Department of Critical and Intensive Care Medicine, Shiga University of Medical Science, Shiga, Japan ; The Japanese Society on Thrombosis and Hemostasis Post-Marketing Surveillance Committee for Recomodulin® Injection, Tokyo, Japan.
Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
J Intensive Care. 2014 Apr 30;2(1):30. doi: 10.1186/2052-0492-2-30. eCollection 2014.
Thrombomodulin alfa (TM-α, recombinant thrombomodulin) significantly improved disseminated intravascular coagulation (DIC) when compared with heparin therapy in a phase III study. Post-marketing surveillance of TM-α was performed to evaluate the effects and safety in patients with sepsis-induced DIC.
From May 2008 to April 2010, a total of 1,787 patients with sepsis-induced DIC treated with TM-α were registered. DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) criteria. The DIC resolution and survival rates on day 28 after the last TM-α administration, and changes in DIC, systemic inflammatory response syndrome (SIRS), and sequential organ failure assessment (SOFA) scores and coagulation and inflammation markers were evaluated.
The most frequent underlying disease was infectious focus-unknown sepsis (29.8%). The mean ± SD values of age, dose, and the duration of TM-α administration were 64.7 ± 20.3 years, 297.3 ± 111.4 U/kg/day, and 5.6 ± 3.4 days, respectively. A total of 1,320 subjects (73.9%) received combined administration with other anticoagulants. Both coagulation and inflammation markers, such as fibrin/fibrinogen degradation products, prothrombin time ratio, thrombin-antithrombin complex, and C-reactive protein, as well as JAAM DIC, SIRS, and SOFA scores, significantly and simultaneously decreased after TM-α administration (p < 0.001). DIC resolution and 28-day survival rates were 44.4% and 66.0%, respectively. The 28-day survival rate decreased significantly according to the duration of DIC before TM-α administration (p < 0.001). Total adverse drug reactions (ADRs), bleeding ADRs, and serious bleeding adverse events occurred in 126 (7.1%), 98 (5.5%), and 121 (6.8%) subjects, respectively. On day 28, after the last TM-α administration available for an antibody test, only one patient was positive for anti-TM-α antibodies (0.11%).
Our results suggest that TM-α is most effective for treating patients with sepsis-induced DIC when administered within the first 3 days after diagnosis.
在一项三期研究中，与肝素治疗相比，血栓调节蛋白α（TM-α，重组血栓调节蛋白）可显著改善弥漫性血管内凝血（DIC）。为评估 TM-α 在脓毒症诱导的 DIC 患者中的疗效和安全性，开展了 TM-α 的上市后监测。
2008 年 5 月至 2010 年 4 月，共登记了 1787 例接受 TM-α 治疗的脓毒症诱导的 DIC 患者。DIC 根据日本急性医学协会（JAAM）标准诊断。评估最后一次 TM-α 给药后第 28 天的 DIC 缓解率和生存率，以及 DIC、全身炎症反应综合征（SIRS）和序贯器官衰竭评估（SOFA）评分和凝血及炎症标志物的变化。
最常见的基础疾病为感染灶不明的脓毒症（29.8%）。年龄、剂量和 TM-α 给药时间的平均值分别为 64.7±20.3 岁、297.3±111.4 U/kg/天和 5.6±3.4 天。共 1320 例（73.9%）接受了其他抗凝剂的联合治疗。TM-α 给药后，凝血和炎症标志物（如纤维蛋白/纤维蛋白原降解产物、凝血酶原时间比值、凝血酶-抗凝血酶复合物和 C 反应蛋白）以及 JAAM DIC、SIRS 和 SOFA 评分均显著且同时降低（p<0.001）。DIC 缓解率和 28 天生存率分别为 44.4%和 66.0%。28 天生存率随 TM-α 给药前 DIC 持续时间的延长而显著降低（p<0.001）。总药物不良反应（ADR）、出血 ADR 和严重出血不良事件分别发生在 126（7.1%）、98（5.5%）和 121（6.8%）例患者中。在最后一次 TM-α 给药后第 28 天，进行抗体检测时，仅 1 例患者抗 TM-α 抗体阳性（0.11%）。
我们的结果表明，TM-α 对治疗诊断后 3 天内的脓毒症诱导的 DIC 患者最有效。
