- Research article
- Open Access
Impact of gender differences on hemostasis in patients after coronary artery bypass grafts surgeries in the context of tranexamic acid administration
Journal of Cardiothoracic Surgery volume 17, Article number: 123 (2022)
Sex differences present in the blood management of patients after coronary artery bypass grafts (CABG) surgeries. Tranexamic acid (TXA) performed well in maintaining hemostasis during and after surgeries. However, the impact of sex differences on blood control after CABG in patients who received TXA was not investigated.
Overall, 29,536 patients undergoing CABG with TXA administration from 2009 to 2019 in our hospital were included. Propensity score matching was performed. Finally, 6808 males and 6808 females were matched based on 23 covariates.
Female patients had a 0.36-fold lower incidence of reoperations due to major hemorrhage or cardiac tamponade compared to males (1.3% vs. 2.0%, p = 0.001, OR = 0.64, 95%CI = 0.49–0.84). Females had a median of 100 ml less blood loss in 24 h (median 360 vs. 460 ml, p < 0.0001), 150 ml less in 48 h (median 580 vs. 730 ml, p < 0.0001), and 180 ml less in total (median 760 vs. 940 ml, p < 0.0001) than male patients. The red blood cell (RBC) transfusion rate in female was 1.53-fold higher than that in male (33.0% vs. 21.6%, OR = 1.53, 95% CI = 1.43–1.63, p < 0.0001). Females also had higher morbidities than males after CABGs.
Females had less blood loss than males after CABG with the TXA treatment. Females still had a higher RBC transfusion rate after surgery. Morbidities in women were also higher than that in men.
Gender differences are present in the outcomes of coronary artery bypass grafts (CABG) surgeries. Female patients undergoing CABG surgeries were likely to have higher mortality, more comorbidity than male patients [1,2,3,4,5]. The blood transfusion was common in CABG surgeries . In some studies, the female patients had a lower risk of bleeding and reoperation after CABG [7, 8]. However, females were the independent risk factor for the red blood cell infusion in other studies after CABG [9, 10]. So the blood management was different between females and males in patients after CABG surgeries.
The tranexamic acid (TXA) was now used widely as an antifibrinolytic agent during cardiac surgery . The TXA obtained obvious hemostasis in patients who underwent CABG surgeries with less blood loss and lower blood infusion rate . However, the gender effects on blood management in patients receiving CABG surgeries in the context of TXA administration were not evaluated at present. This study aimed to investigate blood loss and transfusion differences between male and female patients with TXA administration during CABG surgeries.
Materials and method
From January 1st, 2009 to December 31st, 2019, 30,259 patients undergoing CABG surgeries in the administration of TXA were included in this retrospective cohort study. Patients aged < 18 years old, enrolled in clinical trials, or with missing values were excluded from this study. Finally, a total of 29,536 (97.6%) patients were included in the following statistical analyses. Among them, there were 22,631 (76.6%) males and 6905 (23.4%) females. The females account for less than 1/4 total patients number (Table 1). The CABG surgeries in this study were not only the isolated CABGs but also CABGs with other surgeries. The high risks surgery included the previous cardiac surgery, emergent surgery, CABG combined with valve operation or CABG combined with aortic or arch operation. The open chamber surgeries included CABG combined with valve surgery or aortic surgery or aneurysm resection.
The study was carried out according to the Declaration of Helsinki 1964 and its subsequent amendments. The Medical Ethics Committee of the Fuwai Hospital approved the protocol. The informed consent was waived because of the retrospective study.
Blood control during operation
TXA was given after anesthesia induction at a median of 53.86 mg/kg with interquartile ranging from 41.09 mg/kg to 69.44 mg/kg. Cell salvage was used routinely for blood conservation (Fresenius Kabi C.A.T.S.®plus, Fresenius Kabi AG, Bad Homburg, Germany). The dose of heparin was given in 400 IU/kg to keep the activated clotting time (ACT) ranging from 400 to 420 s for on-pump CABGs, and 200 IU/kg for off-pump CABGs to keep ACT around 300 s. During the surgery process, additional heparins were given according to the dynamic change of ACT. The protamine was given at a ratio of 1:1 to heparin (1 mg protamine: 100 units of heparin) for neutralization. More protamine was added in consideration of bleeding, ACT and the recommendation of surgeons (Additional file 1).
The primary outcome was red blood cell (RBC) exposure after CABG.
The secondary outcomes were fresh frozen plasma (FFP), platelet (PLT) infusion, the reoperation due to major hemorrhage or cardiac tamponade, blood loss in 24 h, 48 h and total blood loss after surgery.
The safety issues were hospital death, death during the initial 30 postoperative days, postoperative myocardial infarction, stroke, acute kidney injury (AKI), pulmonary embolism, seizure associated with TXA administration, hospital stay, and intensive care unit (ICU) stay time.
The continuous variables in normal distribution were presented as means ± standard deviation (SD) for normal distribution and median and interquartile range (IQR) for non-normal distribution. Numbers and percentages were used for the categorical variables.
The demographic and perioperative information was compared between the male and female patients before propensity score matching (PSM) was performed. The student's t-test was chosen for normal-distribution continuous variables, Mann–Whitney U-test for non-normal distribution variables, and χ2 test or Fisher's exact test for categorical variables. After PSM, the paired-t test was performed for normal distribution data, the Wilcoxon rank test for non-normal distribution data, and the McNemar’s test for categorical data in the demographical and perioperative information. While the conditional logistic regression was performed in the binary outcome evaluation with an odds ratio (OR) and 95% confidence intervals (CI).
The propensity score matching was generated according to 1:1 matching between male and female patients in the entire CABG cohort in the context of TXA administration. The caliper width was 0.01, and the nearest-neighbor matching method without replacement was selected. A total of 23 variables was chosen for PSM based on the clinical and statistical significance (Table 1). In all, 6808 males and 6808 females were selected after being matched. Balances were well kept in the demographical and perioperative data with standardized differences < 0.1 (Table 2, 3, and Figs. 1, 2).
For sensitivity analysis, the binary logistic regression was performed in the entire cohort receiving TXA during CABG surgeries. The gender plus 23 variables mentioned above were chosen as covariates. The binary outcomes were taken as dependent variables. The "enter" method was used, and adjusted OR and 95% CI of outcome variables were generated.
p < 0.05 was considered statistically significant. All statistical analyses were carried out with IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY, USA).
Baseline comparison before PSM
More females received a high dose of TXA (68.6% vs. 51.9% in TXA ≥ 50 mg/kg) than males (Table 2). Also, female patients were older (63.75 ± 7.54 vs. 60.39 ± 8.85, p < 0.0001) and had lower BMI (25.25 ± 3.30 vs. 25.88 ± 3.11, p < 0.0001) than male patients at the age of CABG surgeries (Table 2). The BSA in male was 1.85 ± 0.15 m2 which was larger than 1.62 ± 0.13 m2 in females (p < 0.0001). Also, females undergoing CABG in this study had a higher incidence of insulin-dependent diabetes, hypertension, CKD, and CVA (p < 0.0001) (Table 2). The females had no difference in HGB level (134.54 ± 13.98 vs. 134.60 ± 14.15, p = 0.737) and less thrombocytopenia (7.1% vs. 13.0%, p < 0.0001) compared to males before operation (Table 2). More high-risk surgeries were performed in females than males administrated with TXA(20.6% vs. 18.5%, p < 0.0001) (Table 3).
Primary and secondary outcome evaluation: postoperative blood transfusion and blood loss
Results after PSM
In this study, the RBC transfusion rate in females was 1.53-fold higher than that in males (33.0% vs. 21.6%, OR = 1.53, 95% CI = 1.43–1.63, p < 0.0001) (Table 4). The FFP infusion rate in females was 0.37-fold lower than that in males (10.1% vs. 16.0%, OR = 0.63, 95% CI = 0.58–0.70, p < 0.0001) (Table 4). As for the PLT transfusion rate, there was no differences between the male and female patients (2.7% vs. 2.3%, OR = 1.17, 95% CI = 0.94–1.45, p < 0.0001) (Table 4).
Generally, female patients had less blood loss than males after CABG surgeries with the administration of TXA. Female patients had a 0.36-fold lower incidence of reoperations due to major hemorrhage or cardiac tamponade compared to males (1.3% vs. 2.0%, p = 0.001, OR = 0.64, 95%CI = 0.49–0.84) (Table 4). Also, females had a median of 100 ml less blood loss in 24 h [median 360 ml, IQR (260–490 ml) vs. median 460 ml, IQR (330–610 ml), p < 0.0001], 150 ml less in 48 h [median 580 ml, IQR (440–760 ml) vs. median 730 ml, IQR (550–940 ml), p < 0.0001], and 180 ml less in total [median 760 ml, IQR (570–1070 ml) vs. median 940 ml, IQR (700–1310 ml), p < 0.0001] than male patients (Table 4).
Similar results were found in the sensitivity analyses
Safety issues: post-CABG events between male and female patients
Results after PSM
There were no differences in the ICU and the hospital stay time between males and females. However, the females had higher risks of hospital death (0.4% vs. 0.2%, OR = 1.93, 95% CI = 1.04–3.61, p < 0.0001) and death during the initial 30 postoperative days (0.9% vs. 0.6%, OR = 1.49, 95% CI = 1.01–2.19, p < 0.0001) (Table 5). Also, the risks of stroke and AKI rise 1.76-fold (p < 0.0001) and 1.24-fold (p = 0.005) in the female (Table 5), respectively. No difference was observed in seizure between male and female patients (0.2% vs. 0.2%, p = 0.706).
Similar results were found in the sensitivity analyses
The gender differences in blood management after CABG surgery were reported before [6, 8, 10, 13]. The TXA as an antifibrinolytic agent was widely used in CABGs to maintain hemostasis during the perioperative period and proved to be effective [11, 12]. However, the sex differences in blood control with TXA management in CABG surgeries was still not investigated. Our study focused on patients who received TXA administrations during CABG and further explored the sex differences in blood management and postoperative outcomes in CABG surgeries. In this study, the RBC transfusion rate in females with the management of TXA in CABG surgery was higher than that in males. However, there was lower FFP exposure in females corresponding to the bleeding volume. Females had less blood loss and re-exploration rate than males after surgery. Also, females had a higher risk of hospital death, death during the initial 30 postoperative days, stroke, and AKI than males.
Most studies reported that females underwent CABG at an older age and presented more comorbidities [1, 14,15,16,17,18,19]. In an Australian retrospective cohort study, 21,534 patients undergoing CABGs were included . Among them, 22.2% were female. Among them, 22.2% were female. Female patients were generally older (mean age, 68 vs. 65 years, p < 0.001) and presented more often with hypertension, diabetes mellitus, and cerebrovascular disease . In this study, females accounted for 23.4% of the patients' number. Females were with older age, smaller BMI, and higher incidences of insulin-dependent diabetes, hypertension, chronic kidney disease, and cerebrovascular disease. This was in accordance with literature published before [1, 3, 20].
Some researchers discovered that the reoperation rate for bleeding after CABG was lower in women than in men [1, 4, 21, 22]. In retrospective research by Saxena et al. , females had a lower reoperation rate than males (1.9% vs. 2.5%) and reduced the risk of reoperation by 0.57-fold. Alam et al. found that females also had a lower incidence of reoperation for bleeding (4.2% vs. 4.5%, OR = 0.78) . Mehta et al. revealed that women had a lower risk to bleed after CABG after analyzing 528,686 CABG patients in the Society of Thoracic Surgeons National Cardiac Database from 2004 to 2007 . In our study, the administration of TXA did not influence the gender difference in the bleeding risk after CABGs. The females decreased a 0.36-fold risk of reoperation for cardiac tamponade or major bleeding compared to males. Swaminathan et al.  included 2,272,998 patients who underwent isolated CABG surgery, 27.4% of whom were female. The bleeding after surgery was decreased 0.17-fold by females . Our study revealed similar results that the female chest tube drainage after CABG decreased significantly.
In this study, the females had a higher risk of RBC transfusion despite less blood loss. Many studies reported that female was an independent risk factor for RBC transfusion after CABG [9, 10, 15, 23,24,25]. Schwann and coworkers  found that patients with a low BMI were more hemodiluted and received more transfusions during and after the operation. In this study, the BMI in females was smaller than in males (mean 25.25 vs. 25.88, p < 0.0001). Also, factors such as cardiopulmonary bypass (CPB) or crystalloid solution infusion could influence the hemodilution extent differently by gender. Scott et al.  found that hemodilution during CPB was more pronounced in women than in men (lowest hematocrit on CPB, 23.7% versus 27.6%). In our hospital, the postoperative transfusion threshold was 80 g/L in hemoglobin and was not defined differently according to sex. So based on the more dilution during surgery, women undergoing surgery have a greater likelihood of receiving a blood transfusion than men after surgery . It is likely that at equivalent hematocrits and weights, the total red cell volume for a woman is less than that of a man because of lower lean mass and plasma volume. So any dilutional anemia incurred by undergoing CABG would have a more profound effect on a woman and make them more likely to undergo transfusion . So the female gender was an independent risk factor for RBC transfusion that was not mainly determined by the postoperative blood loss volume.
Koch et al.  revealed no gender differences were found in the transfusion of PLT and cryoprecipitate. FFP transfusions are commonly used in our hospital to control bleeding after surgery, and surgical re-exploration due to major bleeding or cardiac tamponade was always accompanied by FFP infusion. Therefore, it is not surprising that these blood products are a marker of postoperative bleeding. So the females received a lower incidence of FFP transfusion corresponding to less blood loss after CABGs in this study.
Only a few articles published the results of gender differences in bleeding and blood transfusion after CABGs concomitantly [1, 25]. Koch et al.  reported no gender differences in reoperation for tamponade or bleeding combined with lower RBC transfusion in women. Saxena and her colleges found that the females had a 0.43-fold risk of reoperation for bleeding but a 1.77-fold increased risk for RBC transfusion after CABGs in a cohort of 21,534 patients . Nevertheless, the bleeding after surgery in these studies was just qualitative but not quantified. In the study here, we analyzed both bleeding and blood transfusion simultaneously and showed the accurate volume of chest tube drainage in different gender. It would give us a comprehensive and refined perspective on blood management in CABG patients.
Females could increase the risk of hospital death or death during the initial 30 postoperative days in this study. The results were in accordance with the literature before [2,3,4,5, 7, 14, 18, 19, 25]. Shi et al.  reported a meta-analysis incorporating 5,008,262 patients after CABG. The overall 30-day mortality was 4.9% in women versus 3.3% in men. In another meta-analysis by Robinson et al. , 903,346 patients after CABG surgeries were included for analysis. Females were at a 1.77-fold higher risk for operative mortality and a 1.16-higher risk of late mortality compared to males. In our hospital cohort, either the hospital mortality or death during the initial 30 postoperative days was lower than that published before. It was also well-known that the morbidity after CABG was also higher in females than in males . In the meta-analysis by Robinson and his colleges, stroke risk was also increased by 1.35-fold in females. Swaminathan et al.  collected 2,272,998 CABG patients and found that the risk of AKI after surgery was increased in the female gender by a 1.08-fold. In the postoperative event in this cohort, we also found that stroke and AKI were higher after surgery in females than in males.
The TXA was widely used in cardiac surgery as a substitute for aprotinin after 2008 . Series studies validated its specialty in reasonable blood control and low comorbidity [11, 12]. However, the thromboembolic events in the TXA were still considered by anesthesiologists and surgeons. Literature before mainly focused on the impact of gender differences on bleeding or blood transfusion in CABG patients, in which the effect of TXA was unclear. This study focused on patients who received TXA administration during CABGs and investigated the sex impact on hemostasis in this context. The results here were not different from previous literature, which meant that the use of TXA would not influence the gender difference in the CABG outcomes.
There were several limitations in this study. First, this was a retrospective study that included 29,536 patients. The patients' baseline information was not intact as the prospective clinical trial; Second, all patients received TXA in this study, so we could not determine whether there was a sex-treatment interaction; Finally, the PSM were used to simulate a RCT. However, the confounding factors were still present possibly.
In this study, females had less blood loss after CABG and thereby a lower FFP transfusion rate. However, it could not change that females were the risk factor for RBC transfusion after surgery. Meanwhile, morbidities in women were also higher than that in men.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Coronary artery bypass grafts
Activated clotting time
Red blood cell
Fresh frozen plasma
Acute kidney injury
Intensive care unit
Propensity score matching
Body mass index
Chronic kidney disease
International normalized ratio
Activated partial thromboplastin time
Heparin neutralization ratio
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Supported by the National Clinical Research Center of Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences (Grant No. NCRC2020014), and National Natural Science Foundation of China (Grant no. 81400242).
Ethics approval and consent to participate
The study was carried out according to the Declaration of Helsinki 1964 and its subsequent amendments. The Medical Ethics Committee of the Fuwai Hospital approved the protocol. The41.09 mg/kg to 69.44 mg/kg was waived because of the retrospective study.
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Wang, E., Wang, Y., Hu, S. et al. Impact of gender differences on hemostasis in patients after coronary artery bypass grafts surgeries in the context of tranexamic acid administration. J Cardiothorac Surg 17, 123 (2022). https://doi.org/10.1186/s13019-022-01874-y
- Blood transfusion
- Coronary artery bypass grafting
- Tranexamic acid
- Propensity score matching