Sıra | DOSYA ADI | Format | Bağlantı |
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01. | Development Developed Patient Parameters | pptx | Sunumu İndir |
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The relationship between vitamin K content in the body and insufficient coagulation control Kazuo NakamuraNihon Pharmaceutical University, Japan
Prosthetic heart valve thrombosis is a rare but serious complication of a heart valve replacement procedure, most often encountered with mechanical prostheses. Therefore, after prosthetic valve replacement, warfarin is administered to prevent thromboembolic outcomes such as peripheral artery thromboembolism, pulmonary embolism and deep vein thrombosis. Introduction
A dosage of warfarin has been decided mainly on the basis of prothrombin time-international normalized ratio (PT-INR) values. However, despite administration of warfarin, thromboembolic complications develop on occasion. Thrombin generation may play also an important role in the development thromboembolic complications. Therefore, Thrombin-antithrombin III complexes (TAT) and prothrombin fragment 1+2 (F1+2) are being evaluated as parameters of thrombin generation.
Therefore, Thrombin-antithrombin III complexes (TAT) and prothrombin fragment 1+2 (F1+2) are being evaluated as parameters of thrombin generation. We have previously measured various parameters in patients undergoing artificial valve replacement. (Artery; 1992, Nakamura K, Thrombosis Research; 1997, Nakamura K)
We conducted a retrospective analysis of the relationship between poor coagulation control and inhibitory effects of the vitamin K cycle by administration of warfarin in patients undergoing artificial valve replacement.Object
1) Warfarin2) Vitamin (V) K13) Menaquinone (MK)-4, MK-74) VK1-epoxide5) Protein C antigen6) Protein induced by vitamin K absence or antagonists (PIVKA)-II7) Thrombin-antithrombin III complexes (TAT)Blood coagulation-related parameters
1) All patients (n = 15) were treated with warfarin alone after artificial valve replacement. 2) Postoperative administration was started at 3 mg and adjusted to control PT-INR in the range of 1.85 ‒ 2.15. 3) On postoperative day (POD)-7, the patients were classified into two groups.Method1. Patients
4) Group A (n = 5); warfarin of 5 mg/day or more.5) Group B (n=10); warfarin of 3 mg/day. The protocol was approved by the local ethics committee and informed written consent was obtained from all participants.
MenTechnique of operation Aortic valve replacement (AVR)Table 1 CharacteristicsAge (years) Group A (n=5)Group B (n=10)Mitral valve replacement (MVR)AVR + MVR54.3 ± 10.651.4 ± 9.83 4 2 41 32 3Group A: patients received warfarin of 5 mg/day or more.Group B: patients received warfarin of 3 mg/day. n.s.: not significant.P value n.s. n.s. n.s. n.s. n.s.
Blood samples were collected from each patient’s the median cubital vein in tubes containing 3.8% sodium citrate from the heart valve diseases patients. Collected blood samples were immediately centrifuged at 1610 × g (3,000 rpm) for 10 minutes to obtain plasma. 2. Blood sampling
1) 7 days before the operations.2) Post operations; 7th day, 14th day, and 21th day after postoperative initiation of warfarin administration.3) On postoperative day (POD)-7, the patients were classified into two groups.3. Sampling points
1. PT-INR and protein C antigen levels : our previous reports (Nakamura, 1992, 1993). 2. Plasma levels of warfarin, VK1, MK-4, Mk-7, and VK1-epoxide: HPLC 3. Plasma levels of PIVKA-II and TAT: ELISA4. Measurement parameters
02468Before operation7 14 21Days after postoperative initiation of warfarin administration*p < 0.01, compared with group B.Changes in warfarin dose in groups A and B* *(mg/day)Warfarin dose
Changes in warfarin concentration in groups A and B 040080012001600Before operation7 14 21Days after postoperative initiation of warfarin administration*p < 0.01, compared with group B.**(ng/mL)Warfarin concentration
00.511.522.53Before operation7 14 21Days after postoperative initiation of warfarin administration*p < 0.01, compared with group B.Changes in PT-INR in groups A and B*PT-INR
012345Before operation7 14 21Days after postoperative initiation of warfarin administration*p < 0.01, compared with group B.Changes in PC-Ag in groups A and B(μg/mL)*PC-Ag levels
00.250.50.751Changes in VK1 levels in groups A and BBefore operation7 14 21Days after postoperative initiation of warfarin administration*p < 0.01, compared with group B.(ng/mL)***VK1 levels
00.511.522.53Changes in VK1-epoxide levels in groups A and BBefore operation7 14 21Days after postoperative initiation of warfarin administration*p < 0.01, compared with group B.(ng/mL)**VK1-epoxide levels
05101520Changes in PIVKA-II levels in groups A and BBefore operation7 14 21Days after postoperative initiation of warfarin administration*p < 0.01, compared with group B.(AU/mL)**PIVKA II levels
02.557.510Changes in F1+2 levels in groups A and BBefore operation7 14 21Days after postoperative initiation of warfarin administration*p < 0.01, compared with group B.(ng/mL)**F1+2 levels
DiscussionIn this study, no thrombosis developed in any patient during postoperative anticoagulant therapy. We predicted that the VK cycle would be inhibited by warfarin so that much lower levels of VK1 could be obtained (Nakamura, 1994). When PT-INR values on the 7th day in group A were below the therapeutic range, plasma levels of VK1 were significantly higher than those in group B. Our data suggest that the VK content in group A may have been more abundant than in group B.
Consequently, the inhibitory effects of warfarin on the vitamin K cycle in group A may have been insufficient, leading to a greater production of protein C antigen in comparison with group B. Plasma levels of VK1-epoxide on 21st day in group A were double those in group B. These results may be also related with an abundant VK1 content in the bodies of patients in group A. In contrast, in group A the plasma levels of PIVKA-II on the 7th day were extremely low.
These results may reflect an inadequate effect of warfarin on the vitamin K cycle by the 7th day. On the 14th day, plasma levels of TAT were significantly higher in group A than in group B, suggesting that the risk of thrombosis may be increased on the 14th day after the initiation of warfarin administration.
The inhibition of the vitamin K cycle may be inadequate in patients who receive warfarin in a dosage of 5 mg/day or more owing to the abundance of vitamin K in the body. Therefore, these patients may be at a greater risk of postoperative thrombosis after valve replacement surgery. Conclusion
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