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Vol. 5 No. 3 (2026): In memory of Armando D’Angelo
The expanded universe of thrombin: a comprehensive review of its hemostasis-independent roles and structure-function relationships
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 28 August 2026
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Thrombin, the central protease of the coagulation cascade, has long been recognized for its essential role in hemostasis, converting fibrinogen to fibrin and activating platelets. However, a growing body of evidence over the past two decades has firmly established thrombin as a pluripotent mediator operating at the intersection of coagulation, inflammation, immunity, and tissue repair. This manuscript provides a comprehensive review of the hemostasis- and coagulation-independent functions of thrombin, integrating updated evidence with the sophisticated structure-function relationships that govern these diverse activities. We explore the molecular basis of thrombin’s versatility, focusing on its allosteric regulation by sodium ions, its two anion-binding exosites, and its primary signaling mechanism via protease-activated receptors. The discussion extends to thrombin’s critical roles in neurobiology, where it exhibits a dualistic nature in stroke and neurodegeneration, its profound influence on inflammation and immunity, and its paradoxical involvement in cancer progression and angiogenesis. Furthermore, we highlight emerging concepts, including the discovery of its tissue-specific roles. Understanding these multifaceted functions is crucial for developing targeted therapeutic strategies that can modulate thrombin’s pathological actions without compromising its essential hemostatic functions.
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CRediT authorship contribution
SL, MS, AF, and LDG provided thoughts and insight into thrombin function, controlled the bibliographic references and revised the manuscript, RDC designed and wrote the paper.
Data Availability Statement
The datasets used and/or analyzed during the current study are available upon reasonable request from the corresponding author.
How to Cite
1.
Sacco M, Lancellotti S, Ferretti A, Basso M, Di Gennaro L, De Cristofaro R. The expanded universe of thrombin: a comprehensive review of its hemostasis-independent roles and structure-function relationships. Bleeding Thromb Vasc Biol [Internet]. 2026 Aug. 28 [cited 2026 Sep. 17];5(3). Available from: https://www.btvb.org/btvb/article/view/462
Copyright (c) 2026 The Author(s)
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