Fibrinolytic Therapy for Thromboembolic Diseases: Approved Indications and Future Directions (JACC September 2025-2)-Article: Fibrinolytic Therapy for Thromboembolic Diseases: Approved Indications and Future Directions

Article: Fibrinolytic Therapy for Thromboembolic Diseases: Approved Indications and Future Directions

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This state-of-the-art review in the Journal of the American College of Cardiology comprehensively discusses fibrinolytic therapy for thromboembolic diseases, covering its historical development, established uses, evolving roles, and future directions.<br /><br />Fibrinolytic agents act by converting plasminogen to plasmin, leading to fibrin degradation and vessel recanalization. Since the discovery of streptokinase in 1933, several agents such as urokinase, tissue plasminogen activator (tPA, including derivatives alteplase, tenecteplase, and reteplase) have been developed and approved with varying clinical indications.<br /><br />Current approved uses include:<br /><br />- ST-segment elevation myocardial infarction (STEMI): Primary percutaneous coronary intervention (PCI) is preferred. Fibrinolysis is indicated when PCI cannot be performed within 120 minutes after first medical contact, with agents like alteplase, tenecteplase, or reteplase.<br /><br />- Pulmonary embolism (PE): Systemic fibrinolysis is standard for hemodynamically unstable (high-risk) PE but underused due to bleeding risks, especially intracranial hemorrhage. Catheter-directed fibrinolysis at lower doses is under study for intermediate-risk PE to improve safety and efficacy.<br /><br />- Acute ischemic stroke: Intravenous alteplase and tenecteplase are front-line therapies within 4.5 hours of symptom onset, with extended windows guided by advanced neuroimaging in select patients. Tenecteplase shows comparable or slightly superior efficacy and easier administration.<br /><br />- Deep vein thrombosis (DVT): Systemic fibrinolysis is not routine due to bleeding risk. Catheter-directed fibrinolysis may reduce post-thrombotic syndrome in select patients with extensive proximal DVT but with cautious bleeding risk assessment.<br /><br />- Acute limb ischemia: Catheter-directed fibrinolysis is an alternative to surgery for salvageable limbs, though major bleeding risk exists. Ultraslow, low-dose regimens and ultrasound-accelerated methods show promise.<br /><br />Other uses include central venous access device (CVAD) occlusion, mechanical prosthetic valve thrombosis (MPVT), left ventricular thrombus, left ventricular assist device (LVAD) thrombosis, central retinal artery occlusion, and cerebral venous sinus thrombosis. Evidence varies, often limited to observational data or smaller trials.<br /><br />Safety remains a critical concern due to hemorrhagic complications. Strategies like reduced dosing, catheter-directed delivery, and novel fibrinolytic agents aim to optimize benefit-risk balance.<br /><br />Future directions include novel agents targeting fibrinolysis regulators (e.g., alpha-2 antiplasmin inhibitors), improved delivery systems (e.g., nanocarriers), and personalized risk stratification. Ongoing randomized controlled trials are evaluating new regimens and indications.<br /><br />Notably, there is underrepresentation of women, elderly, and minorities in fibrinolytic therapy trials, limiting applicability. Enhanced diversity in research is needed.<br /><br />In summary, fibrinolytic therapy remains essential for select thromboembolic conditions with evolving applications. Advances in agents, delivery, and patient selection promise safer, more effective treatment to improve outcomes in thromboembolic diseases.

Keywords

fibrinolytic therapy

thromboembolic diseases

streptokinase

tissue plasminogen activator

STEMI

pulmonary embolism

acute ischemic stroke

deep vein thrombosis

catheter-directed fibrinolysis

hemorrhagic complications