Sepsis is a common critical illness in intensive care units (ICU), characterized by a dysregulated host response to infection (Singer et al., 2016; Giamarellos-Bourboulis et al., 2024). A study indicated that the global mortality of sepsis patients is close to 20%, making it one of the major disease burdens on global health (Rudd et al., 2020). The main pathophysiological mechanism of sepsis involves the interaction between inflammation and coagulation (Ghasemzadeh and Hosseini, 2013). During sepsis, the coagulation system is activated at the site of infection (Engelmann and Massberg, 2013). Firstly, thrombin and thromboxane A2 (TXA2), two potent platelet activators, promote platelet activation by binding to protease-activated receptors (PAR) and TXA2 receptors, respectively (Engelmann and Massberg, 2013; Wang et al., 2018). Secondly, in the process of endothelial cell injury and apoptosis induced by sepsis, von Willebrand factor (vWF), expressed during these events, further enhances platelet activation and aggregation through glycoprotein receptors (GPVI and GPIbα--IX-V) on the platelet membrane (Engelmann and Massberg, 2013; Wang et al., 2018). This imbalance in the “platelets-inflammatory cell-endothelial cell” interaction plays a crucial role in the development of disseminated intravascular coagulation (DIC) and multiple organ dysfunction syndrome (MODS) (Wang et al., 2018). Therefore, by inhibiting platelet activation and reducing the interaction between “platelets-inflammatory cells-endothelial cells”, it may help block the “inflammation-coagulation cascade”, thereby reducing the consumption of platelets and coagulation factors. Additionally, platelets play a vital role in the activation, expansion, and regulation of inflammation (Eisen, 2012; Jung et al., 2012). Platelets also directly kill pathogens by releasing antimicrobial peptides, and enhance host antibacterial capacity by forming platelet-neutrophil extracellular traps (NETs) (Nicolai et al., 2024). Excessive platelet activation may lead to microthrombosis and instead impair tissue perfusion (Yang et al., 2023; Nicolai et al., 2024). Thus, aspirin may improve the immune balance at the site of infection by moderately inhibiting platelet function. Aspirin is the most widely used antiplatelet drug, and it also has anti-inflammatory and immunomodulatory effects (Montinari et al., 2019; Menter and Bresalier, 2023). In septic patients, the use of aspirin can improve their prognosis (Hsu et al., 2022; Chen et al., 2023; Lu et al., 2023; Dong et al., 2024). In addition to exerting antiplatelet and anti-inflammatory effects by inhibiting cyclooxygenase (COX-1 and COX-2), aspirin can also regulate the inflammatory response by inhibiting the NF-κb inflammatory pathway (Ornelas et al., 2017). Moreover, acetylsalicylic acid, a metabolite of aspirin, can inhibit High Mobility Group Box 1 (HMGB1), thereby suppressing the inflammatory response (Venereau et al., 2016). Therefore, aspirin has significant potential to improve the prognosis of infectious diseases by modulating inflammatory responses and coagulation functions.

The liver, a crucial lymphoid organ, is pivotal in regulating immune defense by clearing bacteria or toxins, producing acute-phase proteins or cytokines, and regulating inflammatory metabolism (Nesseler et al., 2012; Yan et al., 2014; Strnad et al., 2017). However, the immune response is a double-edged sword, as an excessive systemic inflammatory response may lead to liver injury (Nesseler et al., 2012; Yan et al., 2014; Strnad et al., 2017). The liver is also a target of sepsis-induced injury, including hypoxic hepatitis caused by shock or hypoxia, cholestasis resulting from dysregulated bile metabolism, hepatocellular damage from drug toxicity, and secondary sclerosing cholangitis (Strnad et al., 2017). Liver dysfunction caused by sepsis is an independent risk factor for multi-organ dysfunction and sepsis-induced mortality (Yan et al., 2014). Sepsis-associated liver injury (SALI) is characterized by INR >1.5, highlighting the critical role of coagulopathy in its pathology (Dellinger et al., 2013; Xie et al., 2022; Cui et al., 2023; Yi et al., 2024). Aspirin’s anti-inflammatory and antiplatelet properties can help reduce inflammation responses and the risk of DIC(Wang et al., 2018; Al-Husinat et al., 2023), which may play a positive role in modulating the inflammatory responses and coagulation function in SALI. Jiang et al. also found that aspirin can improve the prognosis of patients with SALI by regulating the homeodomain-interacting protein kinase 2 (HIPK2) (Jiang et al., 2018). Therefore, investigating the relationship between aspirin use and the prognosis of SALI patients is crucial, as it helps to elucidate its potential benefits in mitigating inflammatory responses and coagulation abnormalities. To this end, we conducted this study to explore the association between aspirin use and the prognosis of SALI patients.

In this study, we found that aspirin was significantly associated with 30-day mortality in patients with SALI, regardless of aspirin dose and timing. Previous studies reported that the mortality of SALI patients was approximately 29.3%–43.5% (Liu et al., 2022; Wen et al., 2024; Yi et al., 2024). Consistent with previous studies, our study found that the 30-day mortality of SALI patients was 33.3% (219/657), with 36.5% in the non-aspirin group and 26.7% in the aspirin group. The use of aspirin significantly improved the prognosis of SALI patients.

A population-based cohort study conducted by Hsu et al., with a median follow-up of 6.2 years involving 29,690 participants, found that aspirin use did not improve the long-term outcomes of sepsis patients (Hsu et al., 2018). Similar to the results of Hsu et al., another large randomized controlled trial conducted by Eisen et al. included 16,703 sepsis patients aged 70 years and older (Eisen et al., 2021). After a median follow-up of 4.6 years, the study results showed that, compared to the control group, patients receiving low-dose aspirin did not show lower mortality (HR, 1.08; 95%CI, 0.82–1.43; P = 0.57), but increased risk of gastrointestinal bleeding and hemorrhagic stroke. Therefore, Eisen et al. did not support the use of aspirin as a preventive measure for sepsis. However, Annane highlighted the following limitations in these two studies (Annane, 2021): First, both studies diagnosed sepsis using the Systemic Inflammatory Response Syndrome (SIRS) criteria, which lack precision and may have led to the exclusion of some sepsis patients and the inclusion of a considerable number of non-sepsis patients. Second, the follow-up duration might still have been too short to fully observe the long-term effects of aspirin on septic patients. Therefore, Annane believed that the potential impact of aspirin on the long-term outcomes of sepsis patients cannot be completely ruled out. Recent studies on aspirin and sepsis have suggested that the use of aspirin can reduce the 28-day, 60-day, 90-day, and 1-year mortality in sepsis patients with damage to various organs (Chen et al., 2023; Lu et al., 2023; Dong et al., 2024). However, our study only found that aspirin could reduce 30-day mortality and ICU mortality, indicating an effect on short-term outcomes in SALI patients. Trauer et al. conducted a meta-analysis of previous studies of aspirin intervention in sepsis and showed that aspirin reduced short-term mortality in septic patients (Trauer et al., 2017). Based on the above, there are significant differences in the effects of aspirin on outcomes in septic patients. Most previous studies have suggested that aspirin fails to improve long-term outcomes in these patients (Trauer et al., 2017; Hsu et al., 2018; Annane, 2021). However, some recent studies have presented an opposite view (Chen et al., 2023; Lu et al., 2023; Dong et al., 2024). Whether aspirin improves long-term outcomes in septic patients remains to be further explored. According to our findings, we believe that aspirin can improve short-term outcomes in septic patients, which is consistent with other findings. We believe that these differences may be related to the diagnostic methods of sepsis, the presence of concomitant organ failure, and the underlying comorbidities of the patients.

Different doses of aspirin have different pharmacological effects (Patrono and Baigent, 2019). Low-dose aspirin primarily inhibits COX-1 to exert an antiplatelet effect, while high-dose aspirin exerts both antiplatelet and anti-inflammatory effects by inhibiting COX-1, COX-2, and NF-κb inflammatory pathway (Ornelas et al., 2017). Although Chen et al. suggested that both the antiplatelet and anti-inflammatory effects of aspirin can benefit sepsis patients, with high-dose aspirin being more effective than low-dose aspirin (Chen et al., 2023). However, our study did not observe any differences in the effects between high-dose and low-dose aspirin, which is consistent with the findings of most studies (Lu et al., 2023; Dong et al., 2024). Actually, low-dose aspirin can exert anti-inflammatory effects by triggering the synthesis of lipoxins (Eisen, 2012; Otto et al., 2013; Toner et al., 2015). Previous studies have shown that long-term use of low-dose aspirin before hospital admission is associated with reduced mortality in patients with sepsis (Tsai et al., 2015; Hsu et al., 2022). This may be because aspirin improves the outcomes of septic patients by enhancing the inflammatory response (Kiers et al., 2016). In addition, the use of aspirin during hospitalization can also reduce the mortality of septic patients (Ouyang et al., 2019; Wang et al., 2023; Dong et al., 2024). The impact of aspirin on the prognosis of septic patients may be independent of the timing of administration. Interestingly, our study found that reduced 30-day mortality in patients with SALI was independent of the timing of aspirin administration, but ICU mortality was lower when administered in the post-ICU. Platelets play an important role in the activation, expansion, and regulation of inflammation, and can enhance host antimicrobial defense, however excessive platelet activation may lead to microthrombosis and instead impair tissue perfusion, so inhibition of platelets has important potential to improve the prognosis of infectious diseases (Eisen, 2012; Jung et al., 2012; Yang et al., 2023; Nicolai et al., 2024). We believe that long-term administration of aspirin before the onset of sepsis mainly reflects its preventive effect, which is primarily focused on enhancing the inflammatory response in sepsis patients. In contrast, the use of aspirin after the onset of sepsis demonstrates its therapeutic effect, mainly through its antiplatelet action.

The liver serves as the primary source of thrombopoietin (TPO) (Qian et al., 1998; Kaushansky, 2005). Liver injury frequently causes thrombocytopenia, which not only impairs coagulation but may also intensify inflammatory responses, thereby forming a “thrombocytopenia-inflammation” vicious cycle (Eisen, 2012; Jung et al., 2012).In sepsis, “platelets-inflammatory cell-endothelial cell” interaction can lead to thrombocytopenia (Engelmann and Massberg, 2013; Wang et al., 2018). In the presence of liver injury, this process further exacerbates “thrombocytopenia-inflammation” vicious cycle. In addition, during liver injury, high expression of COX-1 in liver sinusoidal endothelial cells increases thromboxane A2 production, resulting in endothelial dysfunction and microcirculatory disturbances in the liver (Lin et al., 2017; Gracia-Sancho et al., 2021). Aspirin may improve this situation by inhibiting local thromboxane A2 synthesis (Ornelas et al., 2017). Systemic inflammatory response is one of the important manifestations of sepsis (Giamarellos-Bourboulis et al., 2024). During liver injury, the liver’s ability to clear bacterial endotoxins is impaired, which may exacerbate the systemic inflammatory response (Nesseler et al., 2012; Yan et al., 2014; Strnad et al., 2017). Aspirin may exert a secondary anti-inflammatory effect by inhibiting HMGB1 (Venereau et al., 2016). Our study found that compared with the non - aspirin group, patients in the aspirin group had lower platelet changes and a lower incidence of DIC. Thus, our study proposes that the potential mechanisms by which aspirin improves outcomes in patients with SALI are as follows: 1. During infection, aspirin inhibits excessive platelet activation and reduces platelet consumption, thus slowing down the progression of the “thrombocytopenia - inflammation” vicious cycle; 2. Aspirin reduces the formation of microthrombi by inhibiting the synthesis of thromboxane A2 in the liver, improves the hepatic microcirculation, and slows down the further deterioration of liver injury; 3. In the setting of liver injury, aspirin exerts a secondary anti-inflammatory effect by inhibiting HMGB1, which alleviating the systemic inflammatory response.

Our subgroup analysis showed a better benefit of aspirin in certain specific SALI patients. However, unlike other studies (Chen et al., 2023; Dong et al., 2024), We found that the use of aspirin was associated with a lower risk of mortality in SALI patients without coexisting coronary artery disease (CAD), hypertension, or diabetes. We believe that this difference may be attributed to the relatively small sample size of our study compared to other studies and the small and uneven sample sizes of each subgroup after the subgroup analysis, which contributed to significant heterogeneity in the results. Additionally, we found a significant positive linear correlation between INR and the prognosis of SALI patients. Meantime, Aspirin did not demonstrate significant efficacy in SALI patients with an INR greater than 2.1. This indicates that when SALI patients exhibit severe coagulopathy, the imbalance in the “inflammatory-coagulation cascade” may exceed the regulatory capacity of aspirin. Therefore, careful assessment based on individual differences is essential to ensure the safety and effectiveness of aspirin use.

Our study has several limitations. First, this study was retrospective, and although potential confounding variables were balanced or adjusted using PSM or multivariate regression, unmeasured confounding factors may still have influenced the results. Residual confounding has the potential to introduce bias, leading to an overestimation of the effect size. Therefore, the findings should be interpreted with caution. Second, there were individual differences in patients using aspirin and this difference was ignored in this study. Third, the sample size of the study was small, while our subgroup analysis showed a better benefit of aspirin in certain specific SALI patients, this part of the results requires further investigation considering the small sample size of each subgroup variable and no adjustment for confounding factors. Fourth, a causal relationship between aspirin used and outcome in patients with SALI could not be established. Fifth, there is no gold standard for the diagnosis of SALI, and it is often caused by multiple factors such as ischemia, hypoxia, and biliary obstruction. Therefore, the SALI patients included in this study may represent only a subtype of SALI, and further research is needed to determine whether the findings are fully applicable to all SALI patients. Sixth, although this study imputed missing values through multiple imputation and the missForest method, and selected the dataset that was closest to the distribution of the original data to reduce missing bias, it cannot fully address the risk of violating the missing -at-random (MAR) assumption. Seventh, the MIMIC-IV data lack text records of the reasons for aspirin use. And the absence of data on indications and treatment courses may introduce indication bias. Prospective studies are needed for verification in the future. Eighth, the data of this study are from a tertiary medical center in the United States. Although the MIMIC-IV database already includes multiple ethnic groups, there is still a possibility that the generalizability of the conclusions may be limited. In the future, the generalization of the conclusions requires verification in other regions. Nineth, while we employed advanced causal inference methods to address time-dependent confounding, the observational nature of our data fundamentally limits causal interpretation of treatment timing effects. Small sample sizes in critical subgroups likely introduced residual bias, and immortal time bias remains an insurmountable challenge without prospective treatment assignment. Future randomized trials stratifying by therapeutic time windows are urgently needed to clarify aspirin’s temporal effects in SALI. Therefore, the results of this study need to be further verified through large - scale, prospective, multicenter studies.

The use of aspirin is an independent protective factor for the 30-day mortality in SALI patients, and its use can reduce the 30-day mortality in these patients, regardless of aspirin dose and timing. However, considering the limitations of this study, the clinical application of aspirin should be carefully selected based on individual differences, including indicators such as INR.