Norn Svend, Permin Henrik, Kruse Edith, Kruse Poul R
Dan Medicinhist Arbog. 2014;42:99-119.
The history of the discovery and development of vitamin K and its antagonists, the oral anticoagulants dicoumarol and warfarin, are fascinating, triumphant landmarks in the annals of medicine. Vitamin K was found by Carl Peter Henrik Dam and Fritz Schønheyder from the University of Copenhagen. The discovery was initiated by Dam, by a lucky choice of chicks in the dissertation of sterol metabolism, since the vitamin is not formed by intestinal bacteria in these animals. In these experiments the lack of an unknown factor in the synthetic diet caused internal bleeding similar to that found in scurvy, but the bleeding was not reversed by vitamin C and it could not be explained by the lack of classical vitamins. In 1935 the unknown antihaemorrhagic factor was named vitamin K and a few months later the phenomenon was also observed by H.J. Almquist and E.L.R. Stokstad in Berkeley. The activity of the factor was determined by bioassay in different extracts of green vegetables and alfalfa by Dam and Schønheyder. Vitamin K was isolated in 1939 by Dam and Paul Karrer in Zurich and the structure was determined by Edward Adelbert Doisy. Dam and Doisy were awarded the Nobel Prize in 1943. A dramatic story starts the discovery of dicoumarol. In the 1920s cattle in Canada began dying of internal bleeding with no obvious precipitating cause. Frank W. Schofield, a veterinary pathologist in Alberta, found that the mysterious disease was connected to the consumption of spoiled sweet clover hay and noted a prolonged clotting time. Ten years after a farmer traveled in a blizzard with his dead cow and a milk can of the unclotted blood to the University of Wisconsin. Only the door to the biochemical department of Karl Paul Link was open. This event started the isolation of the anticoagulant agent dicou- marol which was formed by microbial induced oxidation of coumarin in the mouldy sweet clover hay. More than hundred dicoumarol-like anticoagulants were synthesized by Link and his co-workers. A potent hemorrhagic agent named warfarin was first used as an effective rat poison. However, warfarin became the drug of choice and the break- through in the treatment of thromboembolic diseases. Today new oral anticoagulants are competing with warfarin.
维生素K及其拮抗剂（口服抗凝剂双香豆素和华法林）的发现与发展历程，是医学史上引人入胜且成就斐然的里程碑。维生素K由哥本哈根大学的卡尔·彼得·亨里克·达姆（Carl Peter Henrik Dam）和弗里茨·舍恩海德（Fritz Schønheyder）发现。这一发现由达姆发起，源于他在固醇代谢论文中对雏鸡的幸运选择，因为这些动物的肠道细菌无法合成这种维生素。在这些实验中，合成饲料中缺乏一种未知因子导致雏鸡出现类似于坏血病的内出血，但维生素C并不能逆转这种出血现象，而且也无法用缺乏经典维生素来解释。1935年，这种未知的抗出血因子被命名为维生素K，几个月后，加利福尼亚大学伯克利分校的H.J.阿尔姆奎斯特（H.J. Almquist）和E.L.R.斯托克施塔德（E.L.R. Stokstad）也观察到了这一现象。达姆和舍恩海德通过生物测定法测定了绿色蔬菜和苜蓿不同提取物中该因子的活性。1939年，达姆和苏黎世的保罗·卡勒（Paul Karrer）分离出了维生素K，其结构由爱德华·阿德尔伯特·多伊西（Edward Adelbert Doisy）确定。达姆和多伊西于1943年获得诺贝尔奖。双香豆素的发现则开启了一段引人注目的故事。20世纪20年代，加拿大的牛开始无缘无故地死于内出血。阿尔伯塔省的兽医病理学家弗兰克·W·斯科菲尔德（Frank W. Schofield）发现，这种神秘疾病与食用变质的草木樨干草有关，并注意到凝血时间延长。十年后，一位农民带着他死去的奶牛和一罐未凝固的血液在暴风雪中前往威斯康星大学。当时只有卡尔·保罗·林克（Karl Paul Link）所在的生物化学系的门是开着的。这一事件促使人们分离出了抗凝剂双香豆素，它是由发霉的草木樨干草中香豆素的微生物诱导氧化形成的。林克和他的同事合成了一百多种类似双香豆素的抗凝剂。一种名为华法林的强效出血剂最初被用作有效的杀鼠剂。然而，华法林后来成为了治疗血栓栓塞性疾病的首选药物并取得了突破。如今，新型口服抗凝剂正在与华法林展开竞争。
