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Abstract Background: Thromboinflammation is recognized as a central pathological process in sepsis. Sepsis-induced inflammation, triggered by bacterial infection, is tightly linked to a hypercoagulable state and endothelial cell activation. The failure of natural anticoagulant pathways—due to overwhelming thromboinflammation and/or consumption of natural coagulation inhibitors—contributes to the development of disseminated intravascular coagulation (DIC) and clinical deterioration. Excessive expression of tissue factor (TF) by activated endothelial cells and monocytes plays a key role in this process. Release of procoagulant microparticles (MP) is related with amplification of blood borne hypercoagulability in patients with sepsis. The identification of septic patients at risk of deterioration aiming to prompt administration of antithrombotic treatment remains an unmet need. To this aim, the identification of new biomarkers of hypercoagulability is a promising strategy. Among emerging candidates, TF-bearing microparticles (TF⁺-MPs) represent a particularly compelling biomarker with both mechanistic and clinical relevance. Aim: The ROADMAP-Sepsis study evaluated the clinical relevance of TF⁺ -MP activity quantification in relation to systemic inflammation, hypercoagulability, endothelial cell dysfunction and 20-day mortality in patients with sepsis, stratified by DIC status. Methods: In this prospective, observational study, 114 ICU patients with sepsis (according to the Sepsis-3 criteria: documented infection and SOFA score ≥2) and without prior antithrombotic treatment were enrolled. Patients were stratified according to the ISTH-DIC score into a DIC (score ≥5; n=65) and non-DIC groups (n=49). Blood samples were collected within 2 hours of ICU admission into citrated tubes (Vacutainer®). Platelet-poor plasma (PPP) was prepared using standardized protocols for MP analysis. TF⁺-MP activity was measured using a TF-dependent FXa generation assay (CY-Quant MV-TF Activity, Biocytex, France), and total MP concentration was assessed with the ZYMUPHEN MP kit (Hyphen Biomed, France). D-dimer, fibrin degradation products (FDPs), soluble thrombomodulin (sTM), tissue factor pathway inhibitor (TFPI), CRP, IL-1β , Procalcitonin (PCT), and TNF-α , were measured with ELISA kits (Diagnostica Stago). Thrombin generation (TG) in PPP was analyzed by calibrated automated thrombogram (CAT®, Stago) with 5 pM TF PPP-Reagent®. The primary clinical endpoint was 20-day mortality. Results: The DIC group had a significantly higher ISTH score compared to the non-DIC group (p < 0.001). Total MP concentrations did not differ significantly between groups and showed no correlation with DIC or SOFA scores, nor with D-dimer, FDPs, sTM, or TFPI levels. In contrast, TF ⁺-MP activity was significantly elevated in the DIC group versus the non-DIC group (p < 0.001). TF⁺ -MP activity strongly correlated with the ISTH DIC score (r² = 0.9; p = 0.003), SOFA score (r² = 0.8; p = 0.001), D-dimer (p = 0.001), FDP (p = 0.01), and sTM (p = 0.02), but not with TFPI levels. Thrombin generation parameters differed markedly: the DIC group had a significantly longer lag-time and reduced mean rate index (MRI) and Peak of thrombin generation (p = 0.001). Lag time was positively correlated with DIC and SOFA scores, while endogenous thrombin potential (ETP) and peak values were negatively correlated. Inflammatory markers (IL-1β , CRP, TNF-α and PCT) were significantly elevated in the DIC group (p < 0.01). TF⁺ -MP activity correlated significantly with IL-1 β, TNF-α , CRP, and PCT levels. TF⁺ -MP activity was significantly higher in non-survivors compared to survivors at 20 days (p < 0.005), while total MP concentrations did not differ. Conclusion: The ROADMAP-Sepsis study highlights TF⁺ -MP activity as a central mediator of thromboinflammation and a key contributor to the development of DIC, endothelial dysfunction, and increased sepsis severity. Unlike total microparticle levels, TF ⁺-MP activity showed strong correlations with inflammatory markers, markers of hypercoagulability, and 20-day mortality. These findings support the clinical relevance of TF⁺-MP activity as a prognostic biomarker for identifying septic patients at high risk of deterioration. Ongoing studies from our group are focused on validating its incorporation into predictive scoring systems to guide risk stratification and therapeutic decision-making.