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

Abstract

IntroductionTo 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.MethodsWe 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.ResultsAntithrombin 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.ConclusionsModerate doses of antithrombin improve DIC scores, thereby increasing the recovery rate from DIC without any risk of bleeding in DIC patients with sepsis.Trial registrationUMIN Clinical Trials Registry (UMIN-CTR) UMIN000000882

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J‐SSCG 2016)

“…In addition, four Japanese and overseas studies395, 402, 403, 404 were analyzed. The treatment intervention was expected to be beneficial in terms of reduced mortality rate based on an RR of 0.68 (95% CI: 0.49–0.93), but bias risk/indirectness may lower the reliability of the effect estimate.…”

The coagulopathy of acute sepsis

“…Patients with DIC treated with antithrombin over 3 days had faster recovery determined by DIC scores and did not have increased bleeding events. [73] In a nonrandomized larger study, Iba determined that in patients with low baseline antithrombin activity and sepsis, high dose antithrombin therapy 3000 IU/day (AT3000) was associated with improved survival (AT1500 65.2%, AT3000 74.7%). [74] Importantly, these studies used DIC scoring systems to determine overt DIC and proper timing of anticoagulation therapy.…”

Exacerbation of prothrombin time-international normalized ratio before second polymyxin B cartridge hemoperfusion predicts poor outcome of patients with severe sepsis and/or septic shock

“…According to the results shown in Table 2, because the SOFA score, diastolic blood pressure, mean arterial pressure and systolic blood pressure were improved by PMX therapy in both groups, PT-INR is well known to be an important marker of disseminated intravascular coagulation (DIC) [16][17][18]. Because the relationship between DIC and SS is merely regarded as the two sides of the same coin [19], treatment for DIC and SS should be performed synchronously using not only anti-coagulant therapies [20] but also blood purification.…”

“…Comparison of 28-day mortality between groups (∆ 2nd-1st -PT-INR <0.16 and >0 16,. from top to bottom) of patients with severe sepsis and/or septic shock receiving two sessions of PMX.…”