Therapeutic and Adverse Effects of Thrombomodulin Alfa to Treat Sepsis-Induced Disseminated Intravascular Coagulation

Abstract

In the treatment of disseminated intravascular coagulation (DIC), which is a complication of underlying diseases such as infections and malignant tumors, effective plasma concentrations of thrombomodulin (TM) alfa range from 300 to 900 ng/mL; however, appropriate concentrations when treating sepsis-induced DIC are unknown. Thus, our aim was to determine the relationship between plasma concentrations of TM alfa and its therapeutic effects, and hemorrhagic adverse events. First, we calculated the plasma trough concentrations of TM alfa in septic DIC patients. Next, we divided patients into two groups according to their plasma concentrations into a low- and high-concentration group based on a cut-off value of 600 ng/mL. Fourteen and 35 patients were included in the low- and high-concentration groups, respectively. The Japanese Association for Acute Medicine DIC diagnostic criteria score 4 days after TM alfa administration decreased significantly by 2.06 points from baseline in the high-concentration group compared with 0.71 points in the low-concentration group. The 90-day survival rate was significantly higher in the high-concentration group (85.4%) than in the low-concentration group (49.0%) (hazard ratio, 0.27; 95% confidence interval: 0.09–0.86). In contrast, the incidence of serious hemorrhage was not significantly different between the groups. The recommended plasma concentration of TM alfa in the treatment of septic DIC was determined to be higher than 600 ng/mL, and a dose of 380 U/kg (0.06 mg/kg) was necessary to achieve this concentration.

Prognostic Factors in Patients with Septic Disseminated Intravascular Coagulation Treated with Thrombomodulin: The Effect of Reduced Thrombomodulin Dose; a Single-center, Retrospective, Observational Study

“…Renal replacement therapy was performed in 55 patients (53.9%). The median (interquartile range) SOFA score was 11 (9)(10)(11)(12)(13)(14), the median (interquartile range) JAAM-DIC score was 6 (5-7), and the median (interquartile range) SIRS criterion was 3 (2-4). Twenty-ve (24.5%) patients had intra-abdominal infection, 23 (22.5%) had pneumonia, and 17 (16.7%) had urinary tract infection.…”

“…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 signi cantly higher and lower, respectively [13]. Therefore, the TM alfa dosage in patients with severe renal dysfunction might be important in improving the prognosis of patients with septic DIC.…”

“…Therefore, the effective blood concentration might not be reached at a dose of 0.02 mg/kg of TM alfa in patients with renal dysfunction. Imaura et al reported a signi cantly higher 90-day survival rate in patients with plasma levels of TM alfa higher than 600 ng/mL [13]. Therefore, reaching an effective TM alfa plasma concentration seems to be important for improving clinical outcomes.…”

Prognostic factors in patients with septic disseminated intravascular coagulation treated with thrombomodulin: the effect of reduced thrombomodulin dose; a single-center, retrospective, observational study

“…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 [ 13 ]. Therefore, the TM alfa dosage in patients with severe renal dysfunction might be important in improving the prognosis of patients with septic DIC.…”

“…Therefore, the effective blood concentration might not be reached at a dose of 0.02 mg/kg of TM alfa in patients with renal dysfunction. Imaura et al reported a significantly higher 90-day survival rate in patients with plasma levels of TM alfa higher than 600 ng/mL [ 13 ]. Therefore, reaching an effective TM alfa plasma concentration seems to be important for improving clinical outcomes.…”