ABSTRACT:Frailty has emerged as a key component of allo-HCT candidate assessment and is closely associated with transplant outcomes. Exercise-based prehabilitation may improve transplant candidacy, yet real-world implementation is limited. Our institution implemented a structured Frailty Program (FP) to assess frailty and introduce prehabilitation interventions. This study describes the program's evolution and evaluates the impact of prehabilitation. Between April 2021 and April 2025, 185 consecutive allo-HCT candidates were included in 3 sequential FP phases. In the first phase (No-Prehab, n = 76), patients underwent frailty assessment only. In the second phase (Pilot-Prehab, n = 59), patients received a home-based, nonsupervised prehabilitation program. In the third phase (Tele-Prehab, n = 50), patients participated in the HCT Pre-App Program, a structured digital telemedicine intervention supervised by rehabilitation physicians. Frailty was assessed at first consultation and HCT admission using the HCT Frailty Scale. Median prehabilitation duration was 6 weeks. Adherence was high across frailty groups (76%-88%), with no adverse events. Prehabilitation improved frailty status: fit patients increased from 22% to 42% in the Pilot-Prehab cohort (P = .009) and from 34% to 56% in the Tele-Prehab cohort (P = .001). Tele-Prehab independently increased the odds of being fit at admission (odds ratio [OR], 3.86; P = .001) and reduced frailty incidence (OR, 0.17; P = .031). One-year OS and NRM were comparable across cohorts (OS, 74.5%, 84.5%, and 78.1%; P = .367) with a trend toward lower NRM among prehabilitated patients (NRM, 14.6%, 5.1%, and 5.6%; P = .075). Frailty is dynamic in allo-HCT candidates, and results support how home-based digital prehabilitation improves fitness before transplantation.

Endothelial dysfunction (ED) arises in multiple pathologies, and its severity correlates with disease progression. Common ED biomarkers could provide prognostic value for associated complications. This study aims to identify shared ED biomarkers and assess their prognostic significance. Endothelial cells in culture (human microvascular endothelial cells, HMEC-1) were exposed to sera from patients in five disease groups (n = 20 patients/group)-liver cirrhosis with portal hypertension, idiopathic pulmonary arterial hypertension, placental disorders such as intrauterine growth restriction, coronary artery disease with acute myocardial infarction, and chronic kidney disease-or matched controls, in the absence/presence of anti-inflammatory (apixaban) and antioxidant (EUK134) compounds. We explored changes in: VCAM-1, ICAM-1, eNOS, VWF, extracellular matrix thrombogenicity, and reactive oxygen species (ROS). In serum samples, proteomics and metabolomics analyses (including lipids, amino acids, and polar metabolites) were performed through an extraction protocol to identify common ED biomarkers. Expression of VCAM-1, ICAM-1, VWF, platelet adhesion, and ROS increased in most groups versus controls (p < 0.05). Both drugs decreased all biomarker levels except eNOS (n = 6 for in vitro experiments). For serum ED biomarkers, 18 metabolites and 24 proteins showed AUC-ROC and hit rates >77.5%, and six metabolites were associated with event-free survival. These diseases share ED driven by systemic inflammatory, oxidative, and metabolic stress, are partially reversible in vitro, and are linked to biomarkers associated with clinical outcomes. Overall, ED emerges as a modifiable pathological axis with potential prognostic value.

INTRODUCTION:Endothelial dysfunction is key in COVID-19 pathogenesis. This randomized, double-blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS-CoV-2 infection and respiratory failure. METHODS:One-hundred and fifty patients were randomized (2:1) to defibrotide or placebo, stratified by disease severity (WHO COVID-19 severity scale 4/5 vs. 6). The primary endpoint was clinical improvement time (days from first improvement through Day 30). RESULTS:Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p = 0.10). Day-30 (23.0% vs. 22.0%) and Day-60 (26.0% vs. 22.0%) mortality, reduction in mean fraction of inspired oxygen during treatment, and median duration of hospitalization did not differ with defibrotide versus placebo. Defibrotide demonstrated favorable safety, with no differences versus placebo in serious adverse events (34.0% vs. 36.0%), hypotension (16.0% vs. 12.0%), or hemorrhage (13.0% vs. 8.0%). Exploratory pre-specified biomarker analyses showed greater early d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION:Continuous intravenous infusion of defibrotide was safe but did not improve clinical outcomes in severe COVID-19. Further analyses will explore mechanistic actions and pharmacokinetics of defibrotide and the pathophysiology of endothelial dysfunction in COVID-19. TRIAL REGISTRATION:EudraCT identifier: 2020-001409-21. CLINICALTRIALS:gov identifier: NCT04348383.

IntroductionExtracorporeal photopheresis (ECP) is a safe, effective treatment for steroid-refractory acute GVHD (SR-aGVHD). Endothelial damage is a pathological substrate of aGVHD. MethodsEndothelial damage biomarkers were measured in SR-aGVHD patients' plasma before (PRE) and 1-month after initiating ECP as second-line therapy to explore differences by treatment response. ECP-treated SR-aGVHD patients (n=35) were classified into good (GR; n=18) and poor (PR; n=17) responders. Endothelial activation biomarkers (soluble Vascular Cell Adhesion Molecule-1, sVCAM-1; von Willebrand Factor, VWF; thrombomodulin, TM; soluble TNF receptor 1, sTNFR1; angiopoietin 2; ANG2); GVHD markers (suppression tumorigenicity 2, ST2; regenerating islet-derived 3-alpha, REG3alpha; T-cell immunoglobulinmucin-3, TIM3); soluble C5b9 (sC5b9), for complement activation; and circulating dsDNA, for neutrophil extracellular traps (NETs), were analyzed. The endothelial activation and stress index (EASIX) and C-reactive protein were evaluated. ResultsBefore ECP, endothelial damage biomarkers were elevated in all patients, with no significant differences between GR and PR. After 1-month, increased levels of REG3alpha and sC5b9, and decreased levels of TIM3, were observed in samples from PR. A panel combining 5 biomarkers (ST2, VWF, NETs, TIM3, ANG2) could identify GR after 1-month on ECP (likelihood ratio 2.0) and predict ECP response.DiscussionWe propose a simplified endothelial damage biomarker panel capturing early biological signals associated with response to ECP in SR-aGVHD patients.

Background:Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are life-threatening complications that often arise after CAR T-cell immunotherapy. Endothelial dysfunction is believed to play a central role in their development, leading to the interest in biomarker-based tools for diagnosis and differentiating these toxicities from sepsis. This study aimed to evaluate the Endothelial Activation Stress Index (EASIX) and its modified version (m-EASIX, which replaces creatinine with C-reactive protein [CRP] (mg/dL)) as early predictors of severe CRS and ICANS, as well as tools to distinguish CRS from sepsis. Methods:One hundred and nineteen patients treated with CAR T-cell therapy for CD19-positive hematologic malignancies (n=94) or multiple myeloma (n=23) were included. EASIX and m-EASIX scores were measured at various time points: before CAR T-cell infusion, 24-48 hours post-infusion, at CRS or ICANS onset, and after treatment for each toxicity. A comparator group of 129 sepsis patients, including 86 with hematologic malignancies, was also analyzed. Results:Both EASIX and m-EASIX correlated with biomarkers of endotheliopathy, with m-EASIX showing stronger predictive power for severe toxicities and ICU admission. Higher EASIX and m-EASIX values at early time points were associated with worse overall survival (OS). Furthermore, m-EASIX accurately distinguished CRS from sepsis at symptom onset. Conclusions:m-EASIX is a practical and accessible tool for the early prediction of severe CAR T-cell-related toxicities, risk stratification, and differential diagnosis from sepsis, offering potential to guide clinical decision-making and early intervention.

Background Mechanical circulatory support (MCS) systems assist patients with severe cardiac or respiratory failure, but bleeding linked to acquired von Willebrand disease remains a major complication. The T-TAS® 01 system has emerged as a rapid tool for assessing MCS patients’ hemostasis. Objectives To evaluate hemostatic changes during and after MCS support. Secondary objectives included assessing the impact of the in vitro addition of von Willebrand factor concentrates and exploring differences according to the presence of a membrane oxygenator (MO). Methods This prospective, bicentric study included adults requiring MCS, with hemostatic parameters assessed at three predefined timepoints using conventional laboratory assays and T-TAS® 01. Data were analyzed using linear mixed-effects models. In vitro addition of a VWF/FVIII concentrate (Haemate-P®) was evaluated as an exploratory analysis. Results A total of 39 patients were included; 56% experienced bleeding complications, of which 23% were clinically relevant. Significant alterations in hemoglobin, platelet counts, and platelet/VWF function were observed during MCS. T-TAS® 01 demonstrated impaired hemostasis during support, with partial recovery after device removal. In vitro addition of Haemate-P® improved T-TAS® 01 parameters. No consistent differences in overall hemostatic dynamics were observed between MO and non-MO devices. Conclusion MCS is associated with significant and persistent alterations in primary hemostasis. T-TAS® 01 may represent a useful tool for dynamic assessment of these changes. In vitro VWF supplementation improved functional hemostasis parameters, although its clinical implications remain to be established. Differences related to MO presence were not consistent, supporting a shared mechanism of hemostatic dysregulation across MCS devices.

Endothelial dysfunction is central to COVID-19 pathophysiology, contributing to vascular complications and disease progression. However, the mechanisms driving disease evolution and response to endothelial-targeted therapies remain unclear. This study characterizes endothelial activation throughout the course of acute COVID-19 and evaluates the response to potential therapeutic agents.Serum samples from patients admitted due to moderate to severe COVID-19 pneumonia were prospectively collected on three study time points (+1 day, +4 days and +10 days). Human microvascular endothelial cells were cultured in medium supplemented with pooled serum within the same disease stage, with or without defibrotide, apixaban, or tocilizumab. Endothelial activation was assessed by immunofluorescence and quantitative mRNA expression of adhesion molecules, extracellular matrix (ECM) proteins, and innate immunity receptors. ECM reactivity was evaluated using a platelet adhesion assay. Intracellular signaling pathways were analyzed by immunoblotting.One-hundred and two patients were included. Compared to healthy donor plasma, patient plasma induced upregulation of Vascular cell adhesion molecule-1, Toll-like receptor 4, and von Willebrand factor in endothelial cells. This effect decreased over admission days and in response to drugs. Similarly, ECM reactivity was highest at admission and declined as the disease progressed. Vascular-endothelial cadherin was mildly downregulated, but its expression was unaffected by drug treatment in vitro. Defibrotide mitigated COVID-19 serum induced p38MAPK and Erk activation but enhanced Akt phosphorylation.Serum from severe COVID-19 patients induces a proinflammatory and prothrombotic endothelial phenotype, which can be modulated by endothelial-targeted therapies. These findings support the potential clinical value of endothelial-directed treatments.

Hereditary spherocytosis (HS) is the most common congenital red blood cell membrane disorder, characterized by structural protein defects that lead to hemolytic anemia. Although several diagnostic tests exist, including osmotic fragility tests (OFTs), acidified glycerol lysis test (AGLT), and the EMA-binding test (EMA), each presents specific limitations regarding sensitivity, specificity, or technical requirements. Flow cytometric osmotic fragility testing (OFT-FCM) emerges as a promising complementary assay, offering a standardized workflow and rapid turnaround time. We conducted a retrospective study including 106 subjects (20 HS patients and 86 healthy controls) recruited at Hospital Clínic de Barcelona between September 2024 and September 2025. Clinical and laboratory data were collected, and all participants underwent OFT, AGLT, EMA, and OFT-FCM using two acquisition protocols (300 and 214 s). Logistic regression and receiver operating characteristic curve analysis were performed to evaluate diagnostic performance and determine optimal cut-off values. HS patients exhibited significantly altered hematologic parameters compared with controls, including higher reticulocyte counts, red cell distribution width, and mean corpuscular hemoglobin. The EMA-binding test demonstrated high specificity (100%) but lower sensitivity (57.9%). OFT achieved high sensitivity (>97%) but low specificity (<47%). AGLT showed balanced accuracy (sensitivity 68.4%, specificity 96.1%). OFT-FCM yielded areas under the curve of 0.85 for both protocols, with optimal thresholds providing specificities of 95-100% and sensitivities of 57-59%. No significant differences were observed between OFT-FCM and EMA performance. OFT-FCM effectively discriminates HS patients from healthy controls and showed diagnostic performance comparable to EMA and favorable relative to classical OFT and AGLT in this cohort, while offering practical advantages in terms of workflow simplicity and turnaround time, and supporting its use as a complementary flow-cytometric assay within the diagnostic work-up of HS.

Hepatic sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) driven by endothelial injury. Post-transplant cyclophosphamide (PTCy) is widely used for graft-versus-host disease prophylaxis, but data on SOS incidence, risk factors, and outcomes in this setting are limited. The present study investigates the incidence and outcomes of SOS in adults undergoing allo-HCT with PTCy-based prophylaxis. This retrospective single-center study included 374 consecutive adult patients who underwent allo-HCT with PTCy between January 2014 and January 2025. SOS was diagnosed and graded according to established criteria. Endothelial activation was assessed using the Endothelial Activation and Stress Index (EASIX) at predefined peri-transplant time points. SOS occurred in 12 patients (3.2%), with a 100-day cumulative incidence of 2.7%. Six cases (50%) were moderate and 6 (50%) severe. Patients with myelofibrosis were markedly overrepresented (41.7% versus 4.1%; P < .001) and had an increased risk of SOS (hazard ratio [HR] 14.38, P < .001). Median hospitalization was longer in SOS patients (46 versus 29 days; P = .01), and 16.6% required ICU admission. Ten patients (83.3%) received defibrotide and 1 underwent transjugular intrahepatic portosystemic shunting placement. Clinical response was observed in 91.7%, but 7 patients (58.3%) died during follow-up, primarily from nonrelapse mortality (NRM) (median 60 days). Two-year overall survival and NRM were 33.3% and 31.2% in SOS patients versus 71.8% and 12.6% in non-SOS patients. SOS was independently associated with higher NRM (HR 8.4, P < .001) and inferior OS (HR 3.3, P = .001). During the first 100 days, median EASIX values were higher in SOS patients. Higher log2-EASIX at pretransplant evaluation (EASIX-PRE) and day 0 independently predicted SOS (HR 4.6; P = .003). SOS remains an uncommon but clinically significant complication following allo-HCT with PTCy, substantially impacting survival. EASIX is a readily available biomarker that may enable early risk stratification and support individualized preventive strategies in this setting.

Abstract Steroid-refractory acute GVHD (SR-aGVHD) is a severe complication of allogeneic hematopoietic cell transplantation. While endothelial dysfunction is implicated in aGVHD pathophysiology, the status of the endothelium in patients with SR-aGVHD and the effect of the JAK1/2 inhibitor ruxolitinib remain incompletely understood. This study aimed to characterize the endothelial damage phenotype induced by SR-aGVHD serum and to evaluate the potential modulatory effects of ruxolitinib. Human microvascular endothelial cells (HMEC-1) were exposed to serum from SR-aGVHD patients (n = 21) or healthy donors (C), with or without ruxolitinib (0.4 µM). Markers of endothelial activation (VCAM-1, ICAM-1), junctional integrity (VE-cadherin), prothrombotic state (VWF), apoptosis (cleaved caspase 3), and intracellular signalling (JAK-STAT and MAPK pathways) were analyzed by immunofluorescence and immunoblotting. Compared with C, SR-aGVHD serum caused increased VCAM-1 and ICAM-1 expression (P< .05 for both), reduced VE-cadherin (P< .01), elevated VWF production, and cleaved caspase 3 presence (P< .05 for both). These changes were associated with phosphorylation of STAT3 (P< .05), STAT1 (P< .05), and MAPK proteins (Erk1/2, p38, SAP/JNK, and cJun) (P< .05, all). Ruxolitinib treatment mitigated these responses, reducing adhesion molecule expression, restoring VE-cadherin localization, normalizing VWF production, and suppressing apoptosis. These protective effects were associated with inhibition of the activated JAK-STAT and MAPK signalling pathways. SR-aGVHD serum directly induces endothelial activation in vitro, promoting an inflammatory and prothrombotic phenotype. Ruxolitinib counteracts these effects, providing mechanistic insight into its therapeutic efficacy in SR-aGVHD.

Background: Myeloproliferative neoplasms (MPNs) are associated with a high risk of thrombotic complications, particularly splanchnic vein thrombosis (SVT). This study aimed to elucidate the proteomic signature of JAK2V617F-mutated MPN patients with and without SVT, focusing on dysregulated pathways contributing to thrombotic risk. Methods: We conducted a comprehensive proteomic analysis of plasma samples from 28 JAK2V617F-mutated MPN patients (22 with SVT, 6 without thrombosis) and 6 healthy controls. Proteins were quantified using TMT labeling and nanoLC-MS/MS, followed by multivariate and univariate statistical analyses. Findings: A total of 275 high-confidence proteins were identified. Compared to controls, MPN patients exhibited significant dysregulation of complement and coagulation pathways, with upregulation of complement components (C1QA, C1QB, C1QC, C7) and endothelial adhesion molecules (VCAM1, ICAM1), along with downregulation of anticoagulant proteins (PROS1, SERPINA10). SVT patients showed heightened complement activation, markedly increased C7, VCAM1, and von Willebrand factor, and reduced levels of coagulation factors (F9, F10, F11). Hierarchical clustering and pathway enrichment analyses highlighted the central role of complement activation, platelet activation, and endothelial dysfunction in SVT pathogenesis. Serum validation confirmed elevated alternative pathway markers (Ba, Bb) and terminal complement products (C5a, sC5b-9) in SVT, implicating complement activation as a key driver of thrombosis. Interpretation: This study identifies complement activation as a potential key contributor to thrombosis in JAK2V617F MPN patients, particularly those with SVT. The interplay between complement, coagulation, and endothelial dysfunction suggests potential therapeutic targets for reducing thrombotic complications in this high-risk population. Funding: This work was supported by AGAUR, ISCIII, and Novartis.

IntroductionImmune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy resulting from severe ADAMTS13 deficiency. Caplacizumab accelerates platelet recovery, but ~15% of patients remain refractory, and endothelial/microvascular injury or low ADAMTS13 activity may persist despite remission, highlighting the need for biomarkers. We evaluated the Endothelial Activation and Stress Index (EASIX), an endothelial dysfunction surrogate, dynamics and ability to predict refractoriness and mortality in iTTP.MethodsFifty-five adults receiving ≥2 therapies (corticosteroids, plasma exchange, rituximab, and/or caplacizumab) were studied. Clinical and laboratory data were collected at baseline, days 1–2, 7, 14, 21, 28, 35, and at treatment discontinuation, including clinical or ADAMTS13 relapses. EASIX was calculated at each time point; logistic regression and ROC analyses evaluated its predictive performance for refractoriness and mortality. ResultsMedian age was 47 years; 13% were refractory, and 7% died. In responders, EASIX dropped below 1 by day 7, earlier than ADAMTS13 recovery (day 21). Clinical relapses showed EASIX spikes (median 13.2), unlike ADAMTS13-only relapses. Baseline EASIX was higher in refractory patients (752 vs. 91; p=0.007), remaining elevated at days 7 and 14. Higher pre-treatment EASIX predicted refractoriness (OR = 1.003; p=0.021; AUC = 0.811; sensitivity 100%; specificity 58.7%) and mortality (OR = 1.004; p=0.027). DiscussionEASIX may help predict refractoriness and death, improving monitoring in iTTP.

Background JAK2V617F-mutated myeloproliferative neoplasms (MPN) exhibit abnormal proliferation of bone marrow progenitors and increased risk of thrombosis, specifically in splanchnic veins (SVT). The contribution of the endothelium to the development of the prothrombotic phenotype was explored. Material and methods Plasma and serum samples from JAK2V617F MPN patients with (n=26) or without (n=7) thrombotic debut and different treatments, were obtained (n=33). Cultured endothelial cells (ECs) were exposed to serum samples from these patients and from healthy donors as controls. Changes in markers of inflammation (VCAM-1, ICAM-1), cell permeability (VE-cadherin), production of VWF, extracellular matrix (ECM) reactivity, and activation of intracellular signaling pathways related to stress, proliferation, inflammation (Akt, p44/42, IkBa), and JAK2/STAT3 pathway, were assessed by immunofluorescence, flow adhesion, SDS-PAGE and immunoblot. Additionally, circulating markers of endothelial activation and damage (VWF, sVCAM-1, sTNFRI, thrombomodulin, angiopoietin-2, a2-antiplasmin activity, PAI-1) were evaluated in Patients' plasma. Results The in vitro studies showed that EC exposure to MPN thrombotic patients' sera resulted in increased VCAM-1 and ICAM-1, and reduced VE-cadherin expression (p<0.05) at the cell surface. Production and release of VWF to the ECM were higher (p<0.05), with increased platelet adhesion after perfusing whole blood, being more noticeable in response to sera from non-treated patients. Furthermore, intracellular activation of Akt, p44/42, IkBa and JAK2/STAT3 was observed. Moreover, plasma levels of VWF, TNF-R1, VCAM-1, thrombomodulin, and angiopoietin-2 were higher in JAK2V617F+ MPN patients with thrombosis. Conclusion The present findings suggest that circulating factors in MPNs with SVT debut induce endothelial proinflammatory and prothrombotic phenotypes, which are modulated in vitro with MPN treatment.

Post-transplant cyclophosphamide (PTCY, 50 mg/kg/day for 2 days) is effective for GVHD prophylaxis after HLA-matched allogeneic hematopoietic cell transplantation (allo-HCT) but is associated with early toxicities. In November 2021, we implemented a modified platform using reduced-dose PTCY (40 mg/kg; PTCY40) with tacrolimus, plus G-CSF from day +7 and letermovir for CMV-positive patients. Outcomes of 56 patients receiving PTCY40 were compared to 59 historical controls treated with PTCY50. Median follow-up was 15 months. PTCY40 was associated with faster neutrophil and platelet recovery (median 15 versus 19 and 15 versus 21 days, respectively), improved CD4⁺ reconstitution, and fewer bloodstream infections by day +30 (19.6% versus 49.2%, P = .001). Early cardiac events and ICU admissions were numerically lower in the PTCY40 group (day +100: 5.4% versus 10.2%, P = .358; day +180 ICU: 5.4% versus 10.2%, P = .411). The cumulative incidence of grade II-IV acute GVHD was comparable (21.4% versus 18.6%, P = .641), while moderate/severe chronic GVHD was higher but not significant (1-year: 9.5% versus 1.9%, P = .105). Non-relapse mortality was significantly lower with PTCY40 (0% versus 8.6%, P = .032), with similar overall survival (78.2% versus 81.1%, P = .941) and relapse incidence (25.1% versus 24.1%, P = .772). These findings support the safety of this modified GVHD prophylaxis approach.

Endotheliopathy has been increasingly recognized as a key feature of critical illness. Different diseases and syndromes manifest endothelial dysfunction in their severe forms. Septic syndrome, SARS-CoV-2 disease spectrum, and cell therapy-associated toxicities represent paradigmatic examples of endotheliopathy, in intensive care units. As common features, and in response to the environment associated with these conditions, endothelial cells develop a proinflammatory and prothrombotic phenotype, switching its secretion behavior of anticoagulant and profibrinolytic factors toward a hypercoagulative and hypofibrinolytic state. Intravascular microthrombi, release of neutrophil extracellular traps, detached endothelial cells, and exposure of a highly reactive extracellular matrix toward platelets result in turbulent blood flow and agglutination of circulating cells, ultimately leading to tissue hypoperfusion. Levels of endothelial damage biomarkers correlate with disease severity and, therefore, implementation of biomarkers panels could enhance prediction, differential diagnosis, and severity stratification in critical illness conditions. Development of strategies to protect the endothelium could mitigate proinflammatory and procoagulant responses, offering therapeutic potential for the endotheliopathy-associated conditions of critically ill patients.

This study examines engraftment syndrome (ES) and the predictive role of the Endothelial Activation and Stress Index (EASIX) in multiple myeloma (MM) patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We analyzed 187 patients who received at-home auto-HCT (2015-2022), assessing EASIX at pre-apheresis, post-apheresis, and hospital admission. ES occurred in 16.6% despite corticosteroid prophylaxis and G-CSF avoidance, resolving completely with treatment; only one patient required hospitalization. An EASIX cutoff of ≥0.9 may help identify high-risk patients. Higher post-apheresis EASIX values (HR 1.19, p = 0.03) and any grade of mucositis (HR 1.82, p = 0.04) were significantly associated with ES. These findings support EASIX as a valuable tool for risk stratification and personalized interventions, improving ES management. Its incorporation into clinical workflows may optimize outcomes, especially in at-home settings where rapid response is crucial to prevent readmission.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory hematologic malignancies. While its clinical efficacy is well established, CAR T-cell therapy is frequently associated with severe immune-mediated toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), coagulopathy, and hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Increasing evidence suggests that endothelial dysfunction, hemostatic imbalance, and complement activation are key contributors to the pathogenesis of these complications. Substantial research efforts have focused on identifying circulating biomarkers capable of predicting toxicity onset and severity, as well as stratifying patients at risk for early non-relapse mortality. In this review, we summarize the current understanding of the pathophysiological mechanisms underlying early CAR T cell–related toxicities, with particular emphasis on biomarkers of endotheliopathy and related pathways involved in their development. We focus on highlighting translational biomarkers with potential diagnostic, prognostic, and monitoring value that could be implemented in clinical practice to improve patient risk stratification, differential diagnosis, and therapeutic follow-up.