Tocilizumab reduces hypercoagulation in COVID-19 – Perspectives from the coagulation and immunomodulation Covid assessment (Coag-ImmCovA) clinical trial
Lou M. Almskog a)b), Anna Sjöström a)c)1), Jonas Sundén-Cullberg d)e)1), Apostolos Taxiarchis a)c), Anna Ågren a)f)g), Sara Freyland h), Madeleine Börjesson b), Agneta Wikman i)j), Carl Magnus Wahlgren a)k), Michael Wanecek l)m), Jan van der Linden l), Jovan Antovic a)c), Jon Lampa n)2), Maria Magnusson a)g)o)2)
a – Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
b – Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
c – Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden
d – Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
e – Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
f – Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden
g – Coagulation Unit, Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
h – Division of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
i – Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
j – Department of Center for Hematology and Regenerative Medicine (HERM), Karolinska Institutet, Stockholm, Sweden
k – Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden
l – Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
m – Intensive Care Unit, Capio St Göran’s Hospital, Stockholm, Sweden
n – Rheumatology Division, Department of Medicine Solna, Center for Molecular Medicine (CMM), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
o – Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
Abstract
Background
Despite medical interventions, COVID-19 continues to persist at pandemic proportions. A hypercoagulation state was rapidly observed in the severely ill, and the incidence of thromboembolic events remains elevated. Interleukin inhibitors have demonstrated positive effects on the hyperactivation of the immune system in COVID-19, with the interleukin-6 inhibitor tocilizumab showing promising results in reducing mortality. Nevertheless, the impact of interleukin inhibitors on the coagulation system remains incompletely understood.
Methods
In this clinical trial conducted in Stockholm, Sweden, interleukin inhibitors, namely anakinra (ANA) or tocilizumab (TOCI), were randomly administered in addition to standard care (SC) to hospitalized patients with COVID-19. A control group received only SC. The primary outcome sought to measure effects on global hemostasis, as indicated by changes in functional coagulation tests, specifically Rotational Thromboelastometry (ROTEM) or Overall Hemostatic Potential (OHP), visualized through scanning electron microscopy images. Secondary outcomes included effects on conventional coagulation laboratory tests.
Results
The study enrolled 74 patients who were randomized to receive either ANA or TOCI in addition to SC, or SC alone. In the TOCI group, ROTEM variables exhibited less hypercoagulation after 29 days compared with ANA or SC treatment groups, characterized by prolonged clot formation time and decreased clot firmness. OHP decreased, but there were no significant differences among the three treatment groups. Plasma fibrinogen levels, initially elevated, decreased significantly in TOCI recipients over time.
Conclusion
Tocilizumab treatment demonstrated a significant reduction of hypercoagulation in hospitalized COVID-19 patients, by improvements in both global coagulation tests and conventional laboratory tests, in comparison with anakinra or SC alone. This finding underscores the significance of tocilizumab as a viable treatment option in severe COVID-19 cases, with the potential to decrease thrombosis incidence.