ENDOTHELIAL DYSFUNCTION AND THE HEMOSTASIS SYSTEM IN THE POST-COVID PERIOD
DOI:
https://doi.org/10.11603/1811-2471.2024.v.i4.15035Keywords:
COVID-19, post-covid period, hemostasis, endothelial dysfunction, von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (hsCRP)Abstract
SUMMARY. The role of endothelial dysfunction in the severity of coronavirus disease is beyond doubt. Comorbidities such as arterial hypertension, cardiovascular disease and diabetes mellitus, in the pathogenesis of which a significant role is played by impaired normal vascular endothelial function, are recognised as risk factors associated with severe COVID-19 and death. Despite the intensive research caused by the SARS-CoV-2 pandemic, the role of endothelial dysfunction and low-intensity inflammation in the pathogenesis of complications and the course of the recovery period after the disease is still insufficiently understood. This issue is particularly important because the entry gate for the virus, ACE2 receptors, is expressed in the endothelium, and the risk and frequency of thrombotic complications increases dramatically.
The aim of the study was to evaluate changes in biomarkers of endothelial dysfunction that regulate the haemostatic system in patients in the post-COVID period.
Material and мethods. The study involved 191 patients in the period 1–90 days after the last negative PCR test, including 58 (30.37 %) men and 133 (69.63 %) women aged 18 to 80 years. The average age was (49.76±13.38) years. Depending on the severity of the coronavirus disease, patients were divided into the following groups: mildly ill patients (HQM), moderately ill patients (HMO), oxygen-dependent patients (HSV) and critically ill patients (HCR). General clinical methods and analysis of available medical records were used to examine patients. The levels of von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and high-sensitivity C-reactive protein CRP (hsCRP) in the enrolled patients were determined by enzyme-linked immunosorbent assay using standard ELISA kits.
Results. Patients of HQM group (n=79 or 41.4 %); HMO group (n=74 or 38.7 %); HSV group (n=25 or 13.1 %); critical HCR group (n=13 or 6.8 %) were included. The average age of the subjects differed significantly – the youngest patients were in the HQM group (43.84±13.08 years, the number of patients over 65 years old was 5 out of 79). With increasing severity of the disease, the number of patients over 65 years of age also increased. After analysing the data, all patients were divided into high-risk (HRG, n=163) and low-risk (NRG, n=28) groups. The results of our study indicate that during the three-month convalescent period, profound disorders of the haemostasis system, regulation of vascular tone, and signs of chronic inflammation persist. This is evidenced by a steady increase in biomarkers indicating prothrombotic changes. The levels of tPA, vWF and PAI-1 in severe and critical high-risk patients clearly correlated with the severity of COVID-19 and the presence of comorbidities, such as overweight and obesity, hypertension and cardiovascular disease, regardless of gender. Elevated hsCRP levels within three months after laboratory recovery were observed as well.
Conclusions. Significant abnormalities and dysregulation of endothelial dysfunction indicating prothrombotic changes persist for 90 days after the last negative PCR test. The suppression of endothelial anticoagulant properties, leading to the development of a prothrombotic state, was most pronounced in patients with severe coronavirus disease.
References
Al-Aly, Z., Davis, H., McCorkell, L., Soares, L., Wulf-Hanson, S., Iwasaki, A., & Topol, E. J. (2024). Long COVID science, research and policy. Nature Medicine 2024 30:8, 30(8), 2148-2164. https://doi.org/10.1038/s41591-024-03173-6 DOI: https://doi.org/10.1038/s41591-024-03173-6
Marchetti, M. (2020). COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure. Annals of Hematology, 99, 1701-1707. https://doi.org/10.1007/s00277-020-04138-8 DOI: https://doi.org/10.1007/s00277-020-04138-8
Andrade, B.S., Siqueira, S., de Assis Soares, W.R., de Souza Rangel, F., Santos, N.O., Dos Santos Freitas, A., Ribeiro da Silveira, P., Tiwari, S., Alzahrani, K.J., Góes-Neto, A., Azevedo, V., Ghosh, P., & Barh, D. (2021). Long-covid and post-covid health complications: An up-to-date review on clinical conditions and their possible molecular mechanisms. Viruses, 13(4), 700. https://doi.org/10.3390/v13040700 DOI: https://doi.org/10.3390/v13040700
Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X., Guan, L., Wei, Y., Li, H., Wu, X., Xu, J., Tu, S., Zhang, Y., Chen, H., & Cao, B. (2020). Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet, 395(10229), 1054-1062. https://doi.org/10.1016/S0140-6736(20)30566-3 DOI: https://doi.org/10.1016/S0140-6736(20)30566-3
Tang, N., Li, D., Wang, X., & Sun, Z. (2020). Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Journal of Thrombosis and Haemostasis, 18(4), 844-847. https://doi.org/10.1111/jth.14768 DOI: https://doi.org/10.1111/jth.14768
Yang, J., Zheng, Y., Gou, X., Pu, K., Chen, Z., Guo, Q., Ji, R., Wang, H., Wang, Y., & Zhou, Y. (2020). Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis. International Journal of Infectious Diseases, 94, 91-95. https://doi.org/10.1016/j.ijid.2020.03.017 DOI: https://doi.org/10.1016/j.ijid.2020.03.017
Ruan, Q., Yang, K., Wang, W., Jiang, L., & Song, J. (2020). Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. In Intensive Care Medicine (Vol. 46, Issue 5, pp. 846-848). Springer. https://doi.org/10.1007/s00134-020-05991-x DOI: https://doi.org/10.1007/s00134-020-05991-x
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., … Cao, B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395(10223), 497-506. https://doi.org/10.1016/S0140-6736(20)30183-5 DOI: https://doi.org/10.1016/S0140-6736(20)30183-5
Tufa, A., Gebremariam, T.H., Manyazewal, T., Getinet, T., Webb, D.L., Hellström, P.M., & Genet, S. (2022). Inflammatory mediators profile in patients hospitalized with COVID-19: A comparative study. Frontiers in Immunology, 13, 964179. https://doi.org/10.3389/fimmu.2022.964179 DOI: https://doi.org/10.3389/fimmu.2022.964179
Mangalmurti, N., & Hunter, C. A. (2020). Cytokine Storms: Understanding COVID-19. Immunity, 53(1), 19-25. https://doi.org/10.1016/j.immuni.2020.06.017 DOI: https://doi.org/10.1016/j.immuni.2020.06.017
Konig, M.F., Powell, M.A., Staedtke, V., Bai, R.-Y., Thomas, D.L., Fischer, N.M., Huq, S., Khalafallah, A.M., Koenecke, A., Xiong, R., Mensh, B., Papadopoulos, N., Kinzler, K.W., Vogelstein, B., Vogelstein, J.T., Athey, S., Zhou, S., & Bettegowda, C. (2020). Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists. Journal of Clinical Investigation, 130(7). https://doi.org/10.1172/jci139642 DOI: https://doi.org/10.1172/JCI139642
Marietta, M., Ageno, W., Artoni, A., De Candia, E., Gresele, P., Marchetti, M., Marcucci, R., & Tripodi, A. (2020). COVID-19 and haemostasis: A position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfusion, 18(3), 167-169. https://doi.org/10.2450/2020.0083-20
Zhou, Y., Chi, J., Lv, W., & Wang, Y. (2020). Obesity and diabetes as high-risk factors for severe coronavirus disease 2019 (Covid-19). Diabetes/Metabolism Research and Reviews, 37(2), e3377. https://doi.org/10.1002/DMRR.3377 DOI: https://doi.org/10.1002/dmrr.3377
Ritter, A., Kreis, N. N., Louwen, F., & Yuan, J. (2020). Obesity and covid-19: Molecular mechanisms linking both pandemics. International Journal of Molecular Sciences, 21(16), 1-28. https://doi.org/10.3390/ijms21165793 DOI: https://doi.org/10.3390/ijms21165793
D’Marco, L., Puchades, M.J., Romero-Parra, M., & Gorriz, J.L. (2020). Diabetic Kidney Disease and COVID-19: The Crash of Two Pandemics. Frontiers in Medicine, 7, 199. https://doi.org/10.3389/fmed.2020.00199 DOI: https://doi.org/10.3389/fmed.2020.00199
Guzik, T.J., Mohiddin, S.A., Dimarco, A., Patel, V., Savvatis, K., Marelli-Berg, F.M., Madhur, M.S., Tomaszewski, M., Maffia, P., D’Acquisto, F., Nicklin, S.A., Marian, A.J., Nosalski, R., Murray, E.C., Guzik, B., Berry, C., Touyz, R.M., Kreutz, R., Dao, W.W., … McInnes, I.B. (2020). COVID-19 and the cardiovascular system: Implications for risk assessment, diagnosis, and treatment options. Cardiovascular Research, 116(10), 1666-1687. https://doi.org/10.1093/cvr/cvaa106 DOI: https://doi.org/10.1093/cvr/cvaa106
Del Turco, S., Vianello, A., Ragusa, R., Caselli, C., & Basta, G. (2020). COVID-19 and cardiovascular consequences: Is the endothelial dysfunction the hardest challenge? Thrombosis Research, 196, 143-151. https://doi.org/10.1016/j.thromres.2020.08.039 DOI: https://doi.org/10.1016/j.thromres.2020.08.039
Mengozzi, A., Masi, S., & Virdis, A. (2020). Obesity-Related Endothelial Dysfunction: moving from classical to emerging mechanisms. Endocrine and Metabolic Science, 1(3-4), 100063. https://doi.org/10.1016/j.endmts.2020.100063 DOI: https://doi.org/10.1016/j.endmts.2020.100063
van der Heijden, D.J., van Leeuwen, M.A.H., Janssens, G.N., Lenzen, M.J., van de Ven, P.M., Eringa, E.C., & van Royen, N. (2017). Body mass index is associated with microvascular endothelial dysfunction in patients with treated metabolic risk factors and suspected coronary artery disease. Journal of the American Heart Association, 6(9). https://doi.org/10.1161/JAHA.117.006082 DOI: https://doi.org/10.1161/JAHA.117.006082
Wang, M., Hao, H., Leeper, N. J., & Zhu, L. (2018). Thrombotic regulation from the endothelial cell perspectives. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(6), e90-e95. https://doi.org/10.1161/ATVBAHA.118. 310367 DOI: https://doi.org/10.1161/ATVBAHA.118.310367
Grobler, C., Maphumulo, S.C., Grobbelaar, L.M., Bredenkamp, J.C., Laubscher, G.J., Lourens, P.J., Steenkamp, J., Kell, D.B., & Pretorius, E. (2020). Covid-19: The rollercoaster of fibrin(ogen), d-dimer, von willebrand factor, p-selectin and their interactions with endothelial cells, platelets and erythrocytes. International Journal of Molecular Sciences, 21(14), 1-25. https://doi.org/10.3390/ijms21145168 DOI: https://doi.org/10.3390/ijms21145168
Van Hinsbergh, V.W.M. (2012). Endothelium - Role in regulation of coagulation and inflammation. Seminars in Immunopathology, 34(1), 93–106. https://doi.org/10.1007/s00281-011-0285-5 DOI: https://doi.org/10.1007/s00281-011-0285-5
Nishimura, H., Tsuji, H., Masuda, H., Nakagawa, K., Nakahara, Y., Kitamura, H., Kasahara, T., Sugano, T., Yoshizumi, M., Sawada, S., & Nakagawa, M. (1997). Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. Thrombosis and Haemostasis, 77(6), 1189-1195. https://doi.org/10.1055/s-0038-1656136 DOI: https://doi.org/10.1055/s-0038-1656136
Page, A.V., Conrad Liles, W., & Liles, W.C. (2013). Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence, 4(6), 507-516. https://doi.org/10.4161/viru.24530 DOI: https://doi.org/10.4161/viru.24530
Ghosn, L., Chaimani, A., Evrenoglou, T., Davidson, M., Graña, C., Schmucker, C., Bollig, C., Henschke, N., Sguassero, Y., Nejstgaard, C.H., Menon, S., Nguyen, T. Van, Ferrand, G., Kapp, P., Riveros, C., Ávila, C., Devane, D., Meerpohl, J.J., Rada, G., … Boutron, I. (2021). Interleukin-6 blocking agents for treating COVID-19: a living systematic review. Cochrane Database of Systematic Reviews, 2021(3). https://doi.org/10.1002/14651858.CD013881 DOI: https://doi.org/10.1002/14651858.CD013881
Libby, P., & Lüscher, T. (2020). COVID-19 is, in the end, an endothelial disease. European Heart Journal, 41(32), 3038-3044. https://doi.org/10.1093/eurheartj/ehaa623 DOI: https://doi.org/10.1093/eurheartj/ehaa623
Maamar, M., Artime, A., Pariente, E., Fierro, P., Ruiz, Y., Gutiérrez, S., Tobalina, M., Díaz-Salazar, S., Ramos, C., Olmos, J. M., & Hernández, J. L. (2022). Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study. Current Medical Research and Opinion, 38(6), 1. https://doi.org/10.1080/03007995.2022.2042991 DOI: https://doi.org/10.1080/03007995.2022.2042991
Yong, S.J., Halim, A., Halim, M., Liu, S., Aljeldah, M., Al Shammari, B.R., Alwarthan, S., Alhajri, M., Alawfi, A., Alshengeti, A., Khamis, F., Alsalman, J., Alshukairi, A.N., Abukhamis, N.A., Almaghrabi, F.S., Almuthree, S.A., Alsulaiman, A.M., Alshehail, B.M., Alfaraj, A.H., … Rabaan, A.A. (2023). Inflammatory and vascular biomarkers in post-COVID-19 syndrome: A systematic review and meta-analysis of over 20 biomarkers. Reviews in Medical Virology, 33(2), e2424. https://doi.org/10.1002/RMV.2424 DOI: https://doi.org/10.1002/rmv.2424
Monteiro, C.M.C., Pinheiro, L.F., Izar, M.C., Barros, S.W., Vasco, M.B., Fischer, S.M., Povoa, R.M., Brandão, S.A., Santos, A.O., Oliveira, L., Carvalho, A.C., & Fonseca, F.A.H. (2010). Highly sensitive C-reactive protein and male gender are independently related to the severity of coronary disease in patients with metabolic syndrome and an acute coronary event. Brazilian Journal of Medical and Biological Research, 43(3), 297-302. https://doi.org/10.1590/S0100-879X2010005000008 DOI: https://doi.org/10.1590/S0100-879X2010005000008
Lopez-Castaneda, S., García-Larragoiti, N., Cano-Mendez, A., Blancas-Ayala, K., Damian-Vázquez, G., Perez-Medina, A.I., Chora-Hernández, L.D., Arean-Martínez, C., & Viveros-Sandoval, M.E. (2021). Inflammatory and Prothrombotic Biomarkers Associated With the Severity of COVID-19 Infection. Clinical and Applied Thrombosis/Hemostasis, 27, 1076029621999099. https://doi.org/10.1177/1076029621999099 DOI: https://doi.org/10.1177/1076029621999099
Cabrera-Garcia, D., Miltiades, A., Yim, P., Parsons, S., Elisman, K., Mansouri, M.T., Wagener, G., & Harrison, N.L. (2022). Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients. International Journal of Hematology, 116(6), 937-946. https://doi.org/10.1007/S12185-022-03437-2 DOI: https://doi.org/10.1007/s12185-022-03437-2
Garcia-Larragoiti, N., Cano-Mendez, A., Jimenez-Vega, Y., Trujillo, M., Guzman-Cancino, P., Ambriz-Murillo, Y., & Viveros-Sandoval, M.E. (2023). Inflammatory and Prothrombotic Biomarkers Contribute to the Persistence of Sequelae in Recovered COVID-19 Patients. International Journal of Molecular Sciences, 24(24), 17468. https://doi.org/10.3390/ijms242417468 DOI: https://doi.org/10.3390/ijms242417468
Gralinski, L.E., Bankhead, A., Jeng, S., Menachery, V.D., Proll, S., Belisle, S.E., Matzke, M., Webb-Robertson, B.J.M., Luna, M.L., Shukla, A.K., Ferris, M.T., Bolles, M., Chang, J., Aicher, L., Waters, K.M., Smith, R.D., Metz, T.O., Law, G.L., Katze, M.G., … Baric, R.S. (2013). Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. MBio, 4(4), e00271-13. https://doi.org/10.1128/mBio.00271-13 DOI: https://doi.org/10.1128/mBio.00271-13
