Abstract
The use of antithrombin and thrombomodulin to restore impaired anticoagulant pathways in septic coagulopathy has been shown to significantly increase the resolution rate of disseminated intravascular coagulation. In KyberSept and SCARLET, two large, international, randomized controlled trials in patients with sepsis, these anticoagulants have not shown significantly reduced mortality. The aim of this assessment was to compare the heterogeneity in responses to treatment in the two trials according to different patient phenotypes. Results of the KyberSept and SCARLET trials reported in original and post-hoc publications were analyzed and directly compared for treatment effects in various patient subgroups. In both KyberSept and SCARLET, the septic coagulopathy phenotype that benefited most from endogenous anticoagulant supplementation showed markers of excessive activation of coagulation. Interaction between concomitant thromboprophylactic heparin and the endogenous anticoagulants abrogated the efficacy of both antithrombin and thrombomodulin. In both trials, higher disease severity was associated with better treatment outcome. In conclusion, in two landmark studies of endogenous anticoagulants in patients with sepsis, similar findings of beneficial effects in the coagulopathy phenotype and interactions with heparin comedication and disease severity support the potential roles that thrombomodulin and antithrombin might play in treating septic coagulopathy and disseminated intravascular coagulation. Further prospective validation is warranted. Future trial designs to definitively establish the therapeutic relevance of antithrombin and thrombomodulin in septic coagulopathy should focus on involvement of patients characterized by coagulopathy and disease severity as well as interactions between endogenous anticoagulants and exogenous heparin.