Лабораторные параметры системы гемостаза у пациентов с COVID-19

Новая коронавирусная инфекция (в настоящее время классифицируемая как COVID-19), впервые выявленная в декабре 2019 г. в Ухане (Китайская Народная Республика), способствовала значительному росту смертности в мире. Помимо дыхательной недостаточности, которую развивают практически все пациенты с COVID-19, распространенным нарушением у них является коагулопатия. В настоящее время COVID-19 продолжает быть жизнеугрожающим заболеванием и требует новых разработок и решений для определения профилактических и лечебных стратегий. В исследованиях часто сообщается об аномалии баланса систем свертывания и фибринолиза при COVID-19, однако до сих пор не существует адекватного набора лабораторных тестов, которые бы смогли обеспечить диагностику коагулопатии при данном заболевании. В настоящем обзоре проведен анализ современных исследований, посвященных клиническим проявлениям коагулопатии при COVID-19, а также проведен анализ информативности лабораторных тестов гемостаза в отношении тяжести течения и клинических исходов при данном заболевании.

1. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395: 507–13.

2. Ranucci M., Ballotta A., Di Dedda U., Bayshnikova E., Dei Poli M., Resta M., et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost 2020; 18: 1747–51.

3. Klok F.A., Kruip M.J.H.A., van der Meer N.J.M., Arbous M.S., Gommers D., Kant K.M., et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID- 19: An updated analysis. Thromb Res 2020; 191: 148–50.

4. Llitjos J., Leclerc M., Chochois C., Monsallier J., Ramakers M., Auvray M., et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost 2020; 18: 1743–6.

5. Thachil J., Tang N., Gando S., Falanga A., Cattaneo M., Levi M., et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020; 18: 1023–6.

6. Временные методические рекомендации: профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Версия 10.

7. Elkattawy S., Posimreddy S., Guragai N., Habib M., Shamoon F. Extensive Thrombosis in a Severe COVID- 19 Patient Despite Prophylactic Low Molecular Weight Heparin. Cureus 2020; 12 (10): е11152. DOI: 10.7759/cureus.11152

8. Cui S., Chen S., Li X., Liu S., Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020; 18: 1421–4.

9. Middeldorp S., Coppens M., van Haaps T.F., Foppen M., Vlaar A.P., Müller M.C.C.A., et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (8): 1995– 2002. DOI: 10.1111/jth.14888

10. Helms J., Tacquard C., Severac F., Leonard-Lorant I., Ohana M., Delabranche X., et al. High risk of thrombosis in patients with severe SARSCoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46: 1089–98.

11. Klok F.A., Kruip M.J.H.A., van der Meer N.J.M., Arbous M.S., Gommers D.A.M.P.J., Kant K.M., et al. Incidence of thrombotic complications in critically ill ICU patients with COVID- 19. Thromb Res 2020; 191: 145–7. DOI: 10.1016/j.thromres.2020.04.013

12. Dolhnikoff M., Duarte-Neto A.N., Almeida Monteiro R.A., Silva L.F.F., Oliveira E.P., Saldiva P.H.N., et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost 2020; 18: 1517–9.

13. Carsana L., Sonzogni A., Nasr A., Rossi R.S., Pellegrinelli A., Zerbi P., et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020; 20: 1135–40.

14. Kommoss F.K.F., Schwab C., Tavernar L., Schreck J., Wagner W.L., Merle U., et al. Pathologie der schweren COVID-19-bedingten Lungenschädigung. Dtsch Arzteblatt Int 2020; 117: 500–6.

15. Al-Samkari H., Karp Leaf R.S., Dzik W.H., Carlson J.C., Fogerty A.E., Waheed A., et al. COVID and Coagulation: Bleeding and Thrombotic Manifestations of SARS-CoV2 Infection. Blood 2020; 136 (4): 489–500. DOI: 10.1182/blood.2020006520

16. Paranjpe I., Fuster V., Lala A., Russak A.J., Glicksberg B.S., Levin M.A., et al. Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. J Am Coll Cardiol 2020; 76: 122–4.

17. Han H., Yang L., Liu R., Liu F., Wu K., Li J., et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med CCLM 2020; 58: 1116–20.

18. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.

19. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020; 323: 1061.

20. Yang W., Cao Q., Qin L., Wang X., Cheng Z., Pan A., et al. Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19): A multi-center study in Wenzhou city, Zhejiang, China. J Infect 2020; 80: 388–93.

21. Long H., Nie L., Xiang X., Li H., Zhang X., Fu X., et al. D-Dimer and Prothrombin Time Are the Significant Indicators of Severe COVID-19 and Poor Prognosis. BioMed Res Int 2020; 2020: 1–10.

22. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18: 844–7.

23. Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S., et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med 2020; 180: 934.

24. Wan S., Xiang Y., Fang W., Zheng Y., Li B., Hu Y., et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol 2020; 92: 797–806.

25. Guo T., Fan Y., Chen M., Wu X., Zhang L., He T., et al. Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 2020; 5: 811.

26. Panigada M., Bottino N., Tagliabue P., Grasselli G., Novembrino C., Chantarangkul V., et al. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020; 18: 1738–42.

27. Di Micco P., Russo V., Carannante N., Imparato M., Rodolfi S., Cardillo G., et al. Clotting Factors in COVID-19: Epidemiological Association and Prognostic Values in Different Clinical Presentations in an Italian Cohort. J Clin Med 2020; 9: 1371.

28. Liu Y., Liao W., Wan L., Xiang T., Zhang W. Correlation Between Relative Nasopharyngeal Virus RNA Load and Lymphocyte Count Disease Severity in Patients with COVID-19. Viral Immunol 2021; 34 (5): 330–5. DOI: 10.1089/vim.2020.0062

29. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z., et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395: 1054–62.

30. Tabatabai A., Rabin J., Menaker J., Madathil R., Galvagno S., Menne A., et al. Factor VIII and Functional Protein C Activity in Critically Ill Patients With Coronavirus Disease 2019: A Case Series. А А Pract 2020; 14 (7): e01236.

31. Seitz R., Schramm W. DIC in COVID-19: Implications for prognosis and treatment? J Thromb Haemost 2020; 18: 1798–9.

32. Iba T., Levy J.H., Connors J.M., Warkentin T.E., Thachil J., Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020; 24: 360.

33. Ai T., Yang Z., Hou H., Zhan C., Chen C., Lv W., et al. Correlation of Chest CT and RT-PCR Testing for Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology 2020; 296: E32–40.

34. Lodigiani C., Iapichino G., Carenzo L., Cecconi M., Ferrazzi P., Sebastian T., et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020; 191: 9–14.

35. Iba T., Levy J.H., Levi M., Thachil J. Coagulopathy in COVID-19. J Thromb Haemost 2020; 18: 2103–9.

36. Tang N., Bai H., Chen X., Gong J., Li D., Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18: 1094–9.

37. Streng A.S., Delnoij T.S.R., Mulder M.M.G., Sels J.W.E.M., Wetzels R.J.H., Verhezen P.W.M., et al. Monitoring of Unfractionated Heparin in Severe COVID-19: An Observational Study of Patients on CRRT and ECMO. TH Open 2020; 04: e365–75.

38. von Meijenfeldt F.A., Havervall S., Adelmeijer J., Lundström A., Rudberg A.-S., Magnusson M., et al. Prothrombotic changes in patients with COVID-19 are associated with disease severity and mortality. Res Pract Thromb Haemost 2021; 5: 132–41.

39. Nougier C., Benoit R., Simon M., Desmurs-Clavel H., Marcotte G., Argaud L., et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis. J Thromb Haemost 2020; 18: 2215–9.

40. Billett H.H., Reyes-Gil M., Szymanski J., Ikemura K., Stahl L.R., Lo Y., et al. Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality. Thromb Haemost 2020; 120: 1691–9.

41. Léonard-Lorant I., Delabranche X., Séverac F., Helms J., Pauzet C., Collange O., et al. Acute Pulmonary Embolism in Patients with COVID-19 at CT Angiography and Relationship to D-Dimer Levels. Radiology 2020; 296: E189–91.

42. Blasi A., Meijenfeldt F.A., Adelmeijer J., Calvo A., Ibañez C., Perdomo J., et al. In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation. J Thromb Haemost 2020; 18: 2646–53.

43. Maatman T.K., Jalali F., Feizpour C., Douglas A., McGuire S.P., Kinnaman G., et al. Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease 2019. Crit Care Med 2020; 48 (9): e783-90. DOI: 10.1097/CCM.0000000000004466

44. Hranjec T., Estreicher M., Rogers B., Kohler L., Solomon R., Hennessy S., et al. Integral Use of Thromboelastography With Platelet Mapping to Guide Appropriate Treatment, Avoid Complications, and Improve Survival of Patients With Coronavirus Disease 2019–Related Coagulopathy. Crit Care Explor 2020; 2: e0287.

45. Mortus J.R., Manek S.E., Brubaker L.S., Loor M., Cruz M.A., Trautner B.W., et al. Thromboelastographic Results and Hypercoagulability Syndrome in Patients With Coronavirus Disease 2019 Who Are Critically Ill. JAMA Netw Open. 2020; 3 (6): e2011192.

46. Patel B.V., Arachchillage D.J., Ridge C.A., Bianchi P., Doyle J.F., Garfield B., et al. Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging, and Hematologic Observations. Am J Respir Crit Care Med 2020; 202: 690–9.

47. Wright F.L., Vogler T.O., Moore E.E., Moore H.B., Wohlauer M.V., Urban S., et al. Fibrinolysis Shutdown Correlation with Thromboembolic Events in Severe COVID-19 Infection. J Am Coll Surg 2020; 231: 193–203.e1.

48. Bocci M.G., Maviglia R., Consalvo L.M., Grieco D.L., Montini L., Mercurio G., et al. Thromboelastography clot strength profiles and effect of systemic anticoagulation in COVID- 19 acute respiratory distress syndrome: a prospective, observational study. Eur Rev Med Pharmacol Sci 2020; 24: 12466–79.

49. Mitrovic M., Sabljic N., Cvetkovic Z., Pantic N., Zivkovic Dakic A., Bukumiric Z., et al. Rotational Thromboelastometry (ROTEM) Profiling of COVID-19 Patients. Platelets 2021; 32 (5): 690–6.

50. de la Morena-Barrio M.E., Bravo-Pérez C., Miñano A., de la Morena-Barrio B., Fernandez-Perez M.P., Bernal E., et al. Prognostic value of thrombin generation parameters in hospitalized COVID-19 patients. Sci Rep 2020; 11 (1): 7792. DOI:10.21203/rs.3.rs-115220/v1

51. Бовт Е.А., Бражник В.А., Буланов А.Ю., Васильева Е.Ю., Вуймо Т.А., Затейщиков Д.А. и др. Результаты многоцентрового мониторинга показателей гемостаза у больных COVID-19. Педиатрия 2020; 99: 62–73.

52. Kommoss F.K.F., Schwab C., Tavernar L., Schreck J., Wagner W.L., Merle U., et al. The Pathology of Severe COVID-19-Related Lung Damage. Dtsch Aerztebl Int 2020; 117 (29–30): 500–6. DOI: 10.3238/arztebl.2020.0500

53. Fox S.E., Akmatbekov A., Harbert J.L., Li G., Quincy Brown J., Vander Heide R.S. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir Med 2020; 8 (7): 681–6.

54. Middeldorp S., Coppens M., Haaps T.F., Foppen M., Vlaar A.P., Müller M.C.A., et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18: 1995–2002.

55. Demelo-Rodríguez P., CervillaMuñoz E., Ordieres-Ortega L., Parra-Virto A., Toledano-Macías M., Toledo-Samaniego N., et al. Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels. Thromb Res 2020; 192: 23–6.

56. Barnes G.D., Burnett A., Allen A., Blumenstein M., Clark N.P., Cuker A., et al. Thromboembolism and anticoagulant therapy during the COVID- 19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis 2020; 50: 72–81.

57. Tabatabai A., Rabin J., Menaker J., Madathil R., Galvagno S., Menne A., et al. Factor VIII and Functional Protein C Activity in Critically Ill Patients With Coronavirus Disease 2019: A Case Series. А А Pract 2020; 14 (7): e01236.

58. Panigada M., Bottino N., Tagliabue P., Grasselli G., Novembrino C., Chantarangkul V., et al. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020; 18: 1738–42.

59. Nougier C., Benoit R., Simon M., Desmurs-Clavel H., Marcotte G., Argaud L., et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis. J Thromb Haemost 2020; 18 (9): 2215–9. DOI: 10.1111/jth.15016

60. Benati M., Salvagno G.L., Nitto S.D., Gelati M., Lavorgna B., Fava C., et al. Thrombin Generation in Patients with Coronavirus Disease 2019. Semin Thromb Hemost 2021; 47 (4): 447– 50. DOI: 10.1055/s-0041-1722844