Designing biomarker-selected international trials in sepsis-associated coagulopathy

Sepsis-associated coagulopathy represents a dynamic thromboinflammatory continuum ranging from early, compensated sepsis-induced coagulopathy (SIC) to overt disseminated intravascular coagulation (DIC). Divergent international strategies reflect differences in cohort selection, timing of intervention, and outcome prioritization rather than fundamental biological disagreement. Large randomized trials conducted in unselected sepsis populations have often yielded neutral results, likely due to biological heterogeneity and temporal signal dilution. We propose GLOBAL-SIC/DIC, a pragmatic international registry designed to support biomarker-selected interventional trials. The framework incorporates: (1) early stratification of SIC and overt DIC at enrollment; (2) harmonized serial sampling windows using a minimal, globally feasible core coagulation panel; and (3) a prespecified hierarchical composite endpoint analyzed using the win ratio. The proposed hierarchy prioritizes 28-day mortality, major bleeding, clinically relevant thrombosis, DIC resolution, and organ dysfunction trajectory. This structure integrates survival, safety, and biologically proximal response measures within a single analytic framework. Expanded mechanistic biomarkers, including markers of endothelial injury, complement activation, and fibrinolytic dysregulation, are confined to central-laboratory substudies to preserve operational feasibility. By combining biological enrichment, temporal fidelity, and safety-aware endpoint design, GLOBAL-SIC/DIC provides a scalable platform for registry-to-randomized trial translation. This methodological convergence aligns early-intervention principles with international safety expectations and supports precision phenotyping in future global research on sepsis-associated coagulopathy.