Case Presentation: A 77-year-old female with recently diagnosed atrial fibrillation was discharged on warfarin for anticoagulation. Five days later, she returned with chest discomfort and dyspnea. Electrocardiography showed atrial fibrillation with rapid ventricular response and a new right bundle branch block. Her INR had increased markedly from 1.4 at discharge to 14.1, despite reported ingestion of only two warfarin doses. Her hospitalization was complicated by cardiogenic shock requiring critical care support. Warfarin was discontinued, and she received intravenous vitamin K and fresh frozen plasma, resulting in an improvement of her INR to 2.9. Given the severity and rapidity of INR elevation, hematology pursued pharmacogenomic testing. Results demonstrated complete loss of CYP2C9 enzymatic function along with a VKORC1 promoter variant associated with increased warfarin sensitivity, providing a mechanistic explanation for her profound anticoagulant response. She was transitioned to an alternative anticoagulant with stable follow-up.
Discussion: This case illustrates a rare but clinically important example of extreme warfarin hypersensitivity due to compound pharmacogenomic variants. Although CYP2C9 and VKORC1 polymorphisms account for a substantial portion of interindividual variability in warfarin dose requirements, complete loss-of-function CYP2C9 alleles are uncommon and can produce exaggerated anticoagulation even after minimal exposure. When combined with VKORC1 promoter variants, these genotypes may yield responses that resemble warfarin overdose despite appropriate or even conservative dosing. The case also highlights several important implications for hospital medicine. Hospitalists frequently manage anticoagulation initiation, interpret unexpected INR derangements, and coordinate urgent reversal when necessary. As the frontline clinicians evaluating rapidly evolving therapeutic responses, hospitalists play a central role in distinguishing between dosing errors, hepatic impairment, drug–drug interactions, acute illness effects, and genetically mediated hypersensitivity. Early recognition of disproportionate INR responses, as in this case, is essential to preventing catastrophic bleeding complications. In select scenarios, particularly those involving rapid escalation of INR with minimal warfarin exposure, pharmacogenomic testing can provide diagnostic clarity and guide safer therapeutic decision-making. Although not yet routinely incorporated into inpatient workflows, genotype-guided evaluation may be increasingly relevant as hospital medicine continues to intersect with precision-based approaches to drug safety.
Conclusions: Compound CYP2C9 and VKORC1 variants can cause profound warfarin sensitivity and severe INR elevation shortly after therapy initiation. When anticoagulation responses are discordant with expected pharmacologic patterns, clinicians should consider pharmacogenomic variability in the differential diagnosis. This case underscores the importance of prompt recognition, coordinated reversal strategies, and the potential value of genotype-informed management in improving anticoagulation safety within the inpatient setting.