Marked supratherapeutic anticoagulation following S-1 therapy despite low-dose warfarin in a postgastrectomy Japanese patient: a case report highlighting sequential pharmacokinetic and pharmacodynamic risk factors

Abstract Background The interaction between warfarin and fluoropyrimidines is well established; however, the clinical circumstances in which this interaction progresses to marked supratherapeutic anticoagulation, particularly in patients receiving low doses of warfarin, remain insufficiently characterized. We report a case illustrating how a low warfarin dose requirement and treatment-emergent clinical changes may converge to increase anticoagulant response during and after S-1 therapy. Case presentation A 69-year-old Japanese man with advanced gastric cancer had received warfarin for 5 years for a left ventricular thrombus. After distal gastrectomy, warfarin was maintained at 1.0 mg/day with long-term amiodarone 75 mg/day. At initiation of SOX therapy, the S-1 dose was reduced from the planned body-surface-area-based dose of 120 mg/day to 100 mg/day because of impaired renal function; estimated creatinine clearance was 46.5 mL/min. On day 13, estimated creatinine clearance transiently decreased to 41.1 mL/min, and fever, diarrhea, and anorexia developed. S-1 was completed on day 14, but diarrhea and anorexia persisted. The patient subsequently developed epistaxis and melena. On day 22, the prothrombin time-International Normalized Ratio (PT-INR) exceeded the institutional upper reportable limit (> 8.0), and the hemoglobin level decreased to 7.4 g/dL. Warfarin was discontinued, and menatetrenone was administered. Pharmacogenetic testing showed CYP2C9 rs1057910 A/A ( CYP2C9*3 non-carrier), VKORC1 rs9923231 A/A, CYP4F2 rs2108622 C/C, and GGCX rs699664 G/G. Conclusions This case highlights that marked S-1-associated supratherapeutic anticoagulation can occur despite both a low warfarin dose and a reduced S-1 dose. A low warfarin dose requirement, impaired renal function during S-1 exposure, and persistent gastrointestinal symptoms may act as sequential clinical risk factors. PT-INR monitoring should be intensified when such changes occur and continued after S-1 discontinuation.