Associations of VEGF-A Levels with Traumatic Brain Injury Severity and Outcomes: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study

Biomarkers are needed to characterize mechanistic endophenotypes after neurotrauma and inform prognosis and therapy. Vascular endothelial growth factor-A (VEGF-A) is associated with inflammation and vascular permeability, which are implicated in secondary brain injury. We describe changes in plasma VEGF-A levels at injury (D1) and 2 weeks (W2) postinjury, and their associations with traumatic brain injury (TBI) severity and 6-month (M6) Glasgow Outcome Scale-Extended (GOSE) scores in a subset of Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) participants with TBI ( n = 317), orthopedic trauma controls (OTC, n = 82), and healthy controls (HC, n = 69). D1 VEGF-A levels were higher in TBI (median [IQR] = 175.8 [114.2–273.1]) compared with OTC (134.3 [97.4–200.6], p = 0.001) and HC (133.6 [89.2–188.2], p = 0.003). VEGF-A levels for both Glasgow Coma Scale (GCS) 3–12 (187.1 [131.7–271.6], p < 0.001) and GCS 13–15 with CT lesions (167.6 [111.4–273.9], p = 0.04) were significantly higher than control groups. This was not the case for GCS 13–15 without CT findings (160.5 [99.2–255.7], p = 0.11, p = 0.09 vs. HC and OTC, respectively). D1 levels did not significantly differ between GCS 3–12 and GCS 13–15 ( p = 0.09), but W2 VEGF-A levels remained elevated for GCS 3–12 (231.6 [120.2–511.5], p < 0.0001 vs. HC) while GCS 13–15 returned to HC levels. VEGF-A levels were higher in all TBI participants with intracranial pathology on CT compared with those without (D1: p = 0.024; W2: p < 0.0001). VEGF-A levels for all TBI returned to HC values by M6. D1 VEGF-A levels did not differ by M6 GOSE, but W2 levels were higher in those with moderate functional disability (GOSE 1–6; p = 0.04) and with unfavorable outcomes (GOSE 1–4; p < 0.0001). W2 VEGF-A was associated with increased odds of unfavorable outcome (GOSE 1–4) at M6 (aOR = 1.44 per log unit increase, 95% CI: 1.02–2.05) after accounting for demographic and clinical variables, but D1 levels were not. Our findings suggest that VEGF-A is a candidate biomarker of traumatic vascular injury and may hold promise for identifying and monitoring of a potentially treatable endophenotype after TBI.