Hereditary Transmission of Exceptional Resistance to Coumarin Anticoagulant Drugs

Ra, O'Reilly; Pm, Aggeler; Ms, Hoag; Ls, Leong; Ml, Kropatkin

doi:10.1056/nejm196410152711602

Cited by 127 publications

(60 citation statements)

References 19 publications

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“…The fi rst report in 1964 of the hereditary transmission of a resistance to the action of coumarin anticoagulants was in a family from which the propositus required a daily warfarin dose that was approximately 15-fold higher than normal (145 mg) to achieve stable anticoagulation ( 87 ). At around the same time, reports of the spread of resistance to fi rst generation rodenticides were also being reported ( 88,89 ) and after the introduction of second-generation rodenticides (so called superwarfarins) to these compounds as well ( 90,91 ).…”

Section: Probing the Mechanism Of Warfarin Resistancementioning

confidence: 99%

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

Shearer

Newman

2014

Journal of Lipid Research

183

157

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Section: Probing the Mechanism Of Warfarin Resistancementioning

confidence: 99%

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

Shearer

Newman

2014

Journal of Lipid Research

183

157

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“…Há, ainda, uma resistência de origem genética à warfarina, que pode aumentar a necessidade de suas doses em até 20 vezes, para que se alcance o efeito anticoagulante desejado 9,10 .…”

Section: Introductionunclassified

Complicações da terapia anticoagulante com warfarina em pacientes com doença vascular periférica: estudo coorte prospectivo

et al. 2006

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194 ResumoObjetivo: Estudar prospectivamente a freqüência de complicações em pacientes tratados com warfarina e acompanhados no Ambulatório de Anticoagulação da Faculdade de Medicina de Botucatu da Universidade Estadual Paulista.Métodos: Pacientes sorteados entre os agendados para consulta de junho de 2002 a fevereiro de 2004. Na primeira consulta, foi preenchida ficha com dados de identificação e clínicos. A cada retorno, ou quando o paciente procurou o hospital por intercorrência, foi preenchida ficha com a razão normatizada internacional, existência e tipo de intercorrência e condições de uso dos antagonistas da vitamina K.Resultados: Foram acompanhados 136 pacientes (61 homens e 75 mulheres), 99 com tromboembolismo venoso e 37 com doença arterial; 59 pacientes eram de Botucatu, e 77, de outros municípios. Foram registradas 30 intercorrências: nove não relacionadas ao uso da warfarina e 21 complicações hemorrágicas (38,8 por 100 pacientes/ ano). Uma hematêmese foi considerada grave (1,9 por 100 pacientes/ ano). As demais foram consideradas moderadas ou leves. Não houve óbitos, hemorragia intracraniana ou necrose cutânea. A única associação significante foi da freqüência de hemorragia com nível médio de razão normatizada internacional.Conclusão: Nossos resultados mostram a viabilidade desse tratamento em pacientes vasculares em nosso meio, mesmo em população de baixo nível socioeconômico, quando tratados em ambulatório especializado.Palavras-chave: Anticoagulantes, warfarina, efeitos adversos, doenças vasculares, trombose venosa, embolia pulmonar. AbstractObjective: To prospectively study the frequency of complications in patients treated with warfarin followed at Botucatu Medical School.Methods: Patients randomly selected among those with appointments scheduled from June 2002 to February 2004. At the first appointment, a protocol was filled with identification and clinical data. At every return or when the patient went to the hospital due to clinical events, another form was filled with the international normalized ratio, existence and type of clinical event and the conditions of use of vitamin K antagonists.Results: A total of 136 patients (61 men and 75 women), were followed; 99 patients with venous thromboembolism and 37 with arterial disease; 59 were from Botucatu and 77 were from other municipalities. Thirty clinical events were registered: nine of them were not related to the use of warfarin and 21 were hemorrhagic complications (38.8 per 100 patients-year). One hematemesis was considered severe (1.9 per 100 patients-year). The others were considered moderate or mild. There were no deaths, intracranial hemorrhage or cutaneous necrosis. The only significant association was frequency of hemorrhage and average international normalized ratio level.Conclusion: Our results demonstrate the feasibility of this treatment in vascular patients in our country, even in socially and economically poor populations, when treated in specialized clinics.

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“…The warfarin alcohols have not been previously noted. 6-and 7-Hydroxywarfarin were reported (8) in the urine of an unusual patient who required 145 mg of warfarin daily (10), but the pertinence of this observation to the normal human is uncertain.…”

Section: Resultsmentioning

confidence: 99%

“…Resistance to warfarin has been described in man (10, 21) and animals (22,23) and has been shown to be an inherited phenotype (10,22). The evidence that, after administration of racemic warfarin, only one warfarin enantiomer is converted to a particular metabolite (8) not only emphasizes the stereospecific nature of these reactions but also leads to the speculation that an alteration in a stereospecific enzyme may be responsible for states of unusual warfarin sensitivity or resistance by alterations in the production of a pharmacologically active metabolite.…”

Section: Resultsmentioning

confidence: 99%

Warfarin metabolism in man: identification of metabolites in urine

Lewis¹,

Trager²

1970

J. Clin. Invest.

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A B S T R A C T After administration of the coumarin anticoagulant racemic warfarin to normal humans, seven fluorescent compounds were chromatographically separated from extracts of their urine. Four of these were identified using mass spectrometry, thin-layer chromatography, and ultraviolet absorption spectroscopy. One metabolic pathway, reduction of the acetonyl side chain of warfarin, resulted in the formation of a second asymmetric carbon atom, and two diastereoisomer alcohols were identified. These warfarin alcohols are structurally similar to pharmacologically active coumarin derivatives. They have not been reported in animal studies. In addition, 6-and 7-hydroxywarfarin were identified. These are the first studies to document the metabolic fate of warfarin in the normal human.

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Hereditary Transmission of Exceptional Resistance to Coumarin Anticoagulant Drugs

Cited by 127 publications

References 19 publications

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

Complicações da terapia anticoagulante com warfarina em pacientes com doença vascular periférica: estudo coorte prospectivo

Warfarin metabolism in man: identification of metabolites in urine

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