We conducted a retrospective study on the basis of the traumatology and orthopedic department of the clinic of Rostov State Medical University in 2017–2019. The study was approved by the local independent Committee for Ethics of Rostov State Medical University (29 Nakhichevan Lane, Rostov-on-Don, Russia), Protocol № 18/17 of 23 October 2017. The patient inclusion criteria for the study: joint prophylaxis with hemostatics and anticoagulants, and knee or hip arthroplasty. The exclusion criteria: failure to conduct planned surgery due to the patient’s condition, lack of joint anticoagulant and hemostatic prophylaxis, and no knee or hip arthroplasty. We divided our research into several stages. The first stage involved the selection of medical records of the patients based on the inclusion criteria. The second stage was a retrospective analysis of the selected cases (n=253): an analysis of the anticoagulants and hemostatics used. Stage 3 involved dividing patients into two groups according to the time interval (TI) between the last prescription of a hemostatic agent and the first prescription of an anticoagulant. Stage 4 – assessment of the developed thrombohemorrhagic complications in the early postoperative period. Stage 5 – an analysis of risk factors of the patients and their influence on the development of thrombohemorrhagic complications and assessment of the influence of the initial parameters of the hemostasiogram on the development of thrombosis and bleeding after surgery.

Hemostatics and anticoagulants used in patients after surgery to prevent bleeding and thrombosis

We analyzed the used hemostatics and anticoagulants. Dosages and frequency of administration of the used anticoagulant drugs: heparin – 5000 IU/ml, (5 ml), 4 times a day; enoxaparin sodium – 4000 anti-Xa ME/0.4 ml (40 mg), once a day, subcutaneously; nadroparin calcium – 3800 IU, 0.4 ml, once a day, subcutaneously; dalteparin sodium – 5000 ME (anti-Xa)/0.2 ml, once a day, subcutaneously; parnaparin sodium – 4250 anti-Xa IU/0.4 ml, once a day, subcutaneously; rivaroxaban – 10 mg/15 mg, once a day, orally; dabigatran – 110 mg, 2 tabs once a day or 150 mg 1 capsule 1–2 times a day. The frequency of use of various anticoagulants in patients is presented in Table 1.

Consequently, a large number of patients began anticoagulant prophylaxis with low molecular weight heparins (LMWHs) or unfractionated heparins (UFHs). Five days later, some patients were transferred to new oral anticoagulants (NOACs).

The dosage of hemostatic drugs used were the following: aminocaproic acid 5% – 100 ml; etamsylate 12.5% - 2.0 ml; tranexamic acid 50 mg/ml – 5 ml; aminomethylbenzoic acid – 50/100 mg; aprotinin – 100.000 units. The prevalence of different hemostatics in the patients is shown in Table 2.

About 95% of the patients used only one hemostatic, and about 60% used tranexamic acid. In case of using the two drugs, the first was administered during the operation, and the second – at the end of the first day after the operation. Considering the fact that most patients used tranexamic acid, it should be noted that the antifibrinolytic activity of tranexamic acid can continue in various tissues of the body for up to 17 hours (according to the Register of Medicines of Russia. Encyclopedia of Drugs).

Based on this, we divided our patients into two groups, depending on the TI between the last administration of hemostatics and the first administration of anticoagulants. The first group (Gr.1) consisted of 145 patients, of whom women – 112 (77.24%), and men – 33 (22.76%), with TI≤17 hours. The second group (Gr. 2) included 108 patients, of whom 78 (72.22%) were women and 30 (27.78%) were men, with TI being 18–24 hours. Duration of hospitalization in Gr. 1 for men was 11.87±4.14 days, for women – 11.37±3.87 days. Duration of hospitalization in Gr. 2 for men was 11.63±2.71 days, and for women – 11.55±3.06 days. In Gr. 1, the average age of men was 63.35±9.21 (with 63.35 being the mean and 9.21 being the standard deviation) years, and of women – 64.32±10.22 years. In Gr. 2, the average age of men was 62±13.34 years, and of women – 66.36±10.43 years. We divided the patients in Groups 1 and 2 into age categories (Table 3) in accordance with the classification of the World Health Organization: young age – 18–43 years, middle age – 44–59 years, older age – 60–74 years, senile age – 75–90 years, over 90 – long-livers (Ganin 2019).

Thus, in our study, most of the patients were of older age.

The statistical data were processed on a personal computer using the MS Office software package (Excel 2010) and Statistica 10.0 (StatSoft, USA). All the indicators were checked for normal distribution by the Kolmogorov-Smirnov test. The Mann-Whitney U-test was used to compare the quantitative indicators between the groups and assess their impact on the development of thrombosis and bleeding cases. When comparing qualitative indicators, Pearson’s χ² test was used, with Yates’ correction. For qualitative indicators that demonstrated their influence on the development of thrombosis and bleeding cases, the relative risk (RR) and the limits of the 95% confidence interval (CI) were calculated. The influence of risk factors were analyzed separately for thrombosis and bleeding cases in Groups 1 and 2. Separately for men and women in Groups 1 and 2, the RR and CI of the preoperative hemostasiogram parameters were calculated. Differences were considered statistically significant at p<0.05.

We assessed the comorbid status of patients in Groups 1 and 2 (Table 6). To assess renal function in the patients before surgery, we calculated the glomerular filtration rate (GFR), using the CKD-EPI formula (ml/min/1.73 m²). The obtained data on the value of GFR were analyzed by the standard interpretation (Shutov 2014). High or normal GFR was over 90 ml/min/1.73 m². With GFR from 60 to 89 ml/min/1.73 m² – a mild loss of kidney function. With the GFR level of 45–59 ml/min/1.73 m² – mild to moderate loss of kidney function. With the GFR level of 30–44 ml/min/1.73 m² – moderate to severe loss of kidney function. With the GFR level of 15–29 ml/min/1.73 m² – severe loss of kidney function; and the GFR level under 15 ml/min/1.73 m² indicates kidney failure. We calculated BMI for all the patients, taking into account the standards of its interpretation (Dobszai et al. 2019). We calculated BMI using the formula: weight (kg)/height² (m²). With a body weight deficit, BMI is under 18.5 kg/m². The normal body weight, a BMI ranges from 18.5 to 24.9 kg/m². BMI from 25 to 29.9 kg/m² indicates overweight. With class I obesity, BMI ranges from 30 to 34.9 kg/m². BMI from 35 to 39.9 kg/m² means class II obesity. Class III obesity is diagnosed with a BMI of over 40 kg/m².

Thus, the groups of patient were comparable in terms of gender, age, term of hospitalization, and baseline health (p>0.05).

We analyzed the possibility of the effect of the comorbid pathology shown in Table 6 on the development of thrombosis and bleeding cases in the early postoperative period. Among the patients in Gr. 1 with developed thrombosis, we revealed statistically significant differences in terms of: BMI – between the patients with class II obesity and overweight (p=0.037); age – between patients of young and middle age (p=0.011), young and old age (p=0.015), and old and senile age (p=0.029); a history of myocardial infarction (MI) (p=0.00002), type 2 diabetes mellitus (DM) (p=0.00001), venous pathology (p=0.045), and impaired renal function – between patients with a mild loss and mild to moderate loss of kidney function (p=0.046). In the patients of Gr. 2 who developed thrombosis after surgery, we found significant differences between the patients with class II obesity and overweight (p=0.044), with class II and class I obesity (p=0.039) and between old and senile patients (p=0.037). We also found that in the patients of Gr. 1 and Gr. 2 with thrombosis after surgery, a statistically significant difference in TI was revealed (p=0.023). Among the patients of Gr. 1 with bleeding after endoprosthetics, statistically significant differences were between old and senile patients (p=0.015). In Gr. 2, no analysis of risk factors for cases of bleeding was carried out, as no cases were registered. When analyzing other risk factors among the patients of Groups 1 and 2 with thrombosis and bleeding developing after surgery, no statistically significant differences (p>0.05) were found. Next, we calculated the analysis of the risk ratio and difference for factors that statistically significantly influenced the development of thrombosis or bleeding cases after surgery. We found out that it was statistically significant in the patients of Gr. 1, the presence of class II obesity was associated with an increased risk of thrombosis by 8.75 times (RR=8.75, CI=1.089–69.731), type 2 DM – 21 times (RR=21, CI=4.671–94.405), history of MI – 16.875 times (RR=16.875, CI=5.507–51.337), venous pathology – 8.1 times (RR=8.1, CI=1.015–64.654), and the age of patients over 75 years – 6.8 times (RR=6.8, CI=1.377–33.573), and mild to moderate loss of kidney function – 6.231 times (RR=6.231, CI=1.157–33.554). In the patients of Gr. 2 with cases of thrombosis after surgery, there was no variation in significant factors, so we did not assessment of the ratio and difference of risks. In the patients in Gr. 1, the age over 75 years was associated with a 12-time higher risk of bleeding (RR=12, CI=1.445–99.678).

Along with the assessment of a comorbid status, the baseline hemostasiogram parameters and their effect on the development of thrombosis and bleeding cases after surgery were analyzed. The study of the coagulogram involved the analysis of the following indicators: 1) activated partial thromboplastin time (APTT); 2) prothrombin time (PT); 3) concentration of fibrinogen (Fg); 4) international normalized ratio (INR); 5) number of platelets (PLT). The reference values (norm) were the following: APTT – 22.5–35.5 sec.; PT – 11–15 sec.; Fg – 2.7–4.013 g/L; INR – 0.82–1.11 RU; and PLT – 180–320*10⁹. Table 7 shows the initial preoperative parameters in the patients in Groups 1 and 2, males and females. Figures 1–5 show the relative numbers of the patients in Groups 1 and 2, males and females, with coagulogram indices before surgery which were normal (N), below normal (<N) and above normal (>N).

Figure 1.

The number of patients in Groups 1 and 2, males and females, with levels of platelets (PLT) before surgery: normal (N), below normal (<N), and above normal (>N). In Group 1 – the time interval between the last administration of hemostatics and the first administration of anticoagulants ≤ 17 hours. In Group 2 – the time interval 18–24 hours. * – (between PLTs of women in Groups 1 and 2) >0.05; # – p(between PLTs of men in Groups 1 and 2) >0.05.

Figure 2.

The number of patients in Groups 1 and 2, males and females, with international normalized ratios (INR) before surgery: normal (N), below normal (<N) and above normal (>N). In Group 1 – the time interval between the last administration of hemostatics and the first administration of anticoagulants ≤ 17 hours. In Group 2 – the time interval 18–24 hours. * – p (between INRs of women in Groups 1 and 2) >0.05; # – p (between INRs of men in Groups 1 and 2) >0.05.

Figure 3.

The number of patients in Groups 1 and 2, males and females, with activated partial thromboplastin time (APTT) before surgery: normal (N), below normal (<N), and above normal (>N). In Group 1 – the time interval between the last administration of hemostatics and the first administration of anticoagulants ≤ 17 hours. In Group 2 -– the time interval 18–24 hours. * – p (between APTTs of women in Groups 1 and 2) >0.05, # – p (between APTTs of men in Groups 1 and 2) >0.05.

Figure 4.

The number of patients in Groups 1 and 2, males and females, with prothrombin time (PT) before surgery: normal (N), below normal (<N), and above normal (>N). In Group 1 – the time interval between the last administration of hemostatics and the first administration of anticoagulants ≤ 17 hours. In Group 2 – the time interval 18–24 hours. * – p (between PTs of women in Groups 1 and 2) >0.05, # – p (between PTs of men in Groups 1 and 2) >0.05.

Figure 5.

The number of patients in Groups 1 and 2, males and females, with fibrinogen (Fg) before surgery: normal (N), below normal (<N), and above normal (>N). In Group 1 – the time interval between the last administration of hemostatics and the first administration of anticoagulants ≤ 17 hours. In Group 2 – the time interval 18–24 hours. * – p (between Fg of women in Groups 1 and 2) >0.05, # – p (between Fg of men in Groups 1 and 2) >0.05.

After that, we assessed of the ratios and difference in the risk of thrombosis and bleeding cases, depending on the initial (preoperative) level of the coagulogram, gender and the Group of the patients. In the men of Group 1 with thrombosis after surgery, no statistically significant differences were found between the initial hemostasiological parameters and thrombotic complications. In the women of Gr. 1 with thrombosis after surgery, statistically significant differences were found in the following initial coagulogram indicators: 1) INR: between the patients with values below normal and normal (p=0.00032) and between the patients with values below and above normal (p=0.00001); 2) APTT: between the patients with values below normal and normal (p=0.0037); 3) Fg: between the patients with values below normal and normal (p=0.0062). In Group 2 patients, both men and women, with thrombosis in the early postoperative period, no statistically significant difference were found between the preoperative parameters of the coagulogram and the cases of thrombosis. In Group 1. in men with bleeding after surgery, there were differences in the baseline values of the following indicators: 1) APTT: below normal and normal (p=0.039), above normal and normal (p=0.012); 2) PT: above normal and normal (p=0.042). Among the women of Group 1 with hemorrhagic complications, there were statistically significant differences in the following baseline indicators: 1) APTT: above normal and normal (p=0.00022); 2) Fg: below normal and normal (p=0.00065) and below and above normal (p=0.00001); 3) PLT: below the reference values and normal (p=0.038). When evaluating other baseline hemostasiogram parameters, no statistically significant differences were revealed in the patients with cases of thrombosis and bleeding in Groups 1 and 2, both males and females (p>0.05). For the factors that had a statistically significant effect on the development of thrombosis or bleeding cases in the early postoperative period, with variations, we analyzed the ratio and difference of risks. When analyzing the level of influence of hemostasiogram indicators before surgery on the development of thrombosis in the women of Group 1, we found that INR below normal was associated with a 13.33-time increased risk of thrombosis (RR=13.333, CI=4.49–39.591), and APTT below normal before surgery was associated with a 5.8-time increased risk of thrombosis (RR=5.8, CI=1.357–24.796). In the women of Group 1, a preoperative APTT level above normal was associated with a 28-time increased risk of bleeding (RR=28, CI=3.426–228.831), and low levels of Fg and PLT in the preoperative period were associated with an increased risk of hemorrhages by 23.25 times (RR=23.25, CI=3.117–173.423) and 10.2 times (RR=10.2, CI=1.805–57.619), respectively. We found that in the men of Group 1, a baseline APTT level above normal was associated with an 18-time increased risk of bleeding cases (RR=18, CI=2.679–120.922).

Thus, the overall incidence of thrombosis and bleeding after surgery in the patients of our study was 6.32% and 4.35%, respectively. In other studies related to the analysis of the incidence of thrombosis and bleeding after knee or hip arthroplasty, the similar data are obtained (Ershov et al 2015; Bozhkova et al. 2018). A higher incidence of thrombosis can, firstly, be influenced by the presence of ischemic heart disease and hypertension, because these pathologies can ”shift” the hemostatic system towards hypercoagulation (Krasnova et al. 2019). Secondly, in patients with OA, endothelial dysfunction and baseline hypercoagulability are observed, which also increases the risk of thrombosis (Suzuki et al. 2014). In our study, we found that the use of tranexamic acid with TI between hemostatics and anticoagulants of less than 18 hours was statistically significantly associated with a higher risk of thrombosis cases after arthroplasty. Kim et al. (2018) provided the similar data, but in that study the difference was not statistically significant (Kim et al. 2018), in contrast to our work. We demonstrated the importance of adherence to TI between hemostatics and anticoagulants of at least 18 hours. The frequency of all complications, thrombosis in particular, was higher in Group 1, with a TI under 18 hours. Different studies consider diseases most often associated with OA (according to the Centers for Disease Control and Prevention 2015; Alabut and Sikilinda 2016), and their impact on the risk of thrombosis and bleeding cases is assessed (Boutsiadis et al. 2017; Gronbeck et al. 2019; Sloan et al. 2019). It is important to pay special attention to those risk factors that can provoke the onset of complications in the postoperative period after total knee or hip arthroplasty.

However, it should be noted that our study has some limitations, as it is retrospective and its results should be interpreted with caution.