Beyond conventional mechanisms of prosthetic valve thrombosis: immune, genetic, hematologic, hormonal, and hemodynamic perspectives.

Mechanical prosthetic valve thrombosis (PVT) remains a serious and potentially life-threatening complication of valve replacement therapy. While subtherapeutic anticoagulation and mechanical factors are well-established drivers of PVT, a growing body of evidence indicates that these conventional explanations are insufficient in a substantial subset of patients. Clinicians increasingly encounter PVT despite therapeutic anticoagulation, stable rhythm control, and technically satisfactory prosthesis implantation, suggesting the involvement of additional, less-recognized mechanisms. This review synthesizes current evidence on underrecognised contributors to mechanical PVT, encompassing immune-mediated processes, genetic and molecular susceptibility, dynamic hematologic and biochemical states, hormonal and physiologic conditions, and localized haemodynamic disturbances at the prosthesis-tissue interface. Immune dysregulation, including antiphospholipid antibodies, heparin-induced thrombocytopenia, antifibrinolytic autoantibodies, and hypereosinophilia, may amplify platelet activation and impair fibrinolysis independently of anticoagulation intensity. Genetically determined modifiers such as prothrombotic gene polymorphisms, and protein Z-related pathways, further influence thrombotic propensity. In parallel, transient physiologic states (pregnancy) and highly localized haemodynamic abnormalities, such as paravalvular leaks, may serve as important local triggers for thrombus formation. By integrating these mechanisms into a unified conceptual framework, this review highlights the limitations of an anticoagulation-centered paradigm and supports a more individualized, mechanism-oriented approach to the diagnosis and prevention of unexplained or recurrent PVT.