Acute Traumatic Endotheliopathy in Isolated Severe Brain Injury and Its Impact on Clinical Outcome

Abstract

Study design: Prospective observational cohort. Objective: To investigate the difference in plasma levels of syndecan-1 (due to glycocalyx degradation) and soluble thrombomodulin (due to endothelial damage) in isolated severe traumatic brain injury (TBI) patients with/without early coagulopathy. A secondary objective was to compare the effects of the degree of TBI endotheliopathy on hospital mortality among patients with TBI-associated coagulopathy (TBI-AC). Methods: Data was prospectively collected on isolated severe TBI (sTBI) patients with Glasgow Coma Scale (GCS) ≤8 less than 12 h after injury admitted to a level I trauma centre. Isolated sTBI patients with samples withdrawn prior to blood transfusion were stratified by conventional coagulation tests as coagulopathic (prothrombin time (PT) ≥ 16.7 s, international normalized ratio (INR) ≥ 1.27, and activated partial thromboplastin time (aPTT) ≥ 28.8 s) and non-coagulopathic. Twenty healthy controls were also included. Plasma levels of thrombomodulin and syndecan-1 were estimated by ELISA. With receiver operating characteristic curve (ROC) analysis, we defined endotheliopathy as a syndecan-1 cut-off level that maximized the sum of sensitivity and specificity for predicting TBI-AC. Results: Inclusion criteria were met in 120 cases, with subjects aged 35.5 ± 12.6 years (88.3% males). TBI-AC was identified in 50 (41.6%) patients, independent of age, gender, and GCS, but there was an association with acidosis (60%; p = 0.01). Following isolated sTBI, we found insignificant changes in soluble thrombomodulin (sTM) levels between patients with isolated TBI and controls, and sTM levels were lower in coagulopathic compared to non-coagulopathic patients. Elevations in plasma syndecan-1 (ng/mL) levels were seen compared to control (31.1(21.5–30.6) vs. 24.8(18.5–30.6); p = 0.08). Syndecan-1(ng/mL) levels were significantly elevated in coagulopathic compared to non-coagulopathic patients (33.7(21.6–109.5) vs. 29.9(19.239.5); p = 0.03). Using ROC analysis (area under the curve = 0.61; 95% Confidence Interval (CI) 0.50 to 0.72), we established a plasma syndecan-1 level cutoff of ≥30.5 ng/mL (sensitivity % = 55.3, specificity % = 52.3), with a significant association with TBI-associated coagulopathy. Conclusion: Subsequent to brain injury, elevated syndecan-1 shedding and endotheliopathy may be associated with early coagulation abnormalities. A syndecan-1 level ≥30.5 ng/mL identified patients with TBI-AC, and may be of importance in guiding management and clinical decision-making.

Effect of tranexamic acid on the prognosis of patients with traumatic brain injury undergoing craniotomy: study protocol for a randomised controlled trial

“…35 36 In addition, excessive consumption of coagulation factors and platelet dysfunction, 37 hypoperfusion and protein-C pathway activation, hypothermia, metabolic acidosis and haemodilution can also lead to coagulation dysfunction after TBI. 38 In patients with TBI, the blood-brain barrier is destroyed; Fbg and its degradation products enter the brain and activate the inflammatory reaction cascade and the immune response in the brain, leading to lymphocyte infiltration, glial cell activation, cytokine release and reactive oxygen element production in the brain. These lead to axonal demyelination and neuronal damage.…”

Soluble syndecans: biomarkers for diseases and therapeutic options

“…Furthermore, studies in mice have shown that the inflammatory response to toxins, chemicals, allergens and pathogens is dysregulated in the absence of Sdc1 or when its shedding is inhibited (Kainulainen et al ., ; Kato et al ., ), suggesting that Sdc1 shedding is activated to ensure adequate tissue response to inflammation. Consequently, Sdc1 has been proposed to be a biomarker for sepsis survival after major abdominal surgery, as well as for acute traumatic endotheliopathy in isolated severe brain injury, and for small bowel mucosal damage in children with celiac disease (Yablecovitch et al ., ; Albert et al ., ; Holzmann et al ., ).…”

Detecting Traumatic Brain Injury-Induced Coagulopathy: What We Are Testing and What We Are Not

“…The shedding of syndecan-1 indicates the depletion of protective glycocalyx, also making the endothelium more procoagulant 26 . A study found that patients with TBI-IC had lower plasma levels of soluble thrombomodulin and higher levels of soluble syndecan-1, as compared with patients without coagulopathy 27 . Extracellular vesicles (EVs) released from injured endothelial cells are also increasingly used as a marker for plasma procoagulant activity because they are associated with endothelial injury and also express procoagulant activity 17,28,29 .…”