Terminal complement inhibition is associated with renal, hematologic, and thrombotic complications during septic shock: A global propensity score-matched cohort study

Purpose Terminal complement inhibition with eculizumab or ravulizumab alters host defense and vascular-immune interactions. However, its impact on outcomes during septic shock remains unclear. We investigated the association between terminal complement inhibition and clinical outcomes in patients with septic shock. Materials and methods We conducted a retrospective propensity score-matched cohort study using the TriNetX Global Collaborative Network, a large federated network of electronic health record data from healthcare organizations worldwide. Adult patients with septic shock and an underlying indication for C5 inhibition (atypical hemolytic uremic syndrome, myasthenia gravis, neuromyelitis optica spectrum disorder, or paroxysmal nocturnal hemoglobinuria) were stratified by treatment with eculizumab or ravulizumab. Propensity score matching balanced demographics, comorbidities, underlying disease indications, and severity proxies, yielding two cohorts of 638 patients each. Clinical outcomes were assessed over 31 days, with an additional 7-day sensitivity analysis. Results Patients receiving complement inhibition had higher risks of thrombocytopenia (20.3% vs 8.9%, p < 0.001), acute kidney injury (25.0% vs 13.3%, p < 0.001), and thrombotic disorders (7.8% vs 4.7%, p = 0.021). Renal replacement therapy (8.3% vs 5.1%, p = 0.026) and major adverse cardiovascular events (13.7% vs 9.2%, p = 0.011) were also more frequent. Time-to-event analyses confirmed these findings, and the overall outcome pattern remained consistent in the 7-day sensitivity analysis. Thirty-day mortality did not differ between the matched cohorts. Conclusions In septic shock, terminal complement inhibition was associated with increased renal, hematologic, and thrombotic complications without a significant difference in short-term mortality. These findings identify a clinically vulnerable, currently uncommon but increasingly relevant patient population.