Author + information
- Sou Otuki, MD,
- Daisuke Izumi, MD, PhD∗ (, )
- Masayoshi Suda, MD, PhD,
- Akinori Sato, MD, PhD,
- Yuki Hasegawa, MD,
- Nobue Yagihara, MD, PhD,
- Kenichi Iijima, MD, PhD,
- Masaomi Chinushi, MD, PhD,
- Ichiro Fuse, MD, PhD and
- Tohru Minamino, MD, PhD∗ ( )()
- ↵∗Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachidori, Chuo-ku, Niigata 951-8510, Japan
The mechanisms underlying the lower risk of hemorrhagic complications during treatment with direct oral anticoagulants (DOAC) have not been well clarified. Previous studies have evaluated the effects of DOAC on coagulation factors in the stationary state, but the effects of these agents after vascular injury are unclear. We assumed that DOAC treatment might have more favorable impacts on the coagulation system compared with warfarin treatment. Therefore, we performed this study to evaluate the effects of DOAC (dabigatran, rivaroxaban, and apixaban) and warfarin on the coagulation system at the peak concentration time, trough concentration time, and after vascular injury (Figure 1A).
We enrolled 55 patients on anticoagulant therapy who underwent catheter ablation for atrial fibrillation, and 18 patients without anticoagulant therapy who underwent elective catheter procedures for paroxysmal supraventricular tachycardia or idiopathic ventricular tachycardia as the control group. There were 48 men, and the mean age was 63 ± 11 years (range 40 to 80 years).
At the peak DOAC concentration time, the prothrombin fragments 1+2 (F1+2, a marker of thrombin generation) level was significantly lower in the warfarin, dabigatran, rivaroxaban, and apixaban groups than in the control group (Figure 1B). In addition, the F1+2 level at the peak DOAC concentration time was significantly higher in the dabigatran, rivaroxaban, and apixaban groups than in the warfarin group (Figure 1B).
At the trough DOAC concentration time, the F1+2 level was significantly lower in the warfarin, dabigatran, rivaroxaban, and apixaban groups compared with the control group (Figure 1B). Also, the F1+2 level at the trough DOAC concentration time was significantly higher in the dabigatran, rivaroxaban, and apixaban groups than in the warfarin group (Figure 1B). In all of the DOAC groups, there were no differences of F1+2 levels between the peak and trough DOAC concentration times.
After vascular puncture, the F1+2 level increased significantly in all of the anticoagulant groups (Figure 1B). The warfarin group had a lower F1+2 level after vascular puncture than the control group or the DOAC groups (Figure 1B), whereas there was no significant difference of F1+2 between the control group and any of the DOAC groups. The increase of F1+2 after vascular puncture was larger in the dabigatran group than in the apixaban group, or in the control group and the warfarin group.
At the trough DOAC concentration time, soluble fibrin monomer complex (a maker of coagulation activation) was below the detection limit in all patients using anticoagulants. Some patients receiving DOAC treatment showed an increase of soluble fibrin monomer complex after vascular puncture, but this did not occur in the patients on warfarin therapy. An increase of soluble fibrin monomer complex after vascular puncture was significantly more frequent in the dabigatran group (5 of 9 patients) than in the warfarin group (none of 15 patients, p = 0.003).
At the trough DOAC concentration time, the protein C level (29 ± 18%), protein S level (44 ± 11%), and the factor VII level (23 ± 9%) in warfarin group were significantly lower than in the control group or the DOAC groups (p < 0.01). In the dabigatran group, the protein C level (146 ± 35%, p < 0.01) and protein S level (152 ± 25%, p < 0.01) were significantly higher than in the other groups. After vascular puncture, the protein C level decreased significantly in the control group (–4 ± 7%, p = 0.02) and the DOAC groups (–11 ± 12%, p < 0.001). The protein S level also decreased significantly in the dabigatran group (–15 ± 18%, p = 0.03) and the apixaban group (–11 ± 11%, p = 0.007) after vascular puncture. In contrast, there were no significant differences of the protein C and protein S levels before and after vascular puncture in the warfarin group.
These results suggest that, in contrast to warfarin treatment, DOAC treatment preserves thrombin generation in response to vascular injury and maintains protein C, protein S, and factor VII levels, which could partly explain the lower risk of hemorrhagic complications and thromboembolic events in patients using these anticoagulants. Among DOAC, direct thrombin inhibitors and factor Xa inhibitors may act differently on the coagulation system and this could lead to distinct clinical outcomes (1).
Please note: This work was supported by a Grant-in-Aid for Scientific Research (17H04172, 25870127); a Grant-in-Aid for Scientific Research on Innovative Areas (26115008); a Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology (15K15306) of Japan; and grants from the Takeda Medical Research Foundation, the Japan Foundation for Applied Enzymology, the Takeda Science Foundation, the SENSHIN Medical Research Foundation, the Terumo Foundation, the Manpei Suzuki Diabetes Foundation, the Naito Foundation, and the NOVARITIS foundation (to Dr. Minamino), as well as by a Grant-in-Aid for Scientific Research (15K09068) from Ministry of Education, Culture, Sports, Science and Technology (to Dr. Izumi). All the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr. Minamino has received lecture fees from Amgen Astellas BioPharma, Sanofi, Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma Corporation, Merck Sharp and Dohme K.K., Bayer Yakuhin, Daiichi-Sankyo, and Takeda Pharmaceutical; and research funds from Boehringer Ingelheim, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Daiichi-Sankyo, Pfizer Japan, Bayer Yakuhin, Takeda Pharmaceutical, Bristol-Myers Squibb, Novartis Pharma, and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation