers as predictors of cancer-associated venous thromboembolism: A systematic review. Semin Thromb Hemost. 2024;50(3):384–401. DOI: 10.1055/s-0043-1775856.
  30. 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;29:10760296231195089. DOI: 10.1177/10760296231195089.
  31. 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;173:20–6. DOI: 10.1016/j.thromres.2018.11.010.
  32. Bai H., Shen L., Zhang H., Tang N. Clinical value of TAT, PIC and tPAIC as predictive markers for severe sepsis in pediatric patients. Front Pediatr. 2024;12:1336583. DOI: 10.3389/fped.2024.1336583.
  33. Wada H., Takahashi H., Uchiyama T. et al. The approval of revised diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. ThrombJ. 2017;15:17. DOI: 10.1186/ s12959-017-0142-4.
  34. Yamakawa K., Ohbe H., Hisamune R. et al. Current clinical practice of laboratory testing of the hemostasis and coagulation system in patients with sepsis: A nationwide observational study in Japan. JMA J. 2024;7(2):224–31. DOI: 10.31662/jmaj.2023-0151.
  35. Seidel H., Duncklenberg M., Hertfelder H.J. et al. Establishing expectancy values for fibrin monomer in uncomplicated pregnancy. TH Open. 2024;8(3): e283-e296. DOI: 10.1055/s-0044-1788281.
  36. Byshevsky A.Sh., Polyakova V.A., Rudzevich A. Yu. Hemostasis in physiological pregnancy, pregnancy with arterial hypertension and preeclampsia. Tromboz, gemostaz i reologija. 2010;(4):13–30. (In Russ.).
  37. Mel’nikov A.P., Bogdanova E.V., Akhvlediani K.N. Changes in haemocoagulation during physiological pregnancy. Rossijskij vestnik akushera-ginekologa. 2023;23(2):26–33. (In Russ.). DOI: 10.17116/ rosakush20232302126.
  38. Murashko A.V., Drapkina Yu.S., Koroleva N.S. The course of pregnancy and blood coagulation system. Arhiv akusherstva i ginekologii imeni V.F. Snegireva. 2016;3(4):181–7. (In Russ.).
  39. Sun Q., Lu Y., Zhong J. et al. A retrospective case-control study on the diagnostic values of hemostatic markers in hypertensive disorder of pregnancy. Lab Med. 2023;54(4):392–9. DOI: 10.1093/ labmed/lmac128.
  40. Bitsadze V.O., Akinshina S.V., Andreeva M.D., Makatsariya A.D. Thromboembolic complications related to the use of assistive reproductive treatment. Ovarian hyperstimulation syndrome. Prakticheskaja medicina. 2013;7(76):20–31. (In Russ.).
  41. Vdovichenko J.P., Firsova N.A., Alipova N.F. Hemostasiological aspects of failed in vitro fertilization attempts in women with metabolic syndrome. Reproduktivnoe zdorov’e. Vostochnaja Evropa. 2019;9(6):755–63. (In Russ.).
  42. Cavaillès A., Brinchault-Rabin G., Dixmier A. et al. Comorbidities of COPD. Eur Respir Rev. 2013;22(130):454–75. DOI: 10.1183/09059180.00008612.
  43. ChuchalinA.G., TseimakhI.Ya., MomotA.P. et al. Thrombogenic risk factors in patients with exacerbation of chronic obstructive pulmonary disease. Klinicheskaya medicina. 2015;93(12):18– 23. (In Russ.).
  44. Chuchalin A.G., Tseimakh I.Ya., Momot A.P. et al. Changes in systemic inflammatory and hemostatic response in patients with comorbidity of exacerbation of chronic obstructive pulmonary disease, chronic heart failure and obesity. Pul’monologija. 2014;(6):25– 32. (In Russ.).
  45. Popova E.N., Arkhipova D.V., Kogan E.A. et al. Role of endothelial dysfunction and neoangiogenesis in development of lung fibrosis and pulmonary hypertension in usual interstitial pneumonia. Pul’monologiya. 2004;(3):16–21. (In Russ.).
  46. Ueland T., Michelsen A.E., Tveita A.A. et al. Coagulopathy and adverse outcomes in hospitalized patients with COVID-19: results from the NOR-Solidarity trial. Res Pract Thromb Haemost. 2023;8(1):102289. DOI: 10.1016/j.rpth.2023.102289.
  47. Trutnev V.P., Shtofin S.G., Pikalov I.V., Maier E.O. Approaches to correcting the trombohaemorrhagic complications in surgery of pelvic organs. Vestnik Novosibirskogo gosudarstvennogo universiteta. Seriya: biologiya, klinicheskaya medicina. 2010;8(3):40–6. (In Russ.).
  48. Chen W., Li Y., Wang W. et al. Prognostic value of coagulation markers in patients with colorectal caner: A prospective study. Health Sci Rep. 2024;7(2):e1553. DOI: 10.1002/hsr2.1553.
  49. Zhenilo V.M., Konstantinova G.A., Malygin V.N. The condition of the hemostatic system in malignant tumors of the prostate and bladder. Novye tehnologii. 2012;(1):226–9. (In Russ.).
  50. Slukhanchuk E.V., Bitsadze V.O., Solopova A.G. et al. Interactions between neutrophil extracellular traps and antiphospholipid antibodies in cancer patients. Voprosy ginekologii, akusherstva i perinatologii. 2023;22(3):54–62. (In Russ.). DOI: 10.20953/1726-16782023-3-54-62.
  51. Tanashyan M.M., Kuznetsova P.I., Raskurazhev A.A. et al. Сlinical and neuroimaging patterns of ischemic stroke in Ph-negative myeloproliferative neoplasms. Annaly klinicheskoj i jeksperimental’noj nevrologii. 2024;18(3):14–25 (In Russ.). DOI: 10.17816/ACEN.1164.
  52. 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;24(1):107. DOI: 10.1007/ s10238-024-01371-7.
  53. Guo Q.-Y., Peng J., Shan T.-C., Xu M. Risk factors for mortality in critically ill patients with coagulation abnormalities: A retrospective cohort study. Curr Med Sci. 2024;44(5):912–22. DOI: 10.1007/ s11596-024-2920-0.
  54. Charnaia M.A., Dement’eva I.I. Hemostasis system in the abdominal aorta aneurysms. Kardiologiya i serdechno-sosudistaya hirurgiya. 2017;10(4):4–7. (In Russ.). DOI: 10.17116/kardio20171044-7.
  55. 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;10(10):10170–84. DOI: 10.21037/apm-21-2222.
  56. Gando S., Levi M., Toh C.H. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016;2:16037. DOI: 10.1038/nrdp.2016.37.
  57. LuY., LiD., HuangY. et al. Pretreatment with eupatilin attenuates inflammation and coagulation in sepsis by suppressing JAK2/STAT3 signaling pathway. J Inflamm Res. 2023;16:1027–42. DOI: 10.2147/JIR.S393850.
  58. Iba T., Saitoh D. Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation. J Intensive Care. 2014;2(1):66. DOI: 10.1186/ s40560-014-0051-6.
  59. Pelzer H., Schwarz A., Heimburger N. Determination of human thrombin-antithrombin III complex in plasma with an enzymelinked immunosorbent assay. Thromb Haemost. 1988;59(1):101–6.
  60. Penner J.A. Disseminated intravascular coagulation in patients with multiple organ failure of non-septic origin. Semin Thromb Hemost. 1998;24(1):45–52. DOI: 10.1055/s-2007-995822.
  61. Tala J.A., Polikoff L.A., Pinto M.G. et al.; THEIA Study Investigators. Protein biomarkers for incident deep venous thrombosis in critically ill adolescents: An exploratory study. Pediatr Blood Cancer. 2020;67(4):e28159. DOI: 10.1002/pbc.28159.
  62. Balakrishnan G., Brownlie J., Webber R., Gibson B. Enhanced thrombin generation in patients receiving intensive care. Arch Dis Child. 1991;66(12):1413–5. DOI:10.1136/adc.66.12.1413.
  63. Wada H., Honda G., Kawano N. et al. Severe antithrombin deficiency may be associated with a high risk of pathological progression of DIC with suppressed fibrinolysis. Clin Appl Thromb Hemost. 2020;26:1076029620941112. DOI: 10.1177/1076029620941112.
  64. Wertz J., Doshi A.A., Guyette F.X. et al. Thrombin-antithrombin levels are associated with survival in patients resuscitated from cardiac arrest. Resuscitation. 2013;84(10):1400–3. DOI:10.1016/j.resuscitation.2013.03.022.