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1.What is warfarin?
2.What is the history of warfarin?
3.How does warfarin work?
4.How is warfarin therapy monitored?
1.华法林是什么？
2.华法林的历史？
3.华法林的作用机制？
4.华法林治疗时如何监测？

参考答案
1.华法林是什么？
华法林是美国最常用的口服抗凝药物，麻醉医生也经常遇到需要长期抗凝治疗或围术期预防血栓的患者。
2.华法林的历史？
在20世纪20年代，亚伯达，加拿大，和北达科他的兽医们发现牛出现一种新的疾病，以创伤或手术后发生致死性出血为特征。早期研究发现此疾病是由于牛食用了***的甜苜蓿干草引起的病理性凝血机制紊乱所致。直到1941年，人们进行定量凝血酶原试验后才发现，令人难以琢磨的 “香草木樨病”的致死性药物是3-(a-苯基丙酮)-4-羟基香豆素。1948Link在威斯康辛女校友研究基地（Wisconsin Alumni Research Foundation）合成了的人工合成同源(化合)物，命名为华法林。
有趣的是，双香豆素，这种能够为新的轮车草提供特殊气味的物质，被添加于劣质香烟用作香草香精，在香水中其也被用作香料。
3.华法林的作用机制？
凝血因子II, VII, IX, 和 X 与蛋白C和蛋白S的合成需要最后羧化才能获得生物活性。华法林通过干扰VK的循环应用，使这些凝血因子不能与钙离子螯合，凝血因子无法与磷脂化膜结合。这样华法林通过羧基谷氨酸缺失产生抗凝作用。
4.华法林治疗时如何监测？
可以监测凝血酶原时间(PT)，在试验中应用凝血酶原激酶对抗凝强度进行标准化。制药公司正在设计与国际参考凝血酶原激酶的预定活性相关的，带有国际敏感指数(International Sensitivity Index)的试剂。然后每个实验室计算国际标准化比值以明确患者的凝血酶原时间和实际抗凝强度的关系。

1 What is warfarin?
Warfarin is the most commonly used oral anticoagulant utilized in the United States (1), and is often encountered by anesthesiologists in patients with medical conditions requiring chronic anticoagulation or perioperative thromboembolism prophylaxis.
2 What is the history of warfarin?
In the 1920's, veterinarians in Alberta, Canada and North Dakota noted a new disease in cattle which was characterized by excessive and often fatal bleeding following trauma or surgery. Early work identified this disease as a pathologic clotting mechanism disorder which stemmed from the ingestion of spoiled sweet clover hay. The causative agent of "sweet clover disease" was elusive, however, and it was not until the development of a quantitative prothrombin test when the mystery unraveled, identifying 3,3'-methylene-bis-(4-hydroxycoumarin) in 1941 (2). In 1948 a synthetic congener was synthetized and named warfarin by Link (5) after the Wisconsin Alumni Research Foundation where he worked.
Interestingly coumarin, the substance which gives newly mown hay its characteristic odor, is employed to impart a vanilla flavor to certain inferior tobacco products, and can be found as an ingredient in certain perfumes (2).
3 How does warfarin work?
The synthesis of the clotting factors prothrombin, factors II, VII, IX, and X and proteins C and S requires a final carboxylation step to achieve biologic activity (3). This deficiency of carboxyglutamic acid is produced by warfarin through its interruption of the recycling process of the hydroquinone form of vitamin K. As a result, these clotting factors cannot chelate calcium, and consequently, binding to phosholipid membranes cannot occur. Thus the action depends on the decline of the carboxylated clotting factors.
4 How is warfarin therapy monitored?
Measured by the prothrombin time (PT), problems with standardization of the anticoagulant intensity emerged due to the thromboplastin used in the test. As such, pharmaceutical companies now assign each lot with an ISI (International Sensitivity Index) which relates to the preparations activity against an international reference thromboplastin (4). Individual laboratories then calculate an INR (international normalized ratio) to relate the patient's PT to the intensity of actual anticoagulation.
References:
1.Enneking FK, Benzon H. Oral anticoagulants and regional anesthesia: a perspective. Reg Anesth Pain Med 1998;23 Suppl 2: 140-5.
2.Goodman LS, Gilman A. Anticoagulants. The pharmacologic basis of therapeutics. 2nd ed. New York, The Macmillan Co, 1955; 1509-10.
3.Stanley TB, Humphries J, High KA, Stafford DW. Amino acids responsible for reduced affinities of vitamin K-dependent propeptides for the carboxylase. Biochemistry 1999 Nov 23;38(47):15681-7.
4.Paech M, Anticoagulants and Regional Anesthesia. IARS 2000 Review Course Lectures. Anesth Analg 2000;90:Suppl 35-41.
5.Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future. Circulation 1994 Jan;89(1):432-49.