Abstract
Background: Early treatment of disseminated intravascular coagulation (DIC) can be associated with improved early outcomes. We aimed to evaluate the effectiveness of recombinant human soluble thrombomodulin (rTM) administration in patients with peritonitis-induced DIC. Patients and Methods: We treated 39 patients with DIC or pre-DIC caused by peritonitis at the Department of Surgery and Science, Kyushu University, and related facilities between January and December 2013. Results: Patients surviving to 28 days after DIC treatment had significantly better platelet counts, DIC scores, and sequential organ failure assessment scores at 7 days than did those who died earlier than 28 days. Patients receiving rTM had significantly better overall survival rates at 28 days and the results of multivariate analysis showed that rTM administration for DIC treatment was a prognostic indicator of 28-day survival in patients with peritonitis. Conclusion: rTM administration for the treatment of DIC or pre-DIC complicated by peritonitis had acceptable early outcomes.
Disseminated intravascular coagulation (DIC) is a clinical entity characterized by the systemic activation of coagulation pathways, which leads to fibrin deposition in microvessels and inflammatory reactions. Consumption of platelets and coagulation factors causes clinical bleeding and, with enhanced fibrinolysis, results in organ failure (1, 2). DIC is associated with high mortality in patients with severe sepsis and the clinical course can be rapid and severe (3). Therefore, both early diagnosis and early treatment are required to improve outcomes.
Peritonitis due to gastrointestinal tract perforation or anastomotic leakage after gastrointestinal surgery is a frequent indication for emergency operation and when complicated by DIC, carries a poor prognosis in severe cases (4). However, there have been few reports focusing on DIC treatment in patients with peritonitis.
The novel biological agent, recombinant human soluble thrombomodulin (rTM) was recently approved and has been used clinically for DIC treatment in Japan. rTM is effective in treating DIC (5, 6). Our aim was to clarify the efficacy of rTM administration in patients with peritonitis-induced DIC.
Patients and Methods
We analyzed the records of 100 patients who were diagnosed with DIC or pre-DIC requiring the same treatment as the patients with DIC at the Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, and 15 related facilities between January and December 2013. This retrospective and multicenter study was approved by the Ethics Committees of each hospital (no.25-318) and followed the guidelines of the Declaration of Helsinki. Informed consent was obtained from all patients for use of the details of their records. Of the 100 patients, we retrospectively analyzed data for 39 patients with peritonitis-induced DIC or pre-DIC.
DIC was evaluated using the diagnostic criteria of the Japanese Association for Acute Medicine (JAAM) DIC scoring system. DIC was diagnosed when the DIC score exceeded four points. Patients with pre-DIC were defined as those having a score of ≤ 3 points, but requiring the same treatment as the patients with DIC. The specific identical treatment for DIC and pre-DIC depended on each facility's protocols, as well as those for treating peritonitis. We administered rTM at a dose of 380 U/kg (5). We excluded patients with active life-threatening bleeding resulting in shock and evaluated treatment outcomes according to the overall survival rate at 28 days after initiation of the DIC treatment. We classified patients based on whether they survived to 28 days and whether they received rTM.
Comparison of clinical characteristics of peritonitis in survivors vs. non-survivors 28 days after treatment for disseminated intravascular coagulation (DIC). Values are expressed as number (percentage) or median (range).
Comparison of the clinical characteristics of peritonitis in patients with or without recombinant human soluble thrombomodulin (rTM) administration. Values are expressed as number (percentage) or median (range).
Multivariate analysis for overall survival in patients with peritonitis.
Continuous variables without normal distribution were compared using non-parametric tests and categorical variables were compared using Fisher's exact test. The overall survival rate was calculated using the Kaplan–Meier estimator and compared using the log-rank test, and multivariate analysis was performed using the Cox's proportional hazards model. Differences were considered significant at p<0.05 and all statistical analyses were performed using the JMP software (SAS Institute, NC, USA).
Overall survival curve after initiation of disseminated intravascular coagulation treatment in patients with peritonitis.
Results
Comparison of the clinical and laboratory data between survivors and non-survivors at 28 days after DIC treatment. As shown in Table I, patients surviving at 28 days after treatment for peritonitis-induced DIC or pre-DIC had significantly better platelet counts, DIC scores, and sequential organ failure assessment (SOFA) scores at 7 days than did the non-survivors. Factors at the initiation of DIC treatment did not differ significantly between the two groups.
Comparisons of the clinical and laboratory data between patients with and without rTM administration for DIC treatment. Patients receiving rTM were significantly older and had better platelet counts and SOFA scores 7 days after treatment for peritonitis-induced DIC or pre-DIC than did patients without rTM and they also tended to have a lower 7-day mortality rate (Table II).
Overall survival in patients with peritonitis. The overall survival rate 28 days after initiation of the DIC treatment in patients with peritonitis was 71.8%, and 28 out of the 39 patients were alive after the 28-day observation period (Figure 1).
Survival curves for patients with versus those without rTM administration was significantly better (Figure 2). Multivariate analysis using the Cox's proportional hazards regression model including pretreatment factors identified that rTM administration was an independent prognostic factor (Table III).
Comparison of overall survival curves after initiation of treatment for peritonitis-induced disseminated intravascular coagulation(DIC) or pre-DIC comparing patients administered recombinant human soluble thrombomodulin (rTM) versus those without. The survival rate of patients treated with rTM was significantly higher than those not receiving rTM (p=0.039).
Discussion
Our results showed that rTM administration improved the platelet count and SOFA score at 7 days after DIC treatment and carried a better prognosis than no rTM administration for patients with peritonitis-induced DIC or pre-DIC. rTM administration was also an independent predictor of 28-day survival. To our knowledge, ours is the first clinical study of the effect of rTM administration in patients with peritonitis-induced DIC or pre-DIC.
Early treatment for DIC can be associated with improved outcomes. Approximately 43% (16/39) of patients in our study were classified as pre-DIC status; however, the number of patients who fulfilled the JAAM criteria (DIC score ≥4), SOFA score, cause of peritonitis, location, blood data, and initiation of another DIC treatment at baseline status was not significantly different between those treatise with and without rTM administration, despite the small sample size. Therefore, we believe comparisons between the two groups were valid.
TM is a transmembrane glycoprotein expressed predominately on the luminal surface of endothelial cells lining normal blood vessels that are in constant contact with blood under physiological conditions. TM can bind to activated thrombin, disabling its ability to activate platelets and cleave fibrinogen. The TM–thrombin complex also cleaves protein C to activated protein C, which in turn degrades factor Va and factor VIIIa, preventing further thrombin generation. Exposure of endothelial cells to inflammatory cytokines results in down-regulation of TM and increased thrombogenicity, which could contribute to the development of DIC with concurrent infection (7). In animal studies, rTM administration was effective in the treatment of sepsis. rTM inhibited secretion of cytokines and high-mobility group box 1 protein (8) and the anti-inflammatory action peculiar to these proteins is a reason why rTM is expected to be useful in controlling the inflammatory reaction in peritonitis.
In this study, the SOFA score 7 days after DIC treatment in surviving patients was higher than that of non-surviving patients, and the 7-day SOFA score in patients with rTM administration improved compared with that in patients who did not receive rTM. Yamakawa et al. showed that rTM significantly reduced the SOFA score compared to the control group, and 28-day mortality improved significantly (9). Therefore, the 7-day SOFA score might be influenced by the systemic anti-inflammatory action of rTM. These results indicate that rTM may have a protective effect on organ injury complicated by peritonitis-induced DIC or pre-DIC.
Cox regression analysis indicated that 28-day mortality in patients with rTM administration improved significantly compared with that in patients without rTM, although our study sample size was small. It is thought that rTM affects the treatment not only of overt DIC, as diagnosed by the JAAM criteria (DIC score ≥4), but also of pre-DIC (DIC score <3), complicated by peritonitis.
Despite our encouraging results, there are several limitations to our study. The first is a lack of statistical power given the small sample size, especially for patients without rTM administration. The second is the variability in DIC treatment protocols and selection criteria at each institution. These limitations will need to be addressed in future randomized control trials.
In conclusion, we found that rTM had a significant beneficial effect on 28-day mortality in patients with peritonitis-induced DIC or pre-DIC. Moreover, the SOFA score and platelet count 7 days after DIC treatment improved with rTM administration compared with no rTM administration. Further clinical investigations are necessary to evaluate the effect of rTM on the molecular mechanisms of peritonitis-induced DIC.
Acknowledgements
The Authors are indebted to the physicians and all the clinical study teams at the participating institutions. The following 16 surgical departments participated in the trial: Kyushu University, Tagawa Municipal Hospital, Saiseikai Fukuoka General Hospital, Iizuka Hospital, Saiseikai Karatsu Hospital, Oita Medical Center, Oita Prefectural Hospital, Oita Red Cross Hospital, Nakatsu Municipal Hospital, Fukuoka Higashi Medical Center, Saiseikai Yahata Hospital, Kyushu Central Hospital, Beppu Medical Center, Steel Memorial Yahata Hospital, Social Insurance Nakabaru Hospital, and Shin-Nakama Hospital.
Footnotes
Conflicts of Interest
The Authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
- Received February 25, 2016.
- Revision received April 11, 2016.
- Accepted April 12, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
