臺灣博碩士論文加值系統

高達一半接受抗凝血治療的患者，控制凝血的程度未能穩定維持在治療範圍(Therapeutic target range)之內，導致增加血栓和出血的風險。近年來研究指出飲食中維生素K是干擾長期抗凝血治療穩定的重要因子。本研究之目的為瞭解我國接受Warfarin治療之患者，飲食維生素K以及其他與心血管疾病相關的重要營養素攝取之情形；以及在控制深綠色蔬菜攝取下，穩定患者維生素K攝取，探討是否可以減少不穩定之患者INR之變異，穩定控制抗凝血程度。我們針對北部某醫院神經內科、心臟內科門診中服用Warfarin治療之患者為對象進行試驗。第一部分實驗為檢測半定量食物頻率問卷評估飲食維生素K攝取之效度。分別在第一個星期 (VK-FFQ-1)與第四個星期(VK-FFQ-2)詢問受試者前一個月的蔬菜攝取情況，並於第一、四個星期期間，分別收集4天24小時飲食回憶 (24Hr)作為相對效度檢測。結果顯示VK-FFQ-1所測得維生素K1攝取量高於24Hr所測得結果。第二部分實驗為利用問卷調查Warfarin治療之患者飲食維生素K攝取之情形，以及調整不穩定患者綠葉蔬菜攝取，觀察抗凝血治療穩定之情形。結果顯示抗凝血治療控制穩定之患者平均維生素K1攝取量738.0 ± 286.2 μg/d，不穩定患者為654.6 ± 580.0 μg/d。進一步試驗利用飲食衛教指導，調整不穩定患者綠葉蔬菜攝取，結果顯示維生素K1攝取500-600 μg/d之患者，其INR (International Normalized Ratio)達治療標準的人數較多；且在接受衛教後，受試者飲食中葉酸、鉀、鎂離子與纖維平均攝取量有增加，而體內葉酸與同半胱胺酸濃度並未改變。綜合以上，抗凝血治療控制穩定之患者平均維生素K1攝取量高於不穩定患者；且抗凝血治療控制不穩定之患者，接受本試驗飲食衛教指導後，不穩定之患者的抗凝血治療的穩定性與飲食中其他與心血管疾病相關營養素之攝取有改善。

Up to half of the patients receiving anticoagulants failed to stabilize their status of blood coagulation within target range. Therefore, the risks of thromboembolism and bleeding increased in these patients. Dietary vitamin K has recently been recognized as a key factor that might interfere with long-term oral anticoagulation stability. This study assessed dietary vitamin K and cardiovascular disease (CVD)-protecting nutrients intake of Taiwanese patients receiving anticoagulation therapy. We evaluated whether the INR variability could be reduced and stability of anticoagulation control could be improved following instruction on the management on the daily intake of vitamin K. Patients anticoagulated with warfarin were recruited from the Neurology Clinic and Cardiology Clinic. We first validated a semi-quantitative food frequency questionnaire specifically designed to measure dietary vitamin K intake. Vitamin K FFQ (VK-FFQ) was administered at the beginning (VK-FFQ-1) and at the end (VK-FFQ-2) of one month. Four 24-hour dietary recalls (24hr) were collected between either two VK-FFQs. The average vitamin K intakes calculated from both four 24hr were used as the reference for VK-FFQ-1 and VK-FFQ-2 relative validity respectively. Vitamin K intake measured by the VK-FFQ-1 was significantly higher than that obtained by 24Hr. Secondly, dietary vitamin K intake of the anticoagulation patients in the study were assessed with the questionnaire. We provided patients counseling about green leafy vegetables intake and then evaluated the stability of anticoagulation therapy for unstable patients. The mean daily intake of vitamin K for stable and unstable patients were 738.0 ± 286.2 μg/d and 654.6 ± 580.0 μg/d, respectively. The results indicated the mean intake of vitamin K for patients approaching target INR (International Normalized Ratio) were 500-600 μg/d. The dietary intake of folate, magnesium, potassium and dietary fiber increased with the assistance of dietary counseling. Plasma concentrations of homocysteine and folate did not change during the study. In summary, the mean dietary intake of vitamin K in stable patients was higher than that that of unstable patients. Anticoagulation control and intake of CVD-protecting nutrients were improved in unstable patients receiving counseling on dietary vitamin K management.

第一章 前言 1
第二章 文獻回顧 2
第一節 維生素K之總論 2
一、 維生素K之代謝 2
二、 維生素K之生理功能 3
三、 維生素K的食物來源 7
四、 各國維生素K之飲食建議量 10
第二節 Warfarin之總論 12
一、 Warfarin之簡介 12
二、 Warfarin之抗凝血作用機制 14
三、 Warfarin與基因型之影響 15
四、 Warfarin與藥物和環境因子之交互作用 16
第三節 目前對維生素K與Warfarin之相關研究 22
一、 飲食中維生素K與INR關係 22
二、 補充維生素K與INR反應 23
三、 維生素K與INR其他相關研究 24
四、 飲食維生素K與抗凝血治療衛教之相關研究 25
第四節 綠葉蔬菜攝取與心血管疾病之關係 30
一、 類胡蘿蔔素、維生素C、維生素E與心血管疾病之關係 30
二、 葉酸與心血管疾病之關係 31
三、 鎂、鉀離子、膳食纖維與心血管疾病之關係 31
第五節 研究動機與目的 33
第三章 材料與方法 35
第一節 研究架構及流程 35
一、 研究架構 35
二、 研究流程 36
第二節 研究對象 40
一、 個案來源 40
二、 收案標準與數目 40
第三節 研究材料與工具 41
一、 維生素K含量分類表 41
二、 基本資料問卷 41
三、 半定量維生素K1飲食頻率問卷 42
四、 Warfarin使用者深綠色蔬菜食用衛教單張 43
五、 人體測量及血液生化分析 43
第四節 建立及檢定半定量維生素K飲食頻率問卷 44
一、 問卷設計流程 44
二、 半定量維生素K1飲食頻率問卷 44
三、 二十四小時蔬菜攝取回憶紀錄 45
第五節 資料處理與統計分析 46
一、 描述性統計 (Descriptive statistics) 46
二、 配對平均數差異顯著性檢定 (Paired t-test) 46
三、 皮爾遜積差相關分析 (Pearson correlation) 46
四、 斯皮爾曼等級相關分析 (Spearman rank correlation) 46
五、 Kappa一致性係數 (K coefficient of agreement) 47
六、 百分比一致性 (% agreement) 47
七、 單因子變異數分析 (One-way ANOVA) 47
八、 曼－惠特尼測驗法 (Mann-Whitney test) 47
九、 魏克森配對訊號等級測驗法 (Wilcoxon matched paired signed rank test) 47
十、 卡方檢定 (Chi-square test) 47
第四章 研究結果 48
第一節 維生素K1半定量飲食頻率問卷之相對效度評估 48
一、 基本資料 48
二、 Warfarin治療患者每日維生素K1攝取情形 49
三、 二十四小時飲食紀錄及維生素K1半定量頻率問卷所測量維生素K1之相關性與一致性 49
第二節 Warfarin治療患者抗凝血治療與飲食維生素K1攝取之情形 51
一、 基本資料 51
二、 Warfarin治療患者抗凝血治療與維生素K1攝取狀態 52
第三節 抗凝血不穩定患者飲食維生素K1攝取與抗凝血治療情形 53
一、 抗凝血不穩定患者抗凝血治療與飲食維生素K1攝取情形 53
二、 INR達標患者抗凝血治療與飲食維生素K1攝取情形 54
第四節 其他營養素攝取量與血液生化值變化情形 54
一、 抗凝血控制穩定與不穩定患者其他營養素攝取量之差異 54
二、 抗凝血控制不穩定之患者來自深綠葉出菜之其他營養素攝取量變化情形 55
三、 抗凝血控制不穩定之患者其葉酸與同半胱胺酸濃度變化情形 55
第五章 討論 56
第一節 維生素K1半定量飲食頻率問卷之相對效度探討 56
第二節 Warfarin治療患者抗凝血治療與飲食維生素K1攝取之情形 57
一、 Warfarin治療患者抗凝血治療之情形 57
二、 Warfarin治療患者飲食維生素K1攝取之情形 57
第三節 抗凝血不穩定患者飲食維生素K1攝取與抗凝血治療情形 60
一、 抗凝血不穩定患者飲食維生素K1攝取情形 60
二、 INR達標患者抗凝血治療與飲食維生素K1攝取情形 60
第四節 其他營養素攝取量與血液生化值變化情形 61
一、 抗凝血控制穩定與不穩定患者其他營養素攝取量之差異 61
二、 抗凝血控制不穩定之患者其他營養素攝取量變化情形 61
三、 抗凝血控制不穩定之患者其葉酸與同半胱胺酸濃度變化情形 62
第五節 臨床應用性 63
第六節 研究限制 64
第六章 結論與未來臨床應用 65
第七章 參考文獻 76
附錄 一 人體試驗許可書 94
附錄 二 人體試驗受試者說明及同意書 (問卷信效度檢測) 96
附錄 三 人體試驗受試者說明及同意書 98
附錄 四 國人常用蔬菜維生素K含量分類表 103
附錄 五 基本資料問卷 104
附錄 六 維生素K飲食頻率問卷 106
附錄 七 Warfarin使用者深綠色蔬菜食用衛教單張 108
附錄 八 追蹤過程登記表 110

表 一、維生素 K依賴性(Gla)蛋白的多樣性和人體內扮演的角色 4
表 二、食物中維生素K1的含量 9
表 三、美國、台灣與日本維生素K每日營養素參考攝取量之比較 11
表 四、與Warfarin會產生交互作用之藥物、食物與膳食補充劑 19
表 五、影響Warfarin抗凝血作用之生藥 21
表 六、併服Warfarin後具有潛在交互作用的生藥 21
表 七、飲食中維生素K與INR關係研究之整理比較 27
表 八、補充維生素K與INR反應研究之整理比較 28
表 九、富含維生素K飲食有助與INR穩定之相關研究整理 29
表 十、受試者基本資料 66
表 十一、 以二十四小時飲食紀錄及維生素K1半定量頻率問卷所測病患每日維生素K1平均攝取量之比較 66
表 十二、 二十四小時飲食紀錄及維生素K1半定量頻率問卷所測得病患每日維生素K1平均攝取量之相關性 67
表 十三、 二十四小時飲食記錄及維生素K1半定量頻率問卷所測病患每日維生素K1平均攝取量之一致性及百分比一致性 67
表 十四、抗凝血治療控制穩定與不穩定患者之基本資料 68
表 十五、抗凝血治療控制穩定與不穩定患者Warfarin劑量使用與飲食維生素K1攝取情形 69
表 十六、比較神經內科與心臟內科門診病患Warfarin劑量使用與飲食維生素K1攝取情形 69
表 十七、比較抗凝血治療程度不足與抗凝血治療不穩定之患者Warfarin劑量使用與飲食維生素K1攝取情形 70
表 十八、抗凝血治療控制不穩定之患者不同時間點Warfarin劑量使用與飲食維生素K1攝取情形 70
表 十九、抗凝血治療控制不穩定患者之維生素K1攝取量與INR達治療目標情形 71
表 二十、INR達標患者其不同時間點Warfarin劑量使用與飲食維生素K1攝取情形 71
表 二十一、比較抗凝血治療控制穩定與不穩定患者由深綠色蔬菜攝取之其他營養素攝取 72
表 二十二、比較抗凝血治療控制不穩定患者開始與三個月後由深綠色蔬菜攝取之其他營養素攝取 72
表 二十三、比較抗凝血治療控制不穩定患者開始與三個月後血液生化值改變情形 73

圖 一、維生素K在肝臟的代謝 3
圖 二、血液凝固的連鎖反應路徑 6
圖 三、Warfarin作用與代謝機制 14
圖 四、研究架構 35
圖 五、本研究進行之流程 39
圖 六、問卷設計流程 45
圖 七、患者INR達治療目標之情形 73
圖 八、比較INR達治療目標患者開始與三個月後Warfarin治療情形 74
圖 九、抗凝血治療控制不穩定之患者不同時間點飲食維生素K1攝取情形 75

李建瑩、施宏哲、蔡敏鈴。Warfarin及其他抗凝血劑與草藥的交互作用。藥學雜誌2008; 24: 135-42。

陳雅婷 (2010) 使用全民健康保險研究資料庫研究warfarin處方型態及潛在一級交互作用之風險分析。國立臺灣大學醫學院臨床藥學研究所碩士論文。

黃意婷 (2007) 建構台灣食物維生素K1含量資料庫及其應用。天主教輔仁大學營養科學系碩士論文。

Adams AK, Wermuth EO, McBride PE. Antioxidant vitamins and the prevention of coronary heart disease. Am Fam Physician. 1999; 60: 742-4.

Ansell J, Hirsh J, Dalen J, Bussey H, Anderson D, Poller L, Matchar D. Managing oral anticoagulant therapy. Chest. 2001; 119: 22-38.

Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2008; 133: 160S-98S.

Ansell JE, Buttaro ML, Thomas OV, Knowlton CH. Consensus guidelines for coordinated outpatient oral anticoagulation therapy management. Ann Pharmacother. 1997; 31: 604-15.

Badr M, Yoshihara H, Kauffman F, Thurman R. Menadione causes selective toxicity to periportal regions of the liver lobule. Toxicol Lett. 1987; 35: 241-46.

Bender NK, Kraynak MA, Chiquette E, Linn WD, Clark GM, Bussey HI. Effects of marine fish oils on the anticoagulation status of patients receiving chronic warfarin therapy. J Thromb Thrombolysis. 1998; 5: 257-61.

Booth S. Roles for vitamin K beyond coagulation. Annu Rev Nutr. 2009; 29: 89-110.

Booth SL, Broe KE, Gagnon DR, Tucker KL, Hannan MT, McLean RR, Kiel DP. Vitamin K intake and hip fractures in women: A prospective study. Am J Clin Nutr.1999; 69: 74-9.

Booth SL, Centurelli MA. Vitamin K: a practical guide to the dietary management of patients on warfarin. Nutr Rev. 1999; 57: 288-96.

Booth SL, Rajabi AA. Determinants of vitamin K status in humans. Vitam Horm. 2008; 78: 1-22.

Booth SL, Sokoll LJ, O'Brien ME, Tucker K, Dawson-Hughes B. Assessment of dietary phylloquinone intake and vitamin K status in postmenopausal women. Eur J Clin Nutr. 1995; 49: 832-41.

Boskey AL, Gadaleta S, Gundberg C, Doty SB, Ducy P, Karsenty G. Fourier transform infrared microspectroscopic analysis of bones of osteocalcindeficient mice provides insight into the function of osteocalcin. Bone. 1998; 23: 187-96.

Breckenridge A, Orme M, Wesseling H, Lewis RJ, Gibbons R. Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther.1974; 15: 424-30.

Breckenridge AM. Oral anticoagulant drugs: pharmacokinetic aspects. Hematol. 1978; 15: 19-26.

Cade J, Thompson R, Burley V, Warm D. Development, validation and utilisation of food-frequency questionnaires - a review. Public Health Nutr. 2002; 5: 567-87.

Cazenave JP, Packham MA, Guccione MA, Mustard JF. Effects of penicillin G on platelet aggregation, release and adherence to collagen. Biol Med. 1973; 142: 159-66.

Chan E, McLachlan A, O'Reilly R, Rowland M. Stereochemical aspects of warfarin drug interactions: use of a combined pharmacokinetic-pharmacodynamic model. Clin Pharmacol Ther.1994; 56: 286-94.

Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. Journal of Chronic Diseases.1987; 40: 373-83.

Chenhsu RY, Chiang SC, Chou MH, Lin MF. Long-term treatment with warfarin in Chinese population. Ann Pharmacother. 2000; 34: 1395-401.

Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular risk? Design of clinical trials to test the homocysteine hypothesis of vascular disease. J Cardiovasc Risk. 1998; 5: 249-55.

Coca SG, Perazella MA, Buller GK. The cardiovascular implications of hypokalemia. Am J Kidney Dis. 2005; 45: 233-47.

Criqui MH, Langer RD, Reed DM. Dietary alcohol, calcium, and potassium. Independent and combined effects on blood pressure. Circulation. 1989; 80: 609-14.

Cushman M, Booth SL, Possidente CJ, Davidson KW, Sadowski JA, Bovill EG. The association of vitamin K status with warfarin sensitivity at the onset of treatment. Br J Haematol. 2001; 112: 572-77.

Dale J, Myhre E, Loew D. Bleeding during acetysalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement. Am Heart J. 1980; 99: 746-52.

Damon M, Zhang NZ, Haytowitz DB, Booth SL. Phylloquinone (vitamin K1) content of vegetables. J Food Compost Anal. 2005; 18: 751-58.

Davidson RT, Foley AL, Engelke JA, Suttie JW. Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria. J Nutr. 1998; 128: 220-23.

de Assis MC, Rabelo ER, Avila CW, Polanczyk CA, Rohde LE. Improved oral anticoagulation after a dietary vitamin k-guided strategy: a randomized controlled trial. Circulation. 2009; 120: 1115-22.

Fasco MJ, Hildebrandt EF, Suttie JW. Evidence that warfarin anticoagulant action involves two distinct reductase activities. J Biol Chem. 1982; 257: 11210-12.

Department of Health & Human Services. U.S. Food and Drug Administration. Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication - Safety Review of Post-Market Reports of Serious Bleeding Events. Internet:
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm282820.htm?utm_source=fdaSearch&utm_medium=website&utm_term=Pradaxa&utm_content=13

Ferland G, Sadowski JA. Vitamin K, (phylloquinone) content of green vegetables: effects of plant maturation and geographical growth location. Food Chem. 1992a; 40: 1874-7.

Ferland G, Sadowski JA. Vitamin K1 (phylloquinone) content of edible oils: effects of heating and light exposure. Food Chem. 1992b; 40: 1869-73.

Fiumara K, Goldhaber SZ. A patient's guide to taking coumadin/warfarin. Circulation. 2009; 119: e220-2.

Ford SK, Misita CP, Shilliday BB, Malone RM, Moore CG, Moll S. Prospective study of supplemental vitamin K therapy in patients on oral anticoagulants with unstable international normalized ratios. J Thromb Thrombolysis. 2007; 24: 23-7.

Ford SK, Moll S. Vitamin K supplementation to decrease variability of International Normalized Ratio in patients on vitamin K antagonists a literature review. Curr Opin Hematol. 2008; 15: 504-8.

Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med. 2004; 116: 651-6.

Fraser J D, Price PA. Lung, heart, and kidney express high levels of mRNA for the vitamin K-dependent matrix Gla protein. J. Biol. Chem. 1988; 263: 11033-6.

Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost. 2004; 91: 87-94.

Gaziano JM, Hennekens CH. The role of beta-carotene in the prevention of cardiovascular disease. Ann N Y Acad Sci. 1993; 691; 148-55.

Gebuis EP, Rosendaal FR, van Meegen E, van der Meer FJ. Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study. Haematologica. 2011; 96: 583-9.

Geisen C, Watzka M, Sittinger K, Steffens M, Daugela L, Seifried E, Oldenburg J. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost. 2005; 94: 773-9.

Glynn RJ, Ridker PM, Goldhaber SZ, Zee RY, Buring JE. Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: Report from the Women's Health Study. Circulation. 2007; 116: 1497–503.

Greenberg ER, Baron JA, Karagas MR. Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. JAMA. 1996; 275: 699–703.

Hallak HO, Wedlund PJ, Modi MW, Patel IH, Lewis GL, Woodruff B, Trowbridge AA. High clearance of (S)-warfarin in a warfarin-resistant subject. Br J Clin Pharmacol. 1993; 35: 327-30.

Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011; 123: 1436-50.

Helfant RH. Hypokalemia and arrhythmias. Am J Med. 1986; 80: 13-22.

Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet. 2006; 367: 404-11.

Hignite C, Uetrecht J, Tschanz C, Azarnoff D. Kinetics of R and S warfarin enantiomers. Clin Pharmacol Ther. 1980; 28: 99-105.

Hirauchi K, Sakano T, Notsumoto S, Nagaoka T, Morimoto A, Fujimoto K, Suzuki Y. Measurement of K vitamins in animal tissues by high-performance liquid chromatography with fluorimetrie detection. J Chromatogr. 1989; 497: 131-7.

Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D. Oral Anticoagulants: Mechanism of Action, Clinical Effectiveness, and Optimal Therapeutic Range. Chest. 2001; 119: 8S-21S.

Hoang QQ, Sicheri F, Howard AJ, Yang DS. Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature. 2003; 425: 973-97.

Holbrook AM, Pereira JA, Labiris R. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005; 165: 131-7.

Houston MC, Harper KJ. Potassium, magnesium, and calcium: Their role in both the cause and treatment of hypertension. J Clin Hypertens (Greenwich). 2008; 10: 3–11.

Warren Grant Magnuson Clinical Center, National Institutes of Health Drug Interaction Task Force. Important information to know when you are taking: Coumadin® and vitamin K. Available at: http:// ods.od.nih.gov/factsheets/cc/coumadin1.pdf. Accessed January 26, 2005.

James AH, Britt RP, Raskino CL, Thompson SG. Factors affecting the maintenance dose of warfarin. J Clin Pathol. 1992; 45. 704-6.

Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, McLachlan AJ. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2005; 59: 425-32.

Johnson MA. Influence of vitamin K on anticoagulant therapy depends on vitamin K status and the source and chemical forms of vitamin K. Nutr Rev. 2005; 63: 91-7.

Kamao M, Suhara Y, Tsugawa N, Uwano M, Yamaguchi N, Uenishi K, Okano T. Vitamin K content of foods and dietary vitamin K intake in Japanese young women. J Nutr Sci Vitaminol (Tokyo). 2007; 53: 464-70.

Kelly JG, O'Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet. 1979; 4: 1-15.

Khan T, Wynne H, Wood P, Torrance A, Hankey C, Avery P, Kamali F. Dietary vitamin K influences intra-individual variability in anticoagulant response to warfarin. Br J Haematol. 2004; 124: 348-54.

Kim KH, Choi WS, Lee JH, Lee H, Yang DH, Chae SC. Relationship between dietary vitamin K intake and the stability of anticoagulation effect in patients taking long-term warfarin. Thromb Haemost. 2010; 104: 755-9.

Kirkwood TB. Calibration of reference thromboplastins and standardisation of the prothrombin time ratio. Thromb Haemost. 1983; 49: 238-44.

Kohlmeier M, Salomon A, Saupe J, Shearer MJ. Transport of vitamin K to bone in humans. Nutrition. 1996; 126: 1192S-6S.

Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL. Antioxidant vitamin supplements and cardiovascular disease. Circulation. 2004; 110: 637-41.

Landbo C, Almdal TP. Interaction between warfarin and coenzyme Q10. Ugeskr Laeger,. 1998; 160: 3226-7.

Lane DA, Ponsford J, Shelley A, Sirpal A, Lip GY. Patient knowledge and perceptions of atrial fibrillation and anticoagulant therapy: effects of an educational intervention programme. Int J Cardiol. 2006; 110: 354-8.

Laux V, Perzborn E, Heitmeier S, von Degenfeld G, Dittrich-Wengenroth E, Buchmüller A, Gerdes C, Misselwitz F. Direct inhibitors of coagulation proteins - the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy? Thromb Haemost. 2009; 102: 892–9.

Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics. 2002; 12: 251-63.

Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature. 2004; 427: 541-4.

Lin YF, Lin SH, Tsai WS, Davids MR, Halperin ML. Severe hypokalemia in a Chinese male. QJM. 2002; 95: 695-704.

Liu S, Buring JE, Sesso HD, Rimm EB, Willett WC, Manson JE. A prospective study of dietary fiber intake and risk of cardiovascular disease among women. J Am Coll Cardiol. 2002; 39: 49-56.

Lubetsky A, Dekel-Stern E, Chetrit A, Lubin F, Halkin H. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost. 1999; 81: 396-399.

Macan H, Uykimpang R, Alconcel M, Takasu J, Razon R, Amagase H, Niihara Y. Aged garlic extract may be safe for patients on warfarin therapy. J Nutr. 2006; 136: 793S-5S.

Matsuyama K, Matsumoto M, Sugita T, Nishizawa J, Yoshida K, Tokuda Y, Matsuo T. Anticoagulant therapy in Japanese patients with mechanical mitral valves. Circ J. 2002; 66: 668-70.

Maillard C, Berruyer M, Serre CM, Dechavanne M, Delmas PD. Protein-S, a vitamin K dependent protein, is a bone matrix component synthesized and secreted by osteoblasts. Endocrinology. 1992; 130: 1599-604.

Manthey J, Stoeppler M, Morgenstern W, Nussel E, Opherk D, Weintraut A, Wesch H, Kubler W. Magnesium and trace metals: Risk factors for coronary heart disease ? Association between blood levels and angiographic findings. Circulation. 1981; 64: 722-9.

Meckley LM, Wittkowsky AK, Rieder MJ, Rettie AE, Veenstra DL. An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients. Thromb Haemost. 2008; 100: 229-39.

Meyer KA, Kushi LH, Jacobs DR, Slavin J, Sellers TA, Folsom AR. Carbohydrates, dietary fiber, and incident type 2 diabetes in older women. Am J Clin Nutr. 2000; 71: 921-30.

Mohutsky MA, Anderson GD, Miller JW, Elmer GW. Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo. Am J Ther. 2006; 13: 24-31.

Mori T, Asano M, Ohtake H, Bitoh A, Sekiguchi S, Matsuo Y, Takaba T. Anticoagulant therapy after prosthetic valve replacement -optimal PT-INR in Japanese patients. Ann Thorac Cardiovasc Surg. 2002; 8: 83-7.

Morris RC, Sebastian A, Forman A, Tanaka M, Schmidlin O. Normotensive salt sensitivity: effects of race and dietary potassium. Hypertension. 1999; 33: 18-23.

Murua A, Quintana I, Galarza C, Alfie J, Kordich L. Unsuspected hyperhomocysteinemia in chronically anticoagulated patients. Blood Coagul Fibrinolysis. 2001; 12:79–80.

O'Reilly RA. Studies on the optical enantiomorphs of warfarin in man. Clin Pharmacol Ther. 1974; 16: 348-54.

O'Reilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med. 1976; 295: 354-7.

O'Reilly RA. Warfarin metabolism and drug-drug interactions. Adv Exp Med Biol. 1987; 214: 205-12.

O'Reilly RA, Trager WF, Motley CH, Howald W. Stereoselective interaction of phenylbutazone with 13C/12C labelled racemates of warfarin in man. J Clin Invest. 1980; 65: 746-53.

Oger E, Lacut K, Le Gal G, Couturaud F, Guénet D, Abalain JH, Edith collaborative study group. Hyperhomocysteinemia and low B vitamin levels are independently associated with venous thromboembolism: results from the EDITH study: a hospital-based case-control study. J Thromb Haemost. 2006; 4: 793-9.

Okano T, Shimomura Y, Yamane M, Suhara Y, Kamao M, Sugiura M, Nakagawa K. Conversion of phylloquinone (Vitamin K1) into menaquinone-4 (Vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice. J Biol Chem. 2008; 283: 11270-9.

Oldenburg J, Watzka M, Rost S, Müller CR. VKORC1: molecular target of coumarins. J Thromb Haemost. 2007; 5 Suppl 1: 1-6.

Orme M, Breckenridge A. Enantiomers of warfarin and phenobarbital. N Engl J Med,. 1976; 295: 1482-3.

Owens JC, Neely WB, Owen WR. Effect of sodium dextrothyroxine in patients receiving anticoagulants. N Engl J Med. 1962; 266: 76-9.

Pan EY, Comperts ED, Millen R, Gilsanz V. Bone mineral density and its association with inherited protein S deficiency. Thromb. 1990; 58: 221-231.

Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. Thromb Haemost. 2001; 86: 569-74.

Pfister R, Sharp SJ, Luben R, Wareham NJ, Khaw KT. Plasma vitamin C predicts incident heart failure in men and women in European Prospective Investigation into Cancer and Nutrition-Norfolk prospective study. Am Heart J. 2011; 162: 246-53.

Presse N, Shatenstein B, Kergoat MJ, Ferland G. Validation of a semi-quantitative food frequency questionnaire measuring dietary vitamin K intake in elderly people. J Am . 2009; 109: 1251-5.

Price PA., Williamson MK. Primary structure of bovine matrix Gla protein, a new vitamin K-dependent bone protein. J Biol Chem. 1985; 260: 14971-5.

Price PA, Williamson MK, Haba T, Dell RB, lee WS. Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc. Nati. Acad. Sci. U.S.A. 1982; 79: 7734-8.

Price PA. Gla-containing proteins of bone. Connect. Tiss. Res. 1989; 21: 51-60.

Pryor WA. Vitamin E and heart disease: Basic science to clinical intervention trials. Free Radic Biol Med. 2000; 28: 141–64.

Quéré I, Perneger TV, Zittoun J, Bellet H, Gris JC, Daurès JP. Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study. Lancet. 2002; 359: 747-52.

Quick AJ. The prothrombin time in hemophilia and in obstructive jaundice. J Biol Chem. 1935; 109: 73-4.

Reese AM, Farnett LE, Lyons RM, Patel B, Morgan L, Bussey HI. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy. 2005; 25: 1746-51.

Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, Trager WF. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol. 1992; 5: 54-9.

Reunanen A, Knekt P, Marniemi J, Maki J, Maatela J, Aromaa A. Serum calcium, magnesium, copper and zinc and risk og cardiovascular death. Eur J Clin Nutr. 1996; 50: 431-7.

Reynolds K, Valdes JrR, Hartung BR, Linder MW. Individualizing warfarin therapy. Per Med. 2007; 4: 11-31.
Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005; 352: 2285-93.

Rombouts EK, Rosendaal FR, van der Meer FJ. Influence of dietary vitamin K intake on subtherapeutic oral anticoagulant therapy. Br J Haematol. 2010; 149: 598-605.

Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Oldenburg J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004; 427: 537-41.

Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A systematic review and meta-analysis. Genetics in Medicine. 2005; 7: 97-104.

Sasaki S. Dietary Reference Intakes (DRIs) in Japan. Asia Pac J Clin Nutr. 2008; 17 Suppl 2: 420-44.

Schmidlin O, Forman A, Tanaka M, Sebastian A, Morris RC. NaCl-induced renal vasoconstriction in salt-sensitive African Americans: antipressor and hemodynamic effects of potassium bicarbonate. Hypertension. 1999; 33: 633-9.

Schulman S, Henriksson K. Interaction of ibuprofen and warfarin on primary haemostasis. Br J Rheumatol. 1989; 28: 46-9.

Schurgers LJ, Shearer MJ, Hamulyák K, Stöcklin E. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood. 2004; 104: 2682-9.

Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. 2002; 1570: 27-32.

Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood. 2007; 109: 2419-23.

Sconce E, Khan T, Mason J, Noble F, Wynne H, Kamali F. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thrombosis and Haemostasis. 2005; 872-5.

Shearer MJ. Vitamin K in parenteral nutrition. Gastroenterology. 2009; 137(5 Suppl): S105-18.

Shearer MJ, Bach A, Kohlmeier M. Chemistry, Nutritional Sources, Tissue Distribution and Metabolism of Vitamin K with Special Reference to Bone Health. J Nutr. 1996; 126: 1181S-6S.

Shechter M, Merz CN, Paul-Labrador M. editors. Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease. Am J Cardiol. 1999; 84: 152–6.

Smith MB, Christensen N, Wang S, Strohecker J, Day JD, Weiss JP, Bunch TJ. Warfarin knowledge in patients with atrial fibrillation: implications for safety, efficacy, and education strategies. Cardiology. 2010; 116: 61-9.

Sobczyńska-Malefora A, Harrington DJ, Lomer MC, Pettitt C, Hamilton S, Rangarajan S. Erythrocyte folate and 5-methyltetrahydrofolate levels decline during 6 months of oral anticoagulation with warfarin. Blood Coagul Fibrinolysis. 2009; 20: 297-302.

Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet. 1994; 344: 1372-3.

Spronk HM, Soute BA, Schurgers LJ, Thijssen HH, De Mey JG, Vermeer C. Tissuespecific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats. J Vasc Res. 2003; 40: 531-7.

Sterns RH, Cox M, Feig PU, Singer I. Internal potassium balance and the control of the plasma potassium concentrations. Medicine. 1981; 60: 339-54.

Subar AF, Dodd KW, Guenther PM, Kipnis V, Midthune D, McDowell M, Krebs-Smith SM. The food propensity questionnaire: Concept, development, and validation for use as a covariate in a model to estimate usual food intake. J Am Diet Assoc. 2006; 106: 1556-63.

Suttie JW. Synthesis of vitamin K-dependent proteins. FASEB J. 1993; 7: 445-52.

Suttie JW, Mummah-Schendel LL, Shah DV, Lyle BJ, Greger JL. Vitamin K deficiency from dietary vitamin K restriction in humans. Am J Clin Nutr. 1988; 47: 475-80.

Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet. 2001; 40: 587-603.

Tanne D, Haim M, Goldbourt U, Boyko V, Doolman R, Adler Y, Brunner D, Behar S, Sela BA et al. Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease. Stroke. 2003; 34: 632-36.

Thane CW, Bolton-Smith C, Coward WA. Comparative dietary intake and sources of phylloquinone (vitamin K1) among British adults in 1986-7 and 2000-1. Br J Nutr. 2007; 96: 1105-15.

Toon S, Low LK, Gibaldi M, Trager WF, O'Reilly RA, Motley CH, Goulart DA. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther. 1986; 39: 15-24.

Vasan RS, Beiser A, D'Agostino RB, Levy D, Selhub J, Jacques PF, Rosenberg IH, Wilson PW. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA. 2003; 289: 1251-57.

Voutilainen S, Rissanen TH, Virtanen J, Lakka TA and Salonen JT. Low dietary folate intake is associated with an excess incidence of acute coronary events: the Kuopio Ischemic Heart Disease Risk Factor Study. Circulation. 2001; 103: 2674 - 80.

Wald DS, Law M, Morris JK et al. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J. 2002; 325: 1202.

Wald DS, Wald NJ, Morris JK, Law M. Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence. BMJ. 2006; 333: 1114-7.

Warren Grant Magnuson Clinical Center, National Institutes of Health Drug Interaction Task Force (2003) Important Information to Know When you are Taking: Coumadin (r) and Vitamin K. Available at: http://ods.od.nih.gov/factsheets/cc/coumadin1.pdf. Accessed on 18 October 2009.

Weitekamp MR, Aber RC. Prolonged bleeding times and bleeding diathesis associated with moxalactam administration. JAMA. 1983; 249: 69-71.

Weiner ID, Wingo CS. Hypokalemia-consequences, causes, and correction. J Am Soc Nephrol. 1997; 8: 1179-88.

Whitlon DS, Sadowski JA, Suttie JW. Mechanisms of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry. 1978; 17: 1371-7.

Wittkowsky AK, Bussey HI, Walker MB, Frei CR. Dietary supplement use among anticoagulation clinic patients. J Thromb Haemost. 2007; 5: 875-7.

Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT. Low dietary folate intake is associated with an excess incidence of acute coronary events: the Kuopio Ischemic Heart Disease Risk Factor Study. Circulation. 2001; 103: 2674-80.

Yu HC, Chan TY, Critchley JA, Woo KS. Factors determining the maintenance dose of warfarin in Chinese patients. QJM. 1996; 89: 127-35.

Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Moss J. Brief communication: American ginseng reduces warfarin's effect in healthy patients: a randomized, controlled trial. Ann Intern Med. 2004; 141: 23-7.

Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Chen YT. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. 2005; 14: 1745-51.

Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John's wort. J Psychopharmacol. 2004; 18: 262-76.

Zucker S, Cathey MH, Sox PJ, Hall EC. Standardization of laboratory tests for controlling anticoagulant therapy. Am J Clin Pathol. 1970; 53: 348-54.