ТЕСТ ГЕНЕРАЦИИ ТРОМБИНА КАК ИНТЕГРАЛЬНЫЙ АНАЛИЗ СИСТЕМЫ ГЕМОСТАЗА: ТЕХНИЧЕСКИЕ ВОЗМОЖНОСТИ И ПРИМЕНЕНИЕ В КЛИНИКО-ЛАБОРАТОРНОЙ ПРАКТИКЕ

Данный обзор литературы посвящен одному из интегральных тестов оценки системы гемостаза — тесту генерации тромбина (ТГТ), его техническим характеристикам, проблемам в стандартизации и возможному клиническому использованию. Оценка генерации тромбина (ГТ) более чувствительна к изменениям, происходящим в системе гемостаза, поскольку учитывает действие как прокоагулянтных, так и антикоагулянтных факторов в процессе образования тромбина. Важно отметить, что существуют варианты постановки ТГТ в богатой тромбоцитами плазме или в цельной крови, что приближает исследователя к условиям in vivo. Однако, несмотря на явные преимущества этого анализа при сравнении со скрининговыми тестами оценки системы гемостаза, существует ряд ограничений, в том числе отсутствие стандартизации, что не позволяет на данный момент внедрить ТГТ в клиническую практику. В данном обзоре обсуждаются технические характеристики ТГТ и варианты наборов реагентов в зависимости от поставленной клинической задачи, а также приводятся результаты последних исследований в области клинического применения ТГТ, демонстрирующие перспективность анализа ГТ для оценки риска как геморрагических осложнений, так и тромботических событий.

1. Depasse F, Binder NB, Mueller J, et al. Thrombin generation assays are versatile tools in blood coagulation analysis: A review of technical features, and applications from research to laboratory routine. J Thromb Haemost. 2021; 19: 2907–2917.

2. Баландина А.Н., Кольцова Е.М., Шибеко А.М. Тромбодинамика: новый подход к диагностике нарушений системы гемостаза. Вопросы гематологии/ онкологии и иммунопатологии в педиатрии.2018; 17: 114–116.

3. Macfarlane RG, Biggs R. A thrombin generation test; the application in haemophilia and thrombocytopenia. J Clin Pathol. 1953; 6: 3–8.

4. Hemker HC, Giesen P, Al Dieri R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb. 2003; 33: 4–15.

5. Ten Cate H. Thrombin generation in clinical conditions. Thromb Res. 2012; 129: 367–370.

6. Tripodi A. Thrombin Generation Assay and Its Application in the Clinical Laboratory. Clin Chem. 2016; 62: 699–707.

7. Panova-Noeva M, van der Meijden PEJ, ten Cate H. Clinical Applications, Pitfalls, and Uncertainties of Thrombin Generation in the Presence of Platelets. J Clin Med. 2019; 9: 92.

8. Regnault V, Béguin S, Lecompte T. Calibrated Automated Thrombin Generation in Frozen-Thawed Platelet-Rich Plasma to Detect Hypercoagulability. PHT. 2003; 33: 23–29.

9. Prior SM, Mann KG, Freeman K, et al. Continuous thrombin generation in whole blood: new applications for assessing activators and inhibitors of coagulation. Anal Biochem. 2018; 551: 19–25.

10. Loeffen R, Kleinegris M-CF, Loubele STBG, et al. Preanalytic variables of thrombin generation: towards a standard procedure and validation of the method. J Thromb Haemost. 2012; 10: 2544–2554.

11. Dargaud Y, Wolberg AS, Gray E, et al. Proposal for standardized preanalytical and analytical conditions for measuring thrombin generation in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 2017; 15: 1704–1707.

12. Salvagno GL, Astermark J, Ekman M, et al. Impact of different inhibitor reactivities with commercial factor VIII concentrates on thrombin generation. Haemophilia. 2007; 13: 51–56.

13. Váradi K, Turecek PL, Schwarz HP. Thrombin generation assay and other universal tests for monitoring haemophilia therapy. Haemophilia. 2004; 10 Suppl 2: 17–21.

14. Pike GN, Cumming AM, Hay CRM, et al. Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. Blood. 2015; 126: 397–405.

15. Ogiwara K, Nogami K, Matsumoto N, et al. A modified thrombin generation assay to evaluate the plasma coagulation potential in the presence of emicizumab, the bispecific antibody to factors IXa/X. Int J Hematol. 2020; 112: 621–630.

16. Binder NB, Depasse F, Mueller J, et al. Clinical use of thrombin generation assays. J Thromb Haemost. 2021; 19: 2918–2929.

17. Teichman J, Chaudhry HR, Sholzberg M. Novel assays in the coagulation laboratory: a clinical and laboratory perspective. Transfus Apher Sci. 2018; 57: 480–484.

18. Váradi K, Negrier C, Berntorp E, et al. Monitoring the bioavailability of FEIBA with a thrombin generation assay. J Thromb Haemost. 2003; 1: 2374–2380.

19. Dargaud Y, Lienhart A, Janbain M, et al. Use of thrombin generation assay to personalize treatment of breakthrough bleeds in a patient with hemophilia and inhibitors receiving prophylaxis with emicizumab. Haematologica. 2018; 103: e181–e183.

20. Valke LLFG, Bukkems LH, Barteling W, et al. Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation. J Thromb Haemost. 2020; 18: 3222–3231.

21. Rugeri L, Beguin S, Hemker C, et al. Thrombingenerating capacity in patients with von Willebrand’s disease. Haematologica. 2007; 92: 1639–1646.

22. van Hylckama Vlieg A, Baglin CA, Luddington R, et al. The risk of a first and a recurrent venous thrombosis associated with an elevated D-dimer level and an elevated thrombin potential: results of the THEVTE study. J Thromb Haemost. 2015; 13: 1642–1652.

23. Simioni P, Castoldi E, Lunghi B, et al. An underestimated combination of opposites resulting in enhanced thrombotic tendency. Blood. 2005; 106: 2363–2365.

24. Alhenc-Gelas M, Canonico M, Picard V. Influence of natural SERPINC1 mutations on ex vivo thrombin generation. J Thromb Haemost. 2010; 8: 845–848.

25. Chaireti R, Jennersjö C, Lindahl TL. Is thrombin generation at the time of an acute thromboembolic episode a predictor of recurrence? The LInköping Study on Thrombosis (LIST)--a 7-year follow-up. Thromb Res. 2013; 131: 135–139.

26. Lim HY, O’Malley C, Donnan G, et al. A review of global coagulation assays — Is there a role in thrombosis risk prediction? Thromb Res. 2019; 179: 45–55.

27. Tripodi A, Martinelli I, Chantarangkul V, et al. The endogenous thrombin potential and the risk of venous thromboembolism. Thromb Res. 2007; 121: 353–359.

28. Zuily S, Ait Aissa K, Membre A, et al. Thrombin generation in antiphospholipid syndrome. Lupus. 2012; 21: 758–760.

29. Liestøl S, Sandset PM, Mowinckel M-C, et al. Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants. J Thromb Haemost. 2007; 5: 2204–2210.

30. Efthymiou M, Lawrie AS, Mackie I, et al. Thrombin generation and factor X assays for the assessment of warfarin anticoagulation in thrombotic antiphospholipid syndrome. Thromb Res. 2015; 135: 1191–1197.

31. Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016; 3: e426-436.

32. Bergstrom CP, Zia A, Sarode R, et al. Thrombin Generation in a patient with Triple Positive Antiphospholipid Syndrome Treated with Three Different Anticoagulants. Transfus Apher Sci. 2020; 59: 102815.

33. Мельничникова О.С., Лапин С.В., Тишков А.В. и др. Тест генерации тромбина в диагностике гиперкоагуляции у пациентов с атеросклерозом. Медицинский Алфавит. 2016; 4: 29–33.

34. Мельничникова О.С., Семенов А.П., Панов А.В. и др. Исследование генерации тромбина у больных со стабильной ишемической болезнью с предшествующим инфарктом миокарда. Трансляционная медицина. 2019; 6: 37–45.

35. Loeffen R, Godschalk TC, van Oerle R, et al. The hypercoagulable profile of patients with stent thrombosis. Heart. 2015; 101: 1126–1132.

36. Напалкова О.С., Эмануэль В.Л., Карпенко М.А. и др. Оценка риска повторной операции реваскуляризации миокарда с помощью теста генерации тромбина. Тромбоз, гемостаз и реология. 2016. С. 65–71.

37. Melnichnikova O, Simakova M, Moiseeva O, et al. The dynamics of thrombin formation in patients with pulmonary arterial hypertension. Thromb Res. 2021; 208: 230–232.

38. Carcaillon L, Alhenc-Gelas M, Bejot Y, et al. Increased thrombin generation is associated with acute ischemic stroke but not with coronary heart disease in the elderly: the Three-City cohort study. Arterioscler Thromb Vasc Biol. 2011; 31: 1445–1451.

39. Ay C, Dunkler D, Simanek R, et al. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol. 2011; 29: 2099–2103.

40. Chistolini A, Ruberto F, Alessandri F, et al. Effect of low or high doses of low-molecular-weight heparin on thrombin generation and other haemostasis parameters in critically ill patients with COVID-19. Br J Haematol. 2020; 190: e214–e218.

41. van de Berg TW, Hulshof A-MM, Nagy M, et al. Suggestions for global coagulation assays for the assessment of COVID-19 associated hypercoagulability. Thromb Res. 2021; 201: 84–89.

42. de la Morena-Barrio ME, Bravo-Pérez C, Miñano A, et al. Prognostic value of thrombin generation parameters in hospitalized COVID-19 patients. Sci Rep. 2021; 11: 7792.

43. Billoir P, Alexandre K, Duflot T, et al. Investigation of Coagulation Biomarkers to Assess Clinical Deterioration in SARS-CoV-2 Infection. Front Med (Lausanne). 2021; 8: 670694.

44. Bouck EG, Denorme F, Holle LA, et al. COVID-19 and Sepsis Are Associated With Different Abnormalities in Plasma Procoagulant and Fibrinolytic Activity. Arterioscler Thromb Vasc Biol. 2021; 41: 401–414.

45. Hardy M, Lecompte T, Douxfils J, et al. Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory. Thrombosis Journal. 2020; 18: 17.

46. Benati M, Salvagno GL, Nitto SD, et al. Thrombin Generation in Patients with Coronavirus Disease 2019. Semin Thromb Hemost. 2021; 47: 447–450.

47. von Meijenfeldt FA, Havervall S, Adelmeijer J, et al. Prothrombotic changes in patients with COVID-19 are associated with disease severity and mortality. Res Pract Thromb Haemost. 2021; 5: 132–141