B64-01 Refractory Venous Thromboembolism and Pulmonary Embolism Despite Multiple Anticoagulants: Multifactorial Anticoagulation Failure Involving Vkorc1 Resistance, Impaired Fibrinolysis, and Extreme Obesity

Abstract Background Recurrent venous thromboembolism (VTE) despite guideline-directed anticoagulation is uncommon and usually reflects overlapping resistance mechanisms rather than a single thrombophilic disorder. This report describes a patient with pharmacogenetic warfarin resistance, impaired fibrinolysis, and extreme obesity who developed new thrombosis while receiving combination antithrombotic therapy. Case Presentation A middle-aged woman with morbid obesity, metabolic comorbidities, and prior cerebral venous thrombosis, deep venous thromboses, and pulmonary emboli was followed for refractory thrombophilia. She had previously experienced recurrent clotting events while on multiple anticoagulants, including warfarin, low-molecular-weight heparin, and direct oral agents. Because of repeated failure, she was managed in the outpatient setting on a regimen combining fondaparinux and dual antiplatelet therapy. Genetic evaluation revealed a variant in VKORC1 consistent with reduced warfarin sensitivity and a PAI-1 4G/4G promoter polymorphism associated with impaired fibrinolysis. Other hypercoagulable and myeloproliferative studies were unremarkable. Despite this intensified regimen, she was later hospitalized with acute dyspnea and new lower-extremity pain. Imaging confirmed fresh femoral vein thrombosis and high suspicion for probable pulmonary embolism superimposed on chronic thromboembolic disease. Given refractoriness to all pharmacologic options, she was referred potential interventional therapy. Discussion VKORC1 polymorphism causes pharmacologic warfarin resistance rather than intrinsic hypercoagulability, while PAI-14G/4G contributes to delayed fibrinolysis and prolonged clot persistence. In the setting of severe obesity and venous stasis, these mechanisms produced complete anticoagulation failure. Recognition of such multifactorial resistance is critical for implementing genotype-guided therapy, alternative drug strategies, and early referral for mechanical or surgical approaches. Conclusion This case highlights the importance of recognizing multifactorial anticoagulation failure, where genetic resistance, impaired fibrinolysis, and extreme obesity converge to produce recurrent thrombosis despite optimal therapy This abstract is funded by: None