Persistently Higher Serum sCD40L Levels Are Associated With Outcome in Septic Patients

Yingjian Liang; Chengrui Zhu; Yini Sun; Zhiliang Li; Liang Wang; Yina Liu; Xin Li; Xiaochun Ma


BMC Anesthesiol. 2021;21(26) 

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It can be concluded from this study that serum sCD40L levels in SS patients persistently increased significantly in the first 3 days after admission to the intensive care unit, and circulating sCD40L levels were increased on the second day of admission in the nonsurviving group compared with the surviving group. A novel finding of this study was that SWS patients also exhibited a slight increase in sCD40L, but the level was not as great as that noted in SS patients.

Several studies have reported that sCD40L levels can predict the prognosis of patients with sepsis.[8,11] In our study, we found that serum sCD40L levels ≥1028.75 pg/mL at day 2 were associated with a higher death risk during the 28-day period in the multiple logistic regression analysis. Serum sCD40L levels could be used as a 28-day mortality biomarker. However, we did not find a relationship between sCD40L levels and sepsis severity criteria, such as APACHE II score and SOFA score. We only observed higher lactatemia in nonsurviving compared with surviving SS patients at day 3 after admission. Serum blood samples were obtained at ICU admission, but APACHE II or SOFA scores were calculated 24 h after admission to the ICU. We were not sure if this time gap affects the association between the two variables.

sCD40L has a dual prothrombotic and proinflammatory role. sCD40L connects to circulating monocytes through its receptor CD40, promoting their adhesion to the vascular endothelium. sCD40L also binds to CD40 on endothelial cell surfaces. Studies have shown that sCD40L stimulates its own expression by interacting with CD40 on the surface of these cells.[12] In sepsis, EC activation induced adhesion receptors and released inflammatory mediators, such as interleukin (IL)-1, IL-6 and tumor necrosis factor.[13,14] sCD40L also affects the neutrophil oxidative burst and neutrophil extracellular trap.[5,15] Previous studies and our studies suggested that sCD40L exhibits no correlation with other coagulation factors except tissue factor (TF).[8] The main reason was that activated ECs initiate the exogenous coagulation pathway by upregulating TF and downregulating the expression of thrombomodulin,[16] favoring a local procoagulant status. In experimental models, sCD40L enhanced platelet activation and aggregation and induced thrombus formation.[17] All these effects contribute to the development of organ dysfunction and death.[18] After intraoperative operation, ECs were damaged, and the body produced a stress response and inflammatory factors.[19] Therefore, the sCD40L level was also increased after surgery in non-sepsis patients. In sepsis patients, EC damage, intravascular microthrombus formation and production of inflammatory factors are more obvious, and sCD40L levels are much higher than those in patients who undergo simple surgery.

We did not find an association between serum sCD40L levels and platelet counts, although 95% sCD40L was derived from platelets.[20] CD40L is stored in α-granules in unstimulated platelets, undergoes conformational changes during platelet activation, migrates to the surface of platelets and is released into the blood.[21] Soluble CD40L enhances platelet activation, aggregation, and platelet-leukocyte conjugation. Therefore, sCD40L was implicated in platelet activation.[12] By interacting with ECs, activated platelets play a key role in inflammatory and procoagulant responses to a pathogen.[22]

There were some limitations in our study. First, the sample size was relatively small. Second, the subjects were obtained from a single center. Third, we only determined sCD40L levels for 3 days after ICU admission but did not observe it for a week or longer; thus, we were unable to better conclude the time course of serum sCD40L levels in sepsis patients. Finally, an association between sCD40L levels and the activation function of platelets has been reported; we did not examine markers of platelet activation to analyze the relationship with sCD40L levels.