The main finding of the present study is that serum sCD40L levels were independently associated with mortality at 30 days in a large series of septic patients.
We found higher serum sCD40L levels in patients with severe sepsis than in healthy controls, in agreement with previous studies [21, 22, 25]. We also found higher circulating sCD40L levels in non-surviving than in surviving patients, as previously reported by Nolan et al. in a small series . In addition, we found that serum sCD40L levels ≥3.50 ng/mL were associated with higher death during the 30-day period in the multiple logistic regression analysis. Impaired prognosis was previously reported in patients with acute coronary artery syndrome and higher sCD40L levels ; however, our study is the first reporting an impaired prognosis in patients with severe sepsis and higher sCD40L levels.
The role of sCD40L in sepsis remains unclear; but it is possible that there are similarities with findings observed in coronary artery disease . CD40L is stored in α-granules in unstimulated platelets but rapidly translocates to the platelet surface when platelets are activated, where it is cleaved and released into circulation as sCD40L. The sCD40L binds to circulating monocytes through its receptor CD40, promoting their adhesion to vascular endothelium. The sCD40L also binds to CD40 on endothelial cell surfaces. Activated endothelial cells produce the overexpression of transcriptional factors such as nuclear factor-kappa B (NF-kß) , with subsequent up-regulation of proinflammatory and prothrombotic factors. Thus, sCD40L could have prothrombotic effects via induction of TF [8–11], diminishing thrombomodulin expression [10, 11], and binding to the glycoprotein IIb/IIIa platelet receptor [12, 13]. All these effects could facilitate the development of vascular thrombosis, organ dysfunction and death.
We report for first time an association between sCD40L and TF levels in patients with severe sepsis, which has been previously described in culture of vascular endothelial cells [8–11]. However, the observed association between sCD40L levels and mortality could not been explained by the TF levels, since there were no significant differences between non-surviving and surviving patients. It is possible that other reported prothrombotic effects of sCD40L, such as reduced thrombomodulin expression [10, 11] and binding to the glycoprotein IIb/IIIa platelet receptor [12, 13] could lead to vascular thrombosis and, finally, death in patients with severe sepsis.
We found a positive association between serum sCD40L levels and platelet count, possibly because platelets are the major source of sCD40L in circulation [4, 5]. However, we did not find this association in thrombocytopenic patients, which may be explained by different underlying mechanisms in septic patients [33, 34], such as immune destruction by platelet antibodies, hematophagocytosis in the bone marrow, reduced production due to bone marrow depression and non-immune destruction by the interaction of activated platelets with endothelium.
We failed to find an association between sCD40L levels and sepsis severity criteria such as lactatemia, APACHE II score, SOFA score, TNF-α or IL-10 levels. This is in agreement with the results by Nolan et al.  reporting no correlation between sCD40L and the concentrations of IL-6, IL-12 or APACHE II. The lack of correlation may be due to a true absence of relationship or that sCD40L levels are underestimated in more severe disease (for example, dilution, leakage to the intersticial space and urin, increased uptake at sites of inflammation, and so on). In addition, sCD40L would most likely response earlier to changes in inflammatory activity that the APACHE, which is a composite of multiple parameters.
Whereas the strength of our study was the relatively large sample size compared with previous reports assessing sCD40L levels in septic patients, some limitations should be recognized. We determined a single testing point for sCD40L levels and we were, therefore, unable to establish the time course of serum sCD40L levels. Data on other coagulation factors were not analyzed. We determined sCD40 levels only in serum and not in plasma samples to evaluate possible differences due to there has been reported higher sCD40L levels in serum than in plasma levels , and in platelet rich plasma than in platelet poor plasma [36, 37]. There has been reporting the association between sCD40L levels and other cytokines as IL-12 or interferon-gamma; however, we have not explored this possible association [6, 38]. Neither, we have explored procalcitonin to determine its association with sCD40L levels. There are been reported an association between sCD40L levels and severity of acute coronary artery syndrome  and between troponin and severity of sepsis [39–41]; however, we have not investigated markers of cardiac damage to explore its association with sCD40L levels. The time until the diagnosis of sepsis can influence the levels of sCD40L observed; however, we have not report it. The serum blood samples for the determination of sCD40L were obtained at moment of sepsis diagnosis and APACHE II was calculated at 24 hours of admission to ICU; thus, we did know if this time-gap can affect in the association between both variables. We have not found significant difference in the survival at 30 days with the use of statins previously to the diagnosis of severe sepsis; and it was not possible to explore the effect of this agent group during the sepsis because in all patients was it suspended.
From a therapeutic perspective, the use of sCD40L modulators could be used as a new class of drugs for the treatment of severe sepsis [42–46]. In one study including patients with coronary artery disease, the use of statins decreased circulating sCD40L levels . Besides, the results of some studies suggest that the use of statins could improve the prognosis in patients with infectious episodes [43–46]. However, in some human and animal studies the use of antibody against CD40L was associated with platelet activation and thromboembolic complications [47–49].