Understanding coagulopathy in covid-19 : evaluating clinical outcomes with rotational thromboelastometry

When the COVID-19 pandemic struck the world in 2020, it placed enormous demands on healthcare and healthcare workers. Hospitals quickly reorganized to prioritize the growing number of patients experiencing respiratory failure, mobilizing stored ventilators and intensive care medications. Early case reports highlighted that severely ill patients often presented with thromboembolic events, prompting the early adoption of anticoagulant therapy as a standard part of care.

The overall aim of this thesis is to investigate how hypercoagulation drives severe COVID-19 disease, impacts clinical outcomes, and its association with the inflammatory response triggered by the SARS-CoV-2 virus.

In Study I, we assessed whether thromboelastometry (ROTEM) at hospital admission could identify hypercoagulopathy and predict disease severity, determined by the level of care required, in COVID-19 patients. We found that ROTEM variables indicated a hypercoagulable state at admission, which was more pronounced in patients with higher disease severity, necessitating care in the Intensive Care Unit (ICU) or intermediate wards compared with those in regular wards. Our results suggest that hypercoagulability in COVID-19 patients is evident early in mild to moderate cases and becomes more prominent in severe COVID-19 pneumonia.

In Study II, we examined various markers of coagulopathy in hospitalized COVID- 19 patients. We developed a pragmatic risk stratification score incorporating ROTEM and other established risk factors to predict 30-day mortality. Additionally, we analyzed the longitudinal changes in ROTEM test results in severe cases. Our findings showed that hypercoagulation, as measured by ROTEM, is a strong predictor of 30-day mortality in COVID-19. Furthermore, the progression of ROTEM data over time supported the hypothesis that hypercoagulation is a driving factor of severe disease.

In Study III, we evaluated the effects of interleukin inhibitors anakinra and tocilizumab on global hemostasis and conventional coagulation tests to determine whether they reduced hypercoagulation patterns compared with standard care alone. Our results indicated that tocilizumab significantly decreased hypercoagulation in hospitalized COVID-19 patients, as evidenced by enhancements in both global coagulation tests and traditional laboratory tests, compared with anakinra or standard care alone.

In the literature review included in the appendix, we explored the concept of immunothrombosis/thromboinflammation, where complex interactions between the immune and coagulation systems trigger each other, potentially complicating the treatment of thromboembolic disease. We concluded that a combination of anticoagulant and anti-inflammatory treatments may be beneficial, and even necessary, to effectively prevent and manage thrombotic disease in patients experiencing hyperinflammatory states, such as COVID-19. In summary, the findings from these studies indicate that the state of hypercoagulation observed in COVID-19 is linked to increased disease severity, poor clinical outcomes, and has an intricate connection to the inflammatory response.

List of scientific papers

I. Almskog L, Wikman A, Svensson J, Wanecek M, Bottai M, van der Linden J, Ågren A. Rotational thromboelastometry results are associated with care level in COVID-19. J Thromb Thrombolysis (2020).7 https://doi.org/10.1007/s11239-020-02312-3

II. Almskog L, Wikman A, Svensson J, Bottai M, Kotormán M, Wahlgren C, Wanecek M, van der Linden J, Ågren A. Hypercoagulation Detected by Rotational Thromboelastometry Predicts Mortality in COVID-19: A Risk Model Based on a Prospective Observational Study. TH Open (2021). https://doi.org/10.1055/a-1725-9221

III. Almskog L, Sjöström A, Sundén-Cullberg J, Taxiarchis A, Ågren A, Freyland S, Börjesson M, Wikman A, Wahlgren C, Wanecek M, van der Linden J, Antovic J, Lampa J, Magnusson M. Tocilizumab reduces hypercoagulation in COVID-19 - Perspectives from the coagulation and immunomodulation Covid assessment (Coag- ImmCovA) clinical trial. Thrombosis Research (2024). https://doi.org/10.1016/j.thromres.2024.109135