The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke
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REVIEW ARTICLE
The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke Fenghui Ye 1 & Hugh J. L. Garton 1 & Ya Hua 1 & Richard F. Keep 1 & Guohua Xi 1 Received: 24 July 2020 / Revised: 22 September 2020 / Accepted: 23 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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 longterm 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. Keywords Thrombin . Thrombin receptors . Cerebral hemorrhage . Cerebral ischemia . Intraventricular hemorrhage . Neuroinflammation . Subarachnoid hemorrhage
Introduction Thrombin, a serine protease, is generated by cleavage during activation of the coagulation cascade to provide hemostasis. Thrombin generation and the coagulation cascade has long been a target for preventing ischemic stroke (e.g., warfarin). More recently, direct thrombin inhibitors are being used clinically (e.g., dabigatran). However, thrombin has many actions outside those directly related to hemostasis that impact cerebrovascular disease, the subject of this review. Prothrombin is predominantly produced by the liver and circulates in the bloodstream until it is cleaved into the active form of thrombin by Factor Xa [1]. However, prothrombin
* Guohua Xi [email protected] 1
Department of Neurosurgery, University of Michigan, R5018 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
can also be produced by neurons and astrocytes [2, 3]. The physiological functions of this brain-derived thrombin are mostly unknown, although there is evidence of its roles in b
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