Natural History and Clinical Associations of Plasma Vascular Endothelial Growth Factor A

Background and Objectives
Severe traumatic brain injury (TBI) is associated with secondary injury and poor outcomes, but the underlying mechanisms are poorly understood. Vascular mechanisms may be important. We aimed to characterize how blood vascular endothelial growth factor A (VEGF-A) levels are affected by TBI, and its associations with secondary injury and functional outcome.
Methods
We retrospectively analyzed data from 2 multicenter, international, prospective observational studies (CREACTIVE and BIO-AX-TBI) with follow-up of up to 1 year. These cohorts comprised adults with moderate-severe TBI (Mayo classification), recruited on admission to hospital (BIO-AX-TBI) and the intensive care unit (ICU) (CREACTIVE). Controls included non-TBI trauma (NTT) and uninjured adults. Plasma VEGF-A levels and TBI biomarkers (neurofilament light, glial fibrillary acidic protein, total tau, ubiquitin C-terminal hydrolase 1, and S100 calcium-binding protein B) were measured on ICU admission and ∼5 days later (CREACTIVE), or at 5 timepoints from admission to 12-month post-TBI (BIO-AX-TBI), and compared with NTT and control groups. In BIO-AX-TBI, MRI assessment was performed at subacute and chronic timepoints. Functional outcomes (Glasgow Outcome Scale–Extended) were measured at 6 and 12 months. Plasma VEGF-A was measured using the OLINK Target 96 Inflammatory platform, which reports in arbitrary standardized units (NPX), and TBI biomarkers were measured using Simoa or Millipore platforms.
Results
Data were available from 195 TBI (21% female, mean age 45.30 years), 24 NTT (8%, 43.98), and 89 CON (44%, 42.39) in BIO-AX-TBI, and 1146 TBI (25%, 56.29) in CREACTIVE. Plasma VEGF-A was elevated acutely after both TBI (estimated mean difference = 0.45NPX, SE = 0.09, p < 0.001) and NTT (estimated mean difference = 0.74NPX, SE = 0.16, p < 0.001), but remained raised after the initial timepoint only in patients with TBI, peaking at day 16. Higher acute VEGF-A was associated with increased odds of refractory raised intracranial pressure (r-rICP) (maximum odds ratio for r-rICP = 1.69, p = 0.031), higher lesion volume (estimated increased lesion volume = 20.14 mL, SE = 8.20 mL, p = 0.02), and worse functional outcomes (maximum odds ratio for worse outcome category = 2.51, p < 0.001).DiscussionThere is a sustained rise in plasma VEGF-A after TBI, which is associated with r-rICP and chronic injury markers, suggesting vascular pathophysiology is important after TBI. Further research is needed to explore mechanisms.