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The aims of this case-control study were to identify in vitamin K antagonist (VKA)-treated unselected patients, factors associated with international normalised ratio (INR) values: (i) greater than 6.0.; and (ii) ranging from 4.0 to 6.0 complicated with bleeding. We also assessed VKA-related morbidity in these patients. During a two-month period, 4,188 consecutive and unselected patients were referred to our Emergency Department. At admission, the medical records of each patient and two age- and sex-matched controls were reviewed for: both duration and indication of VKA therapy, previous medical history of VKA-related haemorrhage, underlying co-morbidities, concomitant medications other than VKA, duration of hospitalization and deaths' causes. Of these 4,188 subjects, 50 case-patients (1.19%) were identified; both case-patients and controls did not differ as regards indications and patterns of VKA therapy. Interestingly, two-thirds of case-patients were women, suggesting that female gender may be a risk factor of VKA over-coagulation onset. We identified the following risk factors of VKA over-coagulation: previous medical history of INR levels over therapeutic range, therapy with antibiotics, amiodarone and proton pump inhibitors, as well as fever. A total of 88% of case-patients were hospitalized; mean duration of patients' hospitalization was seven days [range: 1-56 days]; no patient died from major bleeding. Our study underscores that it is of utmost importance to consider the strength of indication before starting VKA therapy, as this therapy has been responsible for as high as 1.19% of admissions in unselected subjects referred to an Emergency Department. Our data therefore suggest that internists should be aware of VKA-related high morbidity, particularly in situations at risk of VKA over-coagulation.