warfarin is the most commonly used oral anticoagulant both for prophylaxis as well as treatment for arterial and venous thromboembolic conditions .
it has a narrow therapeutic index and is metabolized by hepatic cytochrome p450 2c9 enzyme ( cyp2c9 ) .
various polymorphisms exist in the gene that code for cyp2c9 , of which * 1 is the wild form expressing normal activity . amongst the variants , * 2 and * 3 are more common than the rest and exhibit lesser enzymatic activity .
the anticoagulant effect of warfarin is measured by prothrombin time - international normalized ratio ( pt - inr ) .
warfarin exerts its anticoagulant effect by reducing the regeneration of active vitamin k through inhibition of vitamin k epoxide reductase , encoded by vitamin k epoxide reductase complex subunit 1 gene ( vkorc1 ) .
increased risk of deranged inr or bleeding has been reported in patients harboring mutant form of either cyp2c9 or vkorc1 .
this case report describes a patient on low - dose warfarin , who succumbed to a subdural hematoma and was found to have polymorphic cyp2c9 ( * 1/*3 ) .
a 49-year - old male patient , who was a known case of superior sagittal sinus thrombosis for the past 8 years on tablet warfarin 2.5 mg every night , was brought to the hospital unconscious .
the patient was non - compliant in not following up with his physician nor did he check his pt - inr levels regularly for the past 1 year .
the patient 's relative , however , maintained that the patient was regular in taking the prescribed dose of warfarin ( 2.5 mg ) every night . on physical examination
, he was found to be unconscious ( glasgow coma scale score of 3 ) , pulse was feeble and the blood pressure was not recordable .
a plain computed tomography ( ct ) brain revealed 24.2 mm hyperdense cresentic subdural hematoma in left fronto - temporo - parieto - occipital region with subfalcine extension and midline shift [ figure 1 ] .
his pt - inr was found to be 9 [ normal ( in the absence of anticoagulation therapy ) is 1 and it has to be maintained between 2 and 3 for an appropriate therapeutic effect for warfarin ] .
fresh frozen plasma was initiated at a dose of 15 ml / kg / day .
blood ( 5 ml ) was collected from the patient and genotyping was done for both cyp2c9 and vkorc1 .
cyp2c9 was found to be polymorphic for * 3 ( * 1/*3 ) and vkorc1 was found to be wild - type ( normal ) .
plain ct brain revealing 24.2 mm hyperdense cresentic subdural hematoma ( red arrow ) in left fronto - temporo - parieto - occipital region
pharmacogenetics is the study of genetic influence on inter - individual variation in the response of a drug .
pharmacogenetics has been shown to be of value in detecting an optimal response as well as in preventing adverse reactions following drugs such as warfarin , clopidogrel , and phenytoin .
warfarin is metabolized by cyp2c9 and over 30 polymorphic alleles have been identified in the gene coding for cyp2c9 .
the wild form of the gene is * 1 and the most common polymorphic forms include * 2 and * 3 .
allelic frequency of cyp2c9 * 2 and * 3 in various populations including indians were found to be in the range of 0 - 20% .
a recent systematic review concluded that in comparison to the patients with cyp2c9 * 1/*1 genotype , the cyp2c9 * 1/*2 , cyp2c9 * 1/*3 , cyp2c9 * 2/*2 , cyp2c9 * 2/*3 , and cyp2c9 * 3/*3 patients required warfarin doses that were 19.6 , 33.7 , 36.0 , 56.7 , and 78.1% lower , respectively .
similarly , in the vkorc1 gene , two alleles have been identified in vkorc1 namely g and a. patients with gg ( wild type ) are resistant requiring a higher dose of the drug whereas aa are sensitive requiring a lesser dose and ga requires intermediate .
a randomized clinical trial has also shown that pharmacogenetic - based dosing of warfarin was associated in maintaining the pt - inr levels within the acceptable range for a longer time than by the standard dosing .
united states food and drug administration ( fda ) has recently modified the warfarin labeling by suggesting cyp2c9 and vkorc1 genotyping before initiating the drug to ensure warfarin safety .
our patient had a fatal subdural hematoma despite low - dose ( 2.5 mg hs ) of warfarin .
he had massively deranged inr of 9 , was brought in with glasgow coma scale of 3 .
the * 1/*3 variant cyp2c9 explained this serious adverse event with low - dose warfarin . the * 3 variant is less than 5% as active as the wild type whereas * 2 retains around 12% of the activity .
a recent indian review of oral anticoagulant use revealed lack of proper laboratory facilities , with irregular pt - inr monitoring in 25% patients and deranged inr values in a high proportion of patients .
pharmacogenetic testing needs to be done only once and hence can be considered cost - effective .
studies have shown that along with age , gender , body weight , cyp2c9 and vkorc1 polymorphisms account for almost 64% of the variability in the dose of warfarin required for an individual .
hence , by doing these genetic testing a priori to the treatment initiation , there is a high possibility that the patients may receive an appropriate dose than just by routine practice .
even , several international algorithms for predicting dose of warfarin have been developed with these predicting factors of which , gage 's and wadelius algorithms have been shown to be the most accurate .
recently , an algorithm for indian patients has also been developed , which was found to be more accurate , sensitive and significantly reduced the risk of overestimation of dose of warfarin .
this algorithm can be used for predicting the appropriate dose of warfarin in our population with the genotype details of cyp2c9 and vkorc1 . to conclude
, this case highlights the necessity of adopting the practice of routine genetic testing for cyp2c9 and vkorc1 while initiating warfarin therapy .
 warfarin is the most common and cheap oral anticoagulant currently used in clinical practice . 
 a high inter - individual variation is seen in the response to warfarin . 
 recently , pharmacogenetics has gained importance in managing patients on warfarin , both in predicting the optimum required dose as well as in decreasing the risk of bleeding . 
 this case report is a description of a 49-year - old patient who had a lethal subdural hematoma with low - dose warfarin . 
 he was subsequently found to have cyp2c9 gene polymorphism ( * 1/*3 ) . 
 this case report stresses the importance of pre - prescription assessment of genetic analysis for those initiated on warfarin . 