Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (1). It poses a significant threat to the survival of patients admitted to the intensive care unit (ICU). The incidence and mortality of sepsis remain high, making it one of the leading causes of death in the ICU worldwide (2). The underlying pathophysiological mechanisms of sepsis appear to be complicated and involve disorders in excessive inflammation, immune dysfunction, and multiple organ systems (3, 4). Among all patients with sepsis, those who develop coagulopathy are at higher risk of death (5). Sepsis-induced coagulopathy (SIC) is a serious complication of sepsis, often leading to multiple organ dysfunction syndrome (MODS) and poor prognosis (6, 7). The SIC criteria and its scoring system were constructed in 2017 to categorize coagulopathy in sepsis (8). Subsequently, the Scientific Standardization Committee (SSC) on Disseminated Intravascular Coagulopathy (DIC) of the International Society on Thrombosis and Haemostasis (ISTH) adopted SIC for the diagnosis of early phase DIC in 2019 (9). SIC is characterized by a prolonged international normalized ratio (INR) and reduced platelet counts, which can be attributed to the elevated level of tissue factor on the surface of circulating endothelial cells and the impaired balance between anticoagulant and fibrinolytic pathways when exposed to sepsis (10). Activation of the coagulation system and ensuing thrombin generation is dependent on expression of tissue factor and the simultaneous down-regulation of endothelial-bound anticoagulant mechanisms and endogenous fibrinolysis. Early detection of coagulation disorders is crucial for assessing the severity and predicting the prognosis of sepsis (11). Recent studies have demonstrated that inflammation and coagulation collaboratively contribute to the pathogenesis of organ dysfunction (12).

Antithrombin III (AT-III) is a serine protease inhibitor synthesized in the liver. As a natural anticoagulant, AT-III maintains the balance of coagulation and anticoagulation in the body by irreversibly inhibiting the activity of thrombin and other coagulation factors (13). AT-III, as an important physiological anticoagulant protein in the human body, plays a crucial role in maintaining the balance between coagulation and anticoagulation. In addition, AT-III also has an independent antagonistic effect on inflammatory response, which can promote the synthesis and release of anti-inflammatory mediators, inhibit the synthesis of inflammatory mediators, reduce the adhesion between white blood cells and endothelial cells, alleviate vascular damage, and inhibit the activation of pro-inflammatory cytokines (14). In the pathophysiological process of sepsis, the measured activity of AT-III is significantly reduced, and its mechanism includes excessive thrombin production, increased vascular leakage, impaired synthesis ability, and protease degradation (15). A study by Matsubara and colleagues reported that the activity of AT-III may have potential as a unique biomarker for sepsis and sepsis induced DIC (16). The activity changes of AT-III are closely related to the coagulation status and prognosis of sepsis patients (17–19). The measured activity of AT-III is significantly reduced in patients with sepsis and coagulation dysfunction, which not only helps to identify coagulation dysfunction early, but may also serve as an important indicator for predicting patient prognosis.

Despite the deepening understanding of coagulation dysfunction in sepsis, there are currently no suitable biomarkers for early diagnosis and prognostic evaluation of SIC. Therefore, studying the diagnostic and prognostic value of AT-III activity in SIC may be useful for early identification and intervention of SIC. The aim of this study is to explore the value of AT-III activity in diagnosing SIC and predicting 28- day mortality in SIC patients, in order to provide evidence for early diagnosis and treatment of SIC.

This study found that AT-III activity has good accuracy in diagnosing SIC, and AT-III activity may be a potential biomarker for the diagnosis of SIC. However, AT-III activity is not a significant predictor of mortality in septic patients. AT-III is a 58 kDa plasma glycoprotein synthesized in the liver and belongs to the serine protease inhibitor family. AT-III irreversibly inhibits activated factor X and thrombin in a 1:1 ratio, forming a protease-AT complex. In addition to inhibiting inflammation induced by activated factor X and thrombin, AT-III also participates in the inhibition of vascular endothelial inflammatory responses (22). Sepsis and septic shock often lead to the activation of the coagulation system and the disruption of one of the components of the anticoagulation system, AT-III, resulting in a decrease in AT-III activity.

In our study, we observed a significant reduction in AT-III activity among patients with SIC. The mechanism of reduced AT-III activity in SIC patients has not been fully elucidated and may be related to the following three potential mechanisms (23). First, since the physiological function of AT-III is to neutralize thrombin and other coagulation factors, AT-III is consumed in patients with activated coagulation (24). Second, during sepsis, the synthesis of AT-III in the liver is inhibited, and AT-III activity gradually decreases with the reduced production of AT-III (25). Third, due to the endothelial damage in sepsis leading to increased capillary permeability, circulating AT-III can rapidly leak from the intravascular to the extravascular space. These factors together lead to the reduced AT-III activity in SIC patients (26).

AT-III activity is an important physiological anticoagulant, capable of inhibiting about 80% of the coagulant activity of thrombin and coagulation factors VII, IX, X, XI, and XII. We believe that the reduction in AT-III activity is a critical factor contributing to the worsening of coagulation function in sepsis patients. Specifically, in coagulation dysfunction caused by sepsis, AT-III activity usually decreases and is associated with disease severity and high mortality. The reduction of AT-III activity leads to a decrease in the ability to inactivate thrombin, resulting in further deterioration of coagulation function and even the occurrence of multiple organ dysfunction. Iba et al. (27) reported that in infected patients without organ dysfunction, AT-III activity dropped to about 80% of the normal level, while in sepsis patients with organ dysfunction, it dropped to about 60%, and in sepsis patients with DIC, it dropped to about 40%. In our cohort, we established a threshold of 59.7% for AT-III activity to diagnose SIC. This threshold reflects the progressive decline in AT-III activity as organ dysfunction and coagulation dysfunction advance in sepsis. Our results suggest that monitoring AT-III activity could serve as a valuable tool for early identification and management of SIC, potentially improving clinical outcomes by guiding timely interventions.

Our study results not only validate the findings of previous studies but also provide more specific evidence for the application of AT treatment in patients with sepsis-induced DIC. A nationwide multicenter retrospective observational study showed that patients with sepsis-induced DIC and very low AT-III activity (≤ 43%) are the best indication for AT treatment (28). In addition, no increase in bleeding complications due to AT treatment was found in this patient subgroup. In previous clinical trials, even septic patients with AT-III activity of 70% were approved to start AT treatment. The results of these trials did not clarify the threshold of AT activity at the onset of treatment for sepsis-induced DIC, but these thresholds are likely based on the normal range of AT activity (70–120%) (29). The post hoc analysis of the KyberSept study showed that patients with sepsis-induced DIC were more likely to have AT-III activity < 60% than non-sepsis-induced DIC patients (72 vs. 15%) (30). Moreover, AT treatment can significantly improve the survival rate of patients with sepsis-induced DIC (31), and AT treatment may be more effective for patients with lower AT-III activity.

In our study, we further explored the pathophysiological mechanisms of SIC and the value of its diagnostic markers. SIC is considered to be caused by the activation of systemic intravascular coagulation and microvascular endothelial injury, leading to extensive microvascular thrombosis and organ failure. Many studies have shown that the coagulation dysfunction in sepsis is associated with organ failure and is a risk factor for clinical death (32, 33). Therefore, in order to accurately assess the coagulation function in sepsis, various coagulation markers are clinically measured in sepsis patients, such as fibrin/fibrinogen degradation products (FDP), prothrombin time, platelet count, fibrinogen, INR, and AT-III activity. However, in the complex pathophysiology of sepsis and its accompanying coagulation dysfunction, traditional coagulation markers cannot reflect the full picture of coagulation function and it is also difficult to verify the validity of the markers. Therefore, the clinical significance and effectiveness of various coagulation indicators for the treatment of sepsis are still unclear. Although the results of our study showed no statistical difference in AT-III activity between the 28-day survival group and the death group of SIC patients, and AT-III activity cannot be used as a predictive indicator of 28-day mortality in SIC patients, as a diagnostic indicator for SIC, AT-III has a good performance in both sensitivity and specificity for the diagnosis of SIC. In addition, the results of our study showed that the proportion of shock and the duration of vasopressor use in the high AT-III group (AT-III activity ≥ 59.7%) were lower than those in the low AT-III group (AT-III activity < 59.7%), suggesting that there is a close relationship between decreased AT-III activity and the occurrence of shock in sepsis patients.

In our study, we further validated the significance of AT-III activity detection in the diagnosis of SIC and proposed new insights based on our research findings. On the one hand, abnormal levels of AT-III can serve as an important diagnostic basis for SIC. When the level of AT-III is too low, it may indicate that the body is more prone to forming uncontrollable thrombi, which is consistent with the pathological process of SIC. On the other hand, our study also explored the potential role of AT-III activity in guiding clinical treatment. We found that by monitoring changes in AT-III activity, we can more accurately assess the coagulation status of patients, thereby guiding anticoagulant therapy. For instance, heparin can increase the activity of AT-III by 1,000 times through competitive binding to AT-III and preventing its interaction with heparan sulfate on endothelial cells (34). Since the anticoagulant effect of heparin depends on the activity of AT-III, monitoring the changes in AT-III levels can also assess the coagulation status of patients, guide clinical anticoagulant therapy, and thereby improve the prognosis of patients. In the future, with the continuous progress of medical technology and in-depth research on AT-III, its role in the diagnosis, treatment, and prognostic assessment of SIC will become clearer and more important. Based on our research findings, we believe that developing more sensitive and specific AT-III detection technologies can detect coagulation abnormalities earlier, providing strong support for clinical intervention. At the same time, establishing a comprehensive diagnostic model by combining other biomarkers and clinical information will further improve the diagnostic accuracy and therapeutic efficiency of SIC. In summary, as an indicator that is easy to detect, readily available, and highly universal, AT-III activity has broad application prospects and important clinical value in the diagnosis of SIC. In the future, with ongoing in-depth research and technological development, AT-III activity is expected to play a more important role in the diagnosis and treatment of SIC.

There are several limitations in our study. First, since it is a single-center study, the sample size is relatively small. Second, the dynamic changes of AT-III activity during the sepsis process were not continuously monitored. Third, due to the single-center nature and small heterogeneous patient population, the generalizability of our results is limited. Therefore, larger-scale and multicenter research is still required in the future.

AT-III activity decreases during SIC, and AT-III activity is a potential biomarker for diagnosing SIC with diagnostic efficacy similar to current indicators of SOFA score, INR and platelets.