The coagulation status in women of endometriosis with stage IV

The coagulation status in women of endometriosis with stage IV | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The coagulation status in women of endometriosis with stage IV Lu Wang, Jingxian Ling, Xianghong Zhu, Yan Zhang, Rong Li, Jingjing Huang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3884274/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Endometriosis is considered as a systemic disease with the presence of proinflammatory cytokines in the circulation, which drives hypercoagulable state. Currently, endometriosis is classified into four stages: I (minimal), II (mild), III (moderate) and IV (severe). The aim of this study is to investigate the correlations between inflammatory markers and coagulation factors in patients diagnosed endometriosis with stage IV. Methods This retrospective case–control study included 171 endometriosis patients with stage IV and 84 controls. Continuous data were expressed by mean ± standard deviation. Mann–Whitney U and χ2 tests were used to compare the medians and frequencies among the groups. Spearman analysis was conducted to determine the correlation among the measured parameters. The diagnostic values of the parameters differentiating endometriomas were tested by receiver operating characteristic (ROC) curve. Results The time of activated partial thromboplastin time (APTT) was decreased and the concentration of fibrinogen (FIB) and neutrophil-to-lymphocyte ratio (NLR) were increased in women of endometriosis with stage IV. The APTT were negatively correlated with NLR while the concentrations of FIB were positively correlated with NLR. The ROC analysis showed that the Area under the curve (AUC) of FIB was 0.766 (95% confidence interval:0.717–0.814) with sensitivity and specificity reaching 86.5 and 60.9%, respectively. The AUC of CA125 and CA199 was 0.638 (95% confidence interval: 0.578–0.697), 0.71 (95% confidence interval: 0.656–0.763) with sensitivity and specificity reaching 40.9 and 91.8%, 80.7 and 56.5% respectively. The combination of these factors showed the highest AUC of 0.895 (0.862–0.927) with sensitivity of 88.9% and specificity of 77.7%. Conclusion In the present study, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV. Moreover, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV. Endometriosis Inflammation Hypercoagulability Stage IV Figures Figure 1 Figure 2 Figure 3 Introduction Endometriosis is a chronic disease characterized by the presence of endometrial-like tissue outside the uterus[ 1 ]. This disorder is estimated to affect 5–10% of women of reproductive age[ 2 ]. Endometriosis is observed in 40–50% of women with persistent pelvic pain and up to 50% of women with infertility[ 3 ]. Despite endometriosis is prevalent, its diagnosis is typically delayed by years. The laparoscopy is considered as the gold standard for diagnosis for endometriosis. Heretofore, despite research on biomarkers, there is no reliable blood diagnostic biomarkers for endometriosis[ 4 ]. Currently, endometriosis is usually treated by surgery therapy. Endometriosis is recognized classified into four stages: I (minimal), II (mild), III (moderate) and IV (severe)[ 5 ]. Women of endometriosis with stage IV showed extensive lesions and more pelvic adhesions, which making surgery therapy more difficult[ 6 ]. It is necessary for us to identify the patients of endometriosis with stage IV before surgery, which could help us adequately prepare for surgery. Endometriosis is a systemic inflammatory condition with the presence of proinflammatory cytokines in the circulation[ 7 , 8 ]. In patients with endometriosis, the inflammation leads to the endometriosis-associated pain, endothelial dysfunction and carcinogenesis even though[ 7 , 9 ]. The activation of inflammation also drives hypercoagulable state[ 10 , 11 ]. The decreased levels of thrombin time (TT), activated partial thromboplastin time (APTT) and increased level of tissue factor (TF), fibrinogen have been found in patients with endometriosis[ 12 – 15 ]. However, the correlation between inflammatory markers and coagulation factors in patients of endometriosis with stage IV has not been clearly clarified. In the present study, we aimed to investigate the correlations between inflammatory markers and coagulation factors in patients diagnosed endometriosis with stage IV. We also explored the diagnostic value of these parameters in endometriosis with stage IV, which provide new ideas for diagnosis with auxiliary biomarkers. Methods Patients This research was approved by the ethics committee of the Nanjing Drum Tower Hospital (2024-094-01). A total of 355 patients including 171 endometriosis patients with stage IV and 184 control who underwent surgery between January 2022 and December 2023 was participated. The stage of endometriosis was established according to the revised classification of the American Society for Reproductive Medicine[ 5 ]. The control group included patients with a surgical diagnosis of uterine leiomyomas, tubal pathology, and ovarian benign cysts. All patients included in this research owned a histopathological diagnosis after either laparoscopic or laparotomic surgery. The patients in control group showed no stage of endometriosis by both the surgical and the histopathological examinations. All women have provided their informed consent for their clinical data to be used for researches purposes. The inclusion criteria were as follows: nonpregnant reproductive-age women and a surgical indication for endometriosis or other pelvic diseases. The exclusion criteria were as follows: patients in pregnancy or menopause; patients complicated autoimmune, hematological or blood coagulation diseases; patients with abnormal hepatic and renal function tests; patients who had taken corticosteroids and contraceptives within 3 months before surgery; patients with a diagnosis of malignancy. Blood Assay Before surgery, all patients had routine blood analyses including complete blood count parameters, serum biochemistry, activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), fibrinogen (FIB), neutrophil-to-lymphocyte ratio (NLR), serum carbohydrate antigen (CA) 125 and CA199. The NLR was obtained by dividing the absolute neutrophil count by the absolute lymphocyte count. All blood analyses were established during either the follicular or the luteal phase before surgery. Statistical analysis The data was analyzed by SPSS 22.0 software (Chicago SPSS Co., Ltd.). Continuous data were expressed by mean ± standard deviation. Mann–Whitney U and χ2 tests were used to compare the medians and frequencies among the groups. Spearman analysis was conducted to determine the correlation among the measured parameters. The diagnostic values of the parameters differentiating endometriomas were tested by receiver operating characteristic (ROC) curve. P < 0.05 is considered as statistical difference. Results Patients’ characteristics It was found that there were no statistical differences in age, BMI between Endometriosis with stage IV and Control groups (P > 0.05). Compared with the Control group, the parity was significantly lower, and the incidence of dysmenorrhea was significantly higher in the Endometriosis group (P 0.05, Table 1 ). Table 1 Baseline Characteristics of Controls and Patients of Endometriosis with stage IV. Characteristics Controls Endometriosis with stage IV P.value n = 184 n = 171 Age, years 31.27 ± 5.11 30.81 ± 5.07 0.40 BMI, kg/mq 24.20 ± 4.30 24.14 ± 4.73 0.89 Smoking, n (%) 16.85 24.56 0.07 Previous delivery, n (%) 14.13 11.11 0.39 Dysmenorrhea, n (%) 36.96 42.69 0.27 BMI, body mass index. The comparisons of levels of inflammatory and coagulation markers between Control and Endometriosis with stage IV To explore the coagulation state in women of endometriosis with stage IV, we compared the APTT, TT, PT and FIB between two groups. As shown in Fig. 1A, the time of APTT was significantly decreased in women of endometriosis with stage IV. The concentration of FIB was apparently increased in women of endometriosis with stage IV (Fig. 1D). However, the time of TT and PT showed no difference between two groups (Fig. 1B-C). These results showed that the women of endometriosis with stage IV exhibited a high coagulation state. Meanwhile, we also compared the inflammatory state between two groups. The NLR increased in women of endometriosis with stage IV (Fig. 1E). Besides, we investigated the correlation between coagulation factors and NLR. The correlation analysis showed that the APTT were negatively correlated with NLR while the concentrations of FIB were positively correlated with NLR (Fig. 2A-D). These results showed that the coagulation factors are closely related to inflammation. The diagnostic value of coagulation factors, CA125 and CA199 in Endometriosis with stage IV We investigated the diagnostic effects of coagulation factors, CA125 and CA199 by ROC analysis. As shown in Table 2 and Fig. 3a, in coagulation factors, FIB exhibited maximum Area under the curve (AUC) which was 0.766 (95% confidence interval:0.717–0.814) with sensitivity and specificity reaching 86.5 and 60.9%, respectively. The AUC of CA125 was 0.638 (95% confidence interval: 0.578–0.697) with sensitivity and specificity reaching 40.9 and 91.8%, respectively. Besides, the AUC of CA199 was 0.71 (95% confidence interval: 0.656–0.763) with sensitivity and specificity reaching 80.7and 56.5%, respectively. However, the combination of these factors showed the highest AUC of 0.895 (0.862–0.927) with sensitivity of 88.9% and specificity of 77.7% (Table 2 and Fig. 3b). Table 2 The diagnostic value of coagulation factors, CA125, CA199 and combined factor in patients of endometriosis with stage IV. parameters AUC(95%CI) Sensitvity(%) Specificity(%) cutoff value p APTT 0.651(0.590–0.713) 97.1 50 0.471 < 0.0001 TT 0.695(0.640–0.750) 70.2 68.5 0.387 < 0.0001 PT 0.576(0.512–0.641) 97.1 41.3 0.384 0.013 FIB 0.766(0.717–0.814) 86.5 60.9 0.474 < 0.0001 CA125 0.638(0.578–0.697) 40.9 91.8 0.327 < 0.0001 CA199 0.71(0.656–0.763) 80.7 56.5 0.372 < 0.0001 combined marker 0.895(0.862–0.927) 88.9 77.7 0.666 < 0.0001 APTT, activated partial thromboplastin time; TT, thrombin time; PT, prothrombin time; FIB, fibrinogen; CA125, serum cancer antigen 125; CA199, serum cancer antigen 199. Discussion Endometriosis is a chronic, systemic disease which can cause persistent pelvic and infertility[ 16 ]. The symptoms involve deep dyspareunia, severe dysmenorrhea, as well as bladder and bowel fatigue[ 17 ]. This disorder is so complex and heretofore, has no effective treatment. Both hormonal and surgical therapy are so limited and could not address the systemic syndrome. In addition, endometriosis is related to mental health, social life, affecting work productivity, and lead to a major economic burden[ 18 – 20 ]. Unfortunately, there is no other effective non-invasive diagnostic method besides pathological diagnosis after laparoscopic examination. Inflammation is an important response in the pathogenesis of endometriosis. Inflammation could lead to dysfunction of endothelial, even promote carcinogenesis[ 7 ]. Many inflammatory factors such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-33 and IL-6 were upregulated in peritoneal fluid of women with endometriosis[ 21 , 22 ]. Besides, inflammation cells including neutrophils and macrophages were activated in endometrium of women with endometriosis[ 23 ]. Moreover, increased evidence indicated that there existed a cross-talk between inflammation and coagulation, whereby the initiation of inflammation could lead to the activation of coagulation[ 12 ]. In the present study, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV. CA125 and CA199 often showed diagnostic value of the endometriosis[ 24 , 25 ]. Nevertheless, the predictive value of individual markers was limited. Some studies reported that CA125 combined with NLR showed useful diagnostic value, but the combination was not suitable for advanced endometriosis[ 26 – 28 ]. In our study, we found that coagulation factors combined with CA125 and CA199 were more reliable for identifying the endometriosis with stage IV. We still have some limitations. Firstly, the retrospective design of this study. Secondly, the patients in controls were surgical population. In summary, we confirmed that the coagulation factors were changed in women of endometriosis with stage IV. APTT and FIB showed significantly correlation with NLR. Moreover, the combination of coagulation factors with CA125 and CA199 showed useful diagnostic value for endometriosis with stage IV. Declarations Acknowledgements None. Consent to publication Not applicable. Author contributions LW, CW and HJZ performed the research and revised the paper. JXL, XHZ, YZ, RL, JJH and DDH performed the data extraction and data analysis. All authors read and approved the final manuscript. Funding No specific funding was obtained Availability of data and materials The datasets used and analyzed during this study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study is approved by the Human Ethics Committee of the Nanjing Drum Tower Hospital (2024-094-01) and all women provided written informed consent. Disclosure statement No conflict of interest was reported by the author(s). References Horne AW, Saunders PTK. SnapShot: Endometriosis. Cell. 2019;179(7):1677–7. e1671. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397(10276):839–52. Allaire C, Bedaiwy MA, Yong PJ. Diagnosis and management of endometriosis. CMAJ. 2023;195(10):E363–71. Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379:e070750. Revised American Society for Reproductive Medicine classification of endometriosis. : 1996. Fertil Steril 1997, 67(5):817–821. Zhao H, Zhang J, Bao ZL, Kong J, Wei W, Gu JQ. A preoperative predictive model for stage IV endometriosis. J Obstet Gynaecol. 2023;43(1):2188072. Jiang L, Yan Y, Liu Z, Wang Y. Inflammation and endometriosis. Front Biosci (Landmark Ed). 2016;21(5):941–8. Vallee A, Lecarpentier Y. Curcumin and Endometriosis. Int J Mol Sci 2020, 21(7). Wei Y, Liang Y, Lin H, Dai Y, Yao S. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J Neuroinflammation. 2020;17(1):80. Choi G, Schultz MJ, Levi M, van der Poll T. The relationship between inflammation and the coagulation system. Swiss Med Wkly. 2006;136(9–10):139–44. Witkowski M, Landmesser U, Rauch U. Tissue factor as a link between inflammation and coagulation. Trends Cardiovasc Med. 2016;26(4):297–303. Vigano P, Ottolina J, Sarais V, Rebonato G, Somigliana E, Candiani M. Coagulation Status in Women With Endometriosis. Reprod Sci. 2018;25(4):559–65. Ding S, Lin Q, Zhu T, Li T, Zhu L, Wang J, Zhang X. Is there a correlation between inflammatory markers and coagulation parameters in women with advanced ovarian endometriosis? BMC Womens Health. 2019;19(1):169. Ling X, Wang T. Diagnostic and prognostic value of coagulation-related factors in endometriosis. Am J Transl Res. 2022;14(11):7924–31. Li Y, Liu H, Ye S, Zhang B, Li X, Yuan J, Du Y, Wang J, Yang Y. The effects of coagulation factors on the risk of endometriosis: a Mendelian randomization study. BMC Med. 2023;21(1):195. Shim JY, Laufer MR. Adolescent Endometriosis: An Update. J Pediatr Adolesc Gynecol. 2020;33(2):112–9. Saunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 2021;184(11):2807–24. Chen LC, Hsu JW, Huang KL, Bai YM, Su TP, Li CT, Yang AC, Chang WH, Chen TJ, Tsai SJ, et al. Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal follow-up study. J Affect Disord. 2016;190:282–5. Soliman AM, Yang H, Du EX, Kelley C, Winkel C. The direct and indirect costs associated with endometriosis: a systematic literature review. Hum Reprod. 2016;31(4):712–22. Soliman AM, Coyne KS, Gries KS, Castelli-Haley J, Snabes MC, Surrey ES. The Effect of Endometriosis Symptoms on Absenteeism and Presenteeism in the Workplace and at Home. J Manag Care Spec Pharm. 2017;23(7):745–54. Cheong YC, Shelton JB, Laird SM, Richmond M, Kudesia G, Li TC, Ledger WL. IL-1, IL-6 and TNF-alpha concentrations in the peritoneal fluid of women with pelvic adhesions. Hum Reprod. 2002;17(1):69–75. Kato T, Yasuda K, Matsushita K, Ishii KJ, Hirota S, Yoshimoto T, Shibahara H. Interleukin-1/-33 Signaling Pathways as Therapeutic Targets for Endometriosis. Front Immunol. 2019;10:2021. Leiva MC, Hasty LA, Lyttle CR. Inflammatory changes of the endometrium in patients with minimal-to-moderate endometriosis. Fertil Steril. 1994;62(5):967–72. Rokhgireh S, Mehdizadeh Kashi A, Chaichian S, Delbandi AA, Allahqoli L, Ahmadi-Pishkuhi M, Khodaverdi S, Alkatout I. The Diagnostic Accuracy of Combined Enolase/Cr, CA125, and CA19-9 in the Detection of Endometriosis. Biomed Res Int 2020, 2020:5208279. Chen T, Wei JL, Leng T, Gao F, Hou SY. The diagnostic value of the combination of hemoglobin, CA199, CA125, and HE4 in endometriosis. J Clin Lab Anal. 2021;35(9):e23947. Yavuzcan A, Caglar M, Ustun Y, Dilbaz S, Ozdemir I, Yildiz E, Ozkara A, Kumru S. Evaluation of mean platelet volume, neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in advanced stage endometriosis with endometrioma. J Turk Ger Gynecol Assoc. 2013;14(4):210–5. Kim SK, Park JY, Jee BC, Suh CS, Kim SH. Association of the neutrophil-to-lymphocyte ratio and CA 125 with the endometriosis score. Clin Exp Reprod Med. 2014;41(4):151–7. Tokmak A, Yildirim G, Oztas E, Akar S, Erkenekli K, Gulsen P, Yilmaz N, Ugur M. Use of Neutrophil-to-Lymphocyte Ratio Combined With CA-125 to Distinguish Endometriomas From Other Benign Ovarian Cysts. Reprod Sci. 2016;23(6):795–802. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 01 Apr, 2024 Reviews received at journal 29 Mar, 2024 Reviews received at journal 10 Mar, 2024 Reviewers agreed at journal 06 Mar, 2024 Reviewers agreed at journal 05 Mar, 2024 Reviewers invited by journal 02 Mar, 2024 Editor assigned by journal 02 Mar, 2024 Editor invited by journal 02 Mar, 2024 Submission checks completed at journal 02 Mar, 2024 First submitted to journal 21 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3884274","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276551528,"identity":"991ca0c5-b624-4c6c-954b-1379316c425e","order_by":0,"name":"Lu Wang","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital, Nanjing University","correspondingAuthor":false,"prefix":"","firstName":"Lu","middleName":"","lastName":"Wang","suffix":""},{"id":276551529,"identity":"eab8a569-29ad-436b-9e32-ccbf2d184dd4","order_by":1,"name":"Jingxian Ling","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital, Nanjing 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20:01:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":686202,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3884274/v1/99116887-7c48-47ba-a530-7bb4cf7726a1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The coagulation status in women of endometriosis with stage IV","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a chronic disease characterized by the presence of endometrial-like tissue outside the uterus[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This disorder is estimated to affect 5\u0026ndash;10% of women of reproductive age[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Endometriosis is observed in 40\u0026ndash;50% of women with persistent pelvic pain and up to 50% of women with infertility[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite endometriosis is prevalent, its diagnosis is typically delayed by years. The laparoscopy is considered as the gold standard for diagnosis for endometriosis. Heretofore, despite research on biomarkers, there is no reliable blood diagnostic biomarkers for endometriosis[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrently, endometriosis is usually treated by surgery therapy. Endometriosis is recognized classified into four stages: I (minimal), II (mild), III (moderate) and IV (severe)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Women of endometriosis with stage IV showed extensive lesions and more pelvic adhesions, which making surgery therapy more difficult[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. It is necessary for us to identify the patients of endometriosis with stage IV before surgery, which could help us adequately prepare for surgery.\u003c/p\u003e \u003cp\u003eEndometriosis is a systemic inflammatory condition with the presence of proinflammatory cytokines in the circulation[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In patients with endometriosis, the inflammation leads to the endometriosis-associated pain, endothelial dysfunction and carcinogenesis even though[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The activation of inflammation also drives hypercoagulable state[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The decreased levels of thrombin time (TT), activated partial thromboplastin time (APTT) and increased level of tissue factor (TF), fibrinogen have been found in patients with endometriosis[\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the correlation between inflammatory markers and coagulation factors in patients of endometriosis with stage IV has not been clearly clarified.\u003c/p\u003e \u003cp\u003eIn the present study, we aimed to investigate the correlations between inflammatory markers and coagulation factors in patients diagnosed endometriosis with stage IV. We also explored the diagnostic value of these parameters in endometriosis with stage IV, which provide new ideas for diagnosis with auxiliary biomarkers.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cb\u003ePatients\u003c/b\u003e \u003c/p\u003e \u003cp\u003e This research was approved by the ethics committee of the Nanjing Drum Tower Hospital (2024-094-01). A total of 355 patients including 171 endometriosis patients with stage IV and 184 control who underwent surgery between January 2022 and December 2023 was participated. The stage of endometriosis was established according to the revised classification of the American Society for Reproductive Medicine[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The control group included patients with a surgical diagnosis of uterine leiomyomas, tubal pathology, and ovarian benign cysts. All patients included in this research owned a histopathological diagnosis after either laparoscopic or laparotomic surgery. The patients in control group showed no stage of endometriosis by both the surgical and the histopathological examinations. All women have provided their informed consent for their clinical data to be used for researches purposes. The inclusion criteria were as follows: nonpregnant reproductive-age women and a surgical indication for endometriosis or other pelvic diseases. The exclusion criteria were as follows: patients in pregnancy or menopause; patients complicated autoimmune, hematological or blood coagulation diseases; patients with abnormal hepatic and renal function tests; patients who had taken corticosteroids and contraceptives within 3 months before surgery; patients with a diagnosis of malignancy.\u003c/p\u003e\n\u003ch3\u003eBlood Assay\u003c/h3\u003e\n\u003cp\u003eBefore surgery, all patients had routine blood analyses including complete blood count parameters, serum biochemistry, activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), fibrinogen (FIB), neutrophil-to-lymphocyte ratio (NLR), serum carbohydrate antigen (CA) 125 and CA199. The NLR was obtained by dividing the absolute neutrophil count by the absolute lymphocyte count. All blood analyses were established during either the follicular or the luteal phase before surgery.\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe data was analyzed by SPSS 22.0 software (Chicago SPSS Co., Ltd.). Continuous data were expressed by mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Mann\u0026ndash;Whitney U and χ2 tests were used to compare the medians and frequencies among the groups. Spearman analysis was conducted to determine the correlation among the measured parameters. The diagnostic values of the parameters differentiating endometriomas were tested by receiver operating characteristic (ROC) curve. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is considered as statistical difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003ePatients\u0026rsquo; characteristics\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIt was found that there were no statistical differences in age, BMI between Endometriosis with stage IV and Control groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Compared with the Control group, the parity was significantly lower, and the incidence of dysmenorrhea was significantly higher in the Endometriosis group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). No statistical difference in the size of ovarian cysts between the Endometriosis and Control groups was observed (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of Controls and Patients of Endometriosis with stage IV.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControls\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEndometriosis with stage IV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP.value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;171\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.27\u0026thinsp;\u0026plusmn;\u0026thinsp;5.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.81\u0026thinsp;\u0026plusmn;\u0026thinsp;5.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/mq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.20\u0026thinsp;\u0026plusmn;\u0026thinsp;4.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.14\u0026thinsp;\u0026plusmn;\u0026thinsp;4.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious delivery, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysmenorrhea, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eBMI, body mass index.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eThe comparisons of levels of inflammatory and coagulation markers between Control and Endometriosis with stage IV\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTo explore the coagulation state in women of endometriosis with stage IV, we compared the APTT, TT, PT and FIB between two groups. As shown in Fig.\u0026nbsp;1A, the time of APTT was significantly decreased in women of endometriosis with stage IV. The concentration of FIB was apparently increased in women of endometriosis with stage IV (Fig.\u0026nbsp;1D). However, the time of TT and PT showed no difference between two groups (Fig.\u0026nbsp;1B-C). These results showed that the women of endometriosis with stage IV exhibited a high coagulation state. Meanwhile, we also compared the inflammatory state between two groups. The NLR increased in women of endometriosis with stage IV (Fig.\u0026nbsp;1E). Besides, we investigated the correlation between coagulation factors and NLR. The correlation analysis showed that the APTT were negatively correlated with NLR while the concentrations of FIB were positively correlated with NLR (Fig.\u0026nbsp;2A-D). These results showed that the coagulation factors are closely related to inflammation.\u003c/p\u003e\n\u003ch3\u003eThe diagnostic value of coagulation factors, CA125 and CA199 in Endometriosis with stage IV\u003c/h3\u003e\n\u003cp\u003eWe investigated the diagnostic effects of coagulation factors, CA125 and CA199 by ROC analysis. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;3a, in coagulation factors, FIB exhibited maximum Area under the curve (AUC) which was 0.766 (95% confidence interval:0.717\u0026ndash;0.814) with sensitivity and specificity reaching 86.5 and 60.9%, respectively. The AUC of CA125 was 0.638 (95% confidence interval: 0.578\u0026ndash;0.697) with sensitivity and specificity reaching 40.9 and 91.8%, respectively. Besides, the AUC of CA199 was 0.71 (95% confidence interval: 0.656\u0026ndash;0.763) with sensitivity and specificity reaching 80.7and 56.5%, respectively. However, the combination of these factors showed the highest AUC of 0.895 (0.862\u0026ndash;0.927) with sensitivity of 88.9% and specificity of 77.7% (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;3b).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe diagnostic value of coagulation factors, CA125, CA199 and combined factor in patients of endometriosis with stage IV.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eparameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAUC(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSensitvity(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSpecificity(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecutoff value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.651(0.590\u0026ndash;0.713)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e97.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.471\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.695(0.640\u0026ndash;0.750)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.387\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.576(0.512\u0026ndash;0.641)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e97.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.384\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.766(0.717\u0026ndash;0.814)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e86.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.474\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.638(0.578\u0026ndash;0.697)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA199\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.71(0.656\u0026ndash;0.763)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e80.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecombined marker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.895(0.862\u0026ndash;0.927)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e88.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.666\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAPTT, activated partial thromboplastin time; TT, thrombin time; PT, prothrombin time; FIB, fibrinogen; CA125, serum cancer antigen 125; CA199, serum cancer antigen 199.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eEndometriosis is a chronic, systemic disease which can cause persistent pelvic and infertility[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The symptoms involve deep dyspareunia, severe dysmenorrhea, as well as bladder and bowel fatigue[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This disorder is so complex and heretofore, has no effective treatment. Both hormonal and surgical therapy are so limited and could not address the systemic syndrome. In addition, endometriosis is related to mental health, social life, affecting work productivity, and lead to a major economic burden[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Unfortunately, there is no other effective non-invasive diagnostic method besides pathological diagnosis after laparoscopic examination.\u003c/p\u003e \u003cp\u003eInflammation is an important response in the pathogenesis of endometriosis. Inflammation could lead to dysfunction of endothelial, even promote carcinogenesis[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Many inflammatory factors such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-33 and IL-6 were upregulated in peritoneal fluid of women with endometriosis[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Besides, inflammation cells including neutrophils and macrophages were activated in endometrium of women with endometriosis[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Moreover, increased evidence indicated that there existed a cross-talk between inflammation and coagulation, whereby the initiation of inflammation could lead to the activation of coagulation[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In the present study, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV.\u003c/p\u003e \u003cp\u003eCA125 and CA199 often showed diagnostic value of the endometriosis[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Nevertheless, the predictive value of individual markers was limited. Some studies reported that CA125 combined with NLR showed useful diagnostic value, but the combination was not suitable for advanced endometriosis[\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In our study, we found that coagulation factors combined with CA125 and CA199 were more reliable for identifying the endometriosis with stage IV.\u003c/p\u003e \u003cp\u003eWe still have some limitations. Firstly, the retrospective design of this study. Secondly, the patients in controls were surgical population. In summary, we confirmed that the coagulation factors were changed in women of endometriosis with stage IV. APTT and FIB showed significantly correlation with NLR. Moreover, the combination of coagulation factors with CA125 and CA199 showed useful diagnostic value for endometriosis with stage IV.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLW, CW and HJZ performed the research and revised the paper. JXL, XHZ, YZ, RL, JJH and DDH performed the data extraction and data analysis. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific funding was obtained\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during this study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is approved by the Human Ethics Committee of the Nanjing Drum Tower Hospital (2024-094-01) and all women provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interest was reported by the author(s).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHorne AW, Saunders PTK. SnapShot: Endometriosis. Cell. 2019;179(7):1677\u0026ndash;7. e1671.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397(10276):839\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAllaire C, Bedaiwy MA, Yong PJ. Diagnosis and management of endometriosis. CMAJ. 2023;195(10):E363\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379:e070750.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRevised American Society for Reproductive Medicine classification of endometriosis. : 1996. \u003cem\u003eFertil Steril\u003c/em\u003e 1997, 67(5):817\u0026ndash;821.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao H, Zhang J, Bao ZL, Kong J, Wei W, Gu JQ. A preoperative predictive model for stage IV endometriosis. J Obstet Gynaecol. 2023;43(1):2188072.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang L, Yan Y, Liu Z, Wang Y. Inflammation and endometriosis. Front Biosci (Landmark Ed). 2016;21(5):941\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVallee A, Lecarpentier Y. Curcumin and Endometriosis. Int J Mol Sci 2020, 21(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei Y, Liang Y, Lin H, Dai Y, Yao S. Autonomic nervous system and inflammation interaction in endometriosis-associated pain. J Neuroinflammation. 2020;17(1):80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChoi G, Schultz MJ, Levi M, van der Poll T. The relationship between inflammation and the coagulation system. Swiss Med Wkly. 2006;136(9\u0026ndash;10):139\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWitkowski M, Landmesser U, Rauch U. 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The effects of coagulation factors on the risk of endometriosis: a Mendelian randomization study. BMC Med. 2023;21(1):195.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShim JY, Laufer MR. Adolescent Endometriosis: An Update. J Pediatr Adolesc Gynecol. 2020;33(2):112\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 2021;184(11):2807\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen LC, Hsu JW, Huang KL, Bai YM, Su TP, Li CT, Yang AC, Chang WH, Chen TJ, Tsai SJ, et al. Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal follow-up study. J Affect Disord. 2016;190:282\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoliman AM, Yang H, Du EX, Kelley C, Winkel C. The direct and indirect costs associated with endometriosis: a systematic literature review. Hum Reprod. 2016;31(4):712\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoliman AM, Coyne KS, Gries KS, Castelli-Haley J, Snabes MC, Surrey ES. The Effect of Endometriosis Symptoms on Absenteeism and Presenteeism in the Workplace and at Home. J Manag Care Spec Pharm. 2017;23(7):745\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheong YC, Shelton JB, Laird SM, Richmond M, Kudesia G, Li TC, Ledger WL. IL-1, IL-6 and TNF-alpha concentrations in the peritoneal fluid of women with pelvic adhesions. Hum Reprod. 2002;17(1):69\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKato T, Yasuda K, Matsushita K, Ishii KJ, Hirota S, Yoshimoto T, Shibahara H. Interleukin-1/-33 Signaling Pathways as Therapeutic Targets for Endometriosis. Front Immunol. 2019;10:2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeiva MC, Hasty LA, Lyttle CR. Inflammatory changes of the endometrium in patients with minimal-to-moderate endometriosis. Fertil Steril. 1994;62(5):967\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRokhgireh S, Mehdizadeh Kashi A, Chaichian S, Delbandi AA, Allahqoli L, Ahmadi-Pishkuhi M, Khodaverdi S, Alkatout I. The Diagnostic Accuracy of Combined Enolase/Cr, CA125, and CA19-9 in the Detection of Endometriosis. \u003cem\u003eBiomed Res Int\u003c/em\u003e 2020, 2020:5208279.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen T, Wei JL, Leng T, Gao F, Hou SY. The diagnostic value of the combination of hemoglobin, CA199, CA125, and HE4 in endometriosis. J Clin Lab Anal. 2021;35(9):e23947.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYavuzcan A, Caglar M, Ustun Y, Dilbaz S, Ozdemir I, Yildiz E, Ozkara A, Kumru S. Evaluation of mean platelet volume, neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in advanced stage endometriosis with endometrioma. J Turk Ger Gynecol Assoc. 2013;14(4):210\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim SK, Park JY, Jee BC, Suh CS, Kim SH. Association of the neutrophil-to-lymphocyte ratio and CA 125 with the endometriosis score. Clin Exp Reprod Med. 2014;41(4):151\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTokmak A, Yildirim G, Oztas E, Akar S, Erkenekli K, Gulsen P, Yilmaz N, Ugur M. Use of Neutrophil-to-Lymphocyte Ratio Combined With CA-125 to Distinguish Endometriomas From Other Benign Ovarian Cysts. Reprod Sci. 2016;23(6):795\u0026ndash;802.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Endometriosis, Inflammation, Hypercoagulability, Stage IV","lastPublishedDoi":"10.21203/rs.3.rs-3884274/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3884274/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEndometriosis is considered as a systemic disease with the presence of proinflammatory cytokines in the circulation, which drives hypercoagulable state. Currently, endometriosis is classified into four stages: I (minimal), II (mild), III (moderate) and IV (severe). The aim of this study is to investigate the correlations between inflammatory markers and coagulation factors in patients diagnosed endometriosis with stage IV.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective case\u0026ndash;control study included 171 endometriosis patients with stage IV and 84 controls. Continuous data were expressed by mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Mann\u0026ndash;Whitney U and χ2 tests were used to compare the medians and frequencies among the groups. Spearman analysis was conducted to determine the correlation among the measured parameters. The diagnostic values of the parameters differentiating endometriomas were tested by receiver operating characteristic (ROC) curve.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe time of activated partial thromboplastin time (APTT) was decreased and the concentration of fibrinogen (FIB) and neutrophil-to-lymphocyte ratio (NLR) were increased in women of endometriosis with stage IV. The APTT were negatively correlated with NLR while the concentrations of FIB were positively correlated with NLR. The ROC analysis showed that the Area under the curve (AUC) of FIB was 0.766 (95% confidence interval:0.717\u0026ndash;0.814) with sensitivity and specificity reaching 86.5 and 60.9%, respectively. The AUC of CA125 and CA199 was 0.638 (95% confidence interval: 0.578\u0026ndash;0.697), 0.71 (95% confidence interval: 0.656\u0026ndash;0.763) with sensitivity and specificity reaching 40.9 and 91.8%, 80.7 and 56.5% respectively. The combination of these factors showed the highest AUC of 0.895 (0.862\u0026ndash;0.927) with sensitivity of 88.9% and specificity of 77.7%.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn the present study, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV. Moreover, we found that inflammatory factors showed significant correlation with APTT or FIB in endometriosis with stage IV.\u003c/p\u003e","manuscriptTitle":"The coagulation status in women of endometriosis with stage IV","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-06 19:53:07","doi":"10.21203/rs.3.rs-3884274/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-01T15:59:46+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-29T19:04:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-10T09:41:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8460083a-03de-4ef8-9b4d-e329e2c1e2c1","date":"2024-03-06T18:03:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30368326-4b46-46f5-8410-de8c93da07ee","date":"2024-03-05T14:39:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-02T16:58:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-02T16:54:58+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-03-02T16:16:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-02T15:57:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2024-01-21T09:17:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"185935e6-0495-47b0-b90e-5372b936aa1f","owner":[],"postedDate":"March 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-24T08:21:39+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-06 19:53:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3884274","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3884274","identity":"rs-3884274","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}