Genetic and environmental factors affecting the coumarin anticoagulant level

This introductory chapter has illustrated that various factors, such as genetic factors, drugs, diet and intercurrent diseases may affect anticoagulation levels. Most of the clinical and pharmacological data related to coumarin anticoagulants have so far been obtained from studying warfarin. Because of the different pharmacokinetic properties of each individual drug, the results of these studies can probably not be directly extrapolated to the other coumarin anticoagulants. Therefore, the aim of this thesis was to study the various genetic and environmental factors affecting the anticoagulation levels of acenocoumarol or phenprocoumon among outpatients of an anticoagulation clinic. In chapter 2 genetic factors influencing the coumarin anticoagulant level are examined. Chapter 2.1 describes how the coumarin anticoagulant dose is affected by polymorphisms of the cytochrome P450 enzyme 2C9 allele. In chapter 2.2 we describe the influence of these polymorphisms on the occurrence of bleeding complications. CYP2C9 variant alleles seem to have several biological consequences. For instance, it has been associated with an increased risk of myocardial infarction in women [57]. Therefore, in chapter 2.3 the risk of myocardial infarction was studied in patients with a CYP2C9 variant allele compared to patients with the wild type genotype. Chapter 2.4 concerns the influence of apolipoprotein E genotype on the coumarin anticoagulant level. In chapter 3, several drugs are identified with a high risk of overanticoagulation during coumarin use. Chapters 3.1 and 3.2 focus on antibacterial drugs and antifungal agents, chapters 3.3 on laxatives, and 3.4 on nonsteroidal anti-inflammatory drugs as risk factors for overanticoagulation. The study described in chapter 4 aims at investigating the influence of heart failure on the anticoagulant level. The role of dietary intake of vitamin K as a risk factor for overanticoagulation is evaluated in chapter 5. Finally, in chapter 6 the strengths and limitations of this thesis are discussed, together with the implications for coumarin anticoagulant therapy, and suggestions for future research are given.

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