Venous thromboembolism is not associated with plasmin(ogen): Re-evaluating plasmin and mechanisms that degrade fibrin

The plasminogen activation and plasmin activity (PA) system is a central mechanism for degrading fibrin and has long been viewed as essential for preventing venous thrombosis/thromboembolism. However, clinical and experimental data challenge this paradigm. Here, we examine evidence that reduced PA does not predispose individuals to venous thrombosis/thromboembolism. We discuss potential mechanisms that may rationalize this apparent paradox, including compensatory vascular and inflammatory pathways that may degrade intravascular fibrin. These data suggest venous thromboembolism is a multifactorial disease in which impaired fibrinolysis is neither necessary nor sufficient to drive thrombosis. We also discuss alternate biological roles of the PA system. Reframing the role of the PA system has important implications for developing therapies that modulate fibrinolysis. A more nuanced understanding of PA biology may enable strategies that balance bleeding risk with efficient clot resolution.