Natural History and Clinical Associations of Plasma Vascular Endothelial Growth Factor A
Changes After Traumatic Brain Injury
Changes After Traumatic Brain Injury
Author(s)
Type
Journal Article
Abstract
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 characterise 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 analysed data from two multi-centre, 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 [NFL], glial fibrillary acidic protein [GFAP], total Tau, UCH-L1, S100B) were measured on ICU admission and ~5 days later (CREACTIVE), or at 5 timepoints from admission to 12 months post-TBI (BIO-AX-TBI), and compared to 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
standardised units (NPX), and TBI biomarkers were measured using Simoa® or Millipore platforms.
Results: Data was available from 195 TBI (21% female, mean age 45.30years), 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 TBI patients, 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=20.14ml, SE=8.20ml, p=0.02), and worse functional outcomes (maximum Odds Ratio for worse outcome category=2.51, p<0.001).
Discussion: There 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.
Methods: We retrospectively analysed data from two multi-centre, 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 [NFL], glial fibrillary acidic protein [GFAP], total Tau, UCH-L1, S100B) were measured on ICU admission and ~5 days later (CREACTIVE), or at 5 timepoints from admission to 12 months post-TBI (BIO-AX-TBI), and compared to 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
standardised units (NPX), and TBI biomarkers were measured using Simoa® or Millipore platforms.
Results: Data was available from 195 TBI (21% female, mean age 45.30years), 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 TBI patients, 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=20.14ml, SE=8.20ml, p=0.02), and worse functional outcomes (maximum Odds Ratio for worse outcome category=2.51, p<0.001).
Discussion: There 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.
Date Issued
2025-12-01
Date Acceptance
2025-09-18
Citation
Neurology Open Access, 2025, 1 (4)
ISSN
2998-7601
Publisher
Lippincott, Williams & Wilkins
Journal / Book Title
Neurology Open Access
Volume
1
Issue
4
Copyright Statement
© 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. his is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
10.1212/WN9.0000000000000039
Publication Status
Published
Article Number
000039
Date Publish Online
2025-11-05