elderly individuals may have many coexisting illnesses and are typically prescribed different types of drugs . therefore , drug interactions are a problem associated with medication . fluoropyrimidines ( eg , 5-fu , uft , ts-1 , and capecitabine ) are used as anticancer agents . a known interaction exists between fluoropyrimidines and warfarin.2 warfarin is an oral anticoagulant , which is often used to prevent thromboembolic complications in cardiovascular diseases . they are well - known to contribute to a large amount of inter - patient variability in warfarin metabolism , which appears to be related to genetic polymorphisms in cytochrome p-450 enzyme 2c9 ( cyp2c9 ) and/or vitamin k epoxide reductase complex 1 ( vkorc1).35 therefore , we examined polymorphisms of cyp2c9 and vkorc1 in this patient . there are only a few reports discussing dah association with warfarin therapy.6,7 we report a case of dah related to combination therapy using uft and warfarin . he had been taking 200 mg aspirin daily , 200 mg ticlopidine hydrochloride daily and 2 mg warfarin daily for 2 years for myocardial infarction after percutaneous coronary intervention . he then developed lung adenocarcinoma ( pt1n0m0 stage ia ) , and a right lower lobectomy was performed . uft generally improves the survival rate among patients with tumors 2 to 3 cm in diameter.8 thus , one month after operation , he began taking 2 capsules of uft ( 200 mg tegafur and 448 mg uracil ) twice daily as an adjuvant therapy . after the operation , he did not consult a cardiovascular physician but continued the same doses of medicines . two months later , he was admitted to our hospital with hemoptysis , cough , and dyspnea . before his symptoms were evaluated , no antibiotics or other drugs , such as those that affect the metabolism of vitamin k , were prescribed . on the other hand , he did not have diarrhea , so we speculated that his colonic flora and vitamin k absorption was normal . the patient had previously been a smoker ( smoking exposure , 100 pack - years ) and he had chronic obstructive pulmonary disease ( gold guideline stage ii ) . physical examination showed that he had many large purpuras on his limbs ; his respiratory rate was 30 breaths / min ; blood pressure , 109/58 mmhg ; heart rate , 76 beats / min ; and body temperature , 37.0 c . results of laboratory investigations were as follows : hemoglobin level , 7.5 g / dl ; wbc count , 8,100 cells/l ; platelet count , 213,000 cells/l ; pt - inr , 8.9 . myeloperoxidase antineutrophil cytoplasmic auto - antibody ( mpo - anca ) , proteinase 3-anca ( pr3-anca ) , antiglomerular basement membrane antibody , antinuclear antibody , and anti chest computed tomography ( ct ) scan showed bilateral ground - glass opacities and multiple low attenuation areas ( fig . histopathological analysis of bloody balf showed hemosiderin - filled macrophages ( > 20% of total alveolar macrophages ) , thereby confirming alveolar hemorrhage ( fig . because of the presence of tarry stools , gastrointestinal fiberscopy was conducted , and no abnormalities were found . uft , warfarin , aspirin , and ticlopidine hydrochloride were discontinued , and 10 mg vitamin k was administered intravenously . his symptoms gradually improved , and bilateral alveolar infiltration resolved after about 2 weeks ( fig . we examined genetic polymorphisms of cytochrome p-450 enzyme 2c9 ( cyp2c9 ) and vitamin k epoxide reductase complex 1 ( vkorc1 ) , which can influence the management of warfarin therapy . the patient had no polymorphisms of cyp2c9 but a homozygous mutation was found in vkorc1 . after prescribing warfarin , aspirin , and ticlopidine hydrochloride ( with no uft ) , the pt - inr was controlled at 2.2 ( inr target range , 2.02.5 ) . at follow - up visits , we report the case of a patient with dah related to combination therapy of uft and warfarin . the patient was prescribed 2 mg warfarin daily for 2 years ; he had no bleeding episodes and pt - inr had been well - controlled , in the range of 2 to 2.5 . however , after uft was started , pt - inr markedly increased to 8.9 . after dah resolved , anticoagulant therapy was restarted , and pt - inr was controlled at 2.2 . dah can occur as a manifestation of various diseases such as wegener s granulomatosis , henochschnlein purpura , microscopic polyangiitis , antiphospholipid antibody syndrome , and goodpasture s syndrome.1 in this case , mpo - anca , pr3-anca , antiglomerular basement membrane antibody , antinuclear antibody , and anti dah can occur as a rare complication of warfarin therapy.6,7 to our knowledge , this is the first case of dah associated with uft and warfarin . recently , saif reported that patients receiving concomitant capecitabine or fluorouracil ( 5-fu ) and warfarin had altered coagulation parameters and consequent bleeding , thus causing shock in some cases.2 warfarin is an oral anticoagulant , which is often used to prevent thromboembolic complications in cardiovascular diseases . they are well - known to contribute to a large amount of inter - patient variability in warfarin metabolism , which appears to be related to genetic polymorphisms in cyp2c9 and/or vkorc1.35 cyp2c9 is a key enzyme in the hepatic metabolism of warfarin , whereas vkorc1 works to maintain sufficient vitamin k levels when dietary vitamin k is limited . uft is an orally available drug whose activity is comparable to that of intravenously administered 5-fu combined with folinic acid . derivatives based on fluoropyrimidines ( eg , 5-fu , uft , ts-1 , and capecitabine ) are used for the management of several malignancies such as lung , pancreatic , upper gastrointestinal , and breast cancers . kato et al reported that uft as a postoperative adjuvant treatment , which can be used to improve the prognosis of patients with completely resected adenocarcinoma ( stage ib).8 uft was administered in this case and such an effect of uft was expected . recently , results of an enzymatic study suggested that 5-fu has inhibitory effects against the activities of microsomal enzymes , including cyp2c.9 on the basis of results of recent studies , we speculated that genetic polymorphisms of cyp2c9 and/or vkorc1 are mechanisms of interaction between fluoropyrimidines and warfarin in our patient . the patient s genotype was cyp2c9 * 1/*1 ; thus , he did not have the polymorphisms of cyp2c9 , but did have a homozygous mutation of vkorc1 a / a . additionally , pt - inr was well - controlled using a small amount of warfarin for therapy . in addition to the inhibitory effects of uft on the activities of cyp2c9 , dah may be induced by a smaller dose of warfarin . however , it is well known that there are no correlations between the metabolism of these drugs and cyp2c9 or vkorc1 . moreover , after re - administration of anticoagulants , pt - inr was controlled ( 2.2 ) , and the patient remained asymptomatic . thus , the interaction between warfarin and another anticoagulant may not be the cause of dah . recently , a report described polymorphisms of cypa6 associated with metabolism of 5-fu.10 the clearance of 5-fu observed in patients with 2 variant alleles was significantly lower than that in patients with wild type alleles . we did not assess for this mutation , but it is possible that our patient has the mutation . when fluoropyrimidines and warfarin are prescribed simultaneously , we recommend that pt - inr should be closely monitored .
a 72-year - old man who received warfarin for myocardial infarction ( prothrombin time - international normalized ratio [ pt - inr ] controlled between 2.2 and 2.5 ) for 2 years . 
 he developed lung cancer , underwent surgery , and received tegafur plus uracil ( uft ) after 1 month . 
 after 2 months , he was admitted for hemoptysis and dyspnea . 
 chest radiography and computed tomography showed bilateral alveolar infiltration ( pt - inr , 8.9 ) . 
 bronchoalveolar lavage fluid ( balf ) disclosed hemorrhagic features in sequential samples . 
 and he was diagnosed with diffuse alveolar hemorrhage ( dah ) . 
 a known interaction exists between fluoropyrimidines and warfarin . 
 so , they were discontinued , and vitamin k was intravenously administered . 
 one day later , the pt - inr returned to 1.14 . the symptoms improved and , alveolar infiltration resolved after 2 weeks . 
 alveolar hemorrhage may be due to an interaction between uft and warfarin . when fluoropyrimidines and warfarin are prescribed simultaneously 
 , we recommend that pt - inr should be closely monitored .