Challenging Anticoagulation With Warfarin and Heparin Following Mechanical Mitral Valve Replacement in a Patient With Infective Endocarditis: A Case Report Highlighting Diagnostic Difficulties

Warfarin remains the cornerstone of anticoagulation therapy following mechanical heart valve replacement. However, challenging anticoagulation responses, resistance to warfarin, and even more rarely to both warfarin and heparin pose significant clinical challenges and complicate management strategies. We describe a 44-year-old male with infective endocarditis who underwent mechanical mitral valve replacement. Post-operatively, despite escalating warfarin doses up to 90 mg/day 15 mg/day, the patient's INR remained persistently subtherapeutic (maximum 1.67), his INR remained below therapeutic levels. A switch to low-molecular-weight heparin also failed to achieve adequate anticoagulation was initiated, but due to unavailability of anti-Xa monitoring, its effectiveness could not be objectively assessed; clinically, there was evidence of ongoing thrombotic risk. Compliance, drug interactions, dietary influences, and malabsorption were considered and excluded. Pharmacogenetic testing and serum warfarin levels were unavailable locally. Definitive testing for pharmacogenetic mutations, serum warfarin levels, and antithrombin III activity was not available at our institution, representing key limitations. This case illustrates an extremely rare instance of dual anticoagulant resistance profound challenges in achieving therapeutic anticoagulation with two standard agents, highlighting the need for a structured diagnostic algorithm including compliance verification, pharmacokinetic and pharmacodynamic assessment, consideration of genetic testing (VKORC1, CYP2C9), and evaluation for antithrombin deficiency. Alternative vitamin K antagonists or direct oral anticoagulants may be considered in select refractory cases, although evidence for their use in mechanical valves is lacking. Alternative vitamin K antagonists (e.g., acenocoumarol) may be considered in refractory cases, but direct oral anticoagulants are strictly contraindicated in mechanical valves based on the RE-ALIGN trial. Clinicians should maintain a high index of suspicion for challenging anticoagulant response resistance when INR remains subtherapeutic despite high doses and evaluate all possible etiologies systematically. This case expands current understanding of refractory anticoagulation following valve replacement and highlights the diagnostic limitations faced in resource-constrained settings.