Replacement of key components of the circulatory system with artificial devices has become the mainstay of therapy for conditions such as end-stage valvular disease or congestive heart failure. Unfortunately, device thrombosis and thromboembolic morbidity persist despite optimized anticoagulation. This work reviews the commonly known causes of device-associated thrombophilia, introduces recent literature concerning the effect of carbon monoxide on coagulation, and presents new patient data linking endogenously produced carbon monoxide with device-associated thrombosis. A new paradigm involving the interaction of red blood cell lysis-induced upregulation of hemoxygenase-1, increased endogenous carbon monoxide, hyperfibrinogenemia, and contact protein/microparticle-induced thrombin generation is presented.