Zhang Jun, Groff Robert F, Chen Xiao-Han, Browne Kevin D, Huang Jason, Schwartz Eric D, Meaney David F, Johnson Victoria E, Stein Sherman C, Rojkjaer Rasmus, Smith Douglas H
Department of Neurosurgery and Penn Center for Brain Injury and Repair, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Exp Neurol. 2008 Apr;210(2):645-55. doi: 10.1016/j.expneurol.2007.12.019. Epub 2008 Jan 5.
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.
人重组活化凝血因子 VII（rFVIIa）已成功用于治疗自发性脑出血。此外，人们对其用于治疗包括创伤在内的其他原因引起的难以控制的出血越来越感兴趣。本研究的目的是使用猪创伤性脑损伤（TBI）的临床相关模型评估 rFVIIa 减轻出血的安全性和潜在有效性。选择了一种双损伤模型，包括（1）通过对暴露的皮质表面施加负压诱导的扩展性脑挫伤，以及（2）头部快速旋转加速诱导弥漫性轴索损伤（DAI）。对 10 只麻醉猪进行损伤。损伤后 5 分钟，静脉注射 720 μg/kg rFVIIa（n = 5）或载体对照（n = 5）。在 TBI 后 30 分钟内和 3 天进行磁共振成像（MRI）研究，以确定脑挫伤的时间性扩展。在第 3 天进行安乐死和组织病理学分析。这包括观察海马神经元变性、轴索病理学和微血栓形成。与载体对照相比，用 rFVIIa 治疗的动物在损伤后 3 天内挫伤体积的扩展明显减少。令人惊讶的是，免疫组织化学分析表明，与载体相比，rFVIIa 治疗使死亡/濒死海马神经元的数量和轴索病理学显著减少。此外，两组之间微血栓的程度没有差异。猪 TBI 后 rFVIIa 治疗减少了出血性脑挫伤体积的扩展，而没有加重微血栓形成的严重程度。最后，rFVIIa 治疗通过减少海马神经元变性以及 DAI 的程度提供了令人惊讶的神经保护作用。
