Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study

Abstract

Introduction: Cross-talk between the coagulation system and inflammatory reactions during sepsis causes organ damage followed by multiple organ dysfunction syndrome or even death. Therefore, anticoagulant therapies have been expected to be beneficial in the treatment of severe sepsis. Recombinant human soluble thrombomodulin (rhTM) binds to thrombin to inactivate coagulation, and the thrombin-rhTM complex activates protein C to produce activated protein C. The purpose of this study was to examine the efficacy of rhTM for treating patients with sepsis-induced disseminated intravascular coagulation (DIC).

Methods: This study comprised 65 patients with sepsis-induced DIC who required ventilatory management. All patients fulfilled the criteria of severe sepsis and the International Society on Thrombosis and Haemostasis criteria for overt DIC. The initial 45 patients were treated without rhTM (control group), and the following 20 consecutive patients were treated with rhTM (0.06 mg/kg/day) for six days (rhTM group). The primary outcome measure was 28-day mortality. Stepwise multivariate Cox regression analysis was used to assess which independent variables were associated with mortality. Comparisons of Sequential Organ Failure Assessment (SOFA) score on sequential days between the two groups were analyzed by repeated measures analysis of variance.

Results: Cox regression analysis showed 28-day mortality to be significantly lower in the rhTM group than in the control group (adjusted hazard ratio, 0.303; 95% confidence interval, 0.106 to 0.871; P = 0.027). SOFA score in the rhTM group decreased significantly in comparison with that in the control group (P = 0.028). In the post hoc test, SOFA score decreased rapidly in the rhTM group compared with that in the control group on day 1 (P < 0.05).

Conclusions: We found that rhTM administration may improve organ dysfunction in patients with sepsis-induced DIC. Further clinical investigations are necessary to evaluate the effect of rhTM on the pathophysiology of sepsis-induced DIC.

Figure 1

Patient flow diagram. rhTM, recombinant human soluble thrombomodulin; DIC, disseminated intravascular coagulation.

Figure 2

Adjusted estimated survival curves by covariates of APACHE II score and sex in final multivariate Cox regression models. The solid line represents patients in the rhTM group, and the dotted line represents patients in the control group. Treatment with rhTM was associated with a significantly higher rate of survival (P = 0.027 by stratified Cox regression analysis). APACHE II, Acute Physiology and Chronic Health Evaluation II; rhTM, recombinant human soluble thrombomodulin.

Figure 3

Serial changes from baseline in SOFA score in the two groups. Data are expressed as group means ± standard error of the mean. SOFA score decreased over time in both groups (P = 0.016). The degree of decrease in SOFA score was significantly greater in the rhTM group than in the control group (P = 0.028). There was no interaction between treatment and time (P = 0.192). The last-observation-carried-forward method of imputation was used for missing data. The imputation was accomplished in a total of 13 values in four patients for the rhTM group and in a total of 83 values in 27 patients for the control group. *P < 0.05 compared to the control group. †P < 0.05 compared to baseline. SOFA, Sequential Organ Failure Assessment; rhTM, recombinant human soluble thrombomodulin.

Figure 4

Serial changes from baseline in levels of CRP in the two groups. Data are expressed as group means ± standard error of the mean. CRP level decreased over time in both groups (P < 0.001). Although CRP level in the rhTM group tended to decrease more than that in the control group, the decrease did not reach statistical significance (P = 0.144). There was no interaction between treatment and time (P = 0.812). The last-observation-carried-forward method of imputation was used for missing data. The imputation was accomplished in a total of six values in one patient for the rhTM group and in a total of 51 values in 12 patients for the control group. †P < 0.05 compared to baseline. CRP, C-reactive protein; rhTM, recombinant human soluble thrombomodulin.

Figure 5

Serial changes from baseline in platelet counts in the two groups. Data are expressed as group means ± standard error of the mean. Platelet counts increased over time in both groups (P < 0.001). Although the changes in platelet counts between the two groups were not significant (P = 0.509), the interaction between treatment and time was statistically significant (P = 0.040). The last-observation-carried-forward method of imputation was used for missing data. The imputation was accomplished in a total of six values in one patient for the rhTM group and in a total of 51 values in 12 patients for the control group. †P < 0.05 compared to baseline. PLT, platelets; rhTM, recombinant human soluble thrombomodulin.

Figure 6

Serial changes from baseline in levels of FDP in the two groups. Data are expressed as group means ± standard error of the mean. The degree of decrease in FDP level was significantly greater in the rhTM group than in the control group (P = 0.017). The decrease of FDP level over time and the interaction between treatment and time were not significant (P = 0.844 and P = 0.525, respectively), probably because of small sample size and considerable variation. Because we included in our analysis only patients for whom baseline values and subsequent values were recorded, only 23 of 45 patients were included in the control group. The last-observation-carried-forward method of imputation was used for missing data. The imputation was accomplished in a total of one value in one patient for the rhTM group and in a total of 12 values in 12 patients for the control group. *P < 0.05 compared to the control group. FDP, fibrinogen degradation products; rhTM, recombinant human soluble thrombomodulin.