Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience

Abstract

ADE = adverse drug event; AEI = American Enterprise Institute; ASPE = allele-specific primer extension; CYP2C9 = cytochrome P450 2C9; INR = international normalized ratio; PCR = polymerase chain reaction; SNP = single-nucleotide polymorphism; VitKH 2 = vitamin K hydroquinone; VKOR = vitamin K epoxide reductase; VKORC1 = VKOR complex, subunit 1 W arfarin is a well-accepted therapy used for the prevention of stroke in patients with atrial fibrillation, for prophylaxis of venous thromboembolism and pulmonary embolism in patients with prosthetic heart valves and myocardial infarction, and for prevention of pulmonary embolism or deep venous thrombosis in patients undergoing orthopedic surgery or with a history of venous or arterial thromboembolism. Many reviews and clinical practice guidelines (summarized by Ansell et al, 1 Baglin et al, 2 Flockhart et al, 3 Husted et al, 4 and Singer et al 5 ) outline the substantial benefits of warfarin therapy for the prevention of strokes in these patients. The American Enterprise Institute (AEI)-Brookings Joint Center for Regulatory Studies Report, which reviewed the use of warfarin in the United States, estimates that approximately 2 million US citizens are prescribed warfarin annually. 6 In 2003, a total of 21.2 million prescriptions were written for oral warfarin in the United States. 7 Warfarin interferes with coagulation by inhibiting regeneration of the reduced form of vitamin K, a cofactor in the γ-glutamyl-carboxylase -mediated activation of coagulation factors II, VII, IX, and X ( Figure 1). The oxidized, inactive form of vitamin K is converted to the reduced form of vitamin K by vitamin K epoxide reductase (VKOR); warfarin inhibits VKOR, resulting in less of the reduced form of vitamin K available to support the factor carboxylation required to sustain the coagulation cascade. 8 Warfarin has a narrow therapeutic index that contributes either to therapeutic failure (potentially leading to stroke or other complications) or therapeutic excess (potentially leading to bleeding and hemorrhage). Many surveys have described the incidence of warfarin-related adverse drugThe antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to ach...

A Rare Cause of Knee Pain Due to WarfarinToxicity: Spontaneous Suprapatellar Hematoma

“…Hasta kanama yönünden araştırıl-malı INR düzeyine ve kanama durumuna göre K vitamini ve/veya TDP verilmeli, 24 saatlik INR takipleri yapılmalı-dır. 8,9 Resim 1 : Resim 1. Hastanın gelişinde çekilen yüzeyel diz ultrografisi ile tespit edilen suprapatellar hematom Sonuç olarak, travma olmadan diz ağrısı ile başvuran; öz-geçmişinde oral antikoagülan kullanım öyküsü bulunan bir hastada suprapatellar hematomda ayırıcı tanıda düşü-nülmelidir.…”

Pharmacogenetics and the Treatment of Thrombophilia

“…The common CYP2C9 alleles *2 and *3, associated with high warfarin sensitivity, are present in approximately 30% of people of European descent (range 13-35%), but are less frequent in those of Asian (1-12%) and African descent (0-12%) [21,25,30]. VKORC1 B haplotype, associated with low warfarin sensitivity, is more common in European and African populations, while 'high sensitivity' A haplotype predominates in Asian populations.…”

“…Carriers of variants associated with 'high sensitivity' at both loci are at much higher risk of over-anticoagulation [31]. On the other hand, individuals who are CYP2C9*1*1-VKORC1BB show less warfarin sensitivity and require higher drug dose for therapeutic anticoagulation [25]. The associated variants in both genes are thought to account for approximately 45% of response variance in European and 30% in African populations [21].…”

“…Larger proportion of the dose variance, up to 30%, is explained by SNPs in the gene VKORC1 [25,29]. VKORC1 encodes vitamin K epoxide reductase complex, the target enzyme inhibited by warfarin; this enzyme is necessary for the recycling of vitamin K and consequently for activation of several clotting factors.…”

“…The identification of these variants, and the potential use of pharmacogenetic testing to predict the appropriate drug dosing have attracted much research interest [23][24][25][26][27][28].…”