The fibrinolytic system in disease: From molecular pathways to clinical outcomes

The fibrinolytic system, essential in maintaining hemostatic balance, tightly regulates blood clot dissolution through a complex interplay of activators (e.g., t-PA, u-PA), inhibitors (e.g., PAI-1, α2-antiplasmin), and modulators such as thrombin-activatable fibrinolysis inhibitor (TAFI). Dysregulation of fibrinolysis contributes significantly to various pathological states. In liver diseases, alterations in fibrinolytic proteins, including elevated tissue plasminogen activator (t-PA) and reduced plasminogen activator inhibitor-1 (PAI-1), predispose patients variably toward bleeding or thrombosis, with clinical implications for management in liver transplantation and cirrhosis. In cardiovascular disease, impaired fibrinolysis, characterized by increased clot density and elevated PAI-1, associates with heightened risks of myocardial infarction, stroke, and peripheral arterial disease, driving current therapeutic strategies toward enhancing fibrinolytic potential. Sepsis frequently induces fibrinolytic shutdown, driven by elevated PAI-1 and TAFI, exacerbating microthrombosis, disseminated intravascular coagulation (DIC), and organ dysfunction, emerging therapeutic targets include PAI-1 modulation. In trauma, fibrinolytic dysregulation manifests as either hyperfibrinolysis, primarily induced by shock-associated elevations in t-PA, or fibrinolysis shutdown, often following severe tissue injury, each demanding distinct therapeutic approaches such as timely antifibrinolytic administration (tranexamic acid) or experimental profibrinolytic treatments. This review highlights critical insights into fibrinolytic mechanisms across these clinical conditions, advocating further research toward refining diagnostics, personalized interventions, and targeted modulation of the fibrinolytic system to optimize clinical outcomes.