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

Abstract

Background:Tocilizumab, an IL-6 receptor antagonist has been used in patients with Coronavirus Disease 2019 (COVID-19) 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 the current study.Methods:A retrospective hospital-based cohort analysis of patients with confirmed COVID-19 who received Tocilizumab during the study period of 03/15/2020 to 05/20/2020. We retrieved demographic, clinical and laboratory data, we excluded patients who were receiving therapeutic anticoagulation therapy prior to Tocilizumab administration. Descriptive analysis was performed, the cause of death and trends of D-dimer and inflammatory markers were studied. Results: Out of the 436 confirmed COVID 19 patients admitted during the study period, 24 met the inclusion criteria. Their median age was 47.5 years old. They were 18 males and 6 females; 15 patients survived, and 9 expired. Of the group that survived, 12 received therapeutic anticoagulation. Of the 7 patients who did not receive therapeutic anticoagulation, 4 expired, 1 from sepsis and 3 probably from thromboembolic complications, compared to 5 deaths in the 17 patients who received therapeutic anticoagulation with 4 dying from sepsis, and one possibly from thromboembolic complications.Conclusions:The interplay between IL-6, IL-6 receptor antagonist and venous thromboembolism are 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.

Thrombotic events following tocilizumab therapy in critically ill COVID-19 patients: a Façade for prognostic markers

“…The reduction however is fairly heterogenous in our small sample size, making larger studies necessary in order to map out and better understand the trend. In fact, a retrospective study in this context have demonstrated variable influences of tocilizumab on markers such as IL-6 and CRP [16]. Other retrospective cohort analyses however report results similar to our findings, with majority of patients experiencing an elevation of D-dimers after Tocilizumab administration, while the inflammatory markers (ferritin, LDH and CRP) gradually decreased [17,18].…”

Platelet-leukocyte crosstalk in COVID-19: How might the reciprocal links between thrombotic events and inflammatory state affect treatment strategies and disease prognosis?

“…Given these preliminary findings, in a larger randomised controlled trials (REMAP/CAP-RE-COVERY trial platform) adding tocilizumab to standard dexamethasone treatment showed superior effect in patients treatment compared to dexamethasone alone [240] with increasing organ support-free days as well as a 1.6-fold increment in chance of survival compared to control. In this regard, some researchers believe that one of the reasons for the better performance of this anti-inflammatory combination is the possible role of tocilizumab in improving coagulation function and thrombotic conditions in patients, especially since recent studies have also showed a lower incidence of thromboembolic events in COVID-19 patients receiving tocilizumab [241] as well as reduced D-dimer levels during infection [242]. In addition to IL-6 inhibition, in some smaller cohorts, researchers also showed that both the blockade of IL-1 receptor with anakinra [243] and IL-1β blocking monoclonal antibodies (canakinumab) can attenuate some inflammatory signals leading to an improved oxygenation associated with survival [244].…”

Tocilizumab in severe COVID-19: A promise fulfilled

“…Interestingly, a prospective cohort study of patients with severe COVID-19 treated with tocilizumab indeed demonstrated that this treatment was associated with a significant improvement of blood coagulation parameters independently of the use of anticoagulants for thrombosis prophylaxis [13]. These findings were recently confirmed in a study focusing on the incidence of thromboembolic events in COVID-19 patients receiving tocilizumab [14].…”