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Persistent hypofibrinolysis in severe COVID-19 associated with elevated fibrinolysis inhibitors activity

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Abstract

Hypercoagulability and reduced fibrinolysis are well-established complications associated with COVID-19. However, the timelines for the onset and resolution of these complications remain unclear. The aim of this study was to evaluate, in a cohort of COVID-19 patients, changes in coagulation and fibrinolytic activity through ROTEM assay at different time points during the initial 30 days following the onset of symptoms in both mild and severe cases. Blood samples were collected at five intervals after symptoms onset: 6–10 days, 11–15 days, 16–20 days, 21–25 days, and 26–30 days. In addition, fibrinogen, plasminogen, PAI-1, and alpha 2-antiplasmin activities were determined. Out of 85 participants, 71% had mild COVID-19. Twenty uninfected individuals were evaluated as controls. ROTEM parameters showed a hypercoagulable state among mild COVID-19 patients beginning in the second week of symptoms onset, with a trend towards reversal after the third week of symptoms. In severe COVID-19 cases, hypercoagulability was observed since the first few days of symptoms, with a tendency towards reversal after the fourth week of symptoms onset. A hypofibrinolytic state was identified in severe COVID-19 patients from early stages and persisted even after 30 days of symptoms. Elevated activity of PAI-1 and alpha 2-antiplasmin was also detected in severe COVID-19 patients. In conclusion, both mild and severe cases of COVID-19 exhibited transient hypercoagulability, reverted by the end of the first month. However, severe COVID-19 cases sustain hypofibrinolysis throughout the course of the disease, which is associated with elevated activity of fibrinolysis inhibitors. Persistent hypofibrinolysis could contribute to long COVID-19 manifestations.

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Acknowledgements

We express our gratitude to all individuals who participated in the study, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), to Faculdade de Medicina da Universidade de São Paulo (FMUSP), CAPES and to all staff involved in the execution of the study.

Funding

Bárbara Gomes Barion received financial support from the Coordination for the Improvement of Higher Education Personnel Brazil (CAPES)—88887.679326/2023–00. This research was supported, in part, by a grant from the Brazilian Ministry of Health (plataformamaisbrasil 038018/2021), and part of study material was provided by Instrumentation Laboratory (Werfen).

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  1. Erica Okazaki and Bárbara Gomes Barion share first authorship.

Authors and Affiliations

  1. University of Sao Paulo Medical School, Sao Paulo, Brazil

    Erica Okazaki, Bárbara Gomes Barion, Giancarlo Fatobene & Bruna del Guerra de Carvalho Moraes

  2. Hospital das Clínicas da Faculdade de Medicina de Sao Paulo da USP, 255 - Cerqueira César, Sao Paulo, SP, 05403-000, Brazil

    Erica Okazaki, Bárbara Gomes Barion, Tania Rubia Flores da Rocha, Giovanna Di Giacomo, Yeh-Li Ho, Cynthia Rothschild, Bianca Stefanello, Paula Ribeiro Villaça, Vanderson Geraldo Rocha & Fernanda Andrade Orsi

  3. Department of Pathology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil

    Fernanda Andrade Orsi

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Contributions

Conceptualization: Barion, B.G; Okazaki, E; Orsi, F.A; Investigation: Barion, B.G; Okazaki, E; Rocha,T.R.F; Ho, Yeh-Li; Rothschild, C; Fatobene, G; Moraes, B.G.C; Stefanello, B; Rocha, V.G; Villaça, P.R; Orsi, F.A; Formal analysis: Barion, B.G; Orsi, F.A; Resources: Rocha, V.G; Orsi, F.A; Writing: Barion, B.G; Okazaki, E; Rocha, T.R.F; Orsi, F.A; Final approval: Orsi, F.A

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Correspondence to Fernanda Andrade Orsi.

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Okazaki, E., Barion, B.G., da Rocha, T.R.F. et al. Persistent hypofibrinolysis in severe COVID-19 associated with elevated fibrinolysis inhibitors activity. J Thromb Thrombolysis 57, 721–729 (2024). https://doi.org/10.1007/s11239-024-02961-8

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