Understanding the pathophysiology of sepsis appears to be an unending task. Mounting evidence points to a role of ADAMTS13 deficiency in inducing massive microvascular thrombosis, with consequent tissue ischemia and organ dysfunction in sepsis.

The main message given in present study is that ADAMTS13 could play a role in pediatric sepsis severity, development of organ dysfunctions, and mortality. ADAMTS13 is, therefore, important for better understanding, and potentially reversing, sepsis pathophysiology. Moreover, if its role is established, ADAMTS13 could be utilized for guiding sepsis management so that a patient with lower ADAMTS13 levels would need closer monitoring and more aggressive treatment.

Consistent with previous pediatric [11, 12] and adult [20] studies, we found that ADAMTS13 level was significantly lower among septic children compared with healthy controls, suggesting a role for ADAMTS13 in sepsis pathophysiology and a potential for being utilized as a diagnostic biomarker for sepsis. However, the latter issue was ignored by previous literature in favor of ADAMTS13 prognostic value.

We have also shown that ADAMTS13 is associated with illness severity as it was significantly lower among patients with septic shock and those with severe sepsis compared with those having sepsis, although the number of patients in the former two groups was low. In comparison, another pediatric study found that ADAMTS13 level was significantly lower in septic shock compared with both sepsis and severe sepsis [11]. On the other hand, we did not find a significant difference in ADAMTS13 level between severe sepsis and septic shock, while previous adult studies yielded conflicting findings [20, 21].

As expected from its biological action, ADAMTS13, in the present study, was significantly lower among patients with MODS and had negative correlation with the organ dysfunction score, pSOFA. Similarly, other studies demonstrated correlations of ADAMTS13 with other adult and pediatric organ dysfunction scores like Pediatric Logistic Organ Dysfunction (PELOD) score [10, 11, 21].

Of note, correlation of ADAMTS13 with pSOFA score on admission was only moderate in our study, implying that ADAMTS13 is not the only determinant of organ dysfunction. It is also possible that consequences of ADAMTS13 deficiency take some time to develop, as suggested by our observation that admission ADAMTS13 level was slightly more accurate in predicting MODS on day3 than on day1, so ADAMTS13 deficiency could serve as a red flag in sepsis.

Unlike its global association with organ dysfunction, ADAMTS13, in the present study, was specifically associated only with respiratory and cardiovascular dysfunction indicators, including mechanical ventilation and vasoactive medication use; vasoactive infusion days; and vasoactive-inotropic score.

Conversely, ADAMTS13 was not correlated with serum creatinine, while previous adult studies gave conflicting findings [20, 22]. Likewise, we failed to find correlation between ADAMTS13 and alanine aminotransferase (ALT) or serum albumin, although liver is the major source of ADAMTS13 production. This is consistent with a previous adult study [22], and suggests that decreased ADAMTS13 synthesis is less important than other mechanisms causing its deficiency in the setting of sepsis.

Similarly, we found no correlation between ADAMTS13 and platelet count, possibly because thrombocytopenia in sepsis arises not only from platelet consumption but from other mechanisms like immune-mediated platelet destruction, platelet sequestration in liver, drug-induced thrombocytopenia, and hemodilution [23]. However, previous studies divided over the correlation of ADAMTS13 with platelet count; some confirmed it [10, 21, 24], while others did not [20, 22].

The above-mentioned discrepancies among studies might arise from differences in sample size (most studies were small), sepsis etiology, or illness severity. Moreover, ADAMTS13 measurement was inconsistent ("antigen", "activity", or both) although ADAMTS13 activity may decrease without concomitant decrease in antigen due to inactivation by various inhibitors [22]. What is more, ADAMTS13 activity is under genetic influences e.g. a single nucleotide polymorphism in ADAMTS13 gene results in a transition of Pro 475 to Ser, with lower ADAMTS13 activity [20, 25].

Organ dysfunction portends death, and this was the case in our study where ADAMTS13 was independent predictor of mortality. This finding is consistent with some adult [21] and pediatric [11] studies, although others failed to replicate this association [12, 20, 24]. These studies are generally small and none can provide conclusive evidence alone.

Additionally, ADAMTS13 was negatively correlated with PIM2 score, which is consistent with previous adult [21] and pediatric [10, 11] studies showing correlations with other mortality predictive scores like Pediatric Risk of Mortality.

The ability of ADAMTS13 to predict mortality in our study was fair, with an AUC of 0.77, which was equal to that reported by another study [11]. This moderate performance is plausible; certainly, there is a role for other molecules involved in coagulation and other factors having direct impact on organ function, including hypoxia, acidosis, toxins, electrolyte imbalance, and metabolic abnormalities.

Importantly, it is oversimplification to assume that lower ADAMTS13 activity leads inevitably to clinical consequences. In fact, there is a role for factors causing endothelial injury. In one study, complete lack of ADAMTS13 in mice produced a pro-thrombotic state but was not sufficient alone to cause TTP except after injection of collagen and epinephrine [26]. Other endogenous molecules can enhance or inhibit thrombosis. For instance, during inflammation, high-density lipoprotein, which possesses antithrombotic properties, decreases while low-density lipoprotein, which possesses pro-thrombotic properties, increases [6]. Consequently, thrombosis is the net effect of many endogenous and exogenous factors, rather than ADAMTS13 alone.

Association of ADAMTS13 with prognosis has therapeutic implications. Recombinant ADAMTS13 could be a future strategy for patients with sepsis and ADAMTS13 deficiency [27]. It is also possible to target ADAMTS13 inhibitors, like IL-6, by such medications as Tocilizumab. Nonetheless, ADAMTS13-based therapies are not entirely experimental; the commonly available antiplatelet agents, particularly aspirin, reduced sepsis-associated mortality in adults according to a recent met-analysis [28]. Of note, antiplatelets not only inhibit thrombus formation but also dampen inflammation triggered by activated platelets [29].

A biological role for therapeutic plasma exchange (TPE) seems particularly plausible in children with sepsis and thrombocytopenia-associated multiple organ failure (TAMOF), in which disseminated microvascular thrombosis occurs. In TAMOF, TPE aims at removing ULVWF and ADAMTS13 inhibitors and restoring ADAMTS13 activity. However, because of limited evidence, the recent surviving sepsis campaign guidelines was not able to make a recommendation for or against TPE in TAMOF [30].

Noteworthy, we found that ADAMTS13 cutoff that discriminated septic from normal children was much higher than that which predicted organ dysfunction or mortality, suggesting that mild ADAMTS13 deficiency is well tolerated and that ADAMTS13-based therapies should be offered only to patients with severe deficiency who are more liable to complications.

Although those therapeutic lines are theoretically appealing, large randomized controlled trials (RCTs) are indispensable. It is prudent not to be too optimistic since the outcome of sepsis is the final product of intricate interplay of many pathways and molecules, with limited contribution of each to the whole scene. This makes it unlikely that benefits from any specific therapy, apart from antimicrobials, will be dramatic.

Overall, the present study adds a new evidence to the limited pediatric literature on the role ADAMTS13 plays in sepsis. Notwithstanding, it has some limitations: the sample size was small. However, prior sample size calculation predicted that a large patient or control group is not needed to demonstrate significant differences. Additionally, we did not compare ADAMTS13 between septic and non-septic critically ill children. Furthermore, we did not repeat ADAMTS13 measurement serially. Undoubtedly, analyzing ADAMTS13 in the subset of patients with sepsis who deteriorated to severe sepsis or septic shock would have shed more light on the role of ADAMTS13 but this was not possible for financial reasons and this can be the subject of future studies. Finally, the mortality rate in our study was high, which could be explained by the limited resources that precluded taking some necessary diagnostic and therapeutic measures. So, some of the current findings might not hold in other settings.