Abstract
BackgroundThrombomodulin 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.MethodsFrom 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.ResultsThe 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%).ConclusionOur results suggest that TM-α is most effective for treating patients with sepsis-induced DIC when administered within the first 3 days after diagnosis.
Highlights
Thrombomodulin alfa (TM-α, recombinant thrombomodulin) significantly improved disseminated intravascular coagulation (DIC) when compared with heparin therapy in a phase III study
In addition to its anticoagulant properties, TM has an anti-inflammatory effect through the generation of activated protein C (APC), and more, directly regulates high mobility group box-1 (HMGB-1) [5] and endotoxin [6] through the lectin-like domain, independent of protein C activation
In response to requests for methods to improve the early diagnosis of DIC accompanying infections in the fields of emergency and ICU care, the Japanese Association for Acute Medicine (JAAM) DIC criteria aimed at achieving early diagnosis were announced in 2006 by the DIC Special Committees [10]
Summary
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. In severe sepsis, disseminated intravascular coagulation (DIC) occurs in about 35% of patients [1]. Thrombomodulin (TM) is a thrombin receptor on the endothelial cell surface that plays an important role in the regulation of intravascular coagulation [4]. TM acts as a negative feedback regulator according to the amount of excessively generated thrombin. In addition to its anticoagulant properties, TM has an anti-inflammatory effect through the generation of APC, and more, directly regulates high mobility group box-1 (HMGB-1) [5] and endotoxin [6] through the lectin-like domain, independent of protein C activation
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