Unfractionated heparin after TBI reduces in vivo cerebrovascular inflammation, brain edema and accelerates cognitive recovery

Abstract

BACKGROUND Severe traumatic brain injury (TBI) may increase the risk of venous thromboembolic complications; however, early prevention with heparinoids is often withheld for its anticoagulant effect. New evidence suggests low molecular weight heparin reduces cerebral edema and improves neurological recovery after stroke and TBI, through blunting of cerebral leukocyte (LEU) recruitment. It remains unknown if unfractionated heparin (UFH) similarly affects brain inflammation and neurological recovery post-TBI. We hypothesized that UFH after TBI reduces cerebral edema by reducing LEU-mediated inflammation and improves neurological recovery. METHODS CD1 male mice underwent either TBI by controlled cortical impact (CCI) or sham craniotomy. UFH (75 U/kg or 225 U/kg) or vehicle (VEH, 0.9% saline) was administered 2, 11, 20, 27, and 34 hours after TBI. At 48 hours, pial intravital microscopy through a craniotomy was used to visualize live brain LEUs interacting with endothelium and microvascular fluorescein isothiocyanate–albumin leakage. Neurologic function (Garcia Neurological Test, GNT) and body weight loss ratios were evaluated 24 and 48 hours after TBI. Cerebral and lung wet-to-dry ratios were evaluated post mortem. ANOVA with Bonferroni correction was used to determine significance (p < 0.05). RESULTS Compared to positive controls (CCI), both UFH doses reduced post-TBI in vivo LEU rolling on endothelium, concurrent cerebrovascular albumin leakage, and ipsilateral cerebral water content after TBI. Additionally, only low dose UFH (75 U/kg) improved GNT at both 24 and 48 hours after TBI. High dose UFH (225 U/kg) significantly increased body weight loss above sham at 48 hours. Differences in lung water content and blood pressure between groups were not significant. CONCLUSIONS UFH after TBI reduces LEU recruitment, microvascular permeability, and brain edema to injured brain. Lower UFH doses concurrently improve neurological recovery whereas higher UFH may worsen functional recovery. Further study is needed to determine if this is caused by increased bleeding from injured brain with higher UFH doses.

Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease

“…Several studies demonstrate that heparin-mediated inhibition of selectins occurs independently of anti-coagulation [ 60 , 91 ]. Consistent with these observations, studies of heparin in experimental TBI [ 86 ] note equivalent efficacy of low, non-anticoagulating heparin doses compared to higher doses with regard to leukocyte extravasation.…”

“…Although studies of heparin in SAH do not address leukocyte extravasation explicitly, several animal models of neuroinflammatory injury suggest that heparins directly inhibit this process. Administration of unfractionated heparin following murine TBI reduces leukocyte extravasation as demonstrated by in vivo microscopy [ 86 ]. Administration of low molecular weight heparin yields similar results [ 87 ].…”

“…In a murine endovascular perforation model of SAH, pretreatment with low dose heparin reduced edema formation at 24 h following injury, with improved early behavioral outcome [ 23 ]. Heparin administration in other forms of experimental brain injury reduces blood-brain barrier dysfunction and edema formation in models as diverse as TBI [ 86 , 87 , 111 , 135 ], ischemic stroke [ 78 , 136 ], intracerebral hemorrhage [ 137 , 138 ], and meningitis [ 88 ]. A human study of TBI patients corroborates these findings, demonstrating more rapid resolution of pathologic CT imaging features, especially edema, with early enoxaparin administration [ 139 ].…”

Unfractionated Heparin Alleviates Human Lung Endothelial Barrier Dysfunction Induced by High Mobility Group Box 1 Through Regulation of P38–GSK3β–Snail Signaling Pathway

“…In addition, UFH shows a wide range of protective function including inflammatory suppression [8], apoptosis prevention [9], reducing microvascular permeability [10]. UFH also functions as a protector of endothelial cells.…”

Regulation of Chemokine Function: The Roles of GAG-Binding and Post-Translational Nitration

“…The administration of a GAG, usually heparin, is a method that has been employed in pre-clinical models to modulate inflammation, and is thought to act through disruption of pre-formed chemokine gradients present on cell surface GAGs. Heparin in various forms inhibits leukocyte recruitment to mouse models of arthritis, traumatic brain injury and lipopolysaccharide (LPS) treatment [ 106 , 107 , 108 ], although its effectiveness depends upon the dose given and the duration of inflammation [ 109 ]. These studies show potential role of GAG mimetics on chemokine-mediated immunomodulation when administered, either local or systemically, however it should be noted that administered heparin is likely to interact with all cytokines due to its highly negative charge, and a more chemokine-specific gradient disruption method could be more beneficial.…”