Introduction

Constrictive pericarditis is a rare and severe disease caused by thickened and inelastic pericardium.1 The etiology of constrictive pericarditis is various including idiopathic, viral, prior cardiac surgery, history of radiotherapy, malignancy and trauma, whereas the most common cause remains to be tuberculosis, especially in developing countries.2–4 The prognosis for constrictive pericarditis is poor, and in most cases conservative treatment only provides temporary relief of symptoms.5 Pericardiectomy is a definitive treatment option, but surgical resection of pericardium carries a high risk of postoperative mortality with reported rate up to 17.6%.6–9

Given the difficulty of predicting precise prognosis in constrictive pericarditis, some easily accessible indicators, such as laboratory indicators, should be considered as predictors for a more accurate prognosis evaluation. Coagulation indicators are frequently screened preoperatively and taken into account during perioperative planning. Abnormal coagulation profiles could result in adverse postoperative outcomes.10,11 Among coagulation indicators, D-dimer has received growing attention especially and is commonly associated with various clinical settings such as inflammation, pneumonia, cancer, septicemia and surgery.12 Nevertheless, it is unclear about the effect of coagulation on postoperative outcomes of constrictive pericarditis. This study aimed to assess whether preoperative coagulation indicators had an impact on postoperative outcomes in constrictive pericarditis, thereby helping surgeons to screen out high-risk patients for early intervention.

MethodsPatients and Data Collection

The study protocol was approved by the Institutional Review Board of Hangzhou Red Cross Hospital (No. 2023140), and considering the nature of the retrospective study, written patient informed consent was waived. A total of 158 patients with clinically diagnosed constrictive pericarditis who underwent radical pericardiectomy at Hangzhou Red Cross Hospital between November 2012 and October 2023 were enrolled in this study. Patients with incomplete coagulation test results were not eligible.

The diagnosis of constrictive pericarditis was primarily based on clinical symptom, cardiac imaging and central venous pressure (CVP).13 Cardiac imaging examinations mainly included echocardiography and chest enhanced computed tomography. Cardiac magnetic resonance was also performed to confirm the diagnosis in some cases. The etiology of constrictive pericarditis was evaluated by pathologic examination and pathogen detection on resected pericardial tissue. All the information was obtained from the database of the Hangzhou Red Cross Hospital. The coagulation test results were collected within one week prior to operating surgery, including D-dimer (DD), activated partial thromboplastin time (APTT), prothrombin time (PT), international normalized ratio (INR), thrombin time (TT) and fibrinogen (FBG).

Surgery and Postoperative Outcomes

All included patients underwent radical pericardiectomy by median sternotomy without the use of cardiopulmonary bypass. The anterolateral pericardium between the two phrenic nerves, the pericardium from superior vena cava-right atrium junction to inferior vena cava-right atrium junction, the pericardium on the great arteries and the basal pericardium over the diaphragmatic surface were all included in the extent of pericardiectomy.14

The primary outcome was postoperative complications which were defined as the comorbidities occurring after pericardiectomy. The major postoperative complications included cardiac complications, pulmonary complications, acute liver or kidney injury and deep vein thrombosis. Cardiac complications included low cardiac output and arrhythmia. The definition of low cardiac output included decrease in the cardiac index to <2.0 liters per minute per square meter of body-surface area and a systolic blood pressure of <90 mmHg with signs of tissue hypoperfusion.15 Pulmonary complications included pneumonia, acute respiratory failure, atelectasis and pulmonary embolism. Other postoperative outcomes that were recorded included duration of intensive care unit (ICU) stay, intubation, vasoactive agents using, chest drainage, hospital stay and in-hospital mortality.

Statistical Analysis

The receiver operating characteristic (ROC) curve was constructed to analyze the correlation between coagulation indicators and postoperative complications, with the calculation of the area under curve (AUC). The cutoff value of coagulation indicator was determined by the ROC curve. The studied patients were divided into two groups according to the cutoff value. The proportions of categorical variables were assessed by Pearson’s chi-square test, corrected chi-square test or Fisher’s exact test. The comparison of continuous variables was tested by the Student’s t-test or Mann–Whitney U-test. Univariable and multivariable logistic regression models were performed to calculate the odds ratio (OR) and 95% confidence interval (CI). Variables with P <0.05 in univariable analysis were entered into a multivariable analysis. These analyses were conducted using R version 4.2.1 (https://www.r-project.org/) and SPSS software (version 24.0, IBM SPSS Inc. United States). The statistical significance was considered as a P <0.05 on two sides.

ResultsROC Curve

A total of 158 patients were available for analysis, and postoperative complications were reported in 59 (37.3%) patients, with cardiac complications in 34 (21.5%) patients, pulmonary complications in 20 (12.7%) patients, acute liver or kidney injury in 14 (8.9%) patients and deep vein thrombosis in 4 (2.5%) patients (Table 1).

Table 1 Postoperative Complications After Pericardiectomy

ROC curve analyses were performed to determine the correlation between coagulation indicators and postoperative complications. As shown in Figure 1A, preoperative DD level could effectively identify patients with postoperative complications from the studied population (AUC 0.771, 95% CI 0.696–0.847, P < 0.001). The value of the remaining indicators in identifying postoperative complications was not significant, with P = 0.658 for APTT, P = 0.082 for PT, P = 0.076 for INR, P = 0.896 for TT and P = 0.587 for FBG (Figure 1B–F).

Figure 1 Analysis of the diagnostic value of coagulation indicators for postoperative complications. (A) ROC curve analysis of the diagnostic value of DD; (B) ROC curve analysis of the diagnostic value of APTT; (C) ROC curve analysis of the diagnostic value of PT; (D) ROC curve analysis of the diagnostic value of INR; (E) ROC curve analysis of the diagnostic value of TT; (F) ROC curve analysis of the diagnostic value of FBG.

Abbreviations: DD, d-dimer; APTT, activated partial thromboplastin time; PT, prothrombin time; INR, international normalized ratio; TT, thrombin time; FBG, fibrinogen.

The results of ROC curve analyses showed that preoperative DD level also had diagnostic value for different types of postoperative complications (Figure 2), including cardiac complications (AUC 0.733, 95% CI 0.639–0.828, P < 0.001), pulmonary complications (AUC 0.739, 95% CI 0.617–0.861, P=0.001) and deep vein thrombosis (AUC 0.945, 95% CI 0.906–0.984, P = 0.002), but the diagnostic value for acute liver or kidney injury was not significant (AUC 0.655, 95% CI 0.510–0.800, P = 0.056).

Figure 2 Analysis of the diagnostic value of D-dimer for different postoperative complications. (A) ROC curve analysis of the diagnostic value for cardiac complications; (B) ROC curve analysis of the diagnostic value for pulmonary complications; (C) ROC curve analysis of the diagnostic value for acute liver or kidney injury; (D) ROC curve analysis of the diagnostic value for deep vein thrombosis.

Baseline Characteristics

In the studied population, a cut-off point of preoperative DD level was established at 2085.5 ug/L from the ROC curve, with a sensitivity of 79.7%, specificity of 62.6% and Youden index of 0.423. According to the cut-off value, 74 (46.8%) patients were assigned to the low DD group and 84 (53.2%) were assigned to the high DD group. The preoperative baseline characteristics of the two groups were presented in Table 2. Compared to the low DD group, a higher proportion of patients in the high DD group had tuberculosis as the etiology of constrictive pericarditis (95.2% vs 85.1%, P = 0.031). Inflammatory indicators such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were also higher in the high DD group (P < 0.001 and P = 0.001, respectively). In the high DD group, the levels of platelets (P = 0.015) and international normalized ratio (INR) (P < 0.001) were higher than the low DD group. Prothrombin time (PT) was longer in the high DD group (P < 0.001). In addition, pericardium was thicker in the high DD group than in the low DD group (P < 0.001). In terms of comorbidities, patients in the high DD group had a higher rate of diabetes (P = 0.013), while other comorbidities were not significantly different between the two groups.

Table 2 Preoperative Baseline Characteristics of the Patients

Postoperative Outcomes

Table 3 presents the results of the comparison of postoperative outcomes. Postoperative brain natriuretic peptide (BNP) level was higher in the high DD group than in the low DD group (P = 0.024). The frequency of postoperative complications was significantly higher in the high DD group (56.0% vs 16.2%, P < 0.001). The durations of vasoactive agents using, intubation and ICU stay were significantly longer in the high DD group (P = 0.018, 0.020 and 0.008, respectively). Longer durations of chest drainage and hospital stay were also observed in the high DD group (P = 0.004 and 0.002, respectively). One patient died in the high DD group, but the difference from the low DD group was not significant.

Table 3 Comparison of Postoperative Outcomes

To further clarify the independent prognostic factors, we assessed the correlation between clinical characteristics and postoperative complications of the patients. The results of univariable and multivariable analyses were presented in Supplemental Table 1. Multivariable analysis showed that high preoperative DD level was the independent risk factor of postoperative complications (OR 6.892, 95% CI 2.604–18.235, P < 0.001) (Table 4).

Table 4 Effect of Preoperative DD Level on Postoperative Complications

Discussion

In this retrospective study, we employed a cohort in a single medical database with numerous clinical variables including coagulation indicators, and presented the results of ROC curves to determine the predictive value of coagulation indicators for postoperative complications. Preoperative DD level had a potential diagnostic value for postoperative complications and was significantly associated with postoperative outcomes among the patients with constrictive pericarditis receiving pericardiectomy. These results could provide some reference value to surgeons in identifying high-risk patients preoperatively.

In majority of cases, constrictive pericarditis is chronic, progressive and life-threatening, and tuberculosis is still the major cause.16 In our study, more than 90% of patients were attributed to tuberculosis, especially in the high DD group. Surgery remains the only effective approach for relieving pericardial constriction but was accompanied with high risk of complications and mortality. Several previous studies have analyzed perioperative characteristics of patients undergoing pericardiectomy and identified some meaningful risk factors such as preoperative functional class, CVP, pulmonary artery pressure, intraoperative fluid infusion rate and extent of resection.17–20 In addition, the use of cardiopulmonary bypass was also associated with poor postoperative outcomes.21,22 However, it has remained unknown about the effect of coagulation indicators on the postoperative outcomes.

Among coagulation indicators including DD, APTT, PT, INR, TT and FBG, we found the specific role of preoperative DD level in evaluating postoperative outcomes in constrictive pericarditis. DD has been broadly employed in the diagnostic assessment of suspected venous thromboembolism and aortic syndrome.23 Moreover, elevated preoperative DD level could independently predict major complications and act as an independent prognostic factor for overall survival and recurrence free survival in patients with malignant diseases.24–26 Previous studies also suggested that increased DD value was observed in virus and tuberculosis infected patients and was associated with the severity of diseases.27,28 However, the relationship between DD and treatment outcomes in inflammatory diseases remains to be further explored.

Our study divided included patients into two groups according to the cutoff value of preoperative DD level. By comparing the baseline characteristics, we observed that patients in the high DD group had higher level of CRP and ESR than those in the low DD group, which could be explained by the higher proportion of patients with tuberculosis in the high DD group, but other important inflammatory parameters such as IL-6 were not evaluated in our study. This finding was consistent with a previous study and suggested that DD could be perceived as a measure of the inflammatory burden.29 Reactive thrombocytosis has already been described in the context of inflammatory conditions.30 Therefore, in patients with high DD, a significantly higher platelet count was also detected in this work. Interestingly, the levels of PT and INR were higher in the high DD group than in the low DD group, but the differences were not necessarily clinically significant.

Furthermore, we should also emphasize that significantly longer durations of postoperative vasoactive agents using, intubation and ICU stay were observed in patients with high preoperative DD level. Similarly, Hui Lian et al analyzed 8813 old patients admitted to ICU and found that DD level at ICU admission was strongly correlated with ventilation time in the old population.31 The rise in DD was shown to be associated with endothelial dysfunction and fibrin accumulating in the alveoli.32 Therefore, it was reasonable that high DD level led to longer durations of postoperative vasoactive agents using and intubation, which could be also a rational explanation for the association between high DD level and longer ICU stay. Our study further added preliminary evidence that high DD level was an independent risk factor for postoperative complications by univariable and multivariable analyses. These results highlighted the possibly of more severe clinical presentation in patients with high DD level.

Certain limitations relevant to this study should be acknowledged. First, because of the retrospective and single-center study design, the generalizability of our results is limited. Second, the sample size in this study is relatively small due to the low prevalence of constrictive pericarditis, so studies with larger sample size are needed to confirm the results. Third, the mechanisms of the link between DD and postoperative outcomes cannot be explicated in this study. Finally, only preoperative DD value is available in this dataset, which prevents us from having information on DD kinetics during the course of constrictive pericarditis.

Conclusion

Our study identified preoperative DD level as a diagnostic factor for postoperative complications, including cardiac complications, pulmonary complications and deep vein thrombosis. High preoperative DD level was significantly linked to poor postoperative outcomes and was an independent predictor of postoperative complications. These results suggested that DD could add useful clue for the risk stratification of patients with constrictive pericarditis undergoing pericardiectomy.

Abbreviations

DD, d-dimer; APTT, activated partial thromboplastin time; PT, prothrombin time; INR, international normalized ratio; TT, thrombin time; FBG, fibrinogen; ROC, receiver operating characteristic; AUC, area under curve; ICU, intensive care unit; OR, odds ratio; CI, confidence interval.

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

The study protocol was approved by the Institutional Review Board of Hangzhou Red Cross Hospital (No. 2023140). Because of the retrospective nature of the study and without any specific intervention, the informed consent has been agreed to be waived. The data were maintained with confidentiality. The present study complied with the Declaration of Helsinki.

Funding

There is no funding to report.

Disclosure

The authors declare that they have no competing interests in this work.

References

1. Hoit BD. Pathophysiology of the Pericardium. Prog Cardiovasc Dis. 2017;59(4):341–348. doi:10.1016/j.pcad.2016.11.001

2. Noubiap JJ, Agbor VN, Ndoadoumgue AL, et al. Epidemiology of pericardial diseases in Africa: a systematic scoping review. Heart. 2019;105(3):180–188. doi:10.1136/heartjnl-2018-313922

3. Dybowska M, Blasinska K, Gatarek J, et al. Tuberculous pericarditis-own experiences and recent recommendations. Diagnostics. 2022;12(3):619. doi:10.3390/diagnostics12030619

4. Ntsekhe M. Pericardial disease in the developing world. Can J Cardiol. 2023;39(8):1059–1066. doi:10.1016/j.cjca.2023.05.005

5. Welch TD. Constrictive pericarditis: diagnosis, management and clinical outcomes. Heart. 2018;104(9):725–731. doi:10.1136/heartjnl-2017-311683

6. Kang SH, Song JM, Kim M, et al. Prognostic predictors in pericardiectomy for chronic constrictive pericarditis. J Thorac Cardiovasc Surg. 2014;147(2):598–605. doi:10.1016/j.jtcvs.2013.01.022

7. Adler Y, Charron P, Imazio M, et al. 2015 ESC guidelines for the diagnosis and management of pericardial diseases: the task force for the diagnosis and management of pericardial diseases of the European Society of Cardiology (ESC)Endorsed by: the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2015;36(42):2921–2964. doi:10.1093/eurheartj/ehv318

8. Bertazzo B, Cicolini A, Fanilla M, Bertolotti A. Surgical treatment of constrictive pericarditis. Brazilian J Cardiovasc Surg. 2023;38(3):320–325.

9. Yesiltas MA, Kavala AA, Turkyilmaz S, et al. Surgical treatment of constrictive pericarditis at a single center: 10 years of experience. Acta chirurgica Belgica. 2024;124(2):107–113. doi:10.1080/00015458.2023.2216377

10. Chung JJ, Dolan MT, Patetta MJ, et al. Abnormal coagulation as a risk factor for postoperative complications after primary and revision total hip and total knee arthroplasty. J Arthroplasty. 2021;36(9):3294–3299. doi:10.1016/j.arth.2021.04.024

11. Luo MH, Luo JC, Zhang YJ, et al. Early postoperative organ dysfunction is highly associated with the mortality risk of patients with type A aortic dissection. Interact Cardiovasc Thoracic Surg. 2022;35(6). doi:10.1093/icvts/ivac266

12. Weitz JI, Fredenburgh JC, Eikelboom JW. A Test in Context: d-Dimer. J Am Colle Cardiol. 2017;70(19):2411–2420. doi:10.1016/j.jacc.2017.09.024

13. Diaz-Arocutipa C, Chumbiauca M, Medina HM, et al. Echocardiographic criteria to differentiate constrictive pericarditis from restrictive cardiomyopathy: a meta-analysis. CJC Open. 2023;5(9):680–690. doi:10.1016/j.cjco.2023.06.002

14. Cho YH, Schaff HV. Extent of pericardial resection for constrictive pericardiectomy. Ann Thorac Surg. 2012;94(6):2180. doi:10.1016/j.athoracsur.2012.04.116

15. Lomivorotov VV, Efremov SM, Kirov MY, et al. Low-cardiac-output syndrome after cardiac surgery. J Cardiothor Vascu Anesthesia. 2017;31(1):291–308. doi:10.1053/j.jvca.2016.05.029

16. Gillombardo CB, Hoit BD. Constrictive pericarditis in the new millennium. J Cardiol. 2023;S0914–S5087(23):00225.

17. Nishimura S, Izumi C, Amano M, et al. Long-term clinical outcomes and prognostic factors after pericardiectomy for constrictive pericarditis in a Japanese population. Circulat J. 2017;81(2):206–212. doi:10.1253/circj.CJ-16-0633

18. Nozohoor S, Johansson M, Koul B, et al. Radical pericardiectomy for chronic constrictive pericarditis. J Cardiac Surg. 2018;33(6):301–307. doi:10.1111/jocs.13715

19. Fang L, Zheng H, Yu W, et al. Effects of intraoperative fluid management on postoperative outcomes after pericardiectomy. Front Surg. 2021;8:673466. doi:10.3389/fsurg.2021.673466

20. Fang LK, Yu GC, Huang JP, et al. Predictors of postoperative complication and prolonged intensive care unit stay after complete pericardiectomy in tuberculous constrictive pericarditis. J Cardiothor Surg. 2020;15(1):148–155. doi:10.1186/s13019-020-01198-9

21. Gatti G, Fiore A, Ternacle J, et al. Pericardiectomy for constrictive pericarditis: a risk factor analysis for early and late failure. Heart Vessels. 2020;35(1):92–103. doi:10.1007/s00380-019-01464-4

22. Rupprecht L, Putz C, Florchinger B, et al. Pericardiectomy for constrictive pericarditis: an institution’s 21 years experience. Thoracic Cardiovasc Surg. 2018;66(8):645–650. doi:10.1055/s-0037-1604303

23. Innocenti F, Lazzari C, Ricci F, et al. D-Dimer tests in the emergency department: current insights. Open Access Emerg Med. 2021;13:465–479. doi:10.2147/OAEM.S238696

24. Chen Q, Zhao H, Wu J, et al. Preoperative D-dimer and gamma-glutamyltranspeptidase predict major complications and survival in colorectal liver metastases patients after resection. Transl Oncol. 2019;12(7):996–1004. doi:10.1016/j.tranon.2019.04.011

25. Otsu T, Hayashi M, Takami H, et al. High preoperative serum D-dimer predicts unfavorable survival outcomes for pancreatic cancer patients. Anticancer Res. 2023;43(7):3173–3181. doi:10.21873/anticanres.16491

26. Zhifei L, Yuexiang L, Shaofei C, et al. Elevated preoperative plasma D-dimer level was an independent prognostic factor for patients with PDAC after curative resection: a retrospective analysis. Japan J Clin Oncol. 2023;53(11):1058–1067. doi:10.1093/jjco/hyad090

27. Mollalign H, Chala D, Beyene D. Clinical features and treatment outcome of coronavirus and tuberculosis co-infected patients: a systematic review of case reports. Infect Drug Resist. 2022;15:4037–4046. doi:10.2147/IDR.S370837

28. Wang Y, Chen Y, Gu L, et al. The clinical characteristics and risk factors for severe COVID-19 in patients with COVID-19 and tuberculosis coinfection. Front Microbiol. 2022;13:1061879. doi:10.3389/fmicb.2022.1061879

29. Lazaros G, Vlachakis PK, Theofilis P, et al. D-dimer as a diagnostic and prognostic plasma biomarker in patients with a first episode of acute pericarditis. Eur J Intern Med. 2023;116:58–64. doi:10.1016/j.ejim.2023.06.017

30. Bleeker JS, Hogan WJ. Thrombocytosis: diagnostic evaluation, thrombotic risk stratification, and risk-based management strategies. Thrombosis. 2011;2011:536062. doi:10.1155/2011/536062

31. Lian H, Cai H, Zhang H, et al. The prediction value of D-dimer on prognosis in intensive care unit among old patients (>/=65 Years): a 9-year single-center retrospective study of 9261 cases. Oxid Med Cell Longev. 2022;2022:2238985. doi:10.1155/2022/2238985

32. Hunt BJ, Levi M. Re The source of elevated plasma D-dimer levels in COVID-19 infection. Br J Haematol. 2020;190(3):e133–e4. doi:10.1111/bjh.16907