Background
Sepsis and septic shock remain the most common cause of death in critically ill patients [
1], and new therapeutic approaches are urgently needed. Ideal management of sepsis and septic shock remains controversial. Current evidence suggests that compliance with the Surviving Sepsis Campaign (SSC) guidelines is associated with decreased mortality [
2‐
4]. Furthermore, it has been reported recently that early lactate clearance has a lower mortality risk than early goal-directed therapy [
5].
Disseminated intravascular coagulation (DIC) is associated with high mortality in patients with sepsis [
6]. Excessive coagulation activation, inhibition of fibrinolysis, and consumption of coagulation inhibitors lead to a hypercoagulable state, resulting in fibrin deposition in microvessels and inflammatory reactions [
7]. Current management of DIC is primarily focused on treating any associated underlying medical condition, although use of supplemental clotting factors or platelets, or anticoagulant therapy may occasionally be required [
8]. In particular, therapeutic intervention directly against coagulation and inflammation for DIC associated with sepsis is effective [
9,
10], and it is generally accepted that early, aggressive treatment of the underlying disease is important. The revised Japanese Association for Acute Medicine (JAAM) criteria allows diagnosis of DIC in the earlier phase of disease than the overt DIC criteria published by the International Society on Thrombosis and Haemostasis (ISTH) [
11].
Recombinant human soluble thrombomodulin (rhTM) is the only agent for the treatment of DIC [
12]. rhTM was approved in 2008 and has been used clinically for DIC treatment in Japan. Several animal studies have demonstrated a reduction in mortality with the administration of rhTM in sepsis models [
13]. Moreover, rhTM prevents endotoxin-induced lung injury in rats by leukocyte activation [
14]. Multicenter retrospective study and meta-analysis have shown that rhTM improves mortality in sepsis patients [
15,
16]. Yamakawa et al. shown that rhTM improves coagulopathy and decreases SOFA score compared with control group in patients with sepsis [
17].
We hypothesized that mortality would be improved after treatment with rhTM in septic patients especially for mild coagulopathy. Therefore, the purpose of this study was to evaluate the efficacy of rhTM for patients with mild coagulopathy compared with those with severe coagulopathy.
Discussion
Although several trials have shown that rhTM reduced mortality in septic patients with DIC [
13,
14,
17], the timing of treatment initiation was unclear. The present study represents the first attempt to evaluate efficacy of rhTM in septic patients with different degree of coagulopathy. This study suggested that treatment with rhTM in septic patients with severe coagulopathy improves mortality compared with those without severe coagulopathy.
The present study included 69 patients with sepsis. There was no difference in baseline characteristics except coagulation tests between severe coagulopathy group and mild coagulopathy group. Platelet count was significantly lower and D-dimer level was significantly higher in the severe coagulopathy group than mild coagulopathy group. The sensitivity of a low fibrinogen level for the diagnosis of DIC according to ISTH criteria was 28% and hypofibrinogenemia has been detected in only severe cases of DIC [
8]. Fibrinogen levels were normal in most of patients in the present study. Therefore, fibrinogen levels showed no significant differences between the two groups. PT ratio was improved significantly in the severe coagulopathy group at day 7. There was significant reduction of SOFA score in severe coagulopathy group within 7 days compared with baseline. Furthermore, at day 7 and 28, the score was trends in lower of the severe coagulopathy group, as compared with mild coagulopathy group. On the other hand, there was no significant reduction of SOFA score in the mild coagulopathy group compared with baseline.
Severe coagulopathy is associated with high mortality in patients with sepsis. Patients with severe coagulopathy had higher mortality than those with mild coagulopathy [
6,
23]. The phase II study shown that rhTM trend toward to improve mortality compared with placebo in patients with sepsis [
24]. The majority of patients included in the study were not severe coagulopathy state (ISTH DIC score < 5). It was considered in the study that rhTM may be more beneficial for subjects with greater coagulation abnormality. Multicenter retrospective study has shown that rhTM improved mortality significantly [
16]. Yoshimura et al. reported that rhTM improves mortality in high risk septic patients (APACHEII 24–29). On the other hand, rhTM did not improve mortality in moderate risk of septic patients (APACHE II score < 24) [
25]. Moreover ISTH score was significantly higher in high risk and very high risk of septic patients compared with moderate risk of septic patients. In addition, the patients included in this study were high risk of septic patients (APACHE II score; 27.1 ± 8.1 and 29.4 ± 11.0).
Generally, it is difficult to determine the survival benefit of a particular lifesaving therapy in a set of patients with a low risk of mortality. This may be one of the reasons why thTM administration does not reduce the mortality risk in patients who are not at high risk in the first place. On the other hand, these results are congruent with recent pathophysiological findings concerning the innate immune response. Under certain circumstances, thrombosis is considered to play a major physiological role, which is specifically named immunothrombosis, in immune defense [
26]. However, aberrant of uncontrolled activation of immunothrombosis is likely to constitute a key event in the development of thrombotic disorders [
27]. In patients in the mild coagulopathy state, rhTM could have inhibited host-defensive thrombosis, which suppress to capture and ensnare pathogens circulating in the blood, and therefore failed to improve mortality. In contrast, immunothrombosis could have been aberrantly activated and proved detrimental to the host in patients in the severe coagulopathy state, which may have improved mortality. SOFA score was trends in lower of the severe coagulopathy group, as compared with mild coagulopathy group. It is considered that rhTM may improve organ dysfunction by improving severe coagulopathy. Furthermore, respiratory component of the SOFA score was significant reduction in the severe coagulopathy group than mild coagulopathy group in the present study.
Several studies have shown that rhTM improves coagulopathy in disseminated intravascular coagulation [
28,
29].
Yamakawa et al. showed that rhTM improves coagulopathy, mortality and SOFA score compared with control group [
17]. It was discussed in the study that suppressing the hypercoagulative state by rhTM administration may potentially prevent the progression to multiple organ failure. rhTM has the effect of directly combining with thrombin. Thrombin – rhTM complex activates protein C. Therefore the anticoagulative effect of rhTM depends on the amount of thrombin available. The subgroup analysis of PROWESS trial has shown that activated protein C improves respiratory dysfunction in patients with sepsis [
30]. Moreover, Ogawa et al., reported the respiratory component of the SOFA score reduced significantly in patients with DIC who treated by rhTM compared with placebo [
31]. The results of this study indicate that respiratory component of the SOFA score was more reduced in the severe coagulopathy group than the mild coagulopathy group. rhTM was considered to improve respiratory dysfunction by more activating protein C in severe coagulopathy state than mild coagulopathy state. Therefore, administrating rhTM might more improve not only coagulopathy but also respiratory dysfunction in patients with severe coagulopathy compared with those without rhTM. We considered that there might be relation among SOFA score and mortality, SOFA score was not selected as covariate for mortality in current study. We considered reason of above was because of small sample size.
We acknowledge several limitations of our observational study design. First, this study was retrospective small scale trial. Second, this study is not a randomized placebo controlled trial. Multiple unmeasured variables might account for the outcome differences observed in this study. Third, this study was carried out in a single institution. Further multicenter, prospective randomized trials are needed to thoroughly evaluate the effects of rhTM on the treatment of septic patients with coagulopathy.