Enhanced Bleeding Risk in an Elderly Dementia Patient Treated With Warfarin and Quetiapine

A 74-year-old man was treated with quetiapine 400 mg/day for 3 years for vascular dementia with severe delusions of reference and persecution. His medical history revealed hypertension. Magnetic resonance imaging of the brain showed many small infarctions of the white matter and bilateral basal ganglia. He developed peripheral deep-vein thrombosis, and warfarin was started at a daily dose of 1.25 mg/day for 1 month. His baseline PT/ aPTT and INR were maintained at a steady level before warfarin was used (INR:1.1). Because of severe psychotic symptoms, he was admitted to an inpatient ward. Admission laboratory studies revealed prolonged PT/ aPTT (25.4 sec/64.4 sec; reference: 10–14 sec./23.9–35.5 sec.) and INR (3.9). We then switched the atypical antipsychotics from quetiapine to sulpiride 200 mg/day, stopped warfarin, and supplied vitamin K 30 mg/day due to the high risk of bleeding. Ten days later, his PT/aPTT and INR returned to normal. He was then restarted on his original dose of warfarin. He was discharged on sulpiride 200 mg/day and warfarin 1.25 mg/day with a therapeutic PT/INR level and normal aPTT.

Although there are two previous case reports about coagulopathy related to a warfarin–quetiapine interaction,^1,2 our case is the first one whose PT/INR level went beyond the therapeutic window for warfarin, and prolonged aPTT was also noted. This meant that both extrinsic and intrinsic coagulant pathways were affected, thus enhancing the bleeding risk for the patient. Several conditions can induce both PT and aPTT prolongation; these include warfarin overdose, disseminated intravascular coagulation, liver failure, and factor V or X deficiency, but none of these was observed in our case.

Two hypotheses may explain the coagulopathy related to a warfarin–quetiapine interaction. Both warfarin (99%) and quetiapine (83%) are bound to plasma protein.^3,4 Both drugs are also competitive inhibitors of the cytochrome P450 system, including CYP3A4 and CYP2C9.^3,4 When compared with the previous two cases, our patient took a larger dose of quetiapine (400 mg versus 200 mg and 12.5 mg) for a longer time use (1 month versus 2 weeks, 3 days). Therefore, the plasma warfarin increase might have been higher and thus affected the intrinsic coagulant pathway with prolonged aPTT. We also confirmed that sulpride could be safely used with warfarin because of its low protein-binding (40%) and minimal metabolism through the CYP system.⁵

Polypharmacy is a critical issue for general hospital and geriatric psychiatry. Even rare drug-drug interactions may result in complicated situations. We should exercise caution in using quetiapine with warfarin; frequent monitoring of PT/PTT/INR is necessary if we prescribe such drugs. More studies are needed to clarify the warfarin-quetiapine interaction.