attempted or accidental superwarfarin exposure has become an important public problem in western countries ( 1 ) , as intoxication can cause prolonged bleeding diathesis , and sometimes fatal results . over 10,000 cases of superwarfarin intoxication were reported in 2008 to the poison control centers toxic exposure surveillance system in the united states ( 2 ) .
in korea , only sporadic reports of superwarfarin intoxication exist without any systemic and detailed investigations to the issue ( 3 - 5 ) .
we conducted an observational study of 10 cases of superwarfarin intoxication in korea , most of them broke out within a year .
case report forms ( crf ) for patients with superwarfarin intoxication were requested to 8 physicians from october 2009 to april 2010 by electronic mails .
a crf contained filling up section for basic information of a patient : age , sex , residence , occupation , past history of disease , and medication history of anti - coagulants or anti - platelet agents , etc .
manifestations of bleeding were surveyed and initial laboratory data including prothrombin time ( pt ) and activated partial thromboplastin time ( aptt ) were collected .
results of plasma mixing test , activity of coagulation factors and serum brodifacoum level test were also recorded .
flow - sheet of treatment and change of laboratory data including pt and aptt of each patient were gathered .
the crfs were analyzed by hong j and bang s - m and the results were reviewed by the other authors .
this study was performed for the public good and had neither risk nor disadvantage for subjects .
therefore , the institutional review board of seoul national hospital bundang hospital permitted this study without acquisition of informed consent ( approval number : b-1007 - 106 - 105 ) .
this study was performed for the public good and had neither risk nor disadvantage for subjects
. therefore , the institutional review board of seoul national hospital bundang hospital permitted this study without acquisition of informed consent ( approval number : b-1007 - 106 - 105 ) .
only one patient ( patient 6 ) lived in a metropolitan city , and outbreaks were nationwide .
most of the cases occurred since 2009 , except for a male patient who diagnosed in 2007 ( 4 ) .
two of them have been previously published as a case report ( 4 , 5 ) . reported bleeding events were oral mucosal bleeding ( 7 patients ) , hematuria ( 4 patients ) , easy bruising ( 5 patients ) , hematoma formation ( 5 patients ) , and epistaxis ( 3 patients ) . patients uniformly showed prolonged pt and aptt with decreased activity of vitamin k dependent coagulation factors .
plasma mixing test and activities of coagulation factors were evaluated in all of the patients and the same result were showed : correction of pt and aptt and decreased activities of factors ii , vii , ix , and x. serum brodifacoum test were requested in 5 of 10 patients by physicians and 4 of them with a positive result were definitely diagnosed as superwarfarin intoxication .
one patient ( patient 2 ) repeatedly denied any contact with rodenticides , but she confessed to trying to kill herself by taking rodenticides after an interview with a psychiatrist .
one patient ( patient 3 ) was initially witnessed ingestion of rodenticides by her neighbors so serum brodifacoum test was not performed .
environmental exposure was a possible cause in 3 patients ( patients 4 , 7 , and 10 ) as they worked as a horticulturist , farmer , and ragman , respectively .
four patients ( patient 1 , 3 , 4 , and 6 ) failed to achieve sufficient correction of pt and aptt initially so they had to increase doses of vitamin k1 administration .
repeated prolongation of pt and aptt due to hasty discontinuation was observed in 6 patients ( patient 1 , 2 , 3 , 4 , 6 , and 8) .
ffp was initially transfused to all of the patients , but repeated ffp transfusion with low doses of vitamin k1 failed to maintain normalization of pt and aptt in 4 patients ( patient 1 , 3 , 4 , and 6 ) .
three patients ( patient 1 , 4 , and 6 ) were completely discontinued vitamin k1 treatment , and their duration of vitamin k1 administration was 7.3 , 6.2 , and 3.3 months , respectively .
all of the patients recovered or are on recovering from pt and aptt prolongation without sequalae and there was no mortality . only a patient (
he confessed that he ingested excessive amount of fluconazole , an anti fungal agent , but repeatedly denied superwarfarin ingestion even positive result of brodifacoum level test was reported .
it seems to be that he needed operation because of potentiated action of brodifacoum by drug interactions with the fluconazole .
only one patient ( patient 6 ) lived in a metropolitan city , and outbreaks were nationwide .
most of the cases occurred since 2009 , except for a male patient who diagnosed in 2007 ( 4 ) .
two of them have been previously published as a case report ( 4 , 5 ) . reported bleeding events were oral mucosal bleeding ( 7 patients ) , hematuria ( 4 patients ) , easy bruising ( 5 patients ) , hematoma formation ( 5 patients ) , and epistaxis ( 3 patients ) . patients uniformly showed prolonged pt and aptt with decreased activity of vitamin k dependent coagulation factors .
plasma mixing test and activities of coagulation factors were evaluated in all of the patients and the same result were showed : correction of pt and aptt and decreased activities of factors ii , vii , ix , and x. serum brodifacoum test were requested in 5 of 10 patients by physicians and 4 of them with a positive result were definitely diagnosed as superwarfarin intoxication .
one patient ( patient 2 ) repeatedly denied any contact with rodenticides , but she confessed to trying to kill herself by taking rodenticides after an interview with a psychiatrist .
one patient ( patient 3 ) was initially witnessed ingestion of rodenticides by her neighbors so serum brodifacoum test was not performed .
environmental exposure was a possible cause in 3 patients ( patients 4 , 7 , and 10 ) as they worked as a horticulturist , farmer , and ragman , respectively .
four patients ( patient 1 , 3 , 4 , and 6 ) failed to achieve sufficient correction of pt and aptt initially so they had to increase doses of vitamin k1 administration .
repeated prolongation of pt and aptt due to hasty discontinuation was observed in 6 patients ( patient 1 , 2 , 3 , 4 , 6 , and 8) .
ffp was initially transfused to all of the patients , but repeated ffp transfusion with low doses of vitamin k1 failed to maintain normalization of pt and aptt in 4 patients ( patient 1 , 3 , 4 , and 6 ) .
three patients ( patient 1 , 4 , and 6 ) were completely discontinued vitamin k1 treatment , and their duration of vitamin k1 administration was 7.3 , 6.2 , and 3.3 months , respectively .
all of the patients recovered or are on recovering from pt and aptt prolongation without sequalae and there was no mortality . only a patient ( patient 5 ) received major surgical procedure , evacuation of hemoperitoneum .
he confessed that he ingested excessive amount of fluconazole , an anti fungal agent , but repeatedly denied superwarfarin ingestion even positive result of brodifacoum level test was reported .
it seems to be that he needed operation because of potentiated action of brodifacoum by drug interactions with the fluconazole .
the discovery of warfarin dates back to outbreaks of cattle death in the northern united states and canada in the 1920s ( 6 ) .
after isolation of the hemorrhagic compound in moldy silage which led to the death of the cattle , first generation anticoagulants including warfarin were introduced .
warfarin is now widely used as a therapeutic anticoagulant , but its use as a rodenticide has declined because many rat populations have developed resistance to it ( 6 ) . to overcome this resistance , second generation anticoagulants ,
they are highly lipid soluble and about 100 times more potent than warfarin because of the phenyl groups replacing the terminal methyl group in the structure ( 7 ) . in a field test ,
1 - 2 days feeding of brodifacoum was sufficient to achieve complete mortality in most of rodent species , compared to 21 days of warfarin ( 8) . the reported half life of brodifacoum in humans is much longer than that of warfarin ( 16 - 36 days vs 17 - 37 hr ) ( 9 ) .
the most common clinical feature of superwarfarin intoxication is bleeding , and this can occur from any mucosal site or organ .
various symptoms of bleeding were reported in the literatures ( 1 , 3 , 4 , 9 - 17 ) as in our study .
superwarfarin intoxication should be suspected in any patient who presents with a suspicious history and marked prolongation of both pt and aptt without advanced liver disease or congenital coagulation factor deficiency .
mixing studies result in complete correction of pt and aptt due to lack of inhibitors . measuring the activity of vitamin k dependent coagulation factors ( factor ii , vii , ix , and x ) , plasma vitamin k levels , or pivka - ii can be helpful in narrowing down the differential diagnosis .
the definitive diagnosis is made by superwarfarin blood level testing with high performance liquid chromatography ( hplc ) an accurate and effective way of determining the presence and concentration of superwarfarin .
recent advances in hplc technology has made considerably accurate and rapid diagnosis possible ( 18 ) , but such technology is not yet easily accessible in korea . in our study , although one patient ( patient 2 ) was highly suspicious for superwarfarin intoxication and she even confessed ingestion , a negative result was reported .
( 9 ) evaluated half - life of brodifacoum in 3 patients with superwarfarin intoxication by measuring serial serum brodifacoum concentrations .
they reported the half - life ranged from 16 to 36 days in 3 patients and serum brodifacoum had been no longer detected after 2 months from the time of initial diagnosis , although bleeding tendency continued more than 100 days .
considering of their result , serum brodifacoum level in the patient of our study might be decreased to undetectable range at the time of sample request , as superwarfarin level test had been requested about 100 days after initial symptom presentation by her physician .
oral vitamin k1 is preferred to intramuscular or intravenous injection , as it avoids hematoma formation and hypersensitivity reactions .
an optimal dose and duration of vitamin k1 therapy has yet to be established ( 19 ) .
however , most previous studies support multiple , prolonged , and high dose vitamin k1 supplementation ( 1 , 14 - 16 , 19 ) . as the half - life of vitamin k1 is 6 hr ( 7 ) , multiple divided doses of vitamin k1 has the advantage of maintaining therapeutic effect
. prolonged use of high dose vitamin k1 is necessary as the half - life of superwarfarins is substantially long ( 9 ) .
early tapering or discontinuation will result in repeat prolongation of pt and aptt even after normal levels have been achieved ( 12 ) .
this repeat prolongation due to hasty discontinuation was observed in 6 of our patients ( patient 1 , 2 , 3 , 4 , 6 , and 8) and in previous reports ( 10 , 14 ) .
a phased and prudent tapering of vitamin k1 with regular follow up is thus mandatory ( 15 ) . in a case
series of 9 patients in taiwan ( 16 ) , treatment duration ranged from 72 to 185 days .
table 2 shows the doses and durations of vitamin k1 therapy performed in our study and several previous reports . in a situation of emergency due to bleeding , transfusion of coagulation factors
is effective , although the effect of this will be transient because of long half - life of superwarfarin .
urgent treatment with vitamin k1 and transfusion of coagulation factors based on clinical suspicion alone is justified because most detailed laboratory tests require several days to weeks . identifying the source of exposure is sometimes challenging in patients who deny ingestion of superwarfarin .
after stabilization of symptoms , psychiatric interview should be recommended for patients in whom intentional administration is highly suspected as patient 2 of this study .
we were unable to definitively identify the route of intoxication in 8 of the patients in this study .
environmental exposure was a possible cause in 3 patients ( patients 4 , 7 , and 10 ) considering their occupations .
as these patients had no symptoms or history of mental illness , and taking into account the potency , lipid solubility and long - half life of superwarfarin , we can cautiously consider transdermal absorption and inhalation as potential routes of their superwarfarin exposure .
such possibilities were highlighted in a previous report on 2 patients who worked in superwarfarin manufacture ( 3 ) .
the incidence of superwarfarin intoxication should be surveyed nationwide in light of these recent cases .
supervision for rodenticide use and education of people who deal with rodenticides in their workplace are also necessary , along with further scientific research to achieve more accurate diagnosis and treatment of superwarfarin intoxication . in conclusion ,
early suspicion with a prompt request of serum brodifacoum test and sufficient dose and duration of vitamin k1 therapy is necessary for effective treatment of superwarfarin intoxication .
further detailed investigation on the possibility and the actual condition of environmental exposure , and improving availability of the blood level test is mandatory .
 this observational study aimed at evaluating recent superwarfarin intoxication of korean patients . 
 ten patients were diagnosed as or highly suspicious for superwarfarin intoxication . 
 case report forms described by attending hematologists of the patients were collected and analyzed . 
 bleeding symptoms were varied among the patients . 
 patients uniformly showed prolonged prothrombin time ( pt ) and activated thromboplastin time ( aptt ) with decreased activity of vitamin k dependent coagulation factors . 
 positive serum brodifacoum test results in 4 of 5 requested patients contributed to confirmatory diagnosis . 
 psychiatric interview revealed an attempted ingestion in one patient . 
 high dose vitamin k1 therapy promptly corrected prolonged pt and aptt , but hasty discontinuation caused repeated bleeding diathesis in 6 patients . 
 route of intoxication was unknown or not definite among 8 of 10 patients . 
 three patients had a possibility of environmental exposure considering their occupations : there might be intoxication by transdermal absorption or inhalation . therefore , high dose and prolonged use of vitamin k1 therapy is necessary for effective detoxification . 
 further detailed investigation on environmental exposure and efforts to improve availability of the blood level test in clinic are requested . 
INTRODUCTION
MATERIALS AND METHODS
Ethics statement
RESULTS
Patient characteristics, symptoms and diagnoses
Treatment
DISCUSSION