Tocilizumab and Thromboembolism in COVID-19: A Retrospective Hospital-Based Cohort Analysis

Abstract

BackgroundTocilizumab, an interleukin-6 (IL-6) receptor antagonist, has been used in patients with coronavirus disease 2019 as an anti-cytokine agent. IL-6 also plays a complex role in hemostasis and thrombosis. We observed a transient elevation of D-dimer in our patients who received tocilizumab, which triggered this study. MethodsA retrospective hospital-based cohort analysis of patients with confirmed COVID-19 who received tocilizumab during the study period of March 15, 2020, to May 20, 2020, was conducted. We retrieved demographic, clinical, and laboratory data, and patients who were receiving therapeutic anticoagulation therapy prior to tocilizumab administration were excluded. Descriptive analysis was performed, and the cause of death and trends of D-dimer and inflammatory markers were studied. ResultsOut of the 436 confirmed COVID-19 patients admitted during the study period, 24 met the inclusion criteria. Their median age was 47.5 years. They were 18 males and 6 females; 15 patients survived and nine expired. Of the group that survived, 12 received therapeutic anticoagulation. Of the seven patients who did not receive therapeutic anticoagulation, four expired (one from sepsis and three probably from thromboembolic complications) compared to five deaths in the 17 patients who received therapeutic anticoagulation (four from sepsis and one possibly from thromboembolic complications). ConclusionsThe interplay between IL-6, IL-6 receptor antagonist, and venous thromboembolism is complex. We observed a transient elevation of D-dimer in COVID-19 patients who received tocilizumab, and a trend toward increased death secondary to thromboembolism. This observation is novel and highlights the potential thrombophilic side effects of tocilizumab.

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“…For example, coagulation factor deficiencies with tocilizumab, and peripheral embolism and thrombosis with sarilumab, are presumably related to the use of these anti-IL6 to treat the pro-coagulative cytokine storm, characteristic of severe COVID-19 ( Kichloo et al, 2020 ; Xu et al, 2020 ), suggesting an indication bias. Nonetheless, it should also be considered that some evidence of thrombophilic side effects of tocilizumab is starting to accumulate ( Chan et al, 2021 ).…”

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“… 13 These findings were recently confirmed in a study focusing on the incidence of thromboembolic events in COVID-19 patients receiving tocilizumab. 14 …”

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“…IL-6 levels exceeding 80 pg/mL are highly predictive of mechanical ventilation use [ 27 ]. There is limited evidence in the available literature on the effect of TCZ on the risk of thrombosis [ 28 , 29 ]. Isolated reports suggest an increased risk of thromboembolism (TE) associated with transient elevations in D-dimer levels [ 29 ], while other studies report a reduced risk of thrombosis in patients treated with TCZ [ 30 ].…”

“…There is limited evidence in the available literature on the effect of TCZ on the risk of thrombosis [ 28 , 29 ]. Isolated reports suggest an increased risk of thromboembolism (TE) associated with transient elevations in D-dimer levels [ 29 ], while other studies report a reduced risk of thrombosis in patients treated with TCZ [ 30 ]. Guidelines indicate that TCZ should only be used in cases with identified cytokine storm; however, the guidelines do not consider its safety among cases with thrombotic events [ 31 ].…”