Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs

Abstract

Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 μg/kg rFVIIa (n = 5) or vehicle control (n = 5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days postinjury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI.

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

“…By comparison with previous studies using the swine model with injury in both planes of rotation, injury parameters included peak angular accelerations of approximately 105,000 rad/sec 2 and peak angular velocities of approximately 290 rad/sec (Kimura et. al., 1996;Meaney et al, 1995;Smith et al, 1997Smith et al, , 2000bZhang et al, 2008). In these previous studies, both planes of head rotation produced extensive axonal pathology, while only axial plane rotation induced prolonged coma.…”

Folic Acid Enhances Early Functional Recovery in a Piglet Model of Pediatric Head Injury

“…However, the piglet offers a better model of the human brain, with similar cortical grey-white differentiation, gyral pattern and physiologic responses to TBI in humans [27,28]. Outcomes assessed in previous swine TBI intervention studies have included mean arterial pressure [29,30,31], intracranial pressure [30,31,32], cerebral blood flow [29,30,31,32], brain tissue oxygen tension [29], cerebral metabolic rate of oxygen [31], immunohistochemistry [29,30,31], histopathology [30,31,33] and lesion volume by magnetic resonance imaging [29,32]. Simple functional testing has been performed in swine TBI studies [32,34] with the use of a veterinary coma scale, similar to the Glasgow Coma Scale [35] used in humans.…”

Therapy Development for Diffuse Axonal Injury

“…As such, there have been very few studies using large animal models of DAI to evaluate therapeutic efficacy. 69 This has stirred renewed interest and refinements in small animal and in vitro models of TAI for more general screening for potential therapies.…”