Background and Objectives: Severe COVID-19 frequently fulfills Sepsis-3 criteria and is characterized by thrombo-inflammation and endothelial injury. We evaluated whether a bedside endothelial activation index (EAI = D-dimer/fibrinogen) identifies biologically distinct phenotypes and relates to interleukin-6 (IL-6) response after therapeutic plasma exchange (TPE), and whether baseline IL-6 predicts a ≥50% IL-6 reduction. Methods: Retrospective single-center ICU cohort of adults with SARS-CoV-2 infection, sepsis-related organ dysfunction, and ≥1 TPE session (n = 51). Patients were stratified by median EAI (low vs. high). Outcomes included peri-procedural biomarker/physiology changes (post–baseline), IL-6 responder status (≥50% reduction), correlations with IL-6 reduction (%), and multivariable predictors of response. Results: Compared with low EAI (n = 25), high EAI (n = 26) had higher baseline D-dimer (6.2 vs. 2.2 µg/mL) and lower fibrinogen (2.9 vs. 7.1 g/L) (both p < 0.001). Low EAI showed larger CRP decreases (ΔCRP −84.0 vs. −2.3 mg/L; p = 0.001) and larger fibrinogen falls (Δ −3.1 vs. −0.4 g/L; p < 0.001), while high EAI had larger D-dimer decreases (Δ −2.5 vs. −0.6 µg/mL; p = 0.004) and a modest SOFA improvement (Δ −0.3 vs. +0.1; p = 0.026). IL-6 responders (n = 20) had higher baseline IL-6 than non-responders (365.2 vs. 47.1 pg/mL; p < 0.001). Baseline IL-6 independently predicted response (per doubling: OR 1.94, 95% CI 1.27–2.95; p = 0.002), while age reduced odds (OR 0.91/year, 95% CI 0.84–0.99; p = 0.032). IL-6 reduction correlated with ΔCRP (ρ = −0.41; p = 0.003) and ΔPaO₂/FiO₂ (ρ = 0.37; p = 0.01). Conclusions: EAI stratifies distinct thrombo-inflammatory patterns around TPE, while baseline IL-6 is the dominant predictor of achieving large IL-6 reductions. To emphasize the novelty and clarify the study objective, this exploratory analysis used a phenotype-stratified framework to test whether a simple bedside endothelial activation index could enrich biological response assessment to adjunctive TPE. The prespecified primary outcome was achievement of a ≥50% IL-6 reduction after completion of the TPE course; secondary outcomes included peri-procedural biomarker, oxygenation, SOFA, and ICU endpoints.

Introduction: Therapeutic plasma exchange (TPE) is increasingly used as an adjunctive intervention in severe, hyperinflammatory critical illness, including COVID-19, yet clinical guidance remains syndromic and evidence is heterogeneous. We present an integrated, interpretable machine-learning framework designed to support protocolizable TPE decision-making by identifying biochemical phenotypes associated with short-horizon laboratory response to TPE. Our dataset consists of real-world intensive care unit cases and captures the treatment heterogeneity and operational constraints that a workable institutional protocol must accommodate, being well-suited as a “protocol seed” for iterative validation. Methods: We jointly analyze a COVID-19 cohort and a non-COVID comparator cohort receiving TPE. Three decision trees were constructed to represent: (1) global biochemical improvement, (2) strict improvement dependent on key inflammatory/coagulation markers, and (3) early interleukin-6 (IL-6) response. The models revealed distinct favorable phenotypes—particularly patients with IL-6 > 86 pg/mL, lactate dehydrogenase (LDH) >346 U/L, lymphopenia, and fibrinogen ≤ 8.3 g/L. Apriori analysis further identified high-confidence patterns linking high values of IL-6 and LDH with TPE responsiveness. We constructed a unified four-tier clinical algorithm for candidate stratification. Results: The resulting logic aligns with how TPE has been applied in practice in published severe COVID-19 series and trials, where candidate selection typically targets cytokine release syndrome-like phenotypes, organ dysfunction, and hyperinflammatory biomarker profiles. We further contextualize these findings against American Society for Apheresis guidance and COVID-era operational considerations, demonstrating convergence while adding quantitative biomarker thresholds. Conclusion: These findings support two complementary perspectives of benefit: (i) an algorithmic framework that provides transparent, protocol-ready guidelines, and (ii) a phenotype-based clinical approach consistent with observed post-TPE marker changes in severe COVID-19 cases. Larger multicenter validation is warranted; however, the present work provides a practical foundation for protocol construction and auditable decision support in settings already performing TPE.

Background and Objectives: In severe COVID-19-associated sepsis, therapeutic plasma exchange (TPE) is used as a rescue strategy to modulate cytokine and coagulation derangements, but its biomarker and organ-failure effects remain incompletely characterised. We evaluated peri-procedural changes in interleukin-6 (IL-6), other inflammatory markers, and Sequential Organ Failure Assessment (SOFA) scores according to TPE intensity, timing, and inflammatory phenotypes. Methods: We conducted a single-centre retrospective cohort study including 102 mechanically ventilated adults with COVID-19-associated sepsis who received ≥1 TPE session. Patients were grouped by number of sessions (1, 2, ≥3), timing (≤14 vs. >14 days from symptom onset), IL-6 responder status (≥50% reduction), and two unsupervised inflammatory–thrombotic clusters. Peri-procedural changes (Δ) in biomarkers and SOFA were compared using non-parametric tests, with multivariable logistic and linear regression exploring predictors of IL-6 response and ΔSOFA. Results: Baseline severity was similar across TPE-intensity groups, with median APACHE II scores of 11–12 and SOFA scores around 7 in all strata. Median IL-6 concentrations declined after TPE in each group (e.g., Δ −59.4 pg/mL after 1 session and Δ −65.1 pg/mL after ≥3 sessions), but between-group differences in ΔIL-6 were not statistically significant (p = 0.276). By contrast, D-dimer exhibited a marked decline only in the 1-session group (median Δ −1.7 mg/L vs. ~0.0 mg/L in the 2- and ≥3-session groups; p < 0.001). Timing (early vs. late TPE) did not materially affect ΔIL-6, ΔCRP, ΔSOFA (median 0.0 in both), or ΔD-dimer. Overall, 50% of patients were IL-6 responders; baseline IL-6 was the only independent predictor (adjusted OR 1.9 per doubling, 95% CI 1.3–2.8). A hyperinflammatory–thrombotic cluster (n = 44) exhibited higher baseline IL-6 (612.3 vs. 92.4 pg/mL), more ≥3-session TPE (65.9% vs. 29.3%), and higher IL-6 responder rates (75.0% vs. 31.0%), but similar 28-day mortality (40.9% vs. 29.3%). Conclusions: In this real-world TPE programme, biochemical improvements—particularly IL-6 and D-dimer reductions in hyperinflammatory–thrombotic patients—were not consistently accompanied by short-term SOFA or survival benefits, underscoring the need for phenotype-guided and trial-based use.

Introduction: TPE (therapeutic plasma exchange) has proven to be an extremely effective treatment for a range of conditions, especially over the past 20 years. Anticoagulation with heparin is currently the accepted recommendation for therapeutic plasma exchange sessions. However, the hypercoagulable state and hyperviscosity in some patients requiring TPE present a challenge, particularly during the first session, due to an increased risk of circuit clotting. Citrate anticoagulation has been proposed for extracorporeal therapies such as hemodiafiltration where heparin is contraindicated. Nevertheless, citrate anticoagulation is still generally avoided in patients undergoing TPE. Materials and Methods: A total of 26 patients underwent 52 TPE sessions using citrate. Fifteen patients received citrate from the beginning of therapy, accounting for 29 sessions, and eleven patients were switched to citrate after initially starting with heparin, when an imminent risk of circuit clotting quickly became evident—23 sessions in total. The imminent risk of circuit clotting was assessed by a continuous and accelerated increase in transmembrane pressure despite heparin anticoagulation. The effectiveness of citrate anticoagulation and its safety for patients were evaluated. Results: Of the 23 sessions where there was a risk of circuit clotting, citrate was added on top of heparin in those sessions; 21 sessions were successfully completed. It can be said that the kits were saved in these cases. Among the 29 TPE sessions that used citrate from the start, 27 were completed successfully, even though the patients were considered to have a hypercoagulable status. No cases of citrate toxicity were identified. Conclusions: TPE with citrate is a safe option for patients. It can preserve TPE kits from the beginning or during treatment in patients with hypercoagulability. Citrate can be also be used when heparin is contraindicated or ineffective.