Changes in Plasma von Willebrand Factor and Cellular Fibronectin in MRI-Defined Traumatic Microvascular Injury

Abstract

The neuropathology of traumatic brain injury (TB) is diverse, including primary injury to neurons, axons, glial cells, vascular structures, and secondary processes, such as edema and inflammation that vary between individual patients. Traumatic microvascular injury is an important endophenotype of TBI-related injury. We studied patients who sustained a TBI requiring ER evaluation and had an MRI performed within 48 h of injury. We classified patients into 3 groups based on their MRI findings: (1) those that had evidence of traumatic microvascular injury on susceptibility or diffusion weighted MRI sequences without frank hemorrhage [Traumatic Vascular Injury (TVI) group; 20 subjects]. (2) those who had evidence of intraparenchymal, subdural, epidural, or subarachnoid hemorrhage [Traumatic Hemorrhage (TH) group; 26 subjects], and (3) those who had no traumatic injuries detected by MRI [MRI-negative group; 30 subjects]. We then measured plasma protein biomarkers of vascular injury [von Willebrand Factor (vWF) or cellular fibronectin (cFn)] and axonal injury (phosphorylated neurofilament heavy chain; pNF-H). We found that the TVI group was characterized by decreased expression of plasma vWF ( p < 0.05 compared to MRI-negative group; p < 0.00001 compared to TH group) ≤48 h after injury. cFN was no different between groups ≤48 h after injury, but was increased in the TVI group compared to the MRI-negative ( p < 0.00001) and TH ( p < 0.00001) groups when measured >48 h from injury. pNF-H was increased in both the TH and TVI groups compared to the MRI-negative group ≤48 h from injury. When we used the MRI grouping and molecular biomarkers in a model to predict Glasgow Outcome Scale-Extended (GOS-E) score at 30–90 days, we found that inclusion of the imaging data and biomarkers substantially improved the ability to predict a good outcome over clinical information alone. These data indicate that there is a distinct, vascular-predominant endophenotype in a subset of patients who sustain a TBI and that these injuries are characterized by a specific biomarker profile. Further work to will be needed to determine whether these biomarkers can be useful as predictive and pharmacodynamic biomarkers for vascular-directed therapies after TBI.

Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness

“…Von Willebrand Factor (vWF), a concatemeric glycoprotein composed of 500‐kDa dimeric units, is synthesized within megakaryocytes and endothelial cells and functions as an integral mediator of both hemostasis and inflammation . In critical illness states, such as trauma, sepsis, and burns, sympathoadrenal activation and loss of the endothelial glycocalyx may instigate a shift toward a prothrombotic vascular endothelium, leading to large, swift increases in vWF, accompanied by concomitant decreases in the vWF cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type‐1 repeats 13) . Much of the work that has previously focused on endotheliopathy of critical injury has targeted markers such as syndecan‐1, soluble thrombomodulin, and plasma adrenaline levels.…”

“…Interestingly, recent data have demonstrated that there is a sustained increase in vWF antigen, vWF activity, and proportion of high‐molecular‐weight vWF forms in the days following traumatic injury, suggesting movement toward a prothrombotic and proinflammatory phenotype within the circulation; furthermore, low ADAMTS13 levels have been linked to worse outcomes in these patients . While knowledge regarding the contribution of vWF to the development of TIC is rather limited, advances with respect to understanding TIC following traumatic brain injury (TBI) are highlighted later in this article and may provide insight into the role that vWF is playing …”

“…Studies have investigated the impact of this response and established vWF as an important biomarker of outcomes after severe TBI. De Oliveira et al 16 demonstrated that a vWF plasma concentration of greater than 234 IU/dL, 24 hours after injury, is sensitive and specific for mortality in patients with severe TBI, and Kumar et al 14 showed that patients with the highest mortality from TBI have both increased vWF antigen levels and vWF collagen binding activity with minimal changes in the vWF antigen to collagen binding ratio . Furthermore, both studies found a concomitant decrease in ADAMTS13 levels in patient populations with the highest mortality, potentially emphasizing the procoagulant and inflammatory vWF functions due to impaired cleavage of high‐molecular‐weight multimers …”

The Role of Blood Biomarkers for Magnetic Resonance Imaging Diagnosis of Traumatic Brain Injury

“…MRI was used to separate patients into those with traumatic microvascular injury (TVI) defined as diffusion weighted MRI without frank hemorrhage, those with frank hemorrhage (TH) and those with no injury on MRI. NF-H was increased in both TH and TVI groups compared to MRI− group within the first 48 h following injury [25]. Importantly, NF-H plasma levels remained elevated after 48 h in the TVI group but not the TH group.…”

Differential Expression of CD31 and Von Willebrand Factor on Endothelial Cells in Different Regions of the Human Brain: Potential Implications for Cerebral Malaria Pathogenesis

“…Impairment of the brain function results from a plethora of cerebrovascular events, including structural and functional dysfunction in cerebral hemodynamics. Cerebrovascular damage occurs in conditions such as stroke [9], cardiovascular [10] and neurodegenerative diseases [11], traumatic brain injury [12], and infectious diseases such as HIV [2] and cerebral malaria [5]. Cerebrovascular damage often involves obstruction of the BBB, which leads to its breakdown and impaired microcirculation.…”