Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis

Abstract

Background Traumatic brain injury (TBI) is known to promote immunosuppression, making patients more susceptible to infection, yet potentially exerting protective effects by inhibiting central nervous system (CNS) reactivity. Plasmin, the effector protease of the fibrinolytic system, is now recognized for its involvement in modulating immune function. Objective To evaluate the effects of plasmin and tranexamic acid (TXA) on the immune response in wild‐type and plasminogen‐deficient (plg−/−) mice subjected to TBI. Methods Leukocyte subsets in lymph nodes and the brain in mice post TBI were evaluated by flow cytometry and in blood with a hemocytometer. Immune responsiveness to CNS antigens was determined by Enzyme‐linked Immunosorbent Spot (ELISpot) assay. Fibrinolysis was determined by thromboelastography and measuring D‐dimer and plasmin‐antiplasmin complex levels. Results Plg−/− mice, but not plg+/+ mice displayed increases in both the number and activation of various antigen‐presenting cells and T cells in the cLN 1 week post TBI. Wild‐type mice treated with TXA also displayed increased cellularity of the cLN 1 week post TBI together with increases in innate and adaptive immune cells. These changes occurred despite the absence of systemic hyperfibrinolysis or coagulopathy in this model of TBI. Importantly, neither plg deficiency nor TXA treatment enhanced the autoreactivity within the CNS. Conclusion In the absence of systemic hyperfibrinolysis, plasmin deficiency or blockade with TXA increases migration and proliferation of conventional dendritic cells (cDCs) and various antigen‐presenting cells and T cells in the draining cervical lymph node (cLN) post TBI. Tranexamic acid might also be clinically beneficial in modulating the inflammatory and immune response after TBI, but without promoting CNS autoreactivity.

Influence of Tranexamic Acid on Inflammatory Signaling in Trauma

“…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.…”

Tranexamic Acid is Associated with Reduced Mortality, Hemorrhagic Expansion, and Vascular Occlusive Events in Traumatic Brain Injury – Meta-analysis of Randomized Controlled Trials

“…19 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 Aside from the included studies, there was an observational study reported that TXA administration in patients with cerebral contusions or traumatic subarachnoid hemorrhage was independently associated with a reduced mortality rate.…”

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

“…TXA has been shown to modulate pulmonary inflammation in trauma-induced acute lung injury [19]. 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].…”