Home Life Sciences Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits
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Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits

  • Lu Yin , Yuan Qi , Zhiru Ge EMAIL logo and Jiajin Li EMAIL logo
Published/Copyright: January 28, 2022
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Open Life Sciences
From the journal Open Life Sciences Volume 17 Issue 1

Abstract

The aim of this study was to explore the effects of dabigatran and rivaroxaban on the activities of various coagulation factors. To achieve that, 60 rabbits were randomly divided into experimental groups that received different doses of dabigatran or rivaroxaban. The effects of dabigatran and rivaroxaban on the activities of FII, FV, FVIII, FX, and activated protein C (APC) were analyzed. In the dabigatran groups, activated partial thromboplastin time and thromboplastin time (TT) were prolonged after drug administration, and the activities of FII, FV, FVIII, and FX were inhibited as the drug concentration increased. Low doses of dabigatran inhibited APC activity. In the rivaroxaban groups, APTT and TT were not significantly prolonged after drug administration. In contrast, the high-dose rivaroxaban group exhibited prolonged PT, and the degree of inhibition of the activities of FII, FV, FVIII, and FX increased as the drug concentration increased. Rivaroxaban had no significant effect on APC activity regardless of dosage. As the drug concentration increased, both NOACs had more significant inhibitory effects on the activities of FII, FV, FVIII, and FX. Low concentrations of dabigatran generated an inhibitory effect on APC activity, while high concentrations of dabigatran had no significant effect. Rivaroxaban had no significant effect on APC activity.

Keywords: dabigatran; rivaroxaban; anticoagulants; thrombin; APC

1 Introduction

Atrial fibrillation (AF) is a common arrhythmia condition. Approximately, one-third of the hospitalized patients with arrhythmia have AF. In 2020, 5.6 million people in the United States suffered from AF, of which half were elderly people over 80 years of age [1]. In patients with concurrent nonvalvular atrial fibrillation (NVAF), the incidence of ischemic stroke is 6 times that of patients without NVAF [2].

Oral anticoagulation therapy is the cornerstone of stroke prevention [3]. The traditional drug warfarin has a definite curative effect [4]. However, this drug has several shortcomings. Its effect can be easily affected by food and other drugs, and it is necessary to monitor the blood coagulation function of patients. Insufficient or excessive anticoagulation may readily occur, leading to an increased risk of ischemia or hemorrhage in patients [5]. Therefore, the development of direct new oral anticoagulants (NOACs) becomes inevitable.

In clinical practice, NOACs mainly include the direct inhibitors of thrombin FII (clotting factor II), i.e., dabigatran, and the inhibitors of coagulation factor FX, i.e., rivaroxaban [6]. Although the mechanisms of action vary among different types of oral anticoagulants, the final effects are all related to the inhibition of FII. Thus, these drugs achieve anticoagulation by reducing the production of thrombin or inhibiting its activity [7].

Dabigatran and rivaroxaban are both newly developed nonvitamin K-dependent anticoagulants [7,8]. Compared with the traditional anticoagulant warfarin, these drugs have advantages such as a single target, fast effects, short half-life, no need to monitor blood coagulation, and less interaction with drugs and food [9]. At present, both oral dabigatran (the active ingredient is dabigatran) and rivaroxaban are effectively used in anticoagulation treatment for patients with AF and venous thromboembolism [10].

Although dabigatran and rivaroxaban are specific inhibitors of FII and FX, studies have found that the activities of other coagulation factors are also altered in patients who take dabigatran and rivaroxaban [11,12]. However, in the abovementioned studies, experiments were conducted in vitro using the blood of volunteers. Therefore, the present study examined the changes in the activities of FII, FV, FVIII, FX, and activated protein C (APC) in healthy experimental animals after the administration of various concentrations of dabigatran and rivaroxaban. The present study intended to explore whether different NOACs had different effects on thrombin activity.

2 Methods

2.1 Grouping of the research animals

A total of 60 healthy New Zealand white rabbits weighing 2.0–2.6 kg were selected for this study. The experimental animals were bred and provided by the Animal Experiment Center of Soochow University. They were divided into the dabigatran group and rivaroxaban group according to the principle of randomization. The dabigatran group was further divided into the blank control, 1, 5, 10, 20, and 40 mg/kg groups [13], with 6 animals in each group. The rivaroxaban group was divided into the blank control and the 0.3, 1, and 3 mg/kg groups [14], and each group contained six animals.

  1. Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals.

2.2 Animal experiment methods

Dabigatran capsules, with the active form of the prodrug dabigatran etexilate, were provided by Boehringer–Ingelheim. After the tablets were crushed, the stock solution was prepared in dimethyl sulfoxide (DMSO) in a volume ratio of 1:9. On the day of the experiment, the stock solution was further diluted in DMSO with different concentrations prepared according to the rabbit’s weight and grouping [15]. According to the Biopharmaceutics Classification System, Rivaroxaban is a class II drug with low solubility and high permeability. The dosage of rivaroxaban was calculated according to the weight and grouping of rabbits. After being crushed, it was slightly dissolved in water and treated by intragastric administration [16]. Before drug administration, 3 mL of blood was collected from the marginal ear vein of each animal into anticoagulant tubes. After blood was collected, the animals were immobilized, and a gavage tube was inserted into the stomach. Animals in the dabigatran groups were gavaged with dabigatran solution at concentrations of 1, 5, 10, 20, and 40 mg/kg, respectively (10 mL each time), and aminals in the blank control group were gavaged with 10 mL of solvent. Animals in the rivaroxaban groups were gavaged with rivaroxaban solution at concentrations of 0.3, 1, and 3 mg/kg respectively (10 mL each time), and animals in the blank control group were gavaged with 10 mL of distilled water. Approximately 2 h after gavage, 3% sodium pentobarbital was injected into the animals through the marginal ear vein at a dose of 1 mL/kg. After the corneal reflex disappeared, with level 1 tension in the limbs, the animals were immobilized on an animal experimental table in the supine position. Blood (3 mL) was collected from the femoral artery, transferred into anticoagulant tubes, and mixed immediately by inverting the tubes. Within 30 min of collection, blood was centrifuged at 2,500 rpm for 15 min. The plasma in the upper layer was collected and stored in −80°C freezer for future assays [17].

2.3 Examination of coagulation factors

The following are the methods and required reagents for assessing various indicators. The Jiangsu Institute of Hematology of the First Affiliated Hospital of Soochow University examined all the blood coagulation indicators and coagulation factor activities using a STAGO compact automatic blood coagulation analyzer (France) in accordance with the manufacturer’s instructions. All related reagents were also provided by the company [17].

The activated partial thromboplastin time (APTT), plasma prothrombin time (PT), and thrombin time (TT) were measured on a STAGO compact automatic coagulometer using a coagulation method-based APTT assay kit, PT assay kit, and TT assay kit by the manufacturer’s instructions.

2.3.1 FII, FV, FVIII, and FX activities

The activities of FII, FV, FVIII, and FX were measured on a STAGO compact automatic coagulometer using coagulation method-based kits. According to the literature, Gerotziafas determined the activities of coagulation factors using a method involving various folds of dilution [10]. Therefore, we also examined the activities of FII, FV, FVIII, and FX after diluting the samples. Specifically, the measured values of the activities of FII, FV, and FVIII fell within the appropriate range after 5-, 50-, and 20-fold dilutions, respectively. Hence, the above method was used to determine the activities of the coagulation factors.

2.3.2 APC activity

APC activity was measured on a STAGO compact automatic coagulometer using an APC activity kit (chromogenic substrate method).

2.4 Statistical analysis

Statistical analysis was performed using the SPSS 19.0 statistical package. Measurement data are expressed as the mean ± standard deviation. Significant differences between measurement data were determined using the paired sample t-test. P values of less than 0.05, 0.01, and 0.001 indicated that the differences were statistically significant. Plots were constructed using GraphPad software. In the figures, # indicates that a difference was not statistically significant (P > 0.05); *P < 0.05; **P < 0.01; and ***P < 0.001.

3 Results

3.1 Effects of various doses of oral dabigatran and rivaroxaban on the coagulation function

3.1.1 Dabigatran groups

Paired t-tests were performed to analyze APTT, PT, and TT in each group before and after drug administration. There was no difference in the APTT between the control group and the 1 mg/kg dose group (P > 0.05) (Figure 1a). APTT became prolonged in the 5 mg/kg dose group, and the difference was statistically significant (P < 0.05). There was no difference in PT among the 1 mg/kg group, the 5 mg/kg group, and the 10 mg/kg group, suggesting that PT was not sensitive to dabigatran dose and only began to become significantly prolonged (P < 0.05) at a higher dose (20 mg/kg) (Figure 1b). In contrast, TT was very sensitive to dabigatran dose and became significantly prolonged in the low-dose group (1 mg/kg) (P < 0.01) (Figure 1c). (Note: In the 40 mg/kg group, the APTT value exceeded the upper limit of measurement (180 s), and the result was replaced with 180 s.)

Figure 1 Effects of various doses of oral dabigatran and rivaroxaban on the activated partial thromboplastin time (APTT; (a) and (d)), the prothrombin time (PT; (b) and (e), and the thrombin time (TT; (c) and (f)) in rabbits. *p < 0.05, **p < 0.01, ***p < 0.001 versus the control group; (mean ± S.D., n = 6).
Figure 1

Effects of various doses of oral dabigatran and rivaroxaban on the activated partial thromboplastin time (APTT; (a) and (d)), the prothrombin time (PT; (b) and (e), and the thrombin time (TT; (c) and (f)) in rabbits. *p < 0.05, **p < 0.01, ***p < 0.001 versus the control group; (mean ± S.D., n = 6).

3.1.2 Rivaroxaban groups

After drug administration, there was no significant difference in PT values among the control group, the 0.3 mg/kg dose group, and the 1.0 mg/kg dose group (P = 0.322). However, the differences between the 3.0 mg/kg dose group and the other three groups were statistically significant (P < 0.01) (Figure 1e). There was no significant difference in the APTT level among the control group, the 0.3 mg/kg dose group, the 1.0 mg/kg dose group, and the 3 mg/kg group (P = 0.246) (Figure 1d). After drug administration, TT gradually became slightly prolonged in each group as the dose of rivaroxaban increased (Figure 1f). However, variance analysis indicated that the change was not statistically significant (P = 0.864). Rivaroxaban had no effect on TT.

3.2 Effects of various doses of oral dabigatran and rivaroxaban on the activities of coagulation factors

FII, FV, FVIII, FX, and APC activities were examined before and after intragastric administration of the two drugs. Changes in the activity of these factors before and after administration of the drugs were analyzed. The degree of activity change before and after administration of the drugs was analyzed, namely, the rate of change = (activity before medication-activity after medication)/activity before medication. The results indicated no significant differences in the activities of FII, FV, FVIII, FX, and APC in the control group before and after treatment (P > 0.05).

In all groups, FII activity decreased after drug administration compared with that before drug administration. Among the dabigatran groups, the decrease in FII activity was statistically significant at 1 mg/kg (P < 0.01). From 5 to 40 mg/kg, FII activity was markedly reduced and the decrease was also statistically significant (P < 0.001) (Figure 2a). Among the rivaroxaban groups, the decrease in FII activity was statistically significant at 0.3 mg/kg (P < 0.05), although it was more significant in the 1 mg/kg group and the 3 mg/kg group (P < 0.01) (Figure 2e). Regarding the rate of inhibition of FII activity, the dabigatran groups exhibited an inhibition efficiency of 15.7% at 1 mg/kg and 41.4% at 40 mg/kg (Figure 2b). The rivaroxaban groups had an inhibition efficiency of 7.9% at 0.3 mg/kg and 22.6% at 3 mg/kg (Figure 2f).

Figure 2 Effects of various doses of oral dabigatran and rivaroxaban on coagulation factor 2 (FII; (a) and (e)), 5 (FV; (c) and (g)) activity in rabbits. (b) and (d) The rate of inhibition of FII and FV activity by dabigatran. (f and h) The rate of inhibition of FII and FV activity by rivaroxaban. *p < 0.05, **p < 0.01, ***p < 0.001 versus the control group; (mean ± S.D., n = 6).
Figure 2

Effects of various doses of oral dabigatran and rivaroxaban on coagulation factor 2 (FII; (a) and (e)), 5 (FV; (c) and (g)) activity in rabbits. (b) and (d) The rate of inhibition of FII and FV activity by dabigatran. (f and h) The rate of inhibition of FII and FV activity by rivaroxaban. *p < 0.05, **p < 0.01, ***p < 0.001 versus the control group; (mean ± S.D., n = 6).

In all groups, FV activity was reduced after drug administration compared with that before drug administration. Among the dabigatran groups, the decrease in FV activity was statistically significant at 1 mg/kg (P < 0.05). From 5 mg/kg to 40 mg/kg, the decrease in FV activity was also significant (P < 0.01) (Figure 2c). Among the rivaroxaban groups, the 0.3 mg/kg group exhibited no significant difference in FV activity before and after drug administration (P > 0.05) (Figure 2g). However, FV activity was significantly decreased in the 1 and 3 mg/kg groups after drug administration (P < 0.01). Regarding the rate of inhibition of FV activity, the dabigatran groups exhibited an inhibition efficiency of 5.4% at 1 mg/kg and 19.2% at 40 mg/kg (Figure 2d). The rivaroxaban groups exhibited an inhibition efficiency of 3.9% at 0.3 mg/kg and 20.3% at 3 mg/kg (Figure 2h).

In all groups, FVIII activity was decreased after drug administration compared with that before drug administration. Among the dabigatran groups, the decrease in FVIII activity was statistically significant at 1 mg/kg (P < 0.05). From the 5 mg/kg group to the 40 mg/kg group, FVIII activity was markedly reduced, and the decrease was also statistically significant (P < 0.001) (Figure 3a). In the group treated with 0.3 mg/kg rivaroxaban, FVIII activity did not change significantly (P > 0.05). However, FVIII activity significantly decreased in the 1 mg/kg group and the 3 mg/kg group (P < 0.01) (Figure 3e). Regarding the rate of inhibition of FV activity, the dabigatran groups exhibited an inhibition efficiency of 17.8% at 1 mg/kg and 52.4% at 40 mg/kg (Figure 3b). The rivaroxaban groups exhibited an inhibition efficiency of 9.8% at 0.3 mg/kg and 23.7% at 3 mg/kg (Figure 3f).

Figure 3 Effects of various doses of oral dabigatran and rivaroxaban on coagulation factor 8 (FVIII; (a) and (e)), 10 (FX; (c) and (g)) activity in rabbits. (b) and (d) The rate of inhibition of FII and FV activity by dabigatran. (f) and (h) The rate of inhibition of FII and FV activity by rivaroxaban. *p < 0.05, **p < 0.01,***p < 0.001 versus the control group; (mean ± S.D., n = 6).
Figure 3

Effects of various doses of oral dabigatran and rivaroxaban on coagulation factor 8 (FVIII; (a) and (e)), 10 (FX; (c) and (g)) activity in rabbits. (b) and (d) The rate of inhibition of FII and FV activity by dabigatran. (f) and (h) The rate of inhibition of FII and FV activity by rivaroxaban. *p < 0.05, **p < 0.01,***p < 0.001 versus the control group; (mean ± S.D., n = 6).

In all groups, FX activity decreased after drug administration compared with that before drug administration. Among the dabigatran groups, FX activity did not change significantly in the 1 mg/kg group. The decrease in FX activity was statistically significant at 5 mg/kg (P < 0.01). From the 5 mg/kg group to the 40 mg/kg group, FX activity was reduced, and the reduction was also statistically significant (P < 0.001) (Figure 3c). In the group treated with 0.3 mg/kg rivaroxaban, FX activity decreased considerably, and the decrease was statistically significant (P < 0.05) (Figure 3g). FX activity was also significantly reduced in the 1 mg/kg group and the 3 mg/kg group (P < 0.01). Regarding the rate of inhibition of FX activity, the dabigatran groups exhibited an inhibition efficiency of 8.6% at 1 mg/kg and 45.3% at 40 mg/kg (Figure 3d). The rivaroxaban groups exhibited an inhibition efficiency of 12% at 0.3 mg/kg and 32.1% at 3 mg/kg (Figure 3h).

3.3 Effects of various doses of oral dabigatran and rivaroxaban on APC activity

APC activity exhibited a small change in all groups after drug administration compared with that before drug administration (Figure 4a). Among the dabigatran groups, APC activity was inhibited only in the 1 mg/kg group (inhibition efficiency: 12.3%) (Figure 4b), and the inhibitory effect was statistically significant (P < 0.05). Rivaroxaban treatment had no significant effect on the rate of inhibition of APC activity (Figures 4c and d).

Figure 4 Effects of various doses of oral dabigatran and rivaroxaban on activated protein C (APC; (a) and (c)) activity in rabbits. (b) and (d) The rate of inhibition of APC activity by dabigatran and rivaroxaban, respectively. *p < 0.05, **p < 0.01, ***p < 0.001 versus the control group (mean ± S.D., n = 6).
Figure 4

Effects of various doses of oral dabigatran and rivaroxaban on activated protein C (APC; (a) and (c)) activity in rabbits. (b) and (d) The rate of inhibition of APC activity by dabigatran and rivaroxaban, respectively. *p < 0.05, **p < 0.01, ***p < 0.001 versus the control group (mean ± S.D., n = 6).

4 Discussion

NOACs mainly include the FII inhibitor dabigatran and the FX inhibitor rivaroxaban [9]. Dabigatran etexilate itself has no activity and is a prodrug. This prodrug is metabolized by serum esterase to dabigatran after oral administration. Dabigatran binds to the fibrin-specific binding site of thrombin. As a result, fibrinogen cannot be converted into fibrin, preventing thrombus formation [18]. Rivaroxaban is a specific inhibitor of factor X. It reaches peak plasma concentration 2–4 h after oral administration. The half-life of rivaroxaban is 9–12 h, and 40% of rivaroxaban is metabolized through the kidneys [19].

To explore the effects of dabigatran and rivaroxaban on the activities of FII and FX, the present study treated healthy rabbits with various concentrations of dabigatran and rivaroxaban and examined the activities of FII and FX before and after treatment. The results showed that the activity of FII decreased as the concentration of dabigatran increased. When the dabigatran concentration was greater than or equal to 10 mg/kg, the decrease in FII activity reached a statistically significant level. Moreover, as the concentration increased, the rate of change increased accordingly. Such results indicate that the degree of FII activity inhibition was increasing. In the experimental groups that received rivaroxaban, FX activity decreased considerably as the rivaroxaban concentration increased. They reached a statistically significant level at 1 mg/kg rivaroxaban. These results confirmed that dabigatran and rivaroxaban effectively inhibited the activity of FII and FX, respectively, in healthy animals.

FX represents the point of convergence of the endogenous and exogenous coagulation pathways. FX forms a prothrombinase complex with factor V, Ca2+, and platelet membrane phospholipids, activating thrombin. One molecule of FX can produce 1,000 molecules of FII. Dabigatran inhibits thrombin activity by directly binding to free or bound thrombin, directly blocking the physiological function of thrombin. In addition, dabigatran also blocks the self-activation of thrombin, further reducing thrombin generation [17,20]. Rivaroxaban, an FXa inhibitor, reduces thrombin generation by inhibiting the formation of the upstream prothrombinase complex [21,22]. Anticoagulant assays of rabbit plasma indicated that both dabigatran and rivaroxaban effectively reduced the activities of FII, FV, FVIII, and FX. NOACs inhibit FII activity and reduce the positive feedback activation of FV and FVIII, thus ultimately reducing the activation of fibrinogen [7]. However, the difference in the anticoagulant mechanisms of the two types of drugs requires further investigation.

Although there is no need to monitor the coagulation function when using dabigatran and rivaroxaban, the examination of coagulation function becomes necessary under some special conditions, such as bleeding, abnormal renal function, chronic liver disease-related abnormal coagulation function, emergency surgery, and suspected drug overdose [23]. Cuker et al. found that APTT and plasma PT were not sensitive to dabigatran [24]. APTT was prolonged more than 2-fold only when the blood concentration of dabigatran was at least 400 ng/mL [25]. Analyses of APTT in AF patients receiving dabigatran indicated that APTT might still be in the normal range even if the concentration of dabigatran was 60 ng/mL. In this study, both APTT and TT became prolonged in the dabigatran groups as the dabigatran concentration increased. The prolongation of APTT and PT was not statistically significant in the 1 mg/kg group. APTT and PT started to become significantly prolonged in the 5 mg/kg group. In the 10 mg/kg group, APTT was prolonged more than 2-fold. In the 40 mg/kg group, APTT reached the upper limit of the detection range. The APTT values of the six rabbits in the 40 mg/kg group were all 180 s, indicating that the detection of APTT and PT was not accurate in the dabigatran group. At present, the more reliable indicators for detecting the activity of dabigatran are the diluted thrombin time and the Russell viper venom clotting time [25]. Regarding FX inhibitors, studies have found that compared with APTT, PT has a better linear relationship with rivaroxaban concentration and anti-FX activity [26,27]. In this study, PT was significantly prolonged in the 0.3 mg/kg rivaroxaban group.

Studies have found that warfarin has an inhibitory effect on vitamin K epoxide reductase and that it has an inhibitory effect on the production of protein C at the initial stage of use, potentially leading to a transient hypercoagulable state and an increased risk of thrombosis [28,29]. Warfarin-caused skin necrosis was also considered to be related to a decrease in protein C [18]. In addition, a study found that the direct thrombin inhibitors ximelagatran and dabigatran increased the incidence of acute coronary events such as myocardial infarction and that a high percentage of these acute coronary syndrome events occurred in the low-dose treatment group [30]. At present, there is no exact mechanism described for this phenomenon. One possible explanation is that warfarin has an antithrombotic effect more potent than that of dabigatran. In addition, damage to the APC system may also be an influencing factor [31]. Recent studies found that blocking APC (through the APC antibody SPC-54) reduced the hemorrhage caused by the FX inhibitor rivaroxaban. However, SPC-54 had no effect on the hemorrhage caused by dabigatran [32]. This finding indicates that FX and FII inhibitors cause hemorrhaging through different mechanisms [33].

This study has limitations. Certain operations such as exposing the femoral artery and drawing blood might slightly activate the coagulation system, resulting in the activation of some coagulation factors. Due to limitations related to the experimental conditions and time, the control variable in this study was drug concentration. The difference in drug absorption among the rabbits was ignored, rendering the study slightly less rigorous. However, the accurate measurement of rivaroxaban concentration by liquid chromatography-mass spectrometry cannot be achieved in clinical practice. Therefore, this study closely reflected situations observed in clinical practice.

5 Conclusion

Both NOACs had inhibitory effects on the activities of FII, FV, FVIII, and FX, and the inhibitory effect was more significant as the drug concentration increased. Low concentrations of dabigatran generated an inhibitory effect on APC activity, while high concentrations of dabigatran had no significant effect. Rivaroxaban had no significant effect on APC activity.

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  1. Funding information: This work was financially supported by the Key Special Project of Pudong New Area Health System (grant no. PWZzk2017-23).

  2. Author contributions: All authors participated in the design, interpretation of the studies, and analysis of the data and manuscript review. Y.L., Q.Y., and J.L. conducted the experiments, Y.L. and Q.Y. wrote the manuscript. Y.L. and Q.Y. contributed equally to this work.

  3. Conflict of interest: The authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2021-08-07
Revised: 2021-10-14
Accepted: 2021-10-20
Published Online: 2022-01-28

© 2022 Lu Yin et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Biomedical Sciences
  2. Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits
  3. The mother of all battles: Viruses vs humans. Can humans avoid extinction in 50–100 years?
  4. Knockdown of G1P3 inhibits cell proliferation and enhances the cytotoxicity of dexamethasone in acute lymphoblastic leukemia
  5. LINC00665 regulates hepatocellular carcinoma by modulating mRNA via the m6A enzyme
  6. Association study of CLDN14 variations in patients with kidney stones
  7. Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook
  8. Regulation of miR-30b in cancer development, apoptosis, and drug resistance
  9. Informatic analysis of the pulmonary microecology in non-cystic fibrosis bronchiectasis at three different stages
  10. Swimming attenuates tumor growth in CT-26 tumor-bearing mice and suppresses angiogenesis by mediating the HIF-1α/VEGFA pathway
  11. Characterization of intestinal microbiota and serum metabolites in patients with mild hepatic encephalopathy
  12. Functional conservation and divergence in plant-specific GRF gene family revealed by sequences and expression analysis
  13. Application of the FLP/LoxP-FRT recombination system to switch the eGFP expression in a model prokaryote
  14. Biomedical evaluation of antioxidant properties of lamb meat enriched with iodine and selenium
  15. Intravenous infusion of the exosomes derived from human umbilical cord mesenchymal stem cells enhance neurological recovery after traumatic brain injury via suppressing the NF-κB pathway
  16. Effect of dietary pattern on pregnant women with gestational diabetes mellitus and its clinical significance
  17. Potential regulatory mechanism of TNF-α/TNFR1/ANXA1 in glioma cells and its role in glioma cell proliferation
  18. Effect of the genetic mutant G71R in uridine diphosphate-glucuronosyltransferase 1A1 on the conjugation of bilirubin
  19. Quercetin inhibits cytotoxicity of PC12 cells induced by amyloid-beta 25–35 via stimulating estrogen receptor α, activating ERK1/2, and inhibiting apoptosis
  20. Nutrition intervention in the management of novel coronavirus pneumonia patients
  21. circ-CFH promotes the development of HCC by regulating cell proliferation, apoptosis, migration, invasion, and glycolysis through the miR-377-3p/RNF38 axis
  22. Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma
  23. Lacunar infarction aggravates the cognitive deficit in the elderly with white matter lesion
  24. Hydroxysafflor yellow A improved retinopathy via Nrf2/HO-1 pathway in rats
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  26. Elevated IL-35 level and iTr35 subset increase the bacterial burden and lung lesions in Mycobacterium tuberculosis-infected mice
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  50. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
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  173. Erratum to “A two-microRNA signature predicts the progression of male thyroid cancer”
  174. Retraction
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https://doi.org/10.1515/biol-2022-0002
Keywords for this article
dabigatran; rivaroxaban; anticoagulants; thrombin; APC
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits
  3. The mother of all battles: Viruses vs humans. Can humans avoid extinction in 50–100 years?
  4. Knockdown of G1P3 inhibits cell proliferation and enhances the cytotoxicity of dexamethasone in acute lymphoblastic leukemia
  5. LINC00665 regulates hepatocellular carcinoma by modulating mRNA via the m6A enzyme
  6. Association study of CLDN14 variations in patients with kidney stones
  7. Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook
  8. Regulation of miR-30b in cancer development, apoptosis, and drug resistance
  9. Informatic analysis of the pulmonary microecology in non-cystic fibrosis bronchiectasis at three different stages
  10. Swimming attenuates tumor growth in CT-26 tumor-bearing mice and suppresses angiogenesis by mediating the HIF-1α/VEGFA pathway
  11. Characterization of intestinal microbiota and serum metabolites in patients with mild hepatic encephalopathy
  12. Functional conservation and divergence in plant-specific GRF gene family revealed by sequences and expression analysis
  13. Application of the FLP/LoxP-FRT recombination system to switch the eGFP expression in a model prokaryote
  14. Biomedical evaluation of antioxidant properties of lamb meat enriched with iodine and selenium
  15. Intravenous infusion of the exosomes derived from human umbilical cord mesenchymal stem cells enhance neurological recovery after traumatic brain injury via suppressing the NF-κB pathway
  16. Effect of dietary pattern on pregnant women with gestational diabetes mellitus and its clinical significance
  17. Potential regulatory mechanism of TNF-α/TNFR1/ANXA1 in glioma cells and its role in glioma cell proliferation
  18. Effect of the genetic mutant G71R in uridine diphosphate-glucuronosyltransferase 1A1 on the conjugation of bilirubin
  19. Quercetin inhibits cytotoxicity of PC12 cells induced by amyloid-beta 25–35 via stimulating estrogen receptor α, activating ERK1/2, and inhibiting apoptosis
  20. Nutrition intervention in the management of novel coronavirus pneumonia patients
  21. circ-CFH promotes the development of HCC by regulating cell proliferation, apoptosis, migration, invasion, and glycolysis through the miR-377-3p/RNF38 axis
  22. Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma
  23. Lacunar infarction aggravates the cognitive deficit in the elderly with white matter lesion
  24. Hydroxysafflor yellow A improved retinopathy via Nrf2/HO-1 pathway in rats
  25. Comparison of axon extension: PTFE versus PLA formed by a 3D printer
  26. Elevated IL-35 level and iTr35 subset increase the bacterial burden and lung lesions in Mycobacterium tuberculosis-infected mice
  27. A case report of CAT gene and HNF1β gene variations in a patient with early-onset diabetes
  28. Study on the mechanism of inhibiting patulin production by fengycin
  29. SOX4 promotes high-glucose-induced inflammation and angiogenesis of retinal endothelial cells by activating NF-κB signaling pathway
  30. Relationship between blood clots and COVID-19 vaccines: A literature review
  31. Analysis of genetic characteristics of 436 children with dysplasia and detailed analysis of rare karyotype
  32. Bioinformatics network analyses of growth differentiation factor 11
  33. NR4A1 inhibits the epithelial–mesenchymal transition of hepatic stellate cells: Involvement of TGF-β–Smad2/3/4–ZEB signaling
  34. Expression of Zeb1 in the differentiation of mouse embryonic stem cell
  35. Study on the genetic damage caused by cadmium sulfide quantum dots in human lymphocytes
  36. Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis
  37. Assessment of the anesthetic effect of modified pentothal sodium solution on Sprague-Dawley rats
  38. Genetic susceptibility to high myopia in Han Chinese population
  39. Potential biomarkers and molecular mechanisms in preeclampsia progression
  40. Silencing circular RNA-friend leukemia virus integration 1 restrained malignancy of CC cells and oxaliplatin resistance by disturbing dyskeratosis congenita 1
  41. Endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime for advanced pulmonary large-cell neuroendocrine carcinoma as a first-line treatment: A case report
  42. The significance of PAK4 in signaling and clinicopathology: A review
  43. Sorafenib inhibits ovarian cancer cell proliferation and mobility and induces radiosensitivity by targeting the tumor cell epithelial–mesenchymal transition
  44. Characterization of rabbit polyclonal antibody against camel recombinant nanobodies
  45. Active legumain promotes invasion and migration of neuroblastoma by regulating epithelial-mesenchymal transition
  46. Effect of cell receptors in the pathogenesis of osteoarthritis: Current insights
  47. MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction
  48. Study of hsa_circRNA_000121 and hsa_circRNA_004183 in papillary thyroid microcarcinoma
  49. BuyangHuanwu Decoction attenuates cerebral vasospasm caused by subarachnoid hemorrhage in rats via PI3K/AKT/eNOS axis
  50. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
  51. Monosodium iodoacetate-induced subchondral bone microstructure and inflammatory changes in an animal model of osteoarthritis
  52. A rare presentation of type II Abernethy malformation and nephrotic syndrome: Case report and review
  53. Rapid death due to pulmonary epithelioid haemangioendothelioma in several weeks: A case report
  54. Hepatoprotective role of peroxisome proliferator-activated receptor-α in non-cancerous hepatic tissues following transcatheter arterial embolization
  55. Correlation between peripheral blood lymphocyte subpopulations and primary systemic lupus erythematosus
  56. A novel SLC8A1-ALK fusion in lung adenocarcinoma confers sensitivity to alectinib: A case report
  57. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes
  58. Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer
  59. BTBD10 inhibits glioma tumorigenesis by downregulating cyclin D1 and p-Akt
  60. Mucormycosis co-infection in COVID-19 patients: An update
  61. Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report
  62. Long non-coding RNA HOXB-AS1 is a prognostic marker and promotes hepatocellular carcinoma cells’ proliferation and invasion
  63. Preparation and evaluation of LA-PEG-SPION, a targeted MRI contrast agent for liver cancer
  64. Proteomic analysis of the liver regulating lipid metabolism in Chaohu ducks using two-dimensional electrophoresis
  65. Nasopharyngeal tuberculosis: A case report
  66. Characterization and evaluation of anti-Salmonella enteritidis activity of indigenous probiotic lactobacilli in mice
  67. Aberrant pulmonary immune response of obese mice to periodontal infection
  68. Bacteriospermia – A formidable player in male subfertility
  69. In silico and in vivo analysis of TIPE1 expression in diffuse large B cell lymphoma
  70. Effects of KCa channels on biological behavior of trophoblasts
  71. Interleukin-17A influences the vulnerability rather than the size of established atherosclerotic plaques in apolipoprotein E-deficient mice
  72. Multiple organ failure and death caused by Staphylococcus aureus hip infection: A case report
  73. Prognostic signature related to the immune environment of oral squamous cell carcinoma
  74. Primary and metastatic squamous cell carcinoma of the thyroid gland: Two case reports
  75. Neuroprotective effects of crocin and crocin-loaded niosomes against the paraquat-induced oxidative brain damage in rats
  76. Role of MMP-2 and CD147 in kidney fibrosis
  77. Geometric basis of action potential of skeletal muscle cells and neurons
  78. Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review
  79. Role of cerebellar cortex in associative learning and memory in guinea pigs
  80. Application of metagenomic next-generation sequencing technique for diagnosing a specific case of necrotizing meningoencephalitis caused by human herpesvirus 2
  81. Case report: Quadruple primary malignant neoplasms including esophageal, ureteral, and lung in an elderly male
  82. Long non-coding RNA NEAT1 promotes angiogenesis in hepatoma carcinoma via the miR-125a-5p/VEGF pathway
  83. Osteogenic differentiation of periodontal membrane stem cells in inflammatory environments
  84. Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway
  85. Continuous renal replacement therapy combined with double filtration plasmapheresis in the treatment of severe lupus complicated by serious bacterial infections in children: A case report
  86. Simultaneous triple primary malignancies, including bladder cancer, lymphoma, and lung cancer, in an elderly male: A case report
  87. Preclinical immunogenicity assessment of a cell-based inactivated whole-virion H5N1 influenza vaccine
  88. One case of iodine-125 therapy – A new minimally invasive treatment of intrahepatic cholangiocarcinoma
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  92. Evaluation of prognostic markers in patients infected with SARS-CoV-2
  93. N6-Methyladenosine-related alternative splicing events play a role in bladder cancer
  94. Characterization of the structural, oxidative, and immunological features of testis tissue from Zucker diabetic fatty rats
  95. Effects of glucose and osmotic pressure on the proliferation and cell cycle of human chorionic trophoblast cells
  96. Investigation of genotype diversity of 7,804 norovirus sequences in humans and animals of China
  97. Characteristics and karyotype analysis of a patient with turner syndrome complicated with multiple-site tumors: A case report
  98. Aggravated renal fibrosis is positively associated with the activation of HMGB1-TLR2/4 signaling in STZ-induced diabetic mice
  99. Distribution characteristics of SARS-CoV-2 IgM/IgG in false-positive results detected by chemiluminescent immunoassay
  100. SRPX2 attenuated oxygen–glucose deprivation and reperfusion-induced injury in cardiomyocytes via alleviating endoplasmic reticulum stress-induced apoptosis through targeting PI3K/Akt/mTOR axis
  101. Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients
  102. Relationship between CRP gene polymorphisms and ischemic stroke risk: A systematic review and meta-analysis
  103. Effects of growth hormone on lipid metabolism and sexual development in pubertal obese male rats
  104. Cloning and identification of the CTLA-4IgV gene and functional application of vaccine in Xinjiang sheep
  105. Antitumor activity of RUNX3: Upregulation of E-cadherin and downregulation of the epithelial–mesenchymal transition in clear-cell renal cell carcinoma
  106. PHF8 promotes osteogenic differentiation of BMSCs in old rat with osteoporosis by regulating Wnt/β-catenin pathway
  107. A review of the current state of the computer-aided diagnosis (CAD) systems for breast cancer diagnosis
  108. Bilateral dacryoadenitis in adult-onset Still’s disease: A case report
  109. A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma
  110. The role of erythrocytes and erythroid progenitor cells in tumors
  111. Relationship between platelet activation markers and spontaneous abortion: A meta-analysis
  112. Abnormal methylation caused by folic acid deficiency in neural tube defects
  113. Silencing TLR4 using an ultrasound-targeted microbubble destruction-based shRNA system reduces ischemia-induced seizures in hyperglycemic rats
  114. Plant Sciences
  115. Seasonal succession of bacterial communities in cultured Caulerpa lentillifera detected by high-throughput sequencing
  116. Cloning and prokaryotic expression of WRKY48 from Caragana intermedia
  117. Novel Brassica hybrids with different resistance to Leptosphaeria maculans reveal unbalanced rDNA signal patterns
  118. Application of exogenous auxin and gibberellin regulates the bolting of lettuce (Lactuca sativa L.)
  119. Phytoremediation of pollutants from wastewater: A concise review
  120. Genome-wide identification and characterization of NBS-encoding genes in the sweet potato wild ancestor Ipomoea trifida (H.B.K.)
  121. Alleviative effects of magnetic Fe3O4 nanoparticles on the physiological toxicity of 3-nitrophenol to rice (Oryza sativa L.) seedlings
  122. Selection and functional identification of Dof genes expressed in response to nitrogen in Populus simonii × Populus nigra
  123. Study on pecan seed germination influenced by seed endocarp
  124. Identification of active compounds in Ophiopogonis Radix from different geographical origins by UPLC-Q/TOF-MS combined with GC-MS approaches
  125. The entire chloroplast genome sequence of Asparagus cochinchinensis and genetic comparison to Asparagus species
  126. Genome-wide identification of MAPK family genes and their response to abiotic stresses in tea plant (Camellia sinensis)
  127. Selection and validation of reference genes for RT-qPCR analysis of different organs at various development stages in Caragana intermedia
  128. Cloning and expression analysis of SERK1 gene in Diospyros lotus
  129. Integrated metabolomic and transcriptomic profiling revealed coping mechanisms of the edible and medicinal homologous plant Plantago asiatica L. cadmium resistance
  130. A missense variant in NCF1 is associated with susceptibility to unexplained recurrent spontaneous abortion
  131. Assessment of drought tolerance indices in faba bean genotypes under different irrigation regimes
  132. The entire chloroplast genome sequence of Asparagus setaceus (Kunth) Jessop: Genome structure, gene composition, and phylogenetic analysis in Asparagaceae
  133. Food Science
  134. Dietary food additive monosodium glutamate with or without high-lipid diet induces spleen anomaly: A mechanistic approach on rat model
  135. Binge eating disorder during COVID-19
  136. Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model
  137. FTO gene expression in diet-induced obesity is downregulated by Solanum fruit supplementation
  138. Physical activity enhances fecal lactobacilli in rats chronically drinking sweetened cola beverage
  139. Supercritical CO2 extraction, chemical composition, and antioxidant effects of Coreopsis tinctoria Nutt. oleoresin
  140. Functional constituents of plant-based foods boost immunity against acute and chronic disorders
  141. Effect of selenium and methods of protein extraction on the proteomic profile of Saccharomyces yeast
  142. Microbial diversity of milk ghee in southern Gansu and its effect on the formation of ghee flavor compounds
  143. Ecology and Environmental Sciences
  144. Effects of heavy metals on bacterial community surrounding Bijiashan mining area located in northwest China
  145. Microorganism community composition analysis coupling with 15N tracer experiments reveals the nitrification rate and N2O emissions in low pH soils in Southern China
  146. Genetic diversity and population structure of Cinnamomum balansae Lecomte inferred by microsatellites
  147. Preliminary screening of microplastic contamination in different marine fish species of Taif market, Saudi Arabia
  148. Plant volatile organic compounds attractive to Lygus pratensis
  149. Effects of organic materials on soil bacterial community structure in long-term continuous cropping of tomato in greenhouse
  150. Effects of soil treated fungicide fluopimomide on tomato (Solanum lycopersicum L.) disease control and plant growth
  151. Prevalence of Yersinia pestis among rodents captured in a semi-arid tropical ecosystem of south-western Zimbabwe
  152. Effects of irrigation and nitrogen fertilization on mitigating salt-induced Na+ toxicity and sustaining sea rice growth
  153. Bioengineering and Biotechnology
  154. Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes
  155. Development of alkaline phosphatase-scFv and its use for one-step enzyme-linked immunosorbent assay for His-tagged protein detection
  156. Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma
  157. Agriculture
  158. Effects of chemical-based fertilizer replacement with biochar-based fertilizer on albic soil nutrient content and maize yield
  159. Genome-wide identification and expression analysis of CPP-like gene family in Triticum aestivum L. under different hormone and stress conditions
  160. Agronomic and economic performance of mung bean (Vigna radiata L.) varieties in response to rates of blended NPS fertilizer in Kindo Koysha district, Southern Ethiopia
  161. Influence of furrow irrigation regime on the yield and water consumption indicators of winter wheat based on a multi-level fuzzy comprehensive evaluation
  162. Discovery of exercise-related genes and pathway analysis based on comparative genomes of Mongolian originated Abaga and Wushen horse
  163. Lessons from integrated seasonal forecast-crop modelling in Africa: A systematic review
  164. Evolution trend of soil fertility in tobacco-planting area of Chenzhou, Hunan Province, China
  165. Animal Sciences
  166. Morphological and molecular characterization of Tatera indica Hardwicke 1807 (Rodentia: Muridae) from Pothwar, Pakistan
  167. Research on meat quality of Qianhua Mutton Merino sheep and Small-tail Han sheep
  168. SI: A Scientific Memoir
  169. Suggestions on leading an academic research laboratory group
  170. My scientific genealogy and the Toronto ACDC Laboratory, 1988–2022
  171. Erratum
  172. Erratum to “Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study”
  173. Erratum to “A two-microRNA signature predicts the progression of male thyroid cancer”
  174. Retraction
  175. Retraction of “Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis”
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