warfarin is the most widely used anticoagulant agent for the prevention of stroke or systemic thromboembolism in patients with atrial fibrillation .
however , warfarin has a narrow therapeutic range of international normalized ratio ( inr ) and is known to have multiple interactions with drugs , food , and herb .
there is some difficulty in deciding a starting dosage of warfarin , because of the large interindividual variation in the dose needed to reach adequate level of inr .
the warfarin dose can be affected by several factors including dietary , demographic factors , drugs and , several pathophysiological conditions ( 1 ) .
genetic factors also play a relevant role in the individual variability of the warfarin dose .
in particular , several single nucleotide polymorphisms of the cytochrome p450 ( cyp ) , subfamily iic , polypeptide 9 ( cyp2c9 ) and vitamin k epoxide reductase ( vkorc1 ) genes can significantly influence the warfarin dose requirement ( 2 ) .
several coagulation and fibrinolytic parameters appear to be affected by thyroid hormone excess ( 3 ) .
we report a patient with atrial fibrillation in whom the concomitant presence of rare genetic abnormality and thyrotoxicosis caused a marked increase in the inr level at the beginning of warfarin therapy .
a 73-yr - old korean male with permanent atrial fibrillation visited outpatient clinic for the management of atrial fibrillation on feb .
21 , 2012 . he had a history of hypertension and colon cancer with liver metastasis . at the age of 68 , he had undergone extended right hemicolectomy with liver tumorectomy due to colon cancer with liver metastasis and received adjuvant chemotherapy for two years .
his current medication included diltiazem ( 90 mg / day ) and aspirin ( 100 mg / day ) , spironolactone ( 25 mg / day ) , hydrochlorothiazide ( 12.5 mg / day ) .
considering his risk for stroke and systemic thromboembolism ( cha2ds2-vasc score 2 ) , oral anticoagulation was recommended for him .
when he revisited the outpatient clinic after six days , his inr was significantly increased to 15 ( fig .
he was admitted for correction of high inr and bleeding tendency on march 12 , 2012 .
his liver function test at the time of admission was normal and he had no short bowel syndrome which would affect drug absorption .
he denied any drug , alcohol , or herbal intake , which may affect inr level .
we also performed a pharmacogenetic test on him to identify genetic susceptibility to warfarin effect .
genomic dna was extracted from peripheral blood leukocytes using dna extract all lysis reagents ( applied biosystems , ca , usa ) .
genotyping for polymorphisms of cyp2c9 ( rs1057910 , cyp2c93 ) and vkorc1 ( rs9934438 , 1173c > t ) variants was performed using taqman drug metabolism genotyping assays and 7500 fast real - time pcr system ( applied biosystems , ca , usa ) .
later , he was found to be an intermediate metabolizer with genotype of cyp2c91/3 and had vkorc1 + 1173tt genotype indicating high warfarin sensitivity ( fig .
then on hospital day ( hd ) 3 , aspirin 100 mg a day was started to replace warfarin .
we measured his plasma warfarin and 7-hydroxy - warfarin concentrations by high - performance liquid chromatography tandem mass spectrometry on hd 0 as a baseline and hd 3 . on hd 0 , total plasma warfarin , 7-hydroxy - warfarin concentration ( 7-oh - warfarin ) , and
the ratio of warfarin/7-oh - warfarin were 0.793 g / ml ( therapeutic range 0.5 to 3.0 g / ml ) , 0.046 g / ml , and 7.2 , respectively . on hd 3 , total plasma warfarin and 7-oh - warfarin levels
were decreased to 0.178 g / ml and 0.01 g / ml , respectively , and the ratio of warfarin/7-oh - warfarin was increased to 18 ( fig .
1 ) . on thorough history taking , he complained of hand tremor with proximal muscle weakness .
he also experienced unexplained body weight loss before admission . from this information , we suspected hyperthyroidism and thyroid function test was performed on hd 3 to confirm the diagnosis .
total t3 , total t4 , tsh , and free t4 were 437.84 ng / dl ( normal range 60 to 181 ng / dl ) , 17.6 g / dl ( normal range 3.2 to 12.6 g / dl ) , 0.01 iu / ml ( normal range 0.64 to 6.27 iu / ml ) , and 6.86 ng / dl ( normal range 0.89 to 1.8 ng / dl ) , respectively .
the results were consistent with hyperthyroidism , so carbimazole ( 20 mg twice daily ) and betaxolol ( 20 mg twice daily ) were started .
, warfarin was discontinued due to the risk of bleeding and instead aspirin was maintained for atrial fibrillation .
we have observed a rare case with genotype of cyp2c91/3 and concomitant hyperthyroidism in which the usual initiation of warfarin therapy caused a dangerous and unexpected elevation of the inr value and led to bleeding complication .
cyp2c9 is a liver enzyme required for the oxidative metabolism of a large number of clinically important drugs , including warfarin .
three alleles , cyp2c91 , 2 , and 3 are present in most ethnic populations .
both cyp2c92 and 3 , and only in carriers of at least 1 copy of cyp2c93 confer significantly higher risk for warfarin over - anticoagulation and hemorrhagic complications compared to wild type allele ( 4 ) .
the frequency of cyp2c9 and vkorc1 1173 c / t polymorphism is largely dependent on ethnicity . in a korean population study ,
the allele frequencies of cyp2c93 and cyp2c91 are reported to be 6% and 93.4% , respectively . but cyp2c92 allele has not been detected .
the frequencies of cyp2c91/3 and 1/1 genotypes are 12% and 86.9% , respectively ( 5 ) .
vkorc1 + 1173tt genotype associated with high warfarin sensitivity predominates in asian population than in non - asian population ( 6 ) .
it has been reported that overt hyperthyroidism exerts a procoagulant effect and increases the risk of thromboembolic events ( 5 ) .
in contrast , thyrotoxicosis has been associated with an increased sensitivity to warfarin , irrespective of the nature of the underlying thyroid disease ( 6 ) .
several studies reported warfarin - induced hypoprothrombinemia in hyperthyroidism with an increased risk of bleeding ( 7 , 8 , 9 , 10 ) . in thyrotoxic patients , warfarin produced a greater fall in factors ( ii and vii ) and a greater increase in prothrombin time than in the euthyroid state ( 11 ) .
furthermore in thyrotoxicosis , the degradation rate of coagulation factors is increased , resulting in their higher plasma clearance and shorter plasma half - life ( 6 ) .
we are presenting a very rare case about a patient with an uncommon genetic susceptibility to warfarin effect and co - existing hyperthyroidism at the beginning of warfarin treatment . from this case
, we learned the clinical usefulness of pharmacogenetic and thyroid function tests in patients with atrial fibrillation , in whom warfarin is considered to prevent stroke or systemic thromboembolism .
 a 73-yr - old korean man with permanent atrial fibrillation visited outpatient clinic with severely increased international normalized ratio ( inr ) values after taking a usual starting dosage of warfarin to prevent thromboembolism . 
 we found out later from his blood tests that he had hyperthyroidism at the time of treatment initiation . 
 his genetic analysis showed cyp2c9 * 1/*3 and vkorc1 + 1173tt genotypes . 
 we suspect that both hyperthyroidism and genetic variant would have contributed to his extremely increased inr at the beginning of warfarin therapy . from this case 
 , we learned that pharmacogenetic and thyroid function test might be useful when deciding the starting dosage of warfarin in patients with atrial fibrillation.graphical abstract 
Graphical Abstract
INTRODUCTION
CASE DESCRIPTION
DISCUSSION