Prehospital tranexamic acid is associated with a dose-dependent decrease in syndecan-1 after trauma: A secondary analysis of a prospective randomized trial

Abstract

BACKGROUND In the Study of Tranexamic Acid During Air and Ground Prehospital Transport (STAAMP) Trial, prehospital tranexamic acid (TXA) was associated with lower mortality in specific patient subgroups. The underlying mechanisms responsible for a TXA benefit remain incompletely characterized. We hypothesized that TXA may mitigate endothelial injury and sought to assess whether TXA was associated with decreased endothelial or tissue damage markers among all patients enrolled in the STAAMP Trial. METHODS We collected blood samples from STAAMP Trial patients and measured markers of endothelial function and tissue damage including syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule-1 at hospital admission (0 hours) and 12 hours, 24 hours, and 72 hours after admission. We compared these marker values for patients in each treatment group during the first 72 hours, and modeled the relationship between TXA and marker concentration using regression analysis to control for potential confounding factors. RESULTS We analyzed samples from 766 patients: 383 placebo, 130 abbreviated dosing, 119 standard dosing, and 130 repeat dosing. Lower levels of syndecan-1, TM, and platelet endothelial cell adhesion molecule measured within the first 72 hours of hospital admission were associated with survival at 30 days (p < 0.001). At hospital admission, syndecan-1 was lower in the TXA group (28.30 [20.05, 42.75] vs. 33.50 [23.00, 54.00] p = 0.001) even after controlling for patient, injury, and prehospital factors (p = 0.001). For every 1 g increase in TXA administered over the first 8 hours of prehospital transport and hospital admission, there was a 4-ng/mL decrease in syndecan-1 at 12 hours controlling for patient, injury, and treatment factors (p = 0.03). CONCLUSION Prehospital TXA was associated with decreased syndecan-1 at hospital admission. Syndecan-1 measured 12 hours after admission was inversely related to the dose of TXA received. Early prehospital and in-hospital TXA may decrease endothelial glycocalyx damage or upregulate vascular repair mechanisms in a dose-dependent fashion. LEVEL OF EVIDENCE Therapeutic/Care Management; Level III.

Missingness matters: a secondary analysis of thromboelastography measurements from a recent prehospital randomized tranexamic acid clinical trial

“… 13 18 19 Alternate hypotheses for TXA’s mechanism of action have been explored, particularly as a pro-endothelial therapeutic agent to reduce glycocalyx shedding. 20 Our results add to the existing literature and our TEG findings correspond to the historic TXA mechanism of action.…”

Endotheliopathy of trauma in children: The association of syndecan-1 with injury and poor outcomes

“…[32][33][34] Multiple adult trauma studies have reported an association between syndecan-1 elevation and poor outcomes. [22][23][24]35,36 Gonzalez Rodriguez et al 22 reported a study of injured adults, defining a cutoff of 40 ng/mL as abnormal and comparing those with higher versus lower levels of syndecan-1; elevated levels were associated with higher injury severity as in this study, as well as mortality and the need for blood product transfusion. In a prospective study of 424 adult subjects, syndecan-1 was an independent predictor of <24-hour, 7-day, and 28-day mortality after controlling for other contributing factors including age, sex, ISS, Glasgow Coma Scale, base excess, platelet count, and hemoglobin.…”

“…Adult, in vitro, and animal models have shown a relationship between early TXA adminis-tration and decreased syndecan-1. 35,53,54 There were too few patients to assess the relationship between syndecan-1, TXA, and outcomes in this cohort. A recent multi-institutional study of children with life-threatening hemorrhage showed a relationship between antifibrinolytic medication administration and improved survival but did not include mechanistic data.…”

Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials

“…It is also hypothesized that adiponectin, produced by adipocytes, may play a restorative role in endothelial function. 26,44,45 Syndecan-1, TM and VEGF have been associated with endothelial cell damage following trauma 26,27,46,47 . Because of the potential relationship between these markers and endothelial function, we categorized these seven markers as endothelial cell damage markers for the purposes of this study.…”