Coagulation Disorders in Patients With Acute Respiratory Distress Syndrome Following Acute Aortic Dissection: A Prospective Observational Study

Abstract

Background:

Coagulation disorders are potentially one of the most important pathogeneses of acute respiratory distress syndrome (ARDS) following acute type A aortic dissection (ATAAD). This study aimed to determine whether aortic dissection singularly and cardiopulmonary bypass (CPB) surgery can activate coagulation pathways, promoting ARDS development in patients with ATAAD.

Methods:

A total of 450 patients who received treatment at Beijing Anzhen Hospital, Capital Medical University, between March 2023 and February 2024 were consecutively enrolled in this prospective cohort study. We analyzed the clinical factors and measured serum coagulation biomarkers by enzyme-linked immunosorbent assay (ELISA) among patients with ATAAD, aortic aneurysm (AA), or unstable angina (UA). Logistic regression, two-way analysis of variance (ANOVA), and Spearman's correlation analysis were performed. Furthermore, the patients with ATAAD were divided into ARDS (based on chest radiographic findings and an oxygenation index ≤300 mmHg) and non-ARDS groups for subgroup comparisons.

Results:

The incidence of postoperative ARDS among patients with ATAAD was 20.7% (13.3% in the AA group and 7.3% in the UA group). Preoperatively, prothrombin time (PT) was longer in patients with ATAAD than in those with AA or UA ((odds ratio (OR): 12.0, 95% confidence interval (CI): 11.5–12.6) vs. (OR: 11.4, 95% CI: 10.9–12.1) vs. (OR: 11.2, 95% CI: 10.8–11.6), respectively; p < 0.001). The D-dimer levels, fibrin degradation products (FDPs), factor XIIa, and factor VIII-Ag (FVIII-Ag) were significantly elevated preoperatively and postoperatively in patients with ATAAD. The FDP levels in the ATAAD subgroup immediately after surgery were significantly higher in the ARDS group compared with those in the non-ARDS group (OR: 2.26, 95% CI: 1.13–4.54; p = 0.022). In addition, a negative correlation existed between the FXII level (correlation coefficient r = –0.682, p = 0.043) at 24 hours after surgery and the oxygenation index.

Conclusion:

Coagulation activation may be caused by aortic dissection singularly and CPB, which promotes postoperative ARDS in patients with ATAAD.

Graphical abstract

Keywords

acute aortic dissection / acute respiratory distress syndrome / coagulation / fibrinolysis / cardiopulmonary bypass

1. Introduction

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common complications that may occur during perioperative management, especially in high-risk populations of patients undergoing surgery [1, 2, 3]. ARDS is a primary cause of postoperative acute hypoxemic respiratory failure and its etiologies are diverse [4, 5, 6, 7]. The occurrence of ARDS has also been investigated following cardiac surgery (CS) involving cardiopulmonary bypass (CPB) procedures [3, 7, 8, 9]. Despite the continual refinement of perioperative management and surgical techniques, up to 20% of patients are affected by this postsurgical complication [3, 10]. Postoperative ARDS can seriously affect patient outcomes, with mortality rates as high as 40–80% in severe cases [2, 7, 11, 12] and functional limitations sometimes persisting 5 years after an ARDS episode [13].

Although the pathogenesis of ARDS is not entirely clear, recent studies suggest that the activation of coagulation is closely related to the development of ARDS [6, 14, 15, 16, 17, 18] and blockade of the initiating steps of the clotting cascade may be beneficial for patients with ARDS [6, 19]. During cardiac surgery, CPB procedures and extensive surgical trauma can induce the widespread activation of the coagulation system [17, 20, 21], and the pathogenesis of acute type A aortic dissection (ATAAD) has been shown to be associated with coagulation disorders [22]. Therefore, both ATAAD itself and CPB can contribute to the development of multiple disorders of the coagulation system; however, there is little data supporting the activation of coagulation cascade plays a role in the etiology of ARDS after aortic surgery.

The occurrence of ALI/ARDS following aortic surgery is unpredictable, although recent studies have suggested that early identification and improved perioperative care can prevent postoperative ALI/ARDS. Although several risk factors have been identified are associated with the occurrence of post-operative ARDS, to our knowledge, barely any study has illustrated the association between coagulation markers and ARDS in ATAAD patients. Therefore, the aim of this study was to explore the correlations between the serum levels of various biomarkers of coagulation and the occurrence of ARDS following aortic surgery, as these markers could serve as reliable predictors of the risk of ALI/ARDS.

2. Methods

2.1 Design and Participants

This single-center prospective observational study was performed at the Center for Cardiac Intensive Care of Beijing Anzhen Hospital, Capital Medical University. A total of 450 patients were consecutively enrolled between March 2023 and February 2024, including 150 patients diagnosed with ATAAD, 150 with aortic aneurysm (AA), and 150 with unstable angina (UA). Patients with ATAAD and AA underwent Sun’s surgery or partial aortic arch replacement, whereas patients with UA underwent off-pump coronary artery bypass grafting (OPCABG).

All adult subjects were over 18 years of age, had been diagnosed with AA (chronic onset), UA and ATAAD (with a time from onset of under two weeks and had been scheduled for emergency surgery). The exclusion criteria were as follows: patients with neoplastic or chronic coagulation and inflammatory disorders; patients with missing specimens or clinical data; and patients who experienced a failed surgical intervention or died within 24 hours after surgery. Clinical data of these patients were collected during the hospitalization period. In addition, nine patients in each group were randomly selected and venous plasma was collected and subjected to enzyme-linked immunosorbent assays (ELISAs) to quantify various markers of coagulation and inflammation. We randomly selected 9 patients from each group by using a random number generator to ensure the reproducibility and validity of the findings.

2.2 Definitions

All subjects underwent contrast-enhanced computed tomography (CT) to confirm the surgeons’ diagnoses of ATAAD [23]. Based on the European Society of Intensive Care Medicine (ESICM) definition [5], ARDS was confirmed via arterial blood gas analysis and chest radiography. These criteria included an acute onset, an oxygenation index (partial pressure of oxygen in arterial blood/fraction of inspired oxygen, PaO₂/FiO₂) \le300 mmHg for ARDS, regardless of the ventilator settings, the appearance of bilateral pulmonary infiltration on chest radiography, and the presence of respiratory failure that could not be fully explained by cardiac failure or fluid overload. Hypertension (HTN) is defined as having a systolic blood pressure (SBP) of \ge140 mmHg and/or a diastolic blood pressure (DBP) of \ge90 mmHg when no antihypertensive drugs are used. The diagnosis of diabetes is based on the recommended standards of the American Diabetes Association (ADA) in 2010. Acute kidney injury (AKI) was confirmed by the guideline published by the Kidney Disease Improving Global Outcomes (KIDGO) in 2012. Heart failure (HF) was defined as left ventricular ejection fraction \le40% accompanied by symptoms and/or signs. Chronic lung diseases (CLD) include chronic obstructive pulmonary disease, bronchiectasis, asthma or tuberculosis, etc. Neurological disease (ND) refer to ischemic/hemorrhagic stroke, brain tumors or brain trauma. Altered consciousness was defined as drowsiness, stupor or coma that occurs before surgery due to various reasons. Chest radiography was performed daily, and the results were interpreted by two radiologists. Blood gas levels were measured every 4 hours. The primary outcome variable was the development of ARDS within two days after surgery.

2.3 Anesthesia and Surgery

Radial artery pressure, dorsalis pedis artery pressure, and central venous pressure were monitored before surgery in all patients using established methods. Anesthesia was administered in accordance with institutional standards. Aortic surgical procedures were performed under general anesthesia, CPB, deep hypothermic circulatory arrest (DHCA), and selective cerebral perfusion were conducted using a modified elephant trunk technique (Sun’s procedure) as previously described [22].

2.4 Clinical Data and Blood Samples

Data related to clinical characteristics, demographic information, medical history, intraoperative variables, and details pertaining to the subsequent course of recovery in the intensive care unit (ICU) post-surgery were recorded. Each patient’s preoperative risk profile was evaluated using the European System for Cardiac Operative Risk Evaluation (EuroSCORE) [24]. The dosage of vasoactive drug administration and organ function were assessed during the first 48 h post-surgery using the vasoactive inotrope score (VIS) [25] and the Sequential Organ Failure Assessment (SOFA) scale [26], respectively.

Blood samples were collected in sodium citrate tubes through a central venous catheter at the following three time points: immediately prior to anesthesia induction; immediately after surgery; and 24 hours after surgery. Samples were centrifuged at 1550 \times g for 15 min at 4 °C, and the supernatants were aliquoted and stored at –80 °C for later analysis. Serum levels of factor XII (FXII), factor XIIa (FXIIa), factor VIII-related antigen (FVIII-Ag), plasmin-antiplasmin complex (PAP), interleukin one beta (IL-1\beta), and tumor necrosis factor-alpha (TNF\alpha) were assayed using ELISA kits (USCN KIT INC, Wuhan, China).

2.5 Statistical Analysis

We used the median to interpolate the missing data of continuous variables and conducted the Kolmogorov-Smirnov test. Continuous variables were expressed as the mean \pm standard deviation and were analyzed using a Student’s t-test for normally distributed data; alternatively, variables with a skewed distribution were expressed as medians and quartiles and were analyzed using a Mann-Whitney U-test. Categorical variables were expressed as numbers and percentages, and a \chi² test or Fisher’s exact test was used to compare groups as appropriate.

The baseline characteristics of the ATAAD group were first compared with those of the AA group and UA group separately, followed by ANOVA across all three groups with Bonferroni correction for multiple comparisons. Patients with ATAAD were further stratified into ARDS and Non-ARDS subgroups, with a comparative analysis conducted on their baseline characteristics. All coagulation biomarkers were normalized and standardized using log- and z-score transformations. Logistic regression models were applied separately in the ATAAD group, AA group and UA group to assess the associations between coagulation biomarkers and postoperative ALI/ARDS, with odds ratios (ORs) and 95% confidence intervals (95% CIs) calculated. Model 1 was a univariate model and Model 2 was adjusted for traditional confounders, including sex, age, body mass index (BMI), HTN, diabetes, AKI, HF, liver dysfunction (LD), CLD, ND, smoking status, alcohol consumption, prior CS, preoperative aspartate aminotransferase (AST) level, and the preoperative oxygenation index (PaO₂/FiO₂, P/F). These covariates include medical history data and some preoperative meaningful indicators (AST and P/F) between the ARDS group and Non-ARDS group in the baseline characteristics (Supplementary Tables 1,2). Collinearity test was conducted in the multivariate analysis (Supplementary Table 3). A two-way ANOVA was used to account for both group and time as independent variables in ELISA. Spearman correlation analysis was used to analyze the associations between variables for inferring coagulation activity and the oxygenation index.

All analyses were performed using R software 4.3.1 (R Foundation, Vienna, Austria) (https://www.r-project.org/) and Prism 10.2 (GraphPad Corp, San Diego, CA, USA). p-value 0.05 indicates statistical significance (p 0.017 indicates statistical significance after Bonferroni correction).

3. Results

3.1 Subject Preoperative Data

Baseline and preoperative laboratory values of the participants are presented in Table 1. Patients in the ATAAD group were younger than those in the AA group (49.1 \pm 11.5 years), whereas the patients with ATAAD exhibited a higher incidence of elevated blood pressure (84% vs 62.7%, respectively). Preoperatively, patients with ATAAD presented with significantly higher D-dimer levels than did those in either the AA group (2589 [978.5–7919] vs 180 [68.3–670.8] ng/mL; p 0.001) or the UA group (2589 [978.5–7919] vs 92.5 [56.0–157.0] ng/mL; p 0.001). The levels of FDPs in the ATAAD group increased significantly at admission (27.5 [10.9–69.3] vs 1.4 [0.5–4.6] µg/mL, p 0.001; 27.5 [10.9–69.3] vs 0.8 [0.5–1.2] µg/mL, p 0.001). However, the levels of fibrinogen (FBG) in the ATAAD group decreased significantly before surgery (2.3 [1.8–2.9] vs 2.9 [2.4–3.4] g/L, p 0.001; 2.3 [1.8–2.9] vs 3.1 [2.6–3.6] g/L, p 0.001).

3.2 Comparison of Coagulation Biomarker Levels Between the ATAAD, AA, and UA Groups

The duration of the CPB procedure was significantly longer in the patients with ATAAD (179 [158–206] min) than it was in the other two groups (p 0.001 for ATAAD vs. AA and for ATAAD vs. UA), as was the aortic cross-clamping time (96.5 [86–116] min; p 0.001 for ATAAD vs. AA and for ATAAD vs. UA). Immediately after surgery, the PaO₂ values (110.0 [85.5–160.5] vs. 151.5 [141.3–206.5] mmHg, ATAAD vs. AA group, p 0.001; vs. 158.0 [120.5–205.8] mmHg, ATAAD vs UA group, p 0.001) decreased and lactic acid (Lac) level increased more significantly in the ATAAD group than in the other two groups. The activated partial thromboplastin time (APTT) at the end of surgery was longer (33.9 [31.0–40.3] s) in the patients with ATAAD than that in the other groups (p = 0.001 for ATAAD vs. AA and for ATAAD vs UA). The D-dimer level in the ATAAD group increased significantly over the 24 hours post-surgery. Similarly, the trend in the levels of FDPs was consistent with that of the D-dimer levels (Table 2). More importantly, ARDS represented 13.8% of total patients and 20.7% of patients with ATAAD.

3.3 Coagulation Activity in the Patients With and Without ARDS in the ATAAD Cohort

The levels of coagulation factors in the patients with ARDS from the ATAAD group are shown in Tables 3,4. Preoperative D-dimer levels were similar between the non-ARDS and ARDS groups (2403.0 [942.0–7524.5] vs 5302 [1184.0–9419.0] ng/mL, p = 0.134). The concentration of the FDPs also tended to rise in the ARDS group before surgery (22.7 [10.2–65.9] vs 49.3 [12.5–80.8] µg/mL, p = 0.098). At the end of surgery, D-dimer levels in the ARDS group were significantly higher than those in the non-ARDS group (3326 [2270.0–5989.0] vs 2281.0 [1135.0–3787.5] ng/mL, p = 0.017). Twenty-four hours after surgery, there was no significant difference between the groups, although the D-dimer levels were significantly elevated in the ARDS group 48 hours after surgery (2017 [935.0–2955.0] vs. 935.0 [869.5–2617.0] ng/mL, p = 0.046). The trend of FDPs levels was consistent with that of the D-dimer levels. In-hospital mortality was significantly higher postoperatively in the patients with ARDS (25.8% vs. 4.2%, p = 0.001).

After all coagulation biomarkers were normalized and standardized using log- and z-score transformations, the results indicated that the levels of FDPs at the end of surgery (OR: 2.26, 95% CI: 1.13–4.54; p = 0.022) was the independent risk factor for the development of ARDS among the patients with ATAAD (Table 5).

3.4 Serum Concentrations of Coagulation Biomarkers

The effects of the different groups and phases on the concentrations of FXII, FXIIa, FVIII-Ag, and PAP are presented in Fig. 1. Preoperatively (immediately prior to anesthesia induction), compared with those in the other two groups, patients with ATAAD presented with significantly higher levels of FXIIa (p = 0.014 and p 0.0001 for ATAAD vs. AA and for ATAAD vs. UA groups, respectively) and FVIII-Ag (p = 0.0002 and p 0.0001 for ATAAD vs. AA and for ATAAD vs. UA groups, respectively). After surgery, FXII, FXIIa, and FVIII-Ag levels were significantly higher in the ATAAD group compared to those in the other groups (Fig. 1a–c), whereas the perioperative PAP levels were similar between the ATAAD and AA groups (p > 0.05, Fig. 1d).

After conducting statistical analysis on the same indicators of the same group at different time points, it was found that the FXII level at 0 h after was significantly higher than that immediately prior to anesthesia induction (p 0.001, Fig. 2a) and the TNF level immediately prior to anesthesia induction was significantly higher than that after surgery (p 0.001, Fig. 2f) in patients with ATAAD. The level of PAP at immediately prior to anesthesia induction was significantly higher than that after surgery (p 0.05, Fig. 2d) in patients with AA. The levels of other biomarkers did not show significant differences at each time point (Fig. 2).

There was a negative correlation between FXII levels and the oxygenation index 24 h post-surgery (Pearson correlation coefficient r = –0.682, p = 0.043), whereas no significant correlations were observed for the other markers or at other time points (Fig. 3). However, a trend was observed in which the oxygenation index decreased as FVIII-Ag levels increased, suggesting that FVIII-Ag may affect lung function.

4. Discussion

The aim of this study was to investigate if coagulation activity could be induced by ATAAD onset or CPB, and to determine the impact of coagulation activity on the development of post-operative ARDS. The results revealed significantly elevated serum concentrations of perioperative coagulation biomarkers in patients with ATAAD who had undergone surgery involving CPB. Meanwhile, the results indicate that the elevation of coagulation biomarkers is a risk factor for the occurrence of ARDS.

4.1 Activation of Coagulation System in Patients With ATAAD

The present study, which used a control group of patients with AA, verified that ATAAD itself can significantly increase the activation of the coagulation system. ATAAD is caused by injury to the aortic intima, where blood gains access to the false lumen formed between the intima and media. The activation of the coagulation system could be induced by contact between blood and the false lumen and the release of coagulant material from the aortic wall into the systemic circulation [26, 27].

Previous studies [28, 29] have demonstrated that ATAAD and the surgical interventions to treat it can cause an increase in the levels of biomarkers that induce the activation of coagulation. The preoperative levels of FDPs and D-dimer become sharply elevated in patients with ATAAD [27, 30]. An increased D-dimer level reflects both the augmented formation of fibrin as well as the degree of subsequent fibrinolysis, and it has been shown to be associated with postoperative adverse events in patients with ATAAD [31, 32]. However, a small number of studies [33, 34] have compared the perioperative coagulation function of patients with ATAAD undergoing emergency surgery and that of patients with AA undergoing elective aortic surgery.

In the present study, intergroup comparisons were performed between patients with ATAAD and those with AA or UA; the results showed that the preoperative (immediately prior to anesthesia induction) levels of FXIIa and FVIII-Ag were significantly higher in the ATAAD group than in the other two groups, whereas the preoperative fibrinogen level was significantly lower, indicating that patients with ATAAD consumed more fibrinogen before surgery. Although patients experiencing chronic aneurysms also presented with higher D-dimer levels, the upregulation was more pronounced in patients with ATAAD. However, whether there is a causal relationship between ATAAD itself and ARDS still requires further research to verify.

4.2 Activation of Coagulation System in Patients After CPB Surgery

In this study, the levels of FXII, FXIIa, FVIII-Ag, D-dimer, and FDPs were elevated in patients with ATAAD and AA, and the elevation was more pronounced in the former group. Meanwhile, the CPB duration was significantly prolonged in ATAAD group. We hypothesize that the coagulation disorder after CPB is related to the activation of the “contact system”.

The “contact system” is a plasma protease cascade that plays an important role in the activation of the coagulation systems; it includes FXII, FXIIa, factor XI (FXI), high-molecular-weight kininogen (HMWK), and prekallikrein, which are associated proteins in the plasma [17]. Contact system activity increases dramatically as blood comes into contact with the artificial materials comprising CPB circuits [35]. Mechanistically, FXII cleaves itself upon contact with various anionic surfaces, resulting in the production of FXIIa, which subsequently converts prekallikrein into active kallikrein. In the plasma, kallikrein generates a positive feedback loop by cleaving additional FXII, which produces more bradykinin from HMWK [17]. Previous studies have shown that active thrombin can induce the release of tissue plasminogen activator in vitro, with bradykinin potentially serving as the predominant stimulus [36, 37]. Meanwhile, the binding of soluble fibrin to CPB circuits promotes plasminogen activation [38, 39].

Previous studies have reported that coagulation disorders can be deteriorated by use of CPB during surgery, especially in conditions that promote deep hypothermia [20, 33, 40, 41]. For example, some groups have reported that CPB causes an increase in the levels of FXIIa and FDPs [17, 20]. A study conducted by Boisclair et al. [42] suggested that FXIIa can serve as a marker of contact system activation in patients undergoing CPB procedures. In addition to producing kallikrein, FXIIa has been reported to convert FXI into FXIa, thereby initiating the activation of the intrinsic pathway [20]. Therefore, the contact system exacerbates the development of coagulation system disorders when CPB is performed, and this effect may be related to the length of time required to complete CPB procedures. FXIIa, D-dimer and FDPs may serve as early biomarkers for identifying high-risk ARDS patients. We should also pay attention to the coagulation system of patients with prolonged CPB duration.

4.3 Correlation Between the Activation of Coagulation and Postoperative ARDS

In the ATAAD group, the concentrations of D-dimer and FDPs increased immediately after surgery in the patients who developed ARDS, indicating that coagulation activity was elevated; however, the PAP concentration did not differ between the ATAAD and AA groups and was lower in patients with hypoxemia. The pathophysiology of ARDS is complex, and the underlying mechanisms have yet to be fully elucidated, especially during acute critical illness [43].

Matthay et al. [44] have speculated that one of the mechanisms underlying ARDS pathogenesis involves the activation and dysregulation of coagulation, both in the lungs and systemically. As a result, increased fibrinolytic activity may be insufficient to counteract the amplified coagulation activity in patients with ARDS. This disequilibrium may lead to fibrin deposition along the denuded alveolar basement membrane, prompting hyaline membrane formation; such lesions can, in turn, decrease lung compliance and increase inspiratory pressures [43]. In addition, the activation of procoagulant pathways may cause microvascular thromboses in the lungs; the increased amount of dead space reduces blood flow and subsequently influences gas exchange in those with ARDS [43, 45, 46]. In this study, the oxygenation index was negatively correlated with the concentration of FXII and was positively correlated with the concentration of PAP 24 hours post-surgery, manifesting as a change in coagulation activity that may be associated with ARDS. However, given the limited sample size, additional research is warranted to validate these findings.

The concentrations of the pro-inflammatory cytokines IL-1\beta and TNF\alpha were also significantly elevated in the ATAAD group. Correlations between ALI and inflammatory responses have been extensively investigated [22, 47]. Both local and systemic acute inflammation are prominent features of ARDS [43], and previous studies have reported that contact with the components of bypass circuits and ischemia–reperfusion injury may upregulate the expression of inflammatory cytokines, thereby leading to the release of coagulation factors [48, 49]. Meanwhile, both FXII and contact activation may induce bradykinin release and complement system activation, further promoting the systemic inflammatory response [48, 49, 50]. These findings indicated that specific interactions between coagulation and inflammation pathways contribute to lung injury.

To date, there has been little evidence to support the possibility that coagulation activation at an early stage following cardiac surgery can increase the likelihood of ARDS development, especially in patients with ATAAD. One of the strengths of this study was the detailed comparison that was performed of the relationships between coagulation disorders and postoperative ARDS between the three groups; however, there were some limitations. Firstly, the study population was derived from a single center, and it was not possible to exclude other factors that may have affected oxygenation; further validation is required with a larger cohort. Secondly, ELISAs were used to test serum samples from just nine randomly selected patients in each group. Future investigations should examine other markers of coagulation and fibrinolysis in larger cohorts. Thirdly, local coagulation and inflammatory activity are also important, as they can influence the occurrence of hypoxemia; further analysis of the coagulation biomarkers will be performed based on bronchoalveolar lavage fluid.

5. Conclusion

In conclusion, the ATAAD- or CPB-induced activation of coagulation pathways can affect gas exchange in the lungs. The early increase in the levels of FXII, FXIIa, D-dimer, and FDPs and the decrease in PAP may play an important role in the mechanisms through which patients with ATAAD develop ARDS following surgical procedures involving CPB. This study offers new insights into the clinical treatment of ARDS using aggressive anticoagulant therapies. Further studies are needed to elucidate the underlying cellular and molecular mechanisms through which the activation of coagulation cascades drives the development of postoperative ARDS in patients with ATAAD.

References

[1] Fanelli V, Vlachou A, Ghannadian S, Simonetti U, Slutsky AS, Zhang H. Acute respiratory distress syndrome: new definition, current and future therapeutic options. Journal of Thoracic Disease. 2013; 5: 326–334. https://doi.org/10.3978/j.issn.2072-1439.2013.04.05.

[2] Villar J, Sulemanji D, Kacmarek RM. The acute respiratory distress syndrome: incidence and mortality, has it changed? Current Opinion in Critical Care. 2014; 20: 3–9. https://doi.org/10.1097/MCC.0000000000000057.

[3] Stephens RS, Shah AS, Whitman GJR. Lung injury and acute respiratory distress syndrome after cardiac surgery. The Annals of Thoracic Surgery. 2013; 95: 1122–1129. https://doi.org/10.1016/j.athoracsur.2012.10.024.

[4] Fernández-Pérez ER, Sprung J, Afessa B, Warner DO, Vachon CM, Schroeder DR, et al. Intraoperative ventilator settings and acute lung injury after elective surgery: a nested case control study. Thorax. 2009; 64: 121–127. https://doi.org/10.1136/thx.2008.102228.

[5] Grasselli G, Calfee CS, Camporota L, Poole D, Amato MBP, Antonelli M, et al. ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies. Intensive Care Medicine. 2023; 49: 727–759. https://doi.org/10.1007/s00134-023-07050-7.

[6] Welty-Wolf KE, Carraway MS, Ortel TL, Piantadosi CA. Coagulation and inflammation in acute lung injury. Thrombosis and Haemostasis. 2002; 88: 17–25.

[7] Milot J, Perron J, Lacasse Y, Létourneau L, Cartier PC, Maltais F. Incidence and predictors of ARDS after cardiac surgery. Chest. 2001; 119: 884–888. https://doi.org/10.1378/chest.119.3.884.

[8] Messent M, Sullivan K, Keogh BF, Morgan CJ, Evans TW. Adult respiratory distress syndrome following cardiopulmonary bypass: incidence and prediction. Anaesthesia. 1992; 47: 267–268. https://doi.org/10.1111/j.1365-2044.1992.tb02134.x.

[9] Sanfilippo F, Palumbo GJ, Bignami E, Pavesi M, Ranucci M, Scolletta S, et al. Acute Respiratory Distress Syndrome in the Perioperative Period of Cardiac Surgery: Predictors, Diagnosis, Prognosis, Management Options, and Future Directions. Journal of Cardiothoracic and Vascular Anesthesia. 2022; 36: 1169–1179. https://doi.org/10.1053/j.jvca.2021.04.024.

[10] Bronicki RA, Hall M. Cardiopulmonary Bypass-Induced Inflammatory Response: Pathophysiology and Treatment. Pediatric Critical Care Medicine: a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2016; 17: S272–S278. https://doi.org/10.1097/PCC.0000000000000759.

[11] Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Incidence and outcomes of acute lung injury. The New England Journal of Medicine. 2005; 353: 1685–1693. https://doi.org/10.1056/NEJMoa050333.

[12] Bellani G, Pham T, Laffey J, LUNG-SAFE Investigators, ESICM Trials Group. Incidence of Acute Respiratory Distress Syndrome–Reply. JAMA. 2016; 316: 347. https://doi.org/10.1001/jama.2016.6471.

[13] Herridge MS, Tansey CM, Matté A, Tomlinson G, Diaz-Granados N, Cooper A, et al. Functional disability 5 years after acute respiratory distress syndrome. The New England Journal of Medicine. 2011; 364: 1293–1304. https://doi.org/10.1056/NEJMoa1011802.

[14] Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. European Journal of Cardio-thoracic Surgery: Official Journal of the European Association for Cardio-thoracic Surgery. 2002; 21: 232–244. https://doi.org/10.1016/s1010-7940(01)01099-5.

[15] Massoudy P, Zahler S, Becker BF, Braun SL, Barankay A, Meisner H. Evidence for inflammatory responses of the lungs during coronary artery bypass grafting with cardiopulmonary bypass. Chest. 2001; 119: 31–36. https://doi.org/10.1378/chest.119.1.31.

[16] Rasmussen BS, Maltesen RG, Pedersen S, Kristensen SR. Early coagulation activation precedes the development of acute lung injury after cardiac surgery. Thrombosis Research. 2016; 139: 82–84. https://doi.org/10.1016/j.thromres.2016.01.015.

[17] Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesthesia and Analgesia. 2011; 113: 1319–1333. https://doi.org/10.1213/ANE.0b013e3182354b7e.

[18] Liu Z, Liu D, Wang Z, Zou Y, Wang H, Li X, et al. Association between inflammatory biomarkers and acute respiratory distress syndrome or acute lung injury risk: A systematic review and meta-analysis. Wiener Klinische Wochenschrift. 2022; 134: 24–38. https://doi.org/10.1007/s00508-021-01971-3.

[19] Welty-Wolf KE, Carraway MS, Miller DL, Ortel TL, Ezban M, Ghio AJ, et al. Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons. American Journal of Respiratory and Critical Care Medicine. 2001; 164: 1988–1996. https://doi.org/10.1164/ajrccm.164.10.2105027.

[20] Paparella D, Brister SJ, Buchanan MR. Coagulation disorders of cardiopulmonary bypass: a review. Intensive Care Medicine. 2004; 30: 1873–1881. https://doi.org/10.1007/s00134-004-2388-0.

[21] Bartoszko J, Karkouti K. Managing the coagulopathy associated with cardiopulmonary bypass. Journal of Thrombosis and Haemostasis: JTH. 2021; 19: 617–632. https://doi.org/10.1111/jth.15195.

[22] Gao Z, Pei X, He C, Wang Y, Lu J, Jin M, et al. Oxygenation impairment in patients with acute aortic dissection is associated with disorders of coagulation and fibrinolysis: a prospective observational study. Journal of Thoracic Disease. 2019; 11: 1190–1201. https://doi.org/10.21037/jtd.2019.04.32.

[23] Nienaber CA, Clough RE. Management of acute aortic dissection. Lancet (London, England). 2015; 385: 800–811. https://doi.org/10.1016/S0140-6736(14)61005-9.

[24] Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). European Journal of Cardio-thoracic Surgery: Official Journal of the European Association for Cardio-thoracic Surgery. 1999; 16: 9–13. https://doi.org/10.1016/s1010-7940(99)00134-7.

[25] Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Medicine. 1996; 22: 707–710. https://doi.org/10.1007/BF01709751.

[26] Evangelista A, Isselbacher EM, Bossone E, Gleason TG, Eusanio MD, Sechtem U, et al. Insights From the International Registry of Acute Aortic Dissection: A 20-Year Experience of Collaborative Clinical Research. Circulation. 2018; 137: 1846–1860. https://doi.org/10.1161/CIRCULATIONAHA.117.031264.

[27] ten Cate JW, Timmers H, Becker AE. Coagulopathy in Ruptured or Dissecting Aortic Aneurysms. The American Journal of Medicine. 1975; 59: 171–176. https://doi.org/10.1016/0002-9343(75)90351-4.

[28] Paparella D, Rotunno C, Guida P, Malvindi PG, Scrascia G, De Palo M, et al. Hemostasis alterations in patients with acute aortic dissection. The Annals of Thoracic Surgery. 2011; 91: 1364–1369. https://doi.org/10.1016/j.athoracsur.2011.01.058.

[29] Guan XL, Wang XL, Liu YY, Lan F, Gong M, Li HY, et al. Changes in the Hemostatic System of Patients With Acute Aortic Dissection Undergoing Aortic Arch Surgery. The Annals of Thoracic Surgery. 2016; 101: 945–951. https://doi.org/10.1016/j.athoracsur.2015.08.047.

[30] Albini P, Barshes NR, Russell L, Wu D, Coselli JS, Shen YH, et al. D-dimer levels remain elevated in acute aortic dissection after 24 h. The Journal of Surgical Research. 2014; 191: 58–63. https://doi.org/10.1016/j.jss.2014.03.074.

[31] Liu T, Zheng J, Zhang YC, Zhu K, Gao HQ, Zhang K, et al. Association Between D-dimer and Early Adverse Events in Patients With Acute Type A Aortic Dissection Undergoing Arch Replacement and the Frozen Elephant Trunk Implantation: A Retrospective Cohort Study. Frontiers in Physiology. 2020; 10: 1627. https://doi.org/10.3389/fphys.2019.01627.

[32] Wu Q, Li J, Chen L, Yan LL, Qiu Z, Shen Y, et al. Efficacy of interleukin-6 in combination with D-dimer in predicting early poor postoperative prognosis after acute stanford type a aortic dissection. Journal of Cardiothoracic Surgery. 2020; 15: 172. https://doi.org/10.1186/s13019-020-01206-y.

[33] Zindovic I, Sjögren J, Bjursten H, Ingemansson R, Ingimarsson J, Larsson M, et al. The Coagulopathy of Acute Type A Aortic Dissection: A Prospective, Observational Study. Journal of Cardiothoracic and Vascular Anesthesia. 2019; 33: 2746–2754. https://doi.org/10.1053/j.jvca.2019.02.013.

[34] Sbarouni E, Georgiadou P, Marathias A, Geroulanos S, Kremastinos DT. D-dimer and BNP levels in acute aortic dissection. International Journal of Cardiology. 2007; 122: 170–172. https://doi.org/10.1016/j.ijcard.2006.11.056.

[35] Campbell DJ, Dixon B, Kladis A, Kemme M, Santamaria JD. Activation of the kallikrein-kinin system by cardiopulmonary bypass in humans. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2001; 281: R1059–70. https://doi.org/10.1152/ajpregu.2001.281.4.R1059.

[36] Booyse FM, Bruce R, Dolenak D, Grover M, Casey LC. Rapid release and deactivation of plasminogen activators in human endothelial cell cultures in the presence of thrombin and ionophore A23187. Seminars in Thrombosis and Hemostasis. 1986; 12: 228–230. https://doi.org/10.1055/s-2007-1003558.

[37] Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. Aprotinin in cardiopulmonary bypass–effects on the Hageman factor (FXII)–Kallikrein system and blood loss. Blood Coagulation & Fibrinolysis: an International Journal in Haemostasis and Thrombosis. 1992; 3: 99–104. https://doi.org/10.1097/00001721-199202000-00014.

[38] Zhao X, Courtney JM, Yin HQ, West RH, Lowe GDO. Blood interactions with plasticised poly (vinyl chloride): influence of surface modification. Journal of Materials Science. Materials in Medicine. 2008; 19: 713–719. https://doi.org/10.1007/s10856-007-3191-6.

[39] van den Goor JM, van Oeveren W, Rutten PM, Tijssen JG, Eijsman L. Adhesion of thrombotic components to the surface of a clinically used oxygenator is not affected by Trillium coating. Perfusion. 2006; 21: 165–172. https://doi.org/10.1191/0267659106pf859oa.

[40] Van Poucke S, Stevens K, Marcus AE, Lancé M. Hypothermia: effects on platelet function and hemostasis. Thrombosis Journal. 2014; 12: 31. https://doi.org/10.1186/s12959-014-0031-z.

[41] Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cascade. Critical Care Medicine. 1992; 20: 1402–1405. https://doi.org/10.1097/00003246-199210000-00007.

[42] Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh S, Hunt B, et al. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood. 1993; 82: 3350–3357.

[43] Bos LDJ, Ware LB. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes. Lancet (London, England). 2022; 400: 1145–1156. https://doi.org/10.1016/S0140-6736(22)01485-4.

[44] Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, et al. Acute respiratory distress syndrome. Nature Reviews. Disease Primers. 2019; 5: 18. https://doi.org/10.1038/s41572-019-0069-0.

[45] Shetty S, Padijnayayveetil J, Tucker T, Stankowska D, Idell S. The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2008; 295: L967–75. https://doi.org/10.1152/ajplung.90349.2008.

[46] MacLaren R, Stringer KA. Emerging role of anticoagulants and fibrinolytics in the treatment of acute respiratory distress syndrome. Pharmacotherapy. 2007; 27: 860–873. https://doi.org/10.1592/phco.27.6.860.

[47] Guan X, Li J, Gong M, Lan F, Zhang H. The hemostatic disturbance in patients with acute aortic dissection: A prospective observational study. Medicine. 2016; 95: e4710. https://doi.org/10.1097/MD.0000000000004710.

[48] Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesthesia and Analgesia. 1997; 85: 766–782. https://doi.org/10.1097/00000539-199710000-00011.

[49] Aljure OD, Fabbro M, 2nd. Cardiopulmonary Bypass and Inflammation: The Hidden Enemy. Journal of Cardiothoracic and Vascular Anesthesia. 2019; 33: 346–347. https://doi.org/10.1053/j.jvca.2018.05.030.

[50] Baumann Kreuziger L, Karkouti K, Tweddell J, Massicotte MP. Antithrombotic therapy management of adult and pediatric cardiac surgery patients. Journal of Thrombosis and Haemostasis: JTH. 2018; 16: 2133–2146. https://doi.org/10.1111/jth.14276.

Funding

National Natural Science Foundation of China(82170491)