Although septic DIC is a disease with a poor prognosis [3-5], few drugs have been proven clinically effective for its treatment. TM alfa is weakly recommended in the Japanese guideline for sepsis 2020, and several reports have been published on the efficacy of TM alfa in septic DIC [15-18]. Furthermore, a recent meta-analysis has shown the benefit of TM alfa in septic DIC resolution and 28-days-all-cause mortality [8-9]. Therefore, TM alfa has become one of the options for septic DIC. However, some of the reports in the meta-analysis excluded patients with severe renal dysfunction [19-21], and the efficacy of TM alfa at a reduced dose of 0.02 mg/kg has not been properly addressed either. Therefore, in this study, we focused on the TM alfa dose and examined how it could affect clinical efficacy in patients with septic DIC.
In this study, a reduced TM alfa dose was identified as a factor associated with the resolution of septic DIC and 30-days-all-cause mortality. These results indicate that TM alfa should be administered at a dose of 0.06 mg/kg regardless of renal function to maintain effective plasma concentrations and achieve full efficacy. In recent years, certain studies reported on the relationship between TM alfa pharmacokinetics and its clinical effects. For example, TM alfa plasma concentrations were reportedly similar in patients with different renal functions (CCr < 10 mL/min vs 10 mL/min ≤ CCr < 30 mL/min vs 30 mL/min ≤ CCr < 60 mL/min vs 60 mL/min ≤ CCr) . In addition, TM alfa is a renal excretory drug, and the 24-hour urinary excretion rate correlates with CCr. Moreover, it has been pointed out that other metabolic processes, such as activated elastase-mediated degradation, might have a compensatory effect on the disappearance of TM alfa in patients with DIC and renal dysfunction [22,23]. Another study on a case of septic DIC with a TM alfa plasma concentration below 600 ng/mL reported that the decrease in the JAAM-DIC score from the baseline 4 days after TM alfa administration and the 90-day survival rate were significantly higher and lower, respectively . Therefore, the TM alfa dosage in patients with severe renal dysfunction might be important in improving the prognosis of patients with septic DIC.
In this study, the SOFA score was a proven independent factor associated with the resolution of DIC and 30-days-all-cause mortality. The SOFA score has been adopted as a diagnostic criterion for sepsis as an indicator of organ damage severity . In a previous study, the SOFA score was reportedly associated with the 28-day mortality in patients with DIC . Therefore, organ damage severity in patients with DIC could be related to prognosis. In addition, when patients with DIC were classified by the SOFA score, TM alfa reportedly improved the survival in a high-risk subset with a SOFA score of 13–17 . In addition to the high risk of death in patients with a high SOFA score, TM alfa might improve clinical outcomes. Therefore, the TM alfa dosage should be determined more carefully.
In this study, the most common sites of infection were the abdomen, lung, and urinary tract, respectively. Interestingly, in the Japanese Sepsis Registry study, the most common sites of infection causing sepsis were the lung, abdomen, and urinary tract, respectively . In a study of Japanese ICUs, the most common sites of infection causing sepsis were the lung, abdormen, and urinary tract, respectively . In an international study, respiratory, intra-abdominal, and bloodstream infections were the most common infectious sites in the ICU . In the present study, intra-abdominal infection was the most common, although the infected sites were similar to those in the previous studies of sepsis. This might be due to the fact that intra-abdominal infections have a higher risk of developing into DIC  since they are often subjected to stress due to surgery in addition to organ damage caused by infection. In the present study, pneumonia was associated with DIC resolution and 30-day all-cause mortality, indicating that pneumonia-associated DIC might be an independent factor in mortality regardless of the TM alfa dose. In the case of sepsis, pneumonia reportedly exhibited a higher in-hospital mortality rate than in the case of intra-abdominal and urinary tract infections . Moreover, a retrospective Japanese nationwide study  reported that TM alfa did not improve the 28-day mortality in pneumonia-associated DIC. The usefulness of TM alfa in the treatment of pneumonia-associated DIC needs to be further investigated.
In this study, the incidence of major bleeding was 1.0% (only one case of bleeding occurred in a patient with reduced dosage), and the overall incidence of bleeding was 12.7%. The background factors related to hemorrhagic complications were investigated but due to the insufficient number of patients, hemorrhage-associated factors could not be identified. In the previous TM alfa randomized controlled trials, no significant difference could be observed in the incidence of major bleeding compared with the placebo control [19,20]. In patients with renal dysfunction, the TM alfa blood concentration reportedly did not increase excessively even at normal doses due to the effect of other compensatory metabolic processes such as activated elastase-mediated degradation [12,22,23]. The TM alfa dose is not expected to be associated with hemorrhagic complications, although further studies would be required in this field.
No previous studies have reported how TM alfa, including its dosage, could affect clinical outcomes. In this study, we showed for the first time that the normal TM alfa dose in patients with severe renal dysfunction might be a factor that improves short-term clinical outcomes without increasing adverse bleeding events. However, this study also has several limitations. First, this was a single-center, retrospective study, and the influence of potential confounders cannot be ruled out.
Second, this study examined DIC resolution and 30-days-all-cause mortality but did not examine the long-term prognosis. In a retrospective study, it is difficult to determine the long-term prognosis in multiple cases, a prospective multicenter study would thus be recommended. Third, the present study did not sufficiently examine bleeding complications. TM alfa safety in patients with severe renal dysfunction has not been clarified, although it would be expected that a normal dose of TM alfa would not cause an excessive concentration increase. The relationship between TM alfa dose and hemorrhagic complications in patients with severe renal dysfunction needs further investigation.