Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs.
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 microg/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 post-injury 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.
Zhang
Jun
J
Department of Neurosurgery and Penn Center for Brain Injury and Repair, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Groff
Robert F
RF
Chen
Xiao-Han
XH
Browne
Kevin D
KD
Huang
Jason
J
Schwartz
Eric D
ED
Meaney
David F
DF
Johnson
Victoria E
VE
Stein
Sherman C
SC
Rojkjaer
Rasmus
R
Smith
Douglas H
DH
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000235:genetics / Q000627:therapeutic use*; D007839:Functional Laterality; D006490:Hemostatics / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000627:therapeutic use*; D013552:Swine; D013997:Time Factors
D006490:Hemostatics; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D015942:Factor VIIa