The expanded universe of thrombin: a comprehensive review of its hemostasis-independent roles and structure-function relationships

Abstract

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.