A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis

Abstract

Introduction: To test the hypothesis that the administration of antithrombin concentrate improves disseminated intravascular coagulation (DIC), resulting in recovery from DIC and better outcomes in patients with sepsis, we conducted a prospective, randomized controlled multicenter trial at 13 critical care centers in tertiary care hospitals.

Methods: We enrolled 60 DIC patients with sepsis and antithrombin levels of 50 to 80% in this study. The participating patients were randomly assigned to an antithrombin arm receiving antithrombin at a dose of 30 IU/kg per day for three days or a control arm treated with no intervention. The primary efficacy end point was recovery from DIC on day 3. The analysis was conducted with an intention-to-treat approach. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) scoring system. The systemic inflammatory response syndrome (SIRS) score, platelet count and global markers of coagulation and fibrinolysis were measured on day 0 and day 3.

Results: Antithrombin treatment resulted in significantly decreased DIC scores and better recovery rates from DIC compared with those observed in the control group on day 3. The incidence of minor bleeding complications did not increase, and no major bleeding related to antithrombin treatment was observed. The platelet count significantly increased; however, antithrombin did not influence the sequential organ failure assessment (SOFA) score or markers of coagulation and fibrinolysis on day 3.

Conclusions: Moderate doses of antithrombin improve DIC scores, thereby increasing the recovery rate from DIC without any risk of bleeding in DIC patients with sepsis.

Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000882.

Figure 1

Effects of antithrombin administration on the antithrombin levels. Significant differences were observed in the time course of the antithrombin levels between the control and antithrombin groups. Black circles, antithrombin (n = 29); white squares, control (n = 25). The results are presented as the mean ± standard deviation (SD).

Figure 2

Effects of antithrombin administration on the International Society on Thrombosis and Haemostasis (ISTH) (top) and Japanese Association for Acute Medicine (JAAM) (bottom) disseminated intravascular coagulation (DIC) scores. Antithrombin treatment resulted in significant decreases in both DIC scores. Black circles, antithrombin (n = 30); white squares, control (n = 28). The results are presented as the mean ± standard deviation (SD).

Figure 3

Disseminated intravascular coagulation (DIC) recovery rates on day 3 after antithrombin treatment. Antithrombin treatment resulted in recovery from DIC significantly more frequently than that observed in the control group. The recovery rate was almost double that of the control group. The results are presented as the mean ± standard deviation (SD).

Figure 4

The Kaplan-Meier survival plots for the 30 patients in the control group (squares) and 30 patients treated with antithrombin (circles).