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The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke

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Abstract

Thrombin is increased in the brain after hemorrhagic and ischemic stroke primarily due to the prothrombin entry from blood either with a hemorrhage or following blood-brain barrier disruption. Increasing evidence indicates that thrombin and its receptors (protease-activated receptors (PARs)) play a major role in brain pathology following ischemic and hemorrhagic stroke (including intracerebral, intraventricular, and subarachnoid hemorrhage). Thrombin and PARs affect brain injury via multiple mechanisms that can be detrimental or protective. The cleavage of prothrombin into thrombin is the key step of hemostasis and thrombosis which takes place in every stroke and subsequent brain injury. The extravascular effects and direct cellular interactions of thrombin are mediated by PARs (PAR-1, PAR-3, and PAR-4) and their downstream signaling in multiple brain cell types. Such effects include inducing blood-brain-barrier disruption, brain edema, neuroinflammation, and neuronal death, although low thrombin concentrations can promote cell survival. Also, thrombin directly links the coagulation system to the immune system by activating interleukin-1α. Such effects of thrombin can result in both short-term brain injury and long-term functional deficits, making extravascular thrombin an understudied therapeutic target for stroke. This review examines the role of thrombin and PARs in brain injury following hemorrhagic and ischemic stroke and the potential treatment strategies which are complicated by their role in both hemostasis and brain.

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Funding

YH, RFK, and GX are supported by grants NS-096917, NS-106746, NS-112394, and NS116786 from the National Institutes of Health (NIH).

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  1. Department of Neurosurgery, University of Michigan, R5018 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA

    Fenghui Ye, Hugh J. L. Garton, Ya Hua, Richard F. Keep & Guohua Xi

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Ye, F., Garton, H.J.L., Hua, Y. et al. The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke. Transl. Stroke Res. 12, 496–511 (2021). https://doi.org/10.1007/s12975-020-00855-4

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