Performances of disseminated intravascular coagulation scoring systems in septic shock patients

Since the currently available disseminated intravascular coagulation (DIC) scoring systems are not easy to use at bedside and physicians are unfamiliar with these scores, Iba et al. recently published recommendations for diagnosis of sepsis-induced DIC [1]. In septic patients with thrombocytopenia, they indeed recommended the use of a two-step process with simple diagnostic criteria for sepsis-induced coagulopathy (prothrombin time, PT/International Normalized Ratio and platelets) plus a Sequential Organ Failure Assessment (SOFA) score (which is the sum of four items: respiratory SOFA, cardiovascular SOFA, hepatic SOFA, renal SOFA), called sepsis-induced coagulopathy (SIC) score, eventually followed by the International Society on Thrombosis and Haemostasis (ISTH) overt-DIC score if SIC score is positive.

There is indeed no gold standard score to clearly define what is DIC and how to diagnose it in septic shock patients, sometimes leading to DIC being referred as “Disseminated International Confusion” [2]. Several scoring systems may be used by critical care physicians, but they all suffer from imperfections. First, the available scores fail to diagnose early asymptomatic DIC, also called “pre-DIC” or “non-overt” stages (coagulation system is activated but compensated); these patients are, however, as severe as those diagnosed with a patent DIC on intensive care unit (ICU) admission, with the same mortality rate [3]. Then, these scores fail to discriminate between patients with a prothrombotic activation of the coagulation and those with hemorrhagic and fibrinolytic states. Treatment of DIC patients probably depends on its stage (thrombotic, hemorrhagic, fibrinolytic), therefore underlying the importance of a prior proper stratification of the patients. Third, the diagnosis performances of the scores are unequal depending on the underlying disease, like is the presentation of DIC in the different clinical conditions (e.g., thrombotic DIC induced by sepsis versus bleeding DIC induced by hematologic malignancies). Different DIC scores or diagnosis markers might therefore be necessary for diagnosis, depending on the pathophysiological underlying condition [4]. Finally, repeating multiple coagulation tests to screen patients is costly [5].

When comparing the main scoring systems, the Japanese Association for Acute Medicine JAAM-DIC criteria were suggested to be more sensitive than the ISTH ones and allow an earlier diagnosis compared to the ISTH score [5]. Consequently, the JAAM-DIC score is preferred for early DIC-specific anticoagulant treatment assignment [6]. Interestingly for sepsis, the JAAM-DIC score does not use the fibrinogen decrease as a criterion, and it takes into account the kinetics of platelet decrease. The JAAM-DIC score has been revised in 2016, in order to align the new definition of sepsis and replace systemic inflammatory response syndrome (SIRS) criterion by antithrombin rate [7]. In spite of these apparent advantages over ISTH overt-DIC score, the JAAM score has been evicted from the last recommendations on DIC diagnosis [1].

We have therefore compared the diagnostic properties and performances in terms of mortality prediction of the different principal scoring systems (the revised version of JAAM-DIC 2016 score, ISTH overt-DIC 2001 score, the association of SIC and JAAM-DIC 2016 scores, and the association SIC and ISTH overt-DIC 2001 scores) in a multicenter prospective cohort of patients admitted on ICU for septic shock.

The present study was performed in order to clarify DIC diagnosis global confusion in septic shock patients. Even if many scores are currently available, it has already been shown that they were not adequate for all diseases and when considering critically ill patients, the only score that has been validated is the JAAM 2006 one [11]. Yet, the identification of patients with septic shock-induced DIC who may benefit from anticoagulant therapy has become a major challenge in ICU [12, 13]. Indeed, if no specific treatment of DIC has proven its efficacy yet, an early diagnosis of DIC would allow the adequate stratification of septic shock patients according to their coagulation activation stage and their appropriate potential enrollment in future clinical trials, between those who might benefit from a specific treatment of coagulopathy and those who are likely not to benefit from it. Then, as we previously assessed, patients with a pre-DIC stage have the same mortality rate as those with patent DIC at ICU admission [3]. Clinical signs may also appear too late compared to the first signs of coagulation activation as shown in the present cohort to hope to improve the patients with a specific treatment, emphasizing the importance of biological scores to make early diagnosis of DIC.

Gando et al. wrote that “scoring systems are successful if clinicians can use them at the bedside, if they are readily available, and if they are easy to use” [11]. In the recommendations recently published [1], Iba et al. reviewed and highlighted the performances of SIC score to predict mortality. SIC score associates “readily available” biological values (platelets and INR) and SOFA score. SOFA score is a composite and complex clinical–biological score, including four items (respiratory SOFA, cardiovascular SOFA, hepatic SOFA, renal SOFA). It may be considered as easy to use at bedside, provided SOFA score is used as a binary score (< 2 or ≥ 2 points). In fact, as all septic shock patients have, by definition, a SOFA score greater than two points at ICU admission, this latter parameter probably does not add much in these patients. SIC would allow the detection of patients with “coagulopathy” who are at high-risk of developing DIC. SIC score was not supposed to be used alone, but combined with ISTH overt-DIC score if SIC score was positive. We have, however, shown that SIC score roughly detected all the patients (84.2%) admitted on ICU for septic shock as having “a coagulopathy”, therefore suggesting that the combination of [SIC and ISTH overt-DIC score if SIC was positive] could probably be simplified by [ISTH overt-DIC score alone]. One could indeed consider that all septic shock patients are at risk of developing DIC. Consistent with this proposal, the first validation study thus showed no advantage of SIC score over ISTH overt-DIC score in diagnosing sepsis associated DIC [14]. This impression of futility is emphasized by the perfect correlation of ISTH overt-DIC alone and its combination with SIC, as all the patients with an ISTH overt-DIC of 5 or more also had a SIC score of 4 or more, and the nearly perfect correlation of JAAM-DIC score alone and SIC combined with JAAM-DIC scores.

The JAAM 2006 score was suggested to be more sensitive than the ISTH overt-DIC score for DIC diagnosis, for example in trauma patients [15], and to allow earlier DIC diagnosis than the ISTH DIC score [5]. From a pathophysiological viewpoint, the JAAM-DIC score would be more suitable than the ISTH overt-DIC to diagnose DIC in septic patients, as it integrates the kinetics of platelet drop, higher D-dimer values and exclude fibrinogen which will remain at falsely normal or even higher levels until the late stage in acute inflammatory processes. Yet, we have shown a strong correlation between ISTH overt-DIC and JAAM-DIC scores {McHugh 2012 #2201}, suggesting that either score could be used for diagnosis of septic shock-induced DIC. When considering the delay for diagnosis, the JAAM-DIC score documented more patients as “DIC positive” than the ISTH overt-DIC one at any timepoint, suggesting that the difference between JAAM-DIC score and the ISTH overt-DIC is possibly more related to the threshold used to define DIC, as suggested by Dempfle et al. [16].

Patients diagnosed with DIC by current DIC scoring systems display an unfavorable clinical outcome, independently of the underlying disease [17]. In a first retrospective analysis of the nationwide survey for recombinant human soluble thrombomodulin, Iba et al. [18] showed that a SIC score of 4 points or more had a higher predictive value for 28-day mortality than the JAAM-DIC score. In this latter cohort, patients with a SIC score above 4 had a 28-day mortality rate of 38.4% and those with a score above 6 had a mortality rate over 45%. Our data show nearly the same mortality rate for a positive SIC score of > 4 points (37.2% at day 28), but higher VPP for ISTH overt-DIC and JAAM-DIC scores for mortality prediction.

Iba et al. [17] also showed that in septic patients with disseminated intravascular coagulation, delta SOFA, delta ISTH overt-DIC score, and delta JAAM-DIC score were correlated with 28-day mortality, with a better accuracy of delta SOFA than delta ISTH overt-DIC score (80.5 versus 66.7%, p < 0.001). In this study, the areas under the curve for mortality were 0.812 for delta SOFA, 0.655 for delta ISTH overt-DIC score, and 0.693 for delta JAAM-DIC score. The delta SOFA has therefore the strongest association with the 28-day mortality in patients with sepsis and DIC [17]. Yet, including points for a SOFA ≥ 2 in SIC score looks useless, as in our cohort, all septic shock patients have a SOFA ≥ 2 on ICU admission (11.0 ± 3.2 points), including patients who were included before the change of definition of sepsis and septic shock.

Our study has several strengths and some limitations. Among the strengths, we have enrolled a large and multicenter cohort of septic shock patients that were well characterized clinically. Then, data collection was prospective, therefore allowing a low rate of missing data. Finally, we have compared the main scores and their revised form, taking into account the recent recommendations for DIC diagnosis.

The main limitation of the study is that we do not have the gold standard comparator that could help assess the validity of other scores. Then we have not compared the performances of the aforementioned scores to the recently identified new diagnostic markers, like endothelial microvesicles, neutrophil fluorescence or the degree of NETs formation [3, 19‐21].

Overall, our data suggest that SIC score is probably not the simple and readily available score that will revolutionize DIC diagnosis. If JAAM-DIC and ISTH overt-DIC scores seem to be both usable in septic shock patients, future research should focus on the validation of early diagnosis tools of sepsis-induced DIC [13]. In the meantime, although JAAM-DIC and ISTH overt-DIC scores may look uneasy to use due to the weighting of items, simple electronic devices may help calculate these scores daily at bedside and one should therefore consider performing these scores regularly in patients at risk of developing DIC, like in septic shock patients.