Fibrinolytic Therapy for Thromboembolic Diseases: Approved Indications and Future Directions

Sina Rashedi¹, Hannah Leyva¹, Nada Hamade¹, Mariana B Pfeferman¹, Luis Ortega-Paz², Parham Sadeghipour³, Azita H Talasaz⁴, Michelle L O'Donoghue⁵, David Jimenez⁶, Manuel Monrea⁷, Christopher D Anderson⁸, Mitchell S V Elkind⁹, Irene M Lang¹⁰, Jeffery I Weitz¹¹, Samuel Z Goldhaber¹², Raffaele De Caterina¹³, Stavros V Konstantinides¹⁴, Gregory Piazza¹², Harlan M Krumholz¹⁵, Eugene Braunwald⁵, Behnood Bikdeli¹⁶

Affiliations

¹ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
² Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA.
³ Vascular Disease and Thrombosis Research Center, Rajaie Cardiovascular Institute, Tehran, Iran; Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran.
⁴ Department of Pharmacotherapy & Outcomes Sciences, Virginia Commonwealth University, Richmond, Virginia, USA; Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Department of Pharmacy Practice, Long Island University, New York, New York, USA; Department of Pharmacy, New York-Presbyterian Hospital, Columbia University Medical Center, New York, New York, USA.
⁵ TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Respiratory Department, Hospital Ramón y Cajal (IRYCIS), Madrid, Spain; Medicine Department, Universidad de Alcalá (IRYCIS), Madrid, Spain; CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain.
⁷ Thromboembolic Disorders, Facultad de Medicina, Universidad Catolica San Antonio de Murcia, Murcia, Spain.
⁸ Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Boston, Massachusetts, USA; McCance Center for Brain Health, Mass General Brigham, Boston, Massachusetts, USA; Department of Neurology, Mass General Brigham, Boston, Massachusetts, USA.
⁹ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
¹⁰ Department of Internal Medicine II, Cardiology and Center of Cardiovascular Medicine, Medical University of Vienna, Vienna, Austria.
¹¹ Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
¹² Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹³ University Cardiology Division, Pisa University Hospital, Pisa, Italy; Postgraduate School of Cardiology, University of Pisa, Pisa, Italy; Fondazione Villa Serena per la Ricerca, Città Sant'Angelo, Pescara, Italy.
¹⁴ Center for Thrombosis and Haemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.
¹⁵ YNHH/ Yale Center for Outcomes Research and Evaluation (CORE), New Haven, Connecticut, USA; Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut, USA.
¹⁶ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; YNHH/ Yale Center for Outcomes Research and Evaluation (CORE), New Haven, Connecticut, USA. Electronic address: bbikdeli@bwh.harvard.edu.

PMID: 41033744
DOI: 10.1016/j.jacc.2025.07.061

Review

Fibrinolytic Therapy for Thromboembolic Diseases: Approved Indications and Future Directions

Sina Rashedi et al. J Am Coll Cardiol. 2025.

. 2025 Oct 7;86(14):1065-1087.

doi: 10.1016/j.jacc.2025.07.061.

Authors

Affiliations

¹ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
² Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA.
³ Vascular Disease and Thrombosis Research Center, Rajaie Cardiovascular Institute, Tehran, Iran; Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran.
⁴ Department of Pharmacotherapy & Outcomes Sciences, Virginia Commonwealth University, Richmond, Virginia, USA; Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Department of Pharmacy Practice, Long Island University, New York, New York, USA; Department of Pharmacy, New York-Presbyterian Hospital, Columbia University Medical Center, New York, New York, USA.
⁵ TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Respiratory Department, Hospital Ramón y Cajal (IRYCIS), Madrid, Spain; Medicine Department, Universidad de Alcalá (IRYCIS), Madrid, Spain; CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain.
⁷ Thromboembolic Disorders, Facultad de Medicina, Universidad Catolica San Antonio de Murcia, Murcia, Spain.
⁸ Program in Medical and Population Genetics, Broad Institute of Harvard and the Massachusetts Institute of Technology, Boston, Massachusetts, USA; McCance Center for Brain Health, Mass General Brigham, Boston, Massachusetts, USA; Department of Neurology, Mass General Brigham, Boston, Massachusetts, USA.
⁹ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
¹⁰ Department of Internal Medicine II, Cardiology and Center of Cardiovascular Medicine, Medical University of Vienna, Vienna, Austria.
¹¹ Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; Department of Medicine and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
¹² Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹³ University Cardiology Division, Pisa University Hospital, Pisa, Italy; Postgraduate School of Cardiology, University of Pisa, Pisa, Italy; Fondazione Villa Serena per la Ricerca, Città Sant'Angelo, Pescara, Italy.
¹⁴ Center for Thrombosis and Haemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.
¹⁵ YNHH/ Yale Center for Outcomes Research and Evaluation (CORE), New Haven, Connecticut, USA; Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, USA; Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut, USA.
¹⁶ Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; YNHH/ Yale Center for Outcomes Research and Evaluation (CORE), New Haven, Connecticut, USA. Electronic address: bbikdeli@bwh.harvard.edu.

PMID: 41033744
DOI: 10.1016/j.jacc.2025.07.061

Abstract

Fibrinolytic therapy plays a pivotal role in the management of thromboembolic diseases by promoting plasmin-mediated fibrin degradation and vessel recanalization, which frequently comes at the cost of increased risk of hemorrhagic events, including intracranial bleeding. Since the discovery of streptokinase in 1933, several additional fibrinolytic agents have been developed. Two plasminogen activators-urokinase and tissue plasminogen activator (tPA)-were identified in human samples. Through recombinant DNA technology, tPA was cloned and modified to produce alteplase. Subsequent efforts to prolong its plasma half-life led to the development of mutant derivatives such as tenecteplase and reteplase. Although fibrinolytic therapy in patients with ST-segment elevation myocardial infarction is currently restricted to those who cannot undergo primary percutaneous coronary intervention within 120 minutes of presentation, it has been a mainstay treatment for acute ischemic stroke and pulmonary embolism (PE) with hemodynamic compromise. Catheter-directed fibrinolysis has been evaluated in patients with intermediate-risk PE, deep vein thrombosis, acute limb ischemia, and after endovascular thrombectomy for ischemic stroke. Fibrinolytic agents have also been used in other clinically important indications, such as central venous access device thrombosis, mechanical prosthetic valve thrombosis, left ventricular assist device thrombosis, central retinal artery occlusion, cerebral venous sinus thrombosis, and left ventricular thrombus. This paper provides a comprehensive overview of the current applications, approved indications, evolving roles, and future directions of fibrinolytic agents in thromboembolic diseases.

Keywords: fibrinolytic agents; thromboembolism; thrombolytic therapy; thrombosis.

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Conflict of interest statement

Funding Support and Author Disclosures Dr O’Donoghue has received grants via Brigham and Women’s Hospital from Amgen, Novartis, and AstraZeneca; has received consulting and/or DSMB fees from Amgen, Novartis, AstraZeneca, Verve, New Amsterdam, and Novo Nordisk. Dr Jiménez is a member of the SC of the PEITHO-3 trial. Dr Monreal has received nonrestricted grants for research from Sanofi and Rovi. Dr Anderson is supported by grants from the National Institutes of Health and the American Heart Association; has received sponsored research support from Bayer AG; and is a member of the Editorial Board of Neurology. Outside the submitted work, Dr Elkind is a paid employee of the American Heart Association. Dr Lang has been an investigator in trials and/or has received consultancy fees, research grants, and membership of scientific advisory boards for AOP-Health, Actelion-Janssen, MSD, United Therapeutics, Pulnovo, Medtronic, Novo Nordisk, and Daiichi-Sankyo. Dr Konstantinides has received grants or contracts to his institution from Bayer AG, Daiichi-Sankyo, Boston Scientific Corp, Penumbra Inc, and Inari Medical; and has received personal consulting fees from Daiichi-Sankyo, Boston Scientific Corp, Inari Medical, and Penumbra Inc, all outside the submitted work. Dr Piazza has received research grants paid to his institution from BMS/Pfizer, Janssen, Alexion, Bayer, Amgen, BSC, Regeneron, and NIH (1R01HL164717-01); and has received consulting fees from BSC, Amgen, NAMSA, BMS/Pfizer, and Janssen. In the past 3 years, Dr Krumholz has received options for Element Science and Identifeye and payments from F-Prime for advisory roles; was a cofounder of and has held equity in Hugo Health; is a cofounder of and holds equity in Refactor Health and ENSIGHT-AI and is associated with research contracts through Yale University from Janssen, Kenvue, Novartis, and Pfizer. Dr Braunwald has received research grants through his institution from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and has consultancies with Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Edgewise, and Verve. Outside the submitted work, Dr Bikdeli has been supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814), has been supported by the Scott Schoen and Nancy Adams IGNITE Award, is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, and has been supported by the Heart and Vascular Center Junior Faculty Award from Brigham and Women’s Hospital; has been a consulting expert on behalf of the plaintiff for litigation related to 2 specific brand models of IVC filters; he has not been involved in the litigation in 2022 to 2025 nor has he received any compensation in 2022 to 2025; is a member of the Medical Advisory Board for the North American Thrombosis Forum (now VascuLearn Network); serves on the Data Safety and Monitoring Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute and Translational Sciences; is a collaborating consultant with the International Consulting Associates and the U.S. Food and Drug Administration in a study to generate knowledge about the utilization, predictors, retrieval, and safety of IVC filters; has received compensation as an Associate Editor for the New England Journal of Medicine, Journal Watch Cardiology, as an Associate Editor for Thrombosis Research, and as an Executive Associate Editor for JACC; is a Section Editor for Thrombosis and Haemostasis (no compensation). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Fibrinolytic Therapy for Thromboembolic Diseases: Approved Indications and Future Directions

Affiliations

Fibrinolytic Therapy for Thromboembolic Diseases: Approved Indications and Future Directions

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Affiliations

Abstract

Conflict of interest statement

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