Baseline Thrombin Generation Markers and Functional Antithrombin Levels in Sepsis Associated Coagulopathies Are Predictive of the Severity of Pathogenesis

Introduction: Severe sepsis remains the most common cause of death in critically ill patients. Thrombin plays a crucial role in the pathogenesis of sepsis associated disseminated intravascular coagulation (DIC). Thrombin generation markers and functional AT levels provide useful prognostic information in the management of these patients. The purpose of this study was to compare the baseline values of such thrombin generation markers of prothrombin fragment (F1.2), thrombin antithrombin complex (TAT) and functional antithrombin levels in patients enrolled in the Phase 2B and a Phase III study to investigate the therapeutic effect of recombinant thrombomodulin (ART-123) in sepsis associated coagulopathy.

Materials and Methods: Plasma samples from seven hundred and fifty eight patients enrolled in the ART-123 study, a phase 2b, international, multicenter, randomized controlled trial, and patients enrolled in an ongoing (n=200) phase III clinical trial were profiled for F1.2 and TAT using commercially available ELISA methods (Siemens, Deerfield, IL, USA). Functional AT activity was measured using a chromogenic substrate method. All of these samples included blood drawn prior to the first of ART-123 or placebo treatment.

Results: The results are tabulated in the following tables.

Phase 2b Study (n=750)

Phase 3 Study (n=176)

Discussion: The inclusion criteria for the phase 2b study was based on the revised ISTH criteria and the phase III study used an INR>1.4, 30K=<PLT<150K, shock, and/or respiratory organ dysfunction as criteria at baseline. The median values were TAT (7.5 ng/ml Phase 2b study; 12.4 ng/ml Phase III), F1.2 ( 305 pmol/L Phase 2b; 401.8 pmol/L Phase III) and AT ( 72.8 %, Phase 2b; 50.3% ,Phase III). There was a difference noted in the markers of thrombin generation between the two studies. The TAT and F1.2 were higher and the AT was lower in the Phase III study suggesting a higher generation of thrombin in this study. Therefore the strict criteria used in the Phase III study shows that this patient group had more activation of coagulation compared to the Phase 2b patients. Furthermore the modified criterion used for the recruitment of patients in the phase III study provides a defined project population to investigate the therapeutic effects of ART-123. These observations also underscore the importance of inclusion criterion for sepsis associated coagulopathy patients to validate the therapeutic effects of newer drugs such as ART-123.