Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management.

Long-acting anticoagulant rodenticides (LAARs) inhibit vitamin K epoxide reductase (VKOR). Related bleeding may present a diagnostic challenge and require administration of blood component therapy, hemostatic agents, and vitamin K. This article intends to provide the reader a comprehensive understanding of LAAR poisoning. An exhaustive literature search of PubMed, Science Direct, US National Library of Medicine Toxicology Data Network, and Google Scholar yielded 174 reported cases of LAAR poisoning from which clinical data were extracted and reviewed. In addition, 25 years of epidemiologic data from the American Association of Poison Control Centers was reviewed. In the United States, on average, there were 10413 exposures reported with 2750 patients treated annually. For 25 years, there were 315951 exposures reported with nearly 90% among children and more than 100000 patients treated in a health care facility. Fortunately, only 2% of all exposures result in morbidity or mortality. Inhalational, transcutaneous, and oral routes of exposure have been documented. Most exposures are unintentional. The most frequently reported bleeding sites are mucocutaneous, with hematuria being the most common feature. Deaths were most commonly associated with intracranial hemorrhage. Long-acting anticoagulant rodenticide-induced paradoxical thrombosis and thrombotic complications accompanying hemostatic therapy have also been observed. Most patients present with coagulation assay values beyond measurable limits. Long-acting anticoagulant rodenticides have an extremely high affinity for VKOR compared with warfarin, characterized by rebound coagulopathy and bleeding after initial treatment and the need for high-dose, long-term therapy with vitamin K1. Treatment of acute hemorrhagic symptoms often required intravenous vitamin K1 in excess of 50 to 100 mg; chronic maintenance with 100 mg PO vitamin K1 daily was the most frequently used dose required to suppress coagulopathy. Treatment courses averaged 168 days. Adjunctive hemostatic therapy with recombinant factor VIIa and prothrombin complex concentrate has been reported, and phenobarbital has been used to expedite LAAR metabolism.

[Has the era of warfarin terminated?].

Warfarin has for a long time been considered the "gold standard" of oral anticoagulant therapy. Positive effects of this agent are unambiguously supported by accumulated evidence-based data convincingly confirming a decrease in the risk for thrombolytic complications in patients with many diseases of the cardiovascular system: atrial fibrillation, thrombosis of deep veins of extremities, pulmonary artery thromboembolism. However, warfarin has a series of disadvantages complicating its practical application: the necessity of individual adjustment of the dose to maintain the International Normalized Ratio (INR) within the limits of the target values, clinically significant interactions with other drugs and foodstuffs. In this connection, the advent of new oral anticoagulants such as dabigatran, rivaroxaban, and apixaban is associated with great hopes concerning increased efficiency and safety of anticoagulant therapy. However, while the results of large-scale clinical trials are promising, the data on using these agents in real clinical practice suggest that prescription and administration of new oral anticoagulants should be approached with great caution, thoroughly weighing potential risks and benefits. Therefore, switching over the patients with the already adjusted dosage of warfarin and stable values of the INR to new drugs seems hardly advisable.

[On the history of vitamin K, dicoumarol and warfarin]. / Pionerer bag vitamin K, dikumarol og warfarin.

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.

[Warfarin - its synthesis and properties in a twenty-year retrospective*]. / Warfarín - jeho syntéza a vlastnosti v dvadsatrocnej retrospektíve*

The review paper deals with some aspects of warfarin history and its use, at the beginning as a rodenticide and later as an anticoagulant. It describes its principal physical-chemical properties and it analyzes schematically the possibilities of its preparation by both selective and non-selective synthesis from coumarin derivatives. A survey of syntheses and its results are tabulated, including the literary references, and the paper is concluded with an evaluation of the prospects of this agent in comparison with alternative anticoagulants and its advantages, disadvantages and prospects.

Introducción / Introduction

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[Fifty years of clinical use of warfarin]. / Cincuenta años de uso clinico de la warfarina.

Warfarin is the most utilized oral anticoagulant for the long term prophylaxes of thrombosis. Its use has been increased as new clinical conditions, capable of leading to thrombosis, have been detected. Due to the special characteristics of warfarin, such as the variability of doses for each individual, the narrow margin between adequate and inadequate doses, interaction with multiple pharmaceutical products, interference of its action by vitamin K present in the diet and the possibility of hemorrhagic complications or thrombotic recurrence, this drug requires a very careful dosage and strict laboratory and clinical monitoring. Despite being in the market for more than de fifty years and its many disadvantages, warfarin has not been substituted for the new oral anticoagulants. In 1999, warfarin was positioned eleventh on the list of the most used medicines in the world.

A tale of two anticoagulants: warfarin and heparin.

This article relays the story of 3 men, Karl Paul Link, who is the discoverer of warfarin, and William Henry Howell and Jay McLean, who are the discoverers of heparin.

The story of the discovery of heparin and warfarin.

Heparin and coumarins have been the mainstay of anticoagulant therapy throughout our working lives. As we stand on the threshold of a new era of anticoagulants it is timely to look back upon their discovery and development. Both have fascinating stories to tell. Jay McLean claimed to have discovered heparin whilst a medical student, although this is disputed. The story of warfarin leads us from a mysterious haemorrhagic disease of cattle to the development of a rat poison which became one of the most commonly prescribed drugs in history. Many people were involved in both stories and we owe them all a debt of gratitude.

Control of coagulation: a gift of Canadian agriculture.

Vitamin K, heparin and their antagonists remain the basis of coagulation therapies today, more than half a century after their discovery. Failure of blood clotting in chicks that were fed a fat-depleted diet was observed by William McFarlane, William Graham Jr. and Frederick Richardson of the Ontario Agricultural College; it led to the search that yielded vitamin K. Investigation of hemorrhagic disease in cattle by Francis Schofield of the Ontario Veterinary College found an anti-thrombin substance in spoiled clover which was later characterized as dicoumarol, a vitamin K antagonist, and led to the development of warfarin. In Toronto, a systematic approach lead by Charles Best resulted in the world's first plentiful supply of purified heparin. Clinical usefulness of heparin in thrombosis, embolism, cardiovascular surgery, dialysis and transplantation was demonstrated first by Gordon Murray and Louis Jaques. The roles and the careers of Canadian coagulation research pioneers are briefly presented in this review, which shows how clinical medicine benefited by the systematic development of agricultural science in Guelph, Ontario.