Analysis of Risk Factors of Venous Thromboembolic Complications and of Different Variants of Anticoagulant Therapy in Patients with New Coronavirus Infection

Abstract

INTRODUCTION: A new coronavirus infection (NCI) is characterized by catastrophic coagulopathy with development of thrombotic and hemorrhagic complications. The choice of an optimal anticoagulant in these patients remains an important issue.

AIM: To evaluate risk factors for venous thromboembolic complications (VTEC), effectiveness and safety of different variants of anticoagulant therapy (ACT) in patients with NCI.

MATERIALS AND METHODS: A prospective study was conducted that involved 370 patients with NCI: group 1 — patients who received low molecular weight heparin (LMWH) — 190 people, group 2 — patients who received unfractionated heparin (UFH) — 123 people, group 3 — patients who took direct oral anticoagulants (DOAC) — 57 individuals. Clinical and anamnestic data, frequency of thrombotic and hemorrhagic complications were evaluated. The study was approved by the Local Ethics Committee and was registered on ClinicalTrials.gov. platform.

RESULTS: The existence of chronic venous diseases increases the risk of development of venous thromboembolism (VTE) in patients with NCI 6.433 times (95% confidence interval (CI) 2.167–19.093)) (р = 0.001), use of UFH instead of LMWH or DOAC — 3.542 times (95% CI 1.149–10.916) (р = 0.028), use of artificial lung ventilation (ALV) — 5.925 times (95% CI 2.034–17.26) (р = 0.001), high D-dimer level — 2.024 times (95% CI 1.231–3.33) (р = 0.005). The level of C-reactive protein and ferritin decreased in all patients in the course of treatment for NCI, with the lowest levels in patients receiving LMWH (С-reactive protein — 5.8 (1.7–15.0) mg/l, р = 0.004; ferritin — 364 (324–497) µg/l, р = 0.001). Lower fibrinogen levels were recorded in patients of group 1 compared to groups 2 and 3 (2.43 (1.9–3.52) g/l versus 3.37 (2.8–4.92) g/l and 4.1 (2.8–5.25) g/l, respectively, р = 0.002). A high frequency of pulmonary embolism with unspecified source was recorded in patients receiving UFH — 11.4% of cases, with this, the frequency of using ALV in the group with UFH was evaluated as high — 21% of cases.

CONCLUSION: Risk factors of VTEC in patients with NCI are both factors typical of VTEC in general (obesity, chronic vein diseases, elevated D-dimer level), and factors specific of NCI (ALV, hypoventilation). Effective and safe anticoagulants in this group of patients are LMWH that demonstrated low frequency of development of VTEC and of hemorrhagic complications.

Keywords

new coronavirus infection / anticoagulant therapy / thrombosis / bleedings / COVID-19

References

[1] Ofitsial’naya informatsiya o koronaviruse v Rossii [Internet]. Available at: https://стопкоронавирус.рф/. Accessed: 2022 September 17. (In Russ).

[2] Официальная информация о коронавирусе в России [Интеренет]. Доступно по: https://стопкоронавирус.рф/. Ссылка активна на 17.09.2022.

[3] Gil–Sala D, Riera C, García–Reyes M, et al. Mortality and bleeding complications of COVID-19 critically ill patients with venous thromboembolism. Int Angiol. 2022;41(1):1-8. doi: 10.23736/s0392-9590.21.04704-0

[4] Gil–Sala D., Riera C., García–Reyes M., et al. Mortality and bleeding complications of COVID-19 critically ill patients with venous thromboembolism // International Angiology. 2022. Vol. 41, No. 1. P. 1–8. doi: 10.23736/s0392-9590.21.04704-0

[5] Kalinin RE, Suchkov IA, Filimonov VB, et al. Venous Thromboembolism in COVID-19 Patients During the First and the Second Waves of the Pandemic: Real-Practice Data. Flebologiya. 2022;16(2):122–9. (In Russ). doi: 10.17116/flebo202216021122

[6] Калинин Р.Е., Сучков И.А., Филимонов В.Б., и др. Венозные тромбоэмболические осложнения у пациентов с COVID-19 во время первой и второй волн пандемии: данные реальной клинической практики // Флебология. 2022. Т. 16, № 2. С. 122–129. doi: 10.17116/flebo202216021122

[7] Rossiyskiye klinicheskiye rekomendatsii po diagnostike, lecheniyu i profilaktike venoznykh tromboembolicheskikh oslozhneniy (VTEO). Flebologiya. 2015;9(4-2):3–52. (In Russ).

[8] Российские клинические рекомендации по диагностике, лечению и профилактике венозных тромбоэмболических осложнений (ВТЭО) // Флебология. 2015. Т. 9, № 4, Вып. 2. С. 3–52.

[9] Kalinin RE, Suchkov IA, Agapov AB. The Effectiveness of the Various Options of Anticoagulant Therapy for the Treatment of the Patients with Thrombosis of the Deep Veins of the Lower Extremities in the Routine Clinical Practice. Flebologiya. 2017;11(1):21–7. (In Russ). doi: 10.17116/flebo201711121-27

[10] Калинин Р.Е., Сучков И.А., Агапов А.Б. Эффективность различных вариантов антикоагулянтной терапии у пациентов с тромбозом глубоких вен нижних конечностей в условиях реальной клинической практики // Флебология. 2017. Т. 11, № 1. С. 21–27. doi: 10.17116/flebo201711121-27

[11] Vremennyye metodicheskiye rekomendatsii Ministerstva zdravookhraneniya RF. Profilaktika, diagnostika i lecheniye novoy koronavirusnoy infektsii (COVID-19). Version 17 (14/12/2022). Available at: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/061/254/original/%D0%92%D0%9C% D0%A0_COVID-19_V17.pdf?1671088207. Accessed: 2023 January 13. (In Russ).

[12] Временные методические рекомендации Министерства здравоохранения РФ. Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Версия 17 (14.12.2022). Доступно по: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/061/254/original/%D0%92%D0%9C%D0%A0_COVID-19_V17.pdf?1671088207. Ссылка активна на 13.01.2023.

[13] Vertkin AL, Avdeev SN, Roitman EV, et al. Treatment of COVID-19 from the perspective of endotheliopathy correction and prevention of thrombotic complications. The agreed position of the experts. Profilakticheskaya Meditsina. 2021;24(4):45–51. (In Russ). doi: 10.17116/profmed20212404145

[14] Верткин А.Л., Авдеев С.Н., Ройтман Е.В., и др. Вопросы лечения COVID-19 с позиции коррекции эндотелиопатии и профилактики тромботических осложнений. Согласованная позиция экспертов // Профилактическая медицина. 2021. Т. 24, № 4. С. 45–51. doi: 10.17116/profmed20212404145

[15] Bellmunt–Montoya S, Riera C, Gil D, et al. COVID-19 Infection in Critically Ill Patients Carries a High Risk of Venous Thrombo-embolism. Eur J Vasc Endovasc Surg. 2021;61(4):628–34. doi: 10.1016/j.ejvs.2020.12.015

[16] Bellmunt–Montoya S., Riera C., Gil D., et al. COVID-19 Infection in Critically Ill Patients Carries a High Risk of Venous Thrombo-embolism // European Journal of Vascular and Endovascular Surgery. 2021. Vol. 61, No. 4. P. 628–634. doi: 10.1016/j.ejvs.2020.12.015

[17] Čelovska D, Wawruch M, Stvrtinová V. COVID-19-associated coagulopathy and immuno-thrombosis. Acta Phlebologica. 2021;22(2):55–60. doi: 10.23736/S1593-232X.21.00510-5

[18] Čelovska D., Wawruch M., Stvrtinová V. COVID-19-associated coagulopathy and immuno-thrombosis // Acta Phlebologica. 2021. Vol. 22, No. 2. P. 55–60. doi: 10.23736/S1593-232X.21.00510-5

[19] Malas MB, Naazie IN, Elsayed N, et al. Thromboembolism Risk of COVID-19 Is High and Associated with a Higher Risk of Mortality: A Systematic Review and Meta-Analysis. EClinicalMedicine. 2020;29:100639. doi: 10.1016/j.eclinm.2020.100639

[20] Malas M.B., Naazie I.N., Elsayed N., et al. Thromboembolism Risk of COVID-19 Is High and Associated with a Higher Risk of Mortality: A Systematic Review and Meta-Analysis // EClinicalMedicine. 2020. Vol. 29. P. 100639. doi: 10.1016/j.eclinm.2020.100639

[21] Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020;18(6):1517–9. doi: 10.1111/jth.14844

[22] Dolhnikoff M., Duarte–Neto A.N., de Almeida Monteiro R.A., et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19 // Journal of Thrombosis and Haemostasis. 2020. Vol. 18, No. 6. P. 1517–1519. doi: 10.1111/jth.14844

[23] Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–8. doi: 10.1056/NEJMoa2015432

[24] Ackermann M., Verleden S.E., Kuehnel M., et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19 // The New England Journal of Medicine. 2020. Vol. 383, No. 2. P. 120–128. doi: 10.1056/NEJMoa2015432

[25] Fox SE, Akmatbekov A, Harbert JL, et al. 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. doi: 10.1016/S2213-2600(20)30243-5

[26] Fox S.E., Akmatbekov A., Harbert J.L., et al. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans // The Lancet. Respiratory Medicine. 2020. Vol. 8, No. 7. P. 681–686. doi: 10.1016/S2213-2600(20)30243-5

[27] Carsana L, Sonzogni A, Nasr A, 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(10):1135–40. doi: 10.1016/S1473-3099(20)30434-5

[28] Carsana L., Sonzogni A., Nasr A., et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study // The Lancet. Infectious Diseases. 2020. Vol. 20, No. 10. P. 1135–1140. doi: 10.1016/S1473-3099(20)30434-5

[29] Bertolidi Lemos AC, do Espírito Santo DA, Salvetti MC, et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thromb Res. 2020;196:359–66. doi: 10.1016/j.thromres.2020.09.026

[30] Bertolidi Lemos A.C., do Espírito Santo D.A., Salvetti M.C., et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID) // Thrombosis Research. 2020. Vol. 196. P. 359–366. doi: 10.1016/j.thromres.2020.09.026

[31] Beun R, Kusadasi N, Sikma M, et al. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol. 2020;42(Suppl 1):19–20. doi: 10.1111/ijlh.13230

[32] Beun R., Kusadasi N., Sikma M., et al. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2 // International Journal of Laboratory Hematology. 2020. Vol. 42, Suppl. 1. P. 19–20, doi: 10.1111/ijlh.13230

[33] Panigada M, Bottino N, Tagliabue P, 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(7):1738–42. doi: 10.1111/jth.14850

[34] Panigada M., Bottino N., Tagliabue P., et al. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thrombo-elastography findings and other parameters of hemostasis // Journal of Thrombosis and Haemostasis. 2020. Vol. 18, No. 7. P. 1738–1742. doi: 10.1111/jth.14850

[35] Borodina IA, Selezneva IA, Borisova OV, et al. Blood groups and secretory state in COVID-19. Nauka Molodykh (Eruditio Juvenium). 2021;9(4):589–96. (In Russ). doi: 10.23888/HMJ202194589-596

[36] Бородина И.А., Селезнева И.А., Борисова О.В., и др. Группы крови и секреторное состояние при COVID-19 // Наука молодых (Eruditio Juvenium). 2021. Т. 9, № 4. С. 589–596. doi: 10.23888/HMJ202194589-596

[37] Mortus JR, Manek SE, Brubaker LS, et al. Thromboelastographic results and hypercoagulability syndrome in patients with coronavirus disease 2019 who are critically III. JAMA Netw Open. 2020;3(6):e2011192. doi: 10.1001/jamanetworkopen.2020.11192

[38] Mortus J.R., Manek S.E., Brubaker L.S., et al. Thromboelastographic Results and Hypercoagulability Syndrome in Patients With Coronavirus Disease 2019 Who Are Critically Ill // JAMA Network Open. 2020. Vol. 3, No. 6. P. e2011192. doi: 10.1001/jamanetwork open.2020.11192

[39] Bitsadze VO, Bredikhin RA, Bulatov VL, et al. Superficial phlebitis and thrombophlebitis. Flebologiya. 2021;15(3):211–44. (In Russ). doi: 10.17116/flebo202115031211

[40] Бицадзе В.О., Бредихин Р.А., Булатов В.Л., и др. Флебит и тромбофлебит поверхностных сосудов // Флебология. 2021. Т. 15, № 3. С. 211–244. doi: 10.17116/flebo202115031211

[41] Agapov AB, Suchkov IA, Ryabkov AN. Direct oral anticoagulants in patients with deep venous thrombosis of lower extremities. Nauka Molodykh (Eruditio Juvenium). 2016;(2):147–57. (In Russ).

[42] Агапов А.Б., Сучков И.А., Рябков А.Н. Прямые пероральные антикоагулянты в лечении тромбоза глубоких вен нижних конечностей // Наука молодых (Eruditio Juvenium). 2016. № 2. С. 147–157.

[43] Petrikov AS, Dudin DV, Popkova LN, et al. Clinical course of deep venous thrombosis of lower limbs in acute period with underlying anticoagulant therapy depending on concentration of D-dimers and C-reactive protein. Nauka Molodykh (Eruditio Juvenium). 2018;6(2):233–41. (In Russ). doi: 10.23888/HMJ201862233-241

[44] Петриков А.С., Дудин Д.В., Попкова Л.Н., и др. Течение тромбоза глубоких вен нижних конечностей в остром периоде на фоне антикоагулянтной терапии в зависимости от содержания D-димеров и С-реактивного белка // Наука молодых (Eruditio Juvenium). 2018. Т. 6, № 2. С. 233–241. doi: 10.23888/HMJ2018 62233-241

[45] Kalinin RE, Suchkov IA, Narizhny MV. Dispensary management of patients with venous thromboembolic complications. I. P. Pavlov Russian Medical Biological Herald. 2011;(3):104–9. (In Russ).

[46] Калинин Р.Е., Сучков И.А., Нарижный М.В. Диспансеризация больных с венозными тромбоэмболическими осложнениями // Российский медико-биологический вестник имени академика И. П. Павлова. 2011. № 3. С. 104–109.

RIGHTS & PERMISSIONS

Kalinin R.E., Suchkov I.A., Agapov A.B., Mzhavanadze N.D., Povarov V.O., Nikiforov A.A.