Tranexamic Acid Influences the Immune Response, but not Bacterial Clearance in a Model of Post-Traumatic Brain Injury Pneumonia

Draxler, Dominik F.; Awad, Milena M.; Hanafi, Gryselda; Daglas, Maria; Ho, Heidi; Keragala, Charithani B.; Galle, Adam; Roquilly, Antoine; Lyras, Dena; Sashindranath, Maithili; Medcalf, Robert L.

doi:10.1089/neu.2018.6030

Cited by 21 publications

(13 citation statements)

References 58 publications

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“…Similarly, TXA has been associated with having pro‐ and/or anti‐inflammatory effects as does plasmin, also dependent on the disease/condition, 22‐25 and can modulate the immune response to brain injury 12,13,26 . Although understudied in TBI, plasmin and plasminogen activators appear to have immunosuppressive effects on functionality and migration of specific immune cells such as dendritic cells (DC) in models of brain injury which can be reversed by TXA, but has also been shown to enhance microglial inflammatory responses 12,13,15 . TXA administered to cardiac surgery patients was shown to reduce infection rates by reversing immunosuppression actions of plasmin 25 …”

Section: Introductionmentioning

confidence: 99%

Sex‐dependent effects of tranexamic acid on blood‐brain barrier permeability and the immune response following traumatic brain injury in mice

Daglas

Galle

Draxler

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Tranexamic acid (TXA) is an anti-fibrinolytic agent used to reduce bleeding in various conditions including traumatic brain injury (TBI). As the fibrinolytic system also influences the central nervous system and the immune response, TXA may also modulate these parameters following TBI. Objectives: To determine the effect of TXA on blood-brain barrier (BBB) integrity and changes in immune and motor function in male and female mice subjected to TBI. Methods: Wild-type and plasminogen deficient (plg−/−) mice were subjected to TBI then administered either TXA/vehicle. The degree of BBB breakdown, intracerebral hemorrhage (ICH), motor dysfunction, and changes in inflammatory subsets in blood and brain were determined. Results and conclusions: Tranexamic acid significantly reduced BBB breakdown, and increased blood neutrophils in male mice 3 hours post-TBI. In contrast, TXA treatment of female mice increased BBB permeability and ICH but had no effect on blood neutrophils at the same time-point. TXA improved motor function in male mice but still increased BBB breakdown in female mice 24 hours post-TBI. Brain urokinase-type plasminogen activator (u-PA) antigen and activity levels were significantly higher in injured females compared to males. Because TXA can promote a pro-fibrinolytic effect via u-PA, these sex differences may be related to brain u-PA levels. TXA also increased monocyte subsets and dendritic cells in the injured brain of wild-type male mice 1 week post-TBI. Plg −/− mice of both sexes had reduced BBB damage and were protected from TBI irrespective of treatment indicating that TXA modulation of the BBB is plasmin-dependent. In conclusion, TXA is protective post-TBI but only in male mice. K E Y W O R D S blood-brain barrier, fibrinolysis, intracerebral hemorrhage, tranexamic acid, traumatic brain injury | 2659 DAGLAS et AL.

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Section: Introductionmentioning

confidence: 99%

Sex‐dependent effects of tranexamic acid on blood‐brain barrier permeability and the immune response following traumatic brain injury in mice

Daglas

Galle

Draxler

et al. 2020

Journal of Thrombosis and Haemostasis

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“…Animal studies of trauma have found results similar to that of Syrovets et al, where Sprague-Dawley rats exposed to hemorrhagic shock for 60 minutes (MAP of 30 mm Hg) had a blunted IL-1 and IL-10 response if treated with TXA and also a reduction in pulmonary edema and mesenteric lymph node hyperplasia, although this study had mixed effects, with some proinflammatory sequela in the TXA group observed to include worse cardiac injury. 27 The ability of TXA to reduce proinflammatory IL1-β levels has also been demonstrated in human clinical studies of cardiac surgery patients, 28 where interestingly TXA also led to reduced postoperative infections (particularly in nondiabetic patients) and generated a more favorable, less immunosuppressed cellular immune profile that has been extensively studied by Draxler et al 29 In another study using a well-known mouse cremaster model of I/R injury, Reichel et al demonstrated that plasmin inhibitors including TXA led to significant reductions in leukocyte adhesion and migration across the microvascular endothelium during the reperfusion phase. 30 They found that this effect was dependent on mast cell activation, where plasmin led to increased RNA expression of 5-lipoxygenase and lyso-PAF-acetyltransferase that facilitated leukotriene and platelet-activating factor production, which are well known to recruit, prime, and activate neutrophils.…”

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confidence: 97%

Influence of Tranexamic Acid on Inflammatory Signaling in Trauma

Barrett

Kong

Yaffe

2020

Semin Thromb Hemost

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Plasmin generation in trauma patients has wide-ranging effects, from breakdown of clots to remodeling the extracellular matrix. An evolving recognition of plasmin as a critical effector molecule in various inflammatory signals and pathways has rendered the study of plasmin(ogen) and its regulation by upstream activators and downstream targets and inhibitors key to understanding the inflammatory responses to trauma. Tranexamic acid, a widely available lysine analogue medication on the World Health Organization's list of essential medicines, has rapidly become one of the most commonly implemented adjunct treatments for bleeding after traumatic injury in clinical practice. In this article, we review the effects, both anti- and proinflammatory, of tranexamic acid, with a focus on the injured trauma patient.

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“…In a TBI animal model, a potentially beneficial inflammatory and immune modulation were demonstrated after TXA administration [20]. Furthermore, TXA was also shown to be associated with elevated immune activation in a post-TBI pneumonia animal model [21].…”

Section: Discussionmentioning

confidence: 98%

Tranexamic acid is associated with reduced mortality, hemorrhagic expansion, and vascular occlusive events in traumatic brain injury – meta-analysis of randomized controlled trials

July

Pranata

2020

BMC Neurol

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Background: This systematic review and meta-analysis aimed to synthesize the latest evidence on the efficacy and safety of tranexamic acid (TXA) on traumatic brain injury (TBI). Methods:We performed a systematic literature search on topics that compared intravenous TXA to placebo in patients with TBI up until January 2020 from several electronic databases.Results: There were 30.522 patients from 7 studies. Meta-analysis showed that TXA was associated with reduced mortality (RR 0.92 [0.88, 0.97], p = 0.002; I 2 : 0%) and hemorrhagic expansion (RR 0.79 [0.64, 0.97], p = 0.03; I 2 : 0%). Both TXA and control group has a similar need for neurosurgical intervention (p = 0.87) and unfavourable Glasgow Outcome Scale (GOS) (p = 0.59). The rate for vascular occlusive events (p = 0.09), and its deep vein thrombosis subgroup (p = 0.23), pulmonary embolism subgroup (p = 1), stroke subgroup (p = 0.38), and myocardial infarction subgroup (p = 0.15) were similar in both groups. Subgroup analysis on RCTs with low risk of bias showed that TXA was associated with reduced mortality and hemorrhagic expansion. TXA was associated with reduced vascular occlusive events (RR 0.85 [0.73, 0.99], p = 0.04; I 2 : 4%). GRADE was performed for the RCT with low risk of bias subgroup, it showed a high certainty of evidence for lower mortality, less hemorrhage expansion, and similar need for neurosurgical intervention in TXA group compared to placebo group.Conclusion: TXA was associated with reduced mortality and hemorrhagic expansion but similar need for neurosurgical intervention and unfavorable GOS. Vascular occlusive events were slightly lower in TXA group on subgroup analysis of RCTs with low risk of bias.

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Tranexamic Acid Influences the Immune Response, but not Bacterial Clearance in a Model of Post-Traumatic Brain Injury Pneumonia

Cited by 21 publications

References 58 publications

Sex‐dependent effects of tranexamic acid on blood‐brain barrier permeability and the immune response following traumatic brain injury in mice

Sex‐dependent effects of tranexamic acid on blood‐brain barrier permeability and the immune response following traumatic brain injury in mice

Influence of Tranexamic Acid on Inflammatory Signaling in Trauma

Tranexamic acid is associated with reduced mortality, hemorrhagic expansion, and vascular occlusive events in traumatic brain injury – meta-analysis of randomized controlled trials

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