Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon

SummaryCoumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of theVKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 andVKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect ofVKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anti-coagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

Brodifacoum Toxicosis in Two Neonatal Puppies

Eight out of a litter of 13 puppies were either born dead or died within 48 hours of birth. Three puppies that died shortly after birth were necropsied. Two puppies had hemorrhage in the thoracic and peritoneal cavities, intestinal serosa, and meninges. The third puppy was smaller than the other two puppies but did not have detectable hemorrhage. Brodifacoum, a second-generation coumarin anticoagulant, was detected in livers from the two puppies with hemorrhage. The dam did not have clinical signs of coagulopathy before or subsequent to whelping. The owners were confident that the dog had not been exposed to rodenticide for at least 4 weeks before whelping. A presumptive diagnosis of in utero brodifacoum toxicity was made. To the authors' knowledge this is the first time a second-generation coumarin anticoagulant has been detected in the liver of a newborn animal. This case is also unique because the dam was unaffected, suggesting that fetuses are more susceptible to brodifacoum toxicity than adult animals.