Heparin Rebound in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting Surgery：A Single-Center Retrospective Study

Heparin Rebound in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting Surgery：A Single-Center Retrospective Study | 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 Heparin Rebound in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting Surgery：A Single-Center Retrospective Study Yang Xu, Fei Jiang, Shan-shan Hu, Jin-quan Wang, Yun-tai Yao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4577442/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Jan, 2025 Read the published version in Journal of Cardiothoracic Surgery → Version 1 posted 18 You are reading this latest preprint version Abstract Background Heparin, an anticoagulant used in cardiac surgery, can result in heparin rebound (HR), where it returns postoperatively despite being neutralized with protamine. This study was designed to investigate the prevalence of HR in patients undergoing off-pump coronary artery bypass grafting (OPCAB) and evaluate the impact of HR on their short-term outcomes. Methods We analyzed 503 OPCAB patients aged 31–80 years from September 2019 to June 2022, who were categorized into HR (n = 56) and Non-HR (n = 447) groups. HR was defined by a 10% increase in activated coagulation time (ACT) after heparin neutralization with protamine, bleeding over 200 mL/h, and abnormal laboratory coagulation examination results. The primary outcome was postoperative bleeding volume. Secondary outcomes included the incidence of postoperative reoperation for bleeding, allogenic blood transfusion incidences and volumes, and laboratory variables. Data were analyzed using t-tests, Mann–Whitney U tests, and Pearson’s χ2 or Fisher’s exact tests. Results Significant differences were observed in preoperative platelet counts ( P < 0.001) and the ACT measured 2 hours post-heparin neutralization ( P = 0.012). The group HR exhibited higher 24-hour bleeding volumes, increased reoperation rates, and greater total bleeding volumes (all P < 0.001). Conclusions Postoperative HR was found to be prevalent in OPCAB patients and increased bleeding risks. These findings indicate the need for future randomized controlled trials to confirm the impact of HR and guide patient blood management. Heparin rebound Bleeding Protamine Activated coagulation time Off-pump coronary artery bypass grafting Figures Figure 1 Introduction Heparin Rebound (HR) is a phenomenon where heparin's anticoagulant effects re-emerge postoperatively after being neutralized with protamine during cardiac surgery [ 1 ]. HR may lead to increased bleeding following surgery, and in cases where prolonged coagulation times and/or continued bleeding are observed, additional doses of protamine may be required. Various definitions of HR can be found in the literature. For example, some groups considered a prolonged coagulation-based laboratory test, such as the activated coagulation time (ACT), activated partial thromboplastin time (APTT), prothrombin time (PT), or international normalized ratio (INR), as an indicator of HR [ 2 – 6 ]. In addition, some groups suggested both increased bleeding (at a rate of more than 200 mL/h) and abnormal laboratory test results for a diagnosis of HR [ 7 ]. Off-pump coronary artery bypass grafting (OPCAB) is widely recognized as a safe procedure for treating ischemic heart disease. Numerous research studies have consistently demonstrated that OPCAB results in fewer complications compared to on-pump coronary artery bypass graft (CABG) [ 8 – 9 ]. However, the authors' conclusions do not adequately consider the multifactorial complexity of postoperative bleeding. While the authors do acknowledge the potential occurrence of the HR phenomenon, which may contribute to abnormal bleeding, further exploration of this topic is necessary. Therefore, additional research is needed to confirm these findings. Consequently, the present study aims to investigate the specific characteristics of HR associated with OPCAB. Methods Study design and population Informed consent was not requested as this study is a retrospective chart review. The study did not involve the identification of patients' personal information. Consecutive patients who underwent primary and isolated OPCAB at a large-volume cardiovascular center between September 2019 and June 2022 were screened for eligibility. The inclusion criteria are as follows: (1) adult patients (> 18 years old); (2) patients undergoing OPCAB; (3) normal preoperative coagulation function. Exclusion criteria include: (1) taking anticoagulant drugs; (2) emergency OPCAB; (3) patients with missing or incomplete outcomes of interest; (4) prior cardiac surgery. Anesthetic and surgical protocol Chronic cardiac medications, such as anti-hypertensive and anti-anginal agents, were continued up to the morning of surgery. Anti-platelet and anticoagulation medications were discontinued before surgery. No anesthetic premedication was given. The anesthetic technique adhered to a standardized protocol. Aspirin alone or in combination with a P2Y12 inhibitor (clopidogrel or ticagrelor) was administered orally after the removal of the chest drainage tube in the postoperative period, as determined by the surgeons. During the coronary graft procedure, all subjects underwent a sternotomy at the median, where the left internal thoracic artery and/or great saphenous veins were extracted. To ensure adequate clot formation, a heparin dosage of 200 µ/kg was administered, which led to an ACT exceeding 300 seconds. Towards the end of the revascularization process, protamine was used to counteract the effects of heparin at a ratio ranging from 0.5 to 1. Additionally, all study participants received intraoperative autologous blood retrieval using cell saver systems. Criteria for allogeneic transfusion and reoperation Postoperative blood loss was assessed by measuring the total amount of fluid collected from the chest drainage tube starting from the end of the surgery until its removal. In order to determine the need for blood transfusion, A large-volume cardiovascular center Hospital followed a specific transfusion protocol. For example, if the hemoglobin level dropped below 8.0 g l − 1 , a red blood cell (RBC) transfusion was initiated. Fresh frozen plasma (FFP) infusion was administered in cases of diffuse bleeding with prothrombin time 1.5 times longer than the baseline value. Platelet concentrate (PC) transfusion was deemed necessary if the platelet count fell below 50×10 9 /l or in instances of platelet (PLT) dysfunction. Reoperation was carried out if the volume of fluid collected from the chest tube exceeded 300 ml h − 1 within the first 2 hours or 200 ml h − 1 for 4 hours. The chest drainage tube was only removed when the rate of fluid discharge was less than 20 ml for a duration of 5 to 6 hours.2.3. Data collection Medical data was gathered from electronic records at a cardiovascular center with a high volume of cases. This gathered information encompasses baseline characteristics comprising age, weight, and height, along with coagulation-related laboratory tests, such as ACT, APTT, PT, PLT count, INR, and heparin sensitivity index (HSI), HSI = (ACT after initial heparin administration – ACT baseline) / initial heparin dose (seconds/(IU/kg)). These personal health records were filled in by a physician at any mandatory, recommended or interim clinical visit. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required. Data collection Data were gathered from hospital electronic medical records, encompassing laboratory test outcomes, perioperative status, and postoperative recuperation. Subsequent to the surgical procedure, the patient was moved to the Intensive Care Unit (ICU), where the nurse recorded the length of mechanical ventilation, chest tube drainage, and other patient parameters. Statistical analysis For continuous variables with non-normalization distribution, median [IQR (lower quartile, upper quartile)] was presented. For continuous variables with normalization distribution, mean (SD) was presented. The normality of quantitative data was examined by the Shapiro–Wilk test. For comparison between groups, continuous and categorical variables were tested by t-test or the Mann–Whitney U test and Pearson’s χ2 or Fisher’s exact test, respectively. P < 0.05 was considered statistically significant. Missing data were treated as missing and omitted from analysis, and no replacement was applied. All statistics were performed using SPSS (version 27.0.1). Results The patient selection process is shown in Fig. 1. Totally, 503 patients were finally included and divided into group HR (n = 56) and group Non-HR (n = 447). Patient characteristics, Preoperative and intraoperative data of the study population were summarized in Table 1 and Table 2 . No significant differences were observed in patient characteristics such as gender, age, body weight, body mass index, smoking, and drinking habits, or blood types between the HR and Non-HR groups. No important differences in patient characteristics and intraoperative volume balance were found between the HR and Non-HR groups. There was no significant difference in preoperative APTT, PLT count, PT, INR, and HSI. Table 1 Preoperative variables Total (n = 503) Group HR (n = 56) Group Non-HR (n = 447) P- Value Patient characteristics Male (n, %) 395(79%) 41(73%) 354(79%) 0.304 Age (years) 62.0(56.0–68.0) 62.5(56.3–68.8) 62.0(56.0–68.0) 0.663 Body weight (kg) 72.9 ± 12.1 72.9 ± 13.3 72.9 ± 12.0 0.967 Body mass index (kg/m 2 ) 25.8 ± 4.2 25.6 ± 4.0 25.8 ± 4.2 0.636 Smoking (n, %) Drinking (n, %) 263(52%) 196(39%) 34(61%) 21(38%) 229(51%) 175(39%) 0.180 0.811 Blood types (n, %) 503[100%] 56[100%] 447[100%] 0.277 Type A (n, %) 149(30%) 22(39%) 127(28%) Type B (n, %) 180(36%) 15(27%) 165(37%) Type AB (n, %) Type O (n, %) Baseline laboratory variables APTT (s) PT (s) INR (s) PLT count (10 9 /l) Hb (g/l) 44(9%) 130(25%) 35.60(33.03–38.18) 13.00(12.60–13.50) 0.98(0.95–1.03) 210.50(174.00-249.00) 135.00(124.25–147.00) 6(11%) 13(23%) 35.7(32.9–39.6) 15.6(14.8–16.5) 0.98(0.93–1.05) 202.0(163.0-250.8) 140.0(125.3-153.5) 38(9%) 117(26%) 35.5(33.0-38.1) 15.6(14.9–16.4) 0.98(0.95–1.02) 211.5(175.0-248.8) 135.0(124.0-146.0) 0.694 0.662 0.710 0.268 0.067 APTT: activated partial thromboplastin time; Hb: hemoglobin; HR: heparin rebound; INR: international normalized ratio; Non-HR: none heparin rebound; PLT: platelet; PT: prothrombin time Table 2 Intraoperative variables ACT: activated coagulation time; HSI: heparin sensitivity index; HR: heparin rebound; Non-HR: none heparin rebound Total (n = 503) Group HR (n = 56) Group Non-HR (n = 447) P- Value Baseline ACT (s) ACT after the initial dose of heparin (s) ACT after protamine reversal (s) Total protamine dosage (mg) HSI (seconds/(IU/kg)) Operative time (min) Intraoperative volume balance Blood loss (ml) Urinary volume (ml) Crystalloid fluid (ml) Colloidal fluid (ml) Crystalloid and colloidal fluid (ml) 110.0(108.0-112.0) 378.0(352.0-430.3) 120.0(117.0-120.0) 150.0(130.0-180.0) 1.33(1.20–1.58) 209.0(180.0-237.0) 450.00(400.00-480.00) 475.50(427.00-536.00) 1500(1100–2000) 500(500–500) 2000(1600–2500) 110.0(107.3–110.0) 383.0(358.3-449.3) 120.0(118.5–120.0) 150.0(148.5–200.0) 1.36(1.19–1.69) 203.0(177.0-229.0) 450.0(425.0-523.0) 516.0(440.0-566.5) 1500(1200–2000) 500(500–500) 2200(1700–2500) 110.0(108.0-113.0) 378.0(352.0-426.8) 120.0(117.0-120.0) 150.0(130–180) 1.32(1.19–1.58) 210.0(181.0-239.0) 450.0(400.0-476.0) 469.0(426.0-536.0) 1500.0(1100.0-2000.0) 500(500–500) 2000(1600–2500) 0.245 0.445 0.942 0.144 0.504 0.134 0.074 0.083 0.467 0.853 0.486 Postoperative variables of included patients were summarized in Table 3 . At univariate analysis, there was difference with respect to preoperative PLT count (132.5(108.5-167.8))10 9 /l vs (164.0(128.3–195.0))10 9 /l, P < 0.001. However, after full antagonism of protamine, during the ACT of 2 hours post-heparin neutralization, a significant difference was identified between the two groups, and there was no notable difference in the total amount of protamine administered. There was a significant difference in the 24-hour bleeding volume ( P = 0.000) and total bleeding volume ( P < 0.001), revealing statistical significance between the two groups. Table 3 Postoperative variables Total (n = 503) Group HR (n = 56) Group Non-HR (n = 447) P- Value Postoperative laboratory variables APTT (s) 43.1(39.2–48.8) 43.3(39.8–50.1) 43.1(39.2–48.7) 0.569 PT (s) 15.6(14.9–16.4) 15.6(14.8–16.5) 15.6(14.9–16.4) 0.586 INR (s) 1.2(1.2–1.3) 1.2(1.2–1.3) 1.2(1.2–1.3) 0.574 PLT count (10 9 /l) 160.0(124.3-194.8) 132.5(108.5-167.8) 164.0(128.3–195.0) < 0.001* Hb (g/l) 114.0(101.0-125.0) 108.5(93.0-122.0) 114.5(102.0-126.0) 0.051 ACT at 2 hours after reversal 176.0(161.0-192.0) 185.0(167.5–214.0) 175.0(161.0-191.0) 0.012* 24-h postoperative bleeding (ml) Total postoperative bleeding (ml) Chest drainage duration (days) Postoperative allogeneic blood transfusion RBC transfusion incidence (n, %) RBC transfusion volume (units) FFP transfusion incidence (n, %) FFP transfusion volume (ml) PC transfusion incidence (n, %) PC transfusion volume (units) Other hemostatic agents (n, %) 460.0(340.0-610.0) 865.0(652.5–1190.0) 4.0(4.0–5.0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 720.0(580.0-847.5) 1205.0(960.0-1515.0) 4(4–6) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 440(320.0-580.0) 830(640-1123.8) 4(4–5) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0.000* < 0.001* 0.305 NA NA NA NA NA NA NA ACT: activated coagulation time; APTT: activated partial thromboplastin time; FFP: fresh frozen plasma; Hb: hemoglobin; HR: heparin rebound; INR: international normalized ratio; Non-HR: none heparin rebound; PC: platelet concentrate; PLT: platelet; PT: prothrombin time; RBC: red blood cell Postoperative outcomes were summarized in Table 4 . There was a significant difference in reoperation for bleeding ( P < 0.01). However, there were no significant differences in mechanical ventilation duration, ICU length of stay, or hospital length of stay between the groups. Table 4 Postoperative outcomes Total (n = 503) Group HR (n = 56) Group Non-HR (n = 447) P- Value Mechanical ventilation duration (hours) ICU length of stay (hours) Hospital length of stay (days) Reoperation for bleeding(n, %) 16.0(13.0–18.0) 45.0(22.0–92.0) 9(7–13) 8(1.59%) 15(12–18) 46(23-90.8) 9.5(7.0–15.0) 6(10.71%) 16(13–18) 45(22–92) 9(7–13) 2(0.45%) 0.836 0.079 0.609 < 0.01* HR: heparin rebound; Non-HR: none heparin rebound; ICU: intensive care unit Discussion Perioperative anticoagulation strategies and antiplatelet therapies play a crucial role in patients undergoing CABG. While protocols for cardiac operations with cardiopulmonary bypass (CPB) are well-established, there is currently no defined strategy for OPCAB procedures [ 10 ]. The objective of this investigation is to examine the elements that contribute to the occurrence of HR, a condition characterized by the premature elimination of sulfated protamine from the bloodstream before heparin, leading to prolonged coagulation time and bleeding [ 11 ]. To prevent heparin rebound, it is advisable to administer an excess of protamine antagonists. This strategy has been validated as effective in reducing postoperative bleeding and shortening the duration of ICU hospitalization. One plausible explanation for heparin rebound is the delayed return of heparin from the space between cells to the circulatory system. In a study conducted by Gravlee and colleagues, an analysis was carried out on variations in the levels of ACT in patients undergoing cardiac surgery at different time points [ 12 ]. The researchers observed that a 15-second increase in ACT, following adequate neutralization, could indicate the occurrence of HR, considering the observed fluctuations [ 13 ]. The present research article is consistent with previous research that has identified HR as a potential factor contributing to bleeding complications following cardiac surgery. However, our study provides novel insights into the distinctive characteristics of HR associated with OPCAB procedures. In particular, the significant disparity in the ACT values measured 2 hours after the administration of the neutralized dose between the two groups highlights the need for a more thorough understanding of the temporal dynamics of HR. Understanding the temporal patterns of HR in the context of OPCAB is crucial for optimizing patient outcomes and minimizing bleeding complications. By recognizing the unique features of HR in this setting, healthcare providers can develop more effective strategies for managing hemostasis and improving surgical outcomes. Our study underscores the importance of further research to elucidate the mechanisms underlying HR in OPCAB procedures and to guide the development of targeted interventions to mitigate its impact on patient health. It is advised to consider an appropriate dosage increase of protamine to minimize the incidence of HR. Nonetheless, the author also recognizes that factors other than HR, including thrombocytopenia, impaired platelet functionality, and coagulation factor insufficiency, may also contribute to an elevation in ACT [ 14 ]. This aspect holds immense significance, as emphasized by Mochizuki and colleagues [ 15 ]. The anticoagulant mechanism of heparin involves binding with Antithrombin III (AT-III), which enhances the formation of a complex between antithrombin and thrombin [ 16 – 18 ]. This complex subsequently deactivates thrombin on the surface of the platelet membrane, leading to anticoagulation [ 19 ]. It is crucial to acknowledge that heparin alone, in its free form, lacks efficacy and must be combined with AT-III to exert its anticoagulant properties. At present, heparin is primarily synthesized from extracts obtained from bovine lung or pig small intestine [ 20 ]. When administered via the intravenous route, heparin exhibits anticoagulant effects lasting for approximately 5–10 minutes, with an overall duration of action of 1–2 hours. In cases of cardiac surgery involving extracorporeal circulation, the recommended intravenous dosage of heparin is 300 IU/kg. Aiming for an anticoagulant ACT value exceeding 480 seconds is desirable, as a lower ACT value below 300 seconds suggests a potential risk of thrombosis, thereby requiring additional supplementation of heparin. This complex hinders heparin from interacting with AT-III, subsequently diminishing its anticoagulant effect. The effects of intravenous administration of protamine are observed within 1 minute and last for approximately 1–2 hours. It is important to note that 1 mg of protamine can counteract 100 IU of heparin. When administering protamine intravenously, the total quantity used should not exceed 5 mL (50 mg), and the infusion should be conducted slowly into the venous system over a period of 10 minutes. The present study demonstrates differences in postoperative platelet count between the two groups. By monitoring postoperative coagulation function, it is possible to preliminarily determine the occurrence of heparin rebound, and increasing the dosage of protamine appropriately can reduce postoperative bleeding for 24 hours. According to a study conducted by Murray and colleagues [ 21 ], it was observed that APTT is highly sensitive to coagulation factor deficiency and heparin. Their findings revealed that approximately 82% of the test samples indicated a lack of coagulation factors or the presence of another coagulation inhibitor unrelated to heparin, as APTT values were standardized after conducting plasma mixing studies. On the other hand, an increase in the international normalized ratio of prothrombin time (PT-INR) particularly occurs when factors II, VII, and X have functional or absolute defects. However, for the PT-INR value to be normal, sufficient levels of factor V, thrombin, and fibrin are also required. Therefore, relying solely on PT-INR to detect heparin activity is not suitable. Another study by Carr and colleagues [ 22 ] indicated that reversing heparin-induced platelet dysfunction requires a higher dose of protamine (140 µg/ml) compared to normalizing APTT alone (40 µg/ml). This suggests that even if APTT is completely corrected, the antiplatelet effect of high-dose heparinization may still persist. Hemorrhage after cardiac surgery is highly likely to be attributed to platelet dysfunction. Based on the current discoveries, upcoming studies should focus on creating increasingly accurate predictive models for HR and evaluating the effectiveness of individualized anticoagulation techniques. Moreover, investigating the influence of various protamine administration schedules on HR and exploring the possible contribution of innovative anticoagulants in heart surgery are promising research avenues to be pursued. There were some limitations worth to be mentioned. Firstly, it was a single-center retrospective study which might have patient selection bias. Secondly, although we estimated the sample size, it might still be insufficient due to heterogeneity resulted from different anesthesiologists, surgeons, and patients. Conclusions HR and incomplete heparin reversal are commonly observed after cardiac surgery with OPCAB, and these phenomena may contribute to an increased risk of postoperative bleeding. To mitigate this risk, it is important to predict the likelihood of heparin rebound in patients by monitoring postoperative platelet count and the ACT values measured 2 hours after the administration of the neutralized dose. By implementing appropriate measures, such as timely intervention, it is possible to prevent postoperative bleeding and the need for reoperation due to bleeding. Abbreviations ACT activated coagulation time APTT activated partial thromboplastin time AT-III antithrombin III CABG coronary artery bypass graft CPB cardiopulmonary bypass FFP fresh frozen plasma HR heparin rebound HSI heparin sensitivity index ICU Intensive Care Unit INR international normalized ratio OPCAB off-pump coronary artery bypass grafting PLT platelet PT prothrombin time PT-INR prothrombin time PC platelet concentrate RBC a red blood cell Declarations Ethics approval and consent to participate The study was approved by our institutional review board (Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences), which waived the requirement for individual patientconsent because only routine patient data were used for this retrospectiveanalysis. All experiments were performed in accordance with relevantguidelines and regulations. Consent for publication Not applicable. Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. Conflict of Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Financial Disclosure This work was partially funded by CAMS Innovation Fund for Medical Sciences (CIFMS)-2021-I2M-C&T-B-038. Author Contributions Conceptualization, methodology, project administration, resource allocation, supervision, visualization, and writing—review and editing: YT-y. Data curation: FJ, YX, SS-h, and JQ-w. Formal analysis: YX. Funding acquisition: FJ, YX, and YT-y. Investigation, validation, and writing of the original draft: YX. Software development: YX. All authors have contributed to the article and approved the final submitted version. Acknowledgments The authors are grateful to all colleagues and patients involved in the current study. Author details 1 Department of Anesthesiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China. 2 Department of Anesthesiology, Gansu Provincial Provincial Maternity and Child Care Hospital, 143 North Road, Qilihe District, Lanzhou 730050, China. 3 Department of Anesthesiology, Lu'an Affiliated Hospital of Anhui Medical University, No.21 West Wanxi Road, Jinan District, Lu'an 237000, China. † Yang Xu and Fei Jiang contributed equally. *Correspondence: Yun-tai Yao, Department of Anesthesiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. No. 167, Beilishi Road, Xicheng District, Beijing 100037, China (E-mail: [email protected] ). References Stone ME, Vespe MW. Heparin Rebound: An In-Depth Review. J Cardiothorac Vasc Anesth. 2023;37(4):601-612. 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Cite Share Download PDF Status: Published Journal Publication published 04 Jan, 2025 Read the published version in Journal of Cardiothoracic Surgery → Version 1 posted Editorial decision: Revision requested 02 Nov, 2024 Reviews received at journal 24 Oct, 2024 Reviews received at journal 24 Oct, 2024 Reviews received at journal 24 Oct, 2024 Reviews received at journal 23 Oct, 2024 Reviews received at journal 23 Oct, 2024 Reviewers agreed at journal 21 Oct, 2024 Reviews received at journal 20 Oct, 2024 Reviewers agreed at journal 20 Oct, 2024 Reviewers agreed at journal 20 Oct, 2024 Reviewers agreed at journal 17 Oct, 2024 Reviewers agreed at journal 16 Oct, 2024 Reviewers agreed at journal 15 Oct, 2024 Reviewers agreed at journal 15 Oct, 2024 Reviewers invited by journal 15 Oct, 2024 Editor assigned by journal 17 Jun, 2024 Submission checks completed at journal 17 Jun, 2024 First submitted to journal 13 Jun, 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. 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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-4577442","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":320586395,"identity":"931555fb-9669-40ee-8918-65808efe6df0","order_by":0,"name":"Yang Xu","email":"","orcid":"","institution":"Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Xu","suffix":""},{"id":320586396,"identity":"b77a9011-c39c-45b0-8bfd-dbd2a1fb92b8","order_by":1,"name":"Fei Jiang","email":"","orcid":"","institution":"Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science","correspondingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Jiang","suffix":""},{"id":320586398,"identity":"83b08753-e9e0-47e0-bb6b-ae8f334b6c53","order_by":2,"name":"Shan-shan Hu","email":"","orcid":"","institution":"Gansu Provincial Provincial Maternity and Child Care Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shan-shan","middleName":"","lastName":"Hu","suffix":""},{"id":320586400,"identity":"abd0018a-a6ae-43be-ad03-c576cd0211ee","order_by":3,"name":"Jin-quan Wang","email":"","orcid":"","institution":"Lu'an Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jin-quan","middleName":"","lastName":"Wang","suffix":""},{"id":320586401,"identity":"e7f4c582-4242-4f57-a8f1-fbb0a5c3e474","order_by":4,"name":"Yun-tai Yao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYNACAyBmb2x88IFI9YwNYC08h5sNZxCvBQQk0tukOYhy0o3c4w9+FByW55d82CDNwGAnp9tAUEteYmOPwWHDmbMTG4wLGJKNzQ4Q1JJj2MBjcJhxw+3EhuQZDAcStxGjpfGPwWH7DTcPNhzmIVZLM9CWxA03GBubidIieeaN4WwZg/TkmT2JzYwzDIjwC9/xHIOPb/5Y2/azH3/+40OFnRxBLQoQBc0wdxJQDgLyDWCqjgilo2AUjIJRMGIBAA+mSbZYtX2SAAAAAElFTkSuQmCC","orcid":"","institution":"Fuwai Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yun-tai","middleName":"","lastName":"Yao","suffix":""}],"badges":[],"createdAt":"2024-06-13 16:12:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4577442/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4577442/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13019-024-03267-9","type":"published","date":"2025-01-04T15:57:24+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60341138,"identity":"14b57921-ed97-492b-ae50-0f85bf93df90","added_by":"auto","created_at":"2024-07-15 18:41:34","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":64011,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4577442/v1/ceffc862eb241adc9b45938a.jpg"},{"id":73093265,"identity":"96e7186d-38b3-4218-af01-3ce0bcef2ade","added_by":"auto","created_at":"2025-01-06 16:12:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":616077,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4577442/v1/545a9354-5b21-4cf0-951a-283e8dcd5145.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Heparin Rebound in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting Surgery：A Single-Center Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHeparin Rebound (HR) is a phenomenon where heparin's anticoagulant effects re-emerge postoperatively after being neutralized with protamine during cardiac surgery [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. HR may lead to increased bleeding following surgery, and in cases where prolonged coagulation times and/or continued bleeding are observed, additional doses of protamine may be required. Various definitions of HR can be found in the literature. For example, some groups considered a prolonged coagulation-based laboratory test, such as the activated coagulation time (ACT), activated partial thromboplastin time (APTT), prothrombin time (PT), or international normalized ratio (INR), as an indicator of HR [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition, some groups suggested both increased bleeding (at a rate of more than 200 mL/h) and abnormal laboratory test results for a diagnosis of HR [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Off-pump coronary artery bypass grafting (OPCAB) is widely recognized as a safe procedure for treating ischemic heart disease. Numerous research studies have consistently demonstrated that OPCAB results in fewer complications compared to on-pump coronary artery bypass graft (CABG) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the authors' conclusions do not adequately consider the multifactorial complexity of postoperative bleeding. While the authors do acknowledge the potential occurrence of the HR phenomenon, which may contribute to abnormal bleeding, further exploration of this topic is necessary.\u003c/p\u003e \u003cp\u003eTherefore, additional research is needed to confirm these findings. Consequently, the present study aims to investigate the specific characteristics of HR associated with OPCAB.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eInformed consent\u003c/strong\u003e \u003cp\u003ewas not requested as this study is a retrospective chart review. The study did not involve the identification of patients' personal information. Consecutive patients who underwent primary and isolated OPCAB at a large-volume cardiovascular center between September 2019 and June 2022 were screened for eligibility. The inclusion criteria are as follows: (1) adult patients (\u0026gt;\u0026thinsp;18 years old); (2) patients undergoing OPCAB; (3) normal preoperative coagulation function. Exclusion criteria include: (1) taking anticoagulant drugs; (2) emergency OPCAB; (3) patients with missing or incomplete outcomes of interest; (4) prior cardiac surgery.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAnesthetic and surgical protocol\u003c/h2\u003e \u003cp\u003eChronic cardiac medications, such as anti-hypertensive and anti-anginal agents, were continued up to the morning of surgery. Anti-platelet and anticoagulation medications were discontinued before surgery. No anesthetic premedication was given. The anesthetic technique adhered to a standardized protocol. Aspirin alone or in combination with a P2Y12 inhibitor (clopidogrel or ticagrelor) was administered orally after the removal of the chest drainage tube in the postoperative period, as determined by the surgeons.\u003c/p\u003e \u003cp\u003eDuring the coronary graft procedure, all subjects underwent a sternotomy at the median, where the left internal thoracic artery and/or great saphenous veins were extracted. To ensure adequate clot formation, a heparin dosage of 200 \u0026micro;/kg was administered, which led to an ACT exceeding 300 seconds. Towards the end of the revascularization process, protamine was used to counteract the effects of heparin at a ratio ranging from 0.5 to 1. Additionally, all study participants received intraoperative autologous blood retrieval using cell saver systems.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCriteria for allogeneic transfusion and reoperation\u003c/h2\u003e \u003cp\u003ePostoperative blood loss was assessed by measuring the total amount of fluid collected from the chest drainage tube starting from the end of the surgery until its removal. In order to determine the need for blood transfusion, A large-volume cardiovascular center Hospital followed a specific transfusion protocol. For example, if the hemoglobin level dropped below 8.0 g l\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, a red blood cell (RBC) transfusion was initiated. Fresh frozen plasma (FFP) infusion was administered in cases of diffuse bleeding with prothrombin time 1.5 times longer than the baseline value. Platelet concentrate (PC) transfusion was deemed necessary if the platelet count fell below 50\u0026times;10\u003csup\u003e9\u003c/sup\u003e/l or in instances of platelet (PLT) dysfunction. Reoperation was carried out if the volume of fluid collected from the chest tube exceeded 300 ml h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e within the first 2 hours or 200 ml h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e for 4 hours. The chest drainage tube was only removed when the rate of fluid discharge was less than 20 ml for a duration of 5 to 6 hours.2.3. Data collection\u003c/p\u003e \u003cp\u003eMedical data was gathered from electronic records at a cardiovascular center with a high volume of cases. This gathered information encompasses baseline characteristics comprising age, weight, and height, along with coagulation-related laboratory tests, such as ACT, APTT, PT, PLT count, INR, and heparin sensitivity index (HSI), HSI = (ACT after initial heparin administration \u0026ndash; ACT baseline) / initial heparin dose (seconds/(IU/kg)).\u003c/p\u003e \u003cp\u003eThese personal health records were filled in by a physician at any mandatory, recommended or interim clinical visit. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eData were gathered from hospital electronic medical records, encompassing laboratory test outcomes, perioperative status, and postoperative recuperation. Subsequent to the surgical procedure, the patient was moved to the Intensive Care Unit (ICU), where the nurse recorded the length of mechanical ventilation, chest tube drainage, and other patient parameters.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFor continuous variables with non-normalization distribution, median [IQR (lower quartile, upper quartile)] was presented. For continuous variables with normalization distribution, mean (SD) was presented. The normality of quantitative data was examined by the Shapiro\u0026ndash;Wilk test. For comparison between groups, continuous and categorical variables were tested by t-test or the Mann\u0026ndash;Whitney U test and Pearson\u0026rsquo;s χ2 or Fisher\u0026rsquo;s exact test, respectively. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Missing data were treated as missing and omitted from analysis, and no replacement was applied. All statistics were performed using SPSS (version 27.0.1).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe patient selection process is shown in Fig.\u0026nbsp;1. Totally, 503 patients were finally included and divided into group HR (n\u0026thinsp;=\u0026thinsp;56) and group Non-HR (n\u0026thinsp;=\u0026thinsp;447).\u003c/p\u003e \u003cp\u003ePatient characteristics, Preoperative and intraoperative data of the study population were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. No significant differences were observed in patient characteristics such as gender, age, body weight, body mass index, smoking, and drinking habits, or blood types between the HR and Non-HR groups. No important differences in patient characteristics and intraoperative volume balance were found between the HR and Non-HR groups. There was no significant difference in preoperative APTT, PLT count, PT, INR, and HSI.\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\u003ePreoperative variables\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;503)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup HR (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup Non-HR (n\u0026thinsp;=\u0026thinsp;447)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e395(79%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41(73%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e354(79%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.304\u003c/p\u003e \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\u003e62.0(56.0\u0026ndash;68.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.5(56.3\u0026ndash;68.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62.0(56.0\u0026ndash;68.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.663\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.9\u0026thinsp;\u0026plusmn;\u0026thinsp;13.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.967\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.636\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking (n, %)\u003c/p\u003e \u003cp\u003eDrinking (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e263(52%)\u003c/p\u003e \u003cp\u003e196(39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34(61%)\u003c/p\u003e \u003cp\u003e21(38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e229(51%)\u003c/p\u003e \u003cp\u003e175(39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.180\u003c/p\u003e \u003cp\u003e0.811\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood types (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e503[100%]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56[100%]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e447[100%]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.277\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType A (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e149(30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e127(28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType B (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e180(36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e165(37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType AB (n, %)\u003c/p\u003e \u003cp\u003eType O (n, %)\u003c/p\u003e \u003cp\u003eBaseline laboratory variables\u003c/p\u003e \u003cp\u003eAPTT (s)\u003c/p\u003e \u003cp\u003ePT (s)\u003c/p\u003e \u003cp\u003eINR (s)\u003c/p\u003e \u003cp\u003ePLT count (10\u003csup\u003e9\u003c/sup\u003e/l)\u003c/p\u003e \u003cp\u003eHb (g/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44(9%)\u003c/p\u003e \u003cp\u003e130(25%)\u003c/p\u003e \u003cp\u003e35.60(33.03\u0026ndash;38.18)\u003c/p\u003e \u003cp\u003e13.00(12.60\u0026ndash;13.50)\u003c/p\u003e \u003cp\u003e0.98(0.95\u0026ndash;1.03)\u003c/p\u003e \u003cp\u003e210.50(174.00-249.00)\u003c/p\u003e \u003cp\u003e135.00(124.25\u0026ndash;147.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(11%)\u003c/p\u003e \u003cp\u003e13(23%)\u003c/p\u003e \u003cp\u003e35.7(32.9\u0026ndash;39.6)\u003c/p\u003e \u003cp\u003e15.6(14.8\u0026ndash;16.5)\u003c/p\u003e \u003cp\u003e0.98(0.93\u0026ndash;1.05)\u003c/p\u003e \u003cp\u003e202.0(163.0-250.8)\u003c/p\u003e \u003cp\u003e140.0(125.3-153.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38(9%)\u003c/p\u003e \u003cp\u003e117(26%)\u003c/p\u003e \u003cp\u003e35.5(33.0-38.1)\u003c/p\u003e \u003cp\u003e15.6(14.9\u0026ndash;16.4)\u003c/p\u003e \u003cp\u003e0.98(0.95\u0026ndash;1.02)\u003c/p\u003e \u003cp\u003e211.5(175.0-248.8)\u003c/p\u003e \u003cp\u003e135.0(124.0-146.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.694\u003c/p\u003e \u003cp\u003e0.662\u003c/p\u003e \u003cp\u003e0.710\u003c/p\u003e \u003cp\u003e0.268\u003c/p\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAPTT: activated partial thromboplastin time; Hb: hemoglobin; HR: heparin rebound; INR: international normalized ratio; Non-HR: none heparin rebound;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003ePLT: platelet; PT: prothrombin time\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \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\u003eIntraoperative variables ACT: activated coagulation time; HSI: heparin sensitivity index; HR: heparin rebound; Non-HR: none heparin rebound\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;503)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup HR (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup Non-HR (n\u0026thinsp;=\u0026thinsp;447)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline ACT (s)\u003c/p\u003e \u003cp\u003eACT after the initial dose of heparin (s)\u003c/p\u003e \u003cp\u003eACT after protamine reversal (s)\u003c/p\u003e \u003cp\u003eTotal protamine dosage (mg)\u003c/p\u003e \u003cp\u003eHSI (seconds/(IU/kg))\u003c/p\u003e \u003cp\u003eOperative time (min)\u003c/p\u003e \u003cp\u003eIntraoperative volume balance\u003c/p\u003e \u003cp\u003eBlood loss (ml)\u003c/p\u003e \u003cp\u003eUrinary volume (ml)\u003c/p\u003e \u003cp\u003eCrystalloid fluid (ml)\u003c/p\u003e \u003cp\u003eColloidal fluid (ml)\u003c/p\u003e \u003cp\u003eCrystalloid and colloidal fluid (ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110.0(108.0-112.0)\u003c/p\u003e \u003cp\u003e378.0(352.0-430.3)\u003c/p\u003e \u003cp\u003e120.0(117.0-120.0)\u003c/p\u003e \u003cp\u003e150.0(130.0-180.0)\u003c/p\u003e \u003cp\u003e1.33(1.20\u0026ndash;1.58)\u003c/p\u003e \u003cp\u003e209.0(180.0-237.0)\u003c/p\u003e \u003cp\u003e450.00(400.00-480.00)\u003c/p\u003e \u003cp\u003e475.50(427.00-536.00)\u003c/p\u003e \u003cp\u003e1500(1100\u0026ndash;2000)\u003c/p\u003e \u003cp\u003e500(500\u0026ndash;500)\u003c/p\u003e \u003cp\u003e2000(1600\u0026ndash;2500)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e110.0(107.3\u0026ndash;110.0)\u003c/p\u003e \u003cp\u003e383.0(358.3-449.3)\u003c/p\u003e \u003cp\u003e120.0(118.5\u0026ndash;120.0)\u003c/p\u003e \u003cp\u003e150.0(148.5\u0026ndash;200.0)\u003c/p\u003e \u003cp\u003e1.36(1.19\u0026ndash;1.69)\u003c/p\u003e \u003cp\u003e203.0(177.0-229.0)\u003c/p\u003e \u003cp\u003e450.0(425.0-523.0)\u003c/p\u003e \u003cp\u003e516.0(440.0-566.5)\u003c/p\u003e \u003cp\u003e1500(1200\u0026ndash;2000)\u003c/p\u003e \u003cp\u003e500(500\u0026ndash;500)\u003c/p\u003e \u003cp\u003e2200(1700\u0026ndash;2500)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e110.0(108.0-113.0)\u003c/p\u003e \u003cp\u003e378.0(352.0-426.8)\u003c/p\u003e \u003cp\u003e120.0(117.0-120.0)\u003c/p\u003e \u003cp\u003e150.0(130\u0026ndash;180)\u003c/p\u003e \u003cp\u003e1.32(1.19\u0026ndash;1.58)\u003c/p\u003e \u003cp\u003e210.0(181.0-239.0)\u003c/p\u003e \u003cp\u003e450.0(400.0-476.0)\u003c/p\u003e \u003cp\u003e469.0(426.0-536.0)\u003c/p\u003e \u003cp\u003e1500.0(1100.0-2000.0)\u003c/p\u003e \u003cp\u003e500(500\u0026ndash;500)\u003c/p\u003e \u003cp\u003e2000(1600\u0026ndash;2500)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.245\u003c/p\u003e \u003cp\u003e0.445\u003c/p\u003e \u003cp\u003e0.942\u003c/p\u003e \u003cp\u003e0.144\u003c/p\u003e \u003cp\u003e0.504\u003c/p\u003e \u003cp\u003e0.134\u003c/p\u003e \u003cp\u003e0.074\u003c/p\u003e \u003cp\u003e0.083\u003c/p\u003e \u003cp\u003e0.467\u003c/p\u003e \u003cp\u003e0.853\u003c/p\u003e \u003cp\u003e0.486\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePostoperative variables of included patients were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. At univariate analysis, there was difference with respect to preoperative PLT count (132.5(108.5-167.8))10\u003csup\u003e9\u003c/sup\u003e/l \u003cem\u003evs\u003c/em\u003e (164.0(128.3\u0026ndash;195.0))10\u003csup\u003e9\u003c/sup\u003e/l, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001. However, after full antagonism of protamine, during the ACT of 2 hours post-heparin neutralization, a significant difference was identified between the two groups, and there was no notable difference in the total amount of protamine administered. There was a significant difference in the 24-hour bleeding volume (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000) and total bleeding volume (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), revealing statistical significance between the two groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostoperative variables\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;503)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup HR (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eGroup Non-HR (n\u0026thinsp;=\u0026thinsp;447)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePostoperative laboratory variables\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAPTT (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.1(39.2\u0026ndash;48.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.3(39.8\u0026ndash;50.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43.1(39.2\u0026ndash;48.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.569\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePT (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.6(14.9\u0026ndash;16.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.6(14.8\u0026ndash;16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.6(14.9\u0026ndash;16.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.586\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eINR (s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2(1.2\u0026ndash;1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.2(1.2\u0026ndash;1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.2(1.2\u0026ndash;1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.574\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePLT count (10\u003csup\u003e9\u003c/sup\u003e/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160.0(124.3-194.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132.5(108.5-167.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e164.0(128.3\u0026ndash;195.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHb (g/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e114.0(101.0-125.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108.5(93.0-122.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e114.5(102.0-126.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eACT at 2 hours after reversal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e176.0(161.0-192.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e185.0(167.5\u0026ndash;214.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e175.0(161.0-191.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.012*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e24-h postoperative bleeding (ml)\u003c/p\u003e \u003cp\u003eTotal postoperative bleeding (ml)\u003c/p\u003e \u003cp\u003eChest drainage duration (days)\u003c/p\u003e \u003cp\u003ePostoperative allogeneic blood transfusion\u003c/p\u003e \u003cp\u003eRBC transfusion incidence (n, %)\u003c/p\u003e \u003cp\u003eRBC transfusion volume (units)\u003c/p\u003e \u003cp\u003eFFP transfusion incidence (n, %)\u003c/p\u003e \u003cp\u003eFFP transfusion volume (ml)\u003c/p\u003e \u003cp\u003ePC transfusion incidence (n, %)\u003c/p\u003e \u003cp\u003ePC transfusion volume (units)\u003c/p\u003e \u003cp\u003eOther hemostatic agents (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e460.0(340.0-610.0)\u003c/p\u003e \u003cp\u003e865.0(652.5\u0026ndash;1190.0)\u003c/p\u003e \u003cp\u003e4.0(4.0\u0026ndash;5.0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e720.0(580.0-847.5)\u003c/p\u003e \u003cp\u003e1205.0(960.0-1515.0)\u003c/p\u003e \u003cp\u003e4(4\u0026ndash;6)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e440(320.0-580.0)\u003c/p\u003e \u003cp\u003e830(640-1123.8)\u003c/p\u003e \u003cp\u003e4(4\u0026ndash;5)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003cp\u003e0.305\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eACT: activated coagulation time; APTT: activated partial thromboplastin time; FFP: fresh frozen plasma; Hb: hemoglobin; HR: heparin rebound; INR: international\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003enormalized ratio; Non-HR: none heparin rebound; PC: platelet concentrate; PLT: platelet; PT: prothrombin time; RBC: red blood cell\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePostoperative outcomes were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. There was a significant difference in reoperation for bleeding (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). However, there were no significant differences in mechanical ventilation duration, ICU length of stay, or hospital length of stay between the groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePostoperative outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;503)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup HR (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup Non-HR (n\u0026thinsp;=\u0026thinsp;447)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP-\u003c/em\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation duration (hours)\u003c/p\u003e \u003cp\u003eICU length of stay (hours)\u003c/p\u003e \u003cp\u003eHospital length of stay (days)\u003c/p\u003e \u003cp\u003eReoperation for bleeding(n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.0(13.0\u0026ndash;18.0)\u003c/p\u003e \u003cp\u003e45.0(22.0\u0026ndash;92.0)\u003c/p\u003e \u003cp\u003e9(7\u0026ndash;13)\u003c/p\u003e \u003cp\u003e8(1.59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(12\u0026ndash;18)\u003c/p\u003e \u003cp\u003e46(23-90.8)\u003c/p\u003e \u003cp\u003e9.5(7.0\u0026ndash;15.0)\u003c/p\u003e \u003cp\u003e6(10.71%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16(13\u0026ndash;18)\u003c/p\u003e \u003cp\u003e45(22\u0026ndash;92)\u003c/p\u003e \u003cp\u003e9(7\u0026ndash;13)\u003c/p\u003e \u003cp\u003e2(0.45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.836\u003c/p\u003e \u003cp\u003e0.079\u003c/p\u003e \u003cp\u003e0.609\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eHR: heparin rebound; Non-HR: none heparin rebound; ICU: intensive care unit\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePerioperative anticoagulation strategies and antiplatelet therapies play a crucial role in patients undergoing CABG. While protocols for cardiac operations with cardiopulmonary bypass (CPB) are well-established, there is currently no defined strategy for OPCAB procedures [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The objective of this investigation is to examine the elements that contribute to the occurrence of HR, a condition characterized by the premature elimination of sulfated protamine from the bloodstream before heparin, leading to prolonged coagulation time and bleeding [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. To prevent heparin rebound, it is advisable to administer an excess of protamine antagonists. This strategy has been validated as effective in reducing postoperative bleeding and shortening the duration of ICU hospitalization. One plausible explanation for heparin rebound is the delayed return of heparin from the space between cells to the circulatory system.\u003c/p\u003e \u003cp\u003eIn a study conducted by Gravlee and colleagues, an analysis was carried out on variations in the levels of ACT in patients undergoing cardiac surgery at different time points [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The researchers observed that a 15-second increase in ACT, following adequate neutralization, could indicate the occurrence of HR, considering the observed fluctuations [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present research article is consistent with previous research that has identified HR as a potential factor contributing to bleeding complications following cardiac surgery. However, our study provides novel insights into the distinctive characteristics of HR associated with OPCAB procedures. In particular, the significant disparity in the ACT values measured 2 hours after the administration of the neutralized dose between the two groups highlights the need for a more thorough understanding of the temporal dynamics of HR. Understanding the temporal patterns of HR in the context of OPCAB is crucial for optimizing patient outcomes and minimizing bleeding complications. By recognizing the unique features of HR in this setting, healthcare providers can develop more effective strategies for managing hemostasis and improving surgical outcomes. Our study underscores the importance of further research to elucidate the mechanisms underlying HR in OPCAB procedures and to guide the development of targeted interventions to mitigate its impact on patient health.\u003c/p\u003e \u003cp\u003eIt is advised to consider an appropriate dosage increase of protamine to minimize the incidence of HR. Nonetheless, the author also recognizes that factors other than HR, including thrombocytopenia, impaired platelet functionality, and coagulation factor insufficiency, may also contribute to an elevation in ACT [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This aspect holds immense significance, as emphasized by Mochizuki and colleagues [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The anticoagulant mechanism of heparin involves binding with Antithrombin III (AT-III), which enhances the formation of a complex between antithrombin and thrombin [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This complex subsequently deactivates thrombin on the surface of the platelet membrane, leading to anticoagulation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. It is crucial to acknowledge that heparin alone, in its free form, lacks efficacy and must be combined with AT-III to exert its anticoagulant properties.\u003c/p\u003e \u003cp\u003eAt present, heparin is primarily synthesized from extracts obtained from bovine lung or pig small intestine [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. When administered via the intravenous route, heparin exhibits anticoagulant effects lasting for approximately 5\u0026ndash;10 minutes, with an overall duration of action of 1\u0026ndash;2 hours. In cases of cardiac surgery involving extracorporeal circulation, the recommended intravenous dosage of heparin is 300 IU/kg. Aiming for an anticoagulant ACT value exceeding 480 seconds is desirable, as a lower ACT value below 300 seconds suggests a potential risk of thrombosis, thereby requiring additional supplementation of heparin. This complex hinders heparin from interacting with AT-III, subsequently diminishing its anticoagulant effect. The effects of intravenous administration of protamine are observed within 1 minute and last for approximately 1\u0026ndash;2 hours. It is important to note that 1 mg of protamine can counteract 100 IU of heparin. When administering protamine intravenously, the total quantity used should not exceed 5 mL (50 mg), and the infusion should be conducted slowly into the venous system over a period of 10 minutes.\u003c/p\u003e \u003cp\u003eThe present study demonstrates differences in postoperative platelet count between the two groups. By monitoring postoperative coagulation function, it is possible to preliminarily determine the occurrence of heparin rebound, and increasing the dosage of protamine appropriately can reduce postoperative bleeding for 24 hours. According to a study conducted by Murray and colleagues [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], it was observed that APTT is highly sensitive to coagulation factor deficiency and heparin. Their findings revealed that approximately 82% of the test samples indicated a lack of coagulation factors or the presence of another coagulation inhibitor unrelated to heparin, as APTT values were standardized after conducting plasma mixing studies. On the other hand, an increase in the international normalized ratio of prothrombin time (PT-INR) particularly occurs when factors II, VII, and X have functional or absolute defects. However, for the PT-INR value to be normal, sufficient levels of factor V, thrombin, and fibrin are also required. Therefore, relying solely on PT-INR to detect heparin activity is not suitable. Another study by Carr and colleagues [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] indicated that reversing heparin-induced platelet dysfunction requires a higher dose of protamine (140 \u0026micro;g/ml) compared to normalizing APTT alone (40 \u0026micro;g/ml). This suggests that even if APTT is completely corrected, the antiplatelet effect of high-dose heparinization may still persist. Hemorrhage after cardiac surgery is highly likely to be attributed to platelet dysfunction.\u003c/p\u003e \u003cp\u003eBased on the current discoveries, upcoming studies should focus on creating increasingly accurate predictive models for HR and evaluating the effectiveness of individualized anticoagulation techniques. Moreover, investigating the influence of various protamine administration schedules on HR and exploring the possible contribution of innovative anticoagulants in heart surgery are promising research avenues to be pursued.\u003c/p\u003e \u003cp\u003eThere were some limitations worth to be mentioned. Firstly, it was a single-center retrospective study which might have patient selection bias. Secondly, although we estimated the sample size, it might still be insufficient due to heterogeneity resulted from different anesthesiologists, surgeons, and patients.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eHR and incomplete heparin reversal are commonly observed after cardiac surgery with OPCAB, and these phenomena may contribute to an increased risk of postoperative bleeding. To mitigate this risk, it is important to predict the likelihood of heparin rebound in patients by monitoring postoperative platelet count and the ACT values measured 2 hours after the administration of the neutralized dose. By implementing appropriate measures, such as timely intervention, it is possible to prevent postoperative bleeding and the need for reoperation due to bleeding.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; activated coagulation time\u003c/p\u003e\n\u003cp\u003eAPTT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;activated partial thromboplastin time\u003c/p\u003e\n\u003cp\u003eAT-III \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;antithrombin III\u003c/p\u003e\n\u003cp\u003eCABG \u0026nbsp; \u0026nbsp; \u0026nbsp; coronary artery bypass graft\u003c/p\u003e\n\u003cp\u003eCPB \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; cardiopulmonary bypass\u003c/p\u003e\n\u003cp\u003eFFP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; fresh frozen plasma\u003c/p\u003e\n\u003cp\u003eHR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;heparin rebound\u003c/p\u003e\n\u003cp\u003eHSI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;heparin sensitivity index\u003c/p\u003e\n\u003cp\u003eICU \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Intensive Care Unit\u003c/p\u003e\n\u003cp\u003eINR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;international normalized ratio\u003c/p\u003e\n\u003cp\u003eOPCAB \u0026nbsp; \u0026nbsp; \u0026nbsp; off-pump coronary artery bypass grafting\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePLT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; platelet\u003c/p\u003e\n\u003cp\u003ePT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;prothrombin time\u003c/p\u003e\n\u003cp\u003ePT-INR \u0026nbsp; \u0026nbsp; \u0026nbsp;prothrombin time\u003c/p\u003e\n\u003cp\u003ePC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;platelet concentrate\u003c/p\u003e\n\u003cp\u003eRBC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;a red blood cell\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by our institutional review board (Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences), which waived the requirement for individual patientconsent because only routine patient data were used for this retrospectiveanalysis. All experiments were performed in accordance with relevantguidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was partially funded by CAMS Innovation Fund for Medical Sciences (CIFMS)-2021-I2M-C\u0026amp;T-B-038.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, methodology, project administration, resource allocation, supervision, visualization, and writing—review and editing: YT-y. Data curation: FJ, YX, SS-h, and JQ-w. Formal analysis: YX. Funding acquisition: FJ, YX, and YT-y. Investigation, validation, and writing of the original draft: YX. Software development: YX. All authors have contributed to the article and approved the final submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to all colleagues and patients involved in\u0026nbsp;the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Anesthesiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science,\u0026nbsp;Xiangyang 441021, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eDepartment of Anesthesiology, Gansu Provincial Provincial Maternity and Child Care Hospital, 143 North Road, Qilihe District, Lanzhou 730050, China.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Anesthesiology, Lu'an Affiliated Hospital of Anhui Medical University, No.21 West Wanxi Road, Jinan District, Lu'an 237000, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e†\u003c/sup\u003e Yang Xu and Fei Jiang contributed equally.\u003c/p\u003e\n\u003cp\u003e*Correspondence: Yun-tai Yao, Department of Anesthesiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. No. 167, Beilishi Road, Xicheng District, Beijing 100037, China (E-mail:\u0026nbsp;\u003ca href=\"mailto:[email protected]\"\[email protected]\u003c/a\u003e).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eStone ME, Vespe MW. Heparin Rebound: An In-Depth Review. J Cardiothorac Vasc Anesth. 2023;37(4):601-612.\u003c/li\u003e\n\u003cli\u003eGravlee GP, Rogers AT, Dudas LM, Taylor R, Roy RC, Case LD, Triscott M, Brown CW, Mark LJ, Cordell AR. Heparin management protocol for cardiopulmonary bypass influences postoperative heparin rebound but not bleeding. Anesthesiology. 1992;76(3):393-401.\u003c/li\u003e\n\u003cli\u003eSubramaniam P, Skillington P, Tatoulis J. Heparin-rebound in the early postoperative phase following cardiopulmonary bypass. Aust N Z J Surg. 1995;65(5):331-3.\u003c/li\u003e\n\u003cli\u003eGollub S. Heparin rebound in open heart surgery. Surg Gynecol Obstet. 1967;124(2):337-46.\u003c/li\u003e\n\u003cli\u003eEllison N, Beatty CP, Blake DR, Wurzel HA, MacVaugh H 3rd. Heparin rebound. Studies in patients and volunteers. J Thorac Cardiovasc Surg. 1974;67(5):723-9.\u003c/li\u003e\n\u003cli\u003eMammen EF, Koets MH, Washington BC, Wolk LW, Brown JM, Burdick M, Selik NR, Wilson RF. Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost. 1985;11(3):281-92.\u003c/li\u003e\n\u003cli\u003eKuitunen AH, Salmenper\u0026auml; MT, Heinonen J, Rasi VP, Myllyl\u0026auml; G. Heparin rebound: a comparative study of protamine chloride and protamine sulfate in patients undergoing coronary artery bypass surgery. J Cardiothorac Vasc Anesth. 1991;5(3):221-6.\u003c/li\u003e\n\u003cli\u003eBachmann F, McKenna R, Cole ER, Najafi H. The hemostatic mechanism after open-heart surgery. I. Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal circulation. J Thorac Cardiovasc Surg. 1975;70(1):76-85.\u003c/li\u003e\n\u003cli\u003eWang C, Jiang Y, Song Y, Wang Q, Tian R, Wang D, Dong N, Jiang X, Chen S, Chen X. Off-pump or on-pump coronary artery bypass at 30 days: A propensity matched analysis. Front Cardiovasc Med. 2022;9:965648.\u003c/li\u003e\n\u003cli\u003eDouketis JD, Spyropoulos AC. Perioperative Management of Anticoagulant and Antiplatelet Therapy. NEJM Evid. 2023;2(6):EVIDra2200322.\u003c/li\u003e\n\u003cli\u003eEFFLER DB, GROVES LK, KOLFF WJ, SONES FM Jr. Disposable membrane oxygenator (heart-lung machine) and its use in experimental surgery. J Thorac Surg. 1956;32(5):620-9.\u003c/li\u003e\n\u003cli\u003eGravlee GP, Arora S, Lavender SW, Mills SA, Hudspeth AS, Cordell AR, James RL, Brockschmidt JK, Stuart JJ. Predictive value of blood clotting tests in cardiac surgical patients. Ann Thorac Surg. 1994;58(1):216-21.\u003c/li\u003e\n\u003cli\u003eGaleone A, Rotunno C, Guida P, Bisceglie A, Rubino G, Schinosa Lde L, Paparella D. Monitoring incomplete heparin reversal and heparin rebound after cardiac surgery. J Cardiothorac Vasc Anesth. 2013;27(5):853-8.\u003c/li\u003e\n\u003cli\u003eGravlee GP, Case LD, Angert KC, et al. Variability of the activated coagulation time. Anesth Analg 1988;67:469\u0026ndash;72.\u003c/li\u003e\n\u003cli\u003eMochizuki T, Olson PJ, Szlam F, Ramsay JG, Levy JH. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg. 1998;87(4):781-5.\u003c/li\u003e\n\u003cli\u003eGindele R, P\u0026eacute;nzes-Daku K, Balogh G, K\u0026aacute;llai J, Bog\u0026aacute;ti R, B\u0026eacute;csi B, Erdődi F, Katona \u0026Eacute;, Bereczky Z. Investigation of the Differences in Antithrombin to Heparin Binding among Antithrombin Budapest 3, Basel, and Padua Mutations by Biochemical and In Silico Methods. Biomolecules. 2021;11(4):544.\u003c/li\u003e\n\u003cli\u003eHashimoto K, Yamagishi M, Sasaki T, Nakano M, Kurosawa H. Heparin and antithrombin III levels during cardiopulmonary bypass: correlation with subclinical plasma coagulation. Ann Thorac Surg. 1994;58(3):799-804; discussion 804-5.\u003c/li\u003e\n\u003cli\u003eChen Y, Zhao J, Yu Y, Liu X, Lin L, Zhang F, Linhardt RJ. Antithrombin III-Binding Site Analysis of Low-Molecular-Weight Heparin Fractions. J Pharm Sci. 2018;107(5):1290-1295.\u003c/li\u003e\n\u003cli\u003eFu X, Lei T, Li SJ, Liu YF, Peng J, Ning JP. Construction of novel antiplatelet modified polyethersulfone membrane and study into its blood compatibility. Mater Sci Eng C Mater Biol Appl. 2022;135:112659.\u003c/li\u003e\n\u003cli\u003eGuan Y, Xu X, Liu X, Sheng A, Jin L, Linhardt RJ, Chi L. Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Lung Heparin and Porcine Intestine Heparin. J Pharm Sci. 2016;105(6):1843-1850.\u003c/li\u003e\n\u003cli\u003eMurray DJ, Brosnahan WJ, Pennell B, Kapalanski D, Weiler JM, Olson J. Heparin detection by the activated coagulation time: a comparison of the sensitivity of coagulation tests and heparin assays. J Cardiothorac Vasc Anesth. 1997;11(1):24-8.\u003c/li\u003e\n\u003cli\u003eCarr ME Jr, Carr SL. At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet effects. Thromb Res. 1994;75(6):617-30.\u003c/li\u003e\n\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":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Heparin rebound, Bleeding, Protamine, Activated coagulation time, Off-pump coronary artery bypass grafting","lastPublishedDoi":"10.21203/rs.3.rs-4577442/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4577442/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHeparin, an anticoagulant used in cardiac surgery, can result in heparin rebound (HR), where it returns postoperatively despite being neutralized with protamine. This study was designed to investigate the prevalence of HR in patients undergoing off-pump coronary artery bypass grafting (OPCAB) and evaluate the impact of HR on their short-term outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe analyzed 503 OPCAB patients aged 31\u0026ndash;80 years from September 2019 to June 2022, who were categorized into HR (n\u0026thinsp;=\u0026thinsp;56) and Non-HR (n\u0026thinsp;=\u0026thinsp;447) groups. HR was defined by a 10% increase in activated coagulation time (ACT) after heparin neutralization with protamine, bleeding over 200 mL/h, and abnormal laboratory coagulation examination results. The primary outcome was postoperative bleeding volume. Secondary outcomes included the incidence of postoperative reoperation for bleeding, allogenic blood transfusion incidences and volumes, and laboratory variables. Data were analyzed using t-tests, Mann\u0026ndash;Whitney U tests, and Pearson\u0026rsquo;s χ2 or Fisher\u0026rsquo;s exact tests.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSignificant differences were observed in preoperative platelet counts (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and the ACT measured 2 hours post-heparin neutralization (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012). The group HR exhibited higher 24-hour bleeding volumes, increased reoperation rates, and greater total bleeding volumes (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePostoperative HR was found to be prevalent in OPCAB patients and increased bleeding risks. These findings indicate the need for future randomized controlled trials to confirm the impact of HR and guide patient blood management.\u003c/p\u003e","manuscriptTitle":"Heparin Rebound in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting Surgery：A Single-Center Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-15 18:41:28","doi":"10.21203/rs.3.rs-4577442/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-02T08:04:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-24T10:35:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-24T09:42:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-24T07:05:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-23T18:43:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-23T11:41:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37622191538258700224671320427040143018","date":"2024-10-21T09:13:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-20T14:15:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"179592698067296012287701781500080493043","date":"2024-10-20T13:56:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"119472266120980874606581363716675602952","date":"2024-10-20T13:39:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"205864775834430162443045732173766937307","date":"2024-10-17T16:51:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"163655968724977781979876175869648204097","date":"2024-10-16T06:23:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"60703726610459132040121976995025081681","date":"2024-10-15T15:11:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128724539055543994027383461066126444789","date":"2024-10-15T13:40:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-15T13:35:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-17T05:35:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-17T05:34:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiothoracic Surgery","date":"2024-06-13T16:11:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ee84455b-8998-4cce-a852-fa2513d27634","owner":[],"postedDate":"July 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-06T16:01:11+00:00","versionOfRecord":{"articleIdentity":"rs-4577442","link":"https://doi.org/10.1186/s13019-024-03267-9","journal":{"identity":"journal-of-cardiothoracic-surgery","isVorOnly":false,"title":"Journal of Cardiothoracic Surgery"},"publishedOn":"2025-01-04 15:57:24","publishedOnDateReadable":"January 4th, 2025"},"versionCreatedAt":"2024-07-15 18:41:28","video":"","vorDoi":"10.1186/s13019-024-03267-9","vorDoiUrl":"https://doi.org/10.1186/s13019-024-03267-9","workflowStages":[]},"version":"v1","identity":"rs-4577442","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4577442","identity":"rs-4577442","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}