A New Biomarker of Traumatic Brain Injury?

Erik Greb

April 26, 2021

Plasma levels of von Willebrand factor may be a useful biomarker of traumatic brain injury (TBI) and its severity, new research suggests.

"Reliable detection of this biomarker at very early time points may allow for prompt TBI detection and therefore intervention," study investigator Rachel Elizabeth Thomas, MD, PhD, a neurology resident at the University of Pennsylvania, Philadelphia, Pennsylvania, told delegates attending the virtual American Academy of Neurology (AAN) 2021 Annual Meeting.

"The level reflects the degree of severity and provides some degree of prognostic information," she added.

A Specific Marker of Acute Injury?

Von Willebrand factor is a glycoprotein released in the endothelium in response to local trauma. It plays a part in hemostasis and inflammation and is an indicator of traumatic microvascular injury. Research has shown that it is a biomarker of cerebrovascular pathology. In addition, increased expression of the factor is associated with vascular and neurodegenerative dementia.

The researchers examined whether von Willebrand factor is a biomarker of mild, repetitive TBI. They measured plasma levels of von Willebrand factor in 17 professional boxers before and after boxing bouts.

Eligible participants were between the of ages 18 years and 35 years. They had a score of ≥1 on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ-3), had competed in at least three 3-minute bouts, and had withstood 25 or more blows to the head.

The investigators compared the plasma levels of von Willebrand factor of the boxers with those of 42 patients who presented to the University of Pennsylvania Trauma Center with TBI and with those of 23 uninjured control persons.

There was no significant difference in plasma levels of von Willebrand factor between boxers before the bout (13.15 µg/mL) and the control persons (6.16 µg/mL). Among the boxers, levels of von Willebrand factor increased by a factor of 1.8 within 30 minutes after bouts, compared with the levels among the control persons. The mean post-bout von Willebrand factor level was 25.09 µg/mL.

"Von Willebrand factor may be more specific for acute injuries, given that it does not seem to stay chronically elevated," said Thomas.

In addition, the researchers found a significant positive correlation (r = 0.51; P = .03) between the fold change in plasma von Willebrand factor levels and the number of blows to the head that the athletes sustained.

They also found a significant positive correlation between fold change in von Willebrand factor and RPQ-3 score (r = 0.69; P = .002). These objective and subjective data suggest that levels of von Willebrand factor reflect injury severity, said Thomas.

Among patients hospitalized with TBI, levels of von Willebrand factor were significantly higher than among control persons (73.2 µg/mL vs 40.8 µg/mL; P < .0009). The investigators found a linear correlation between plasma von Willebrand factor level and RPQ-3 score (r = 0.24) that was not statistically significant.

Levels of von Willebrand factor among patients hospitalized with TBI were higher on average and demonstrated a greater degree of variability than the levels among boxers immediately after a bout.

"This is not unexpected, given that this group represents a more heterogeneous population with varied forms of acute blunt injury, as compared to the boxers, who have undergone relatively repetitive, milder trauma," Thomas told Medscape Medical News.

The traditional biomarkers of neurotrauma reflect neuronal and glial injury, whereas von Willebrand factor is an indicator of vascular trauma.

"Although on its own, von Willebrand factor is not specific to intracranial vascular injury, paired together with markers such as neurofilament light, GFAP [glial fibrillary acidic protein], and tau, it could be utilized to identify TBI-associated microvascular injury and thus delineate between specific TBI endophenotypes," said Thomas. It could distinguish, for example, predominantly neuronal injury from predominantly vascular injury.

Because von Willebrand factor plays a role in the neurovascular unit and is a marker of microvascular injury, the investigators intend to pair measurements of plasma von Willebrand factor with advanced imaging techniques to evaluate cerebral blood flow or cerebrovascular reactivity. Such a study could help determine whether von Willebrand factor levels correlate with the degree of vascular injury and cerebrovascular dysregulation.

Point-of-Care Test?

Commenting on the findings for Medscape Medical News, Kristine O'Phelan, MD, professor of clinical neurology and director of neurocritical care in the Department of Neurology at the University of Miami's Miller School of Medicine, Coral Gables, Florida, said Von Willebrand factor's likely utility would be as a marker of injury in patients with mild TBI or sports-related concussion.

Dr Kristine O'Phelan

Imaging and clinical exams do not always reveal these injuries, O'Phelan added. "Having a biomarker that you can easily test in the blood would be extremely helpful," she said.

The most exciting part of this study is that it indicates the potential to develop a point-of-care test for use on the athletic field or the battlefield for early detection of mild TBI, she added.

The fact that the test for von Willebrand factor has already been developed is an advantage, said O'Phelan. The normal and abnormal values of the test are clearly understood. "I do think that they will still need to calibrate it for head injury, because that's not usually what the test is used for," said O'Phelan.

One of the study's strengths is that the investigators compared patients with TBI to control persons who had exercised, she added, because such a comparison helps clarify the biomarker's relationship to the injury. Another strength is the application of the test to injuries of various types and of different degrees of severity.

But the biomarker will need to be tested in a larger population, said O'Phelan. In addition, there is a need to identify the right patient population for this test, as well as the best time frame for its application and potential factors that could confound the test results.

"I do worry a little bit about using early biomarkers for prognosis, particularly in severe TBI, because there's so many variables that go into outcome," said O'Phelan. This test likely would be administered in the first hours after injury, but many factors might affect patients' outcomes, she added.

One influential factor is age. "If you have a von Willebrand factor of whatever number, that might have different importance in a 30-year-old than in an 80-year-old," said O'Phelan. "We need to understand how to interpret those findings better."

The study was supported by the National Institute for Neurological Disorders and Stroke, the US Department of Defense, and the Pennsylvania Department of Health. Thomas and O'Phelan have disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2021 Annual Meeting: Abstract S26.005. Presented April 21, 2021.

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