Expansion of intracranial hemorrhage by tPA after traumatic brain injury

描述(申请人提供)：颅内出血(ICH)是创伤性脑损伤(TBI)的常见后遗症，也是导致死亡和残疾的主要原因。对于那些在最初的侮辱中幸存下来的人来说，创伤后第一个小时内脑出血的扩大是发病率和死亡率的有力预测因素。然而，目前预防脑出血进展的方法取得的成功有限。脑损伤是高度促凝血剂，脑损伤后释放丰富的组织因子(Tf)，导致局部血小板和凝血蛋白的激活。紧随其后的是全身性凝血酶介导的凝血障碍，限制了非特异性抗纤溶氨甲环酸(TA)的疗效，并可能有助于解释使用重组因子VIIa(RVIIa)后死亡率增加的原因。我们提出了一种新的假说来解释脑出血扩大的病理生理学机制，并提出了一种新的预防方法。我们推测，纤溶起始物，组织型纤溶酶原激活物(TPA)和尿激酶型纤溶酶原激活剂，从损伤的脑中显著释放，导致：1)血栓过早溶解和脑出血扩张；2)tPA过度激活N-甲基-D-天冬氨酸受体(NMDA-Rs)导致的神经毒性，这种毒性不能被TA或rVIIa减弱。为了支持这一假设，我们证明了一种催化 非活性tPA变异体(TPAS481a)，特异性和靶向性地抑制脑内新形成的血栓的溶解：a)减缓脑出血的扩张，b)减少D-二聚体，c)减少血小板减少，d)减少tPA介导的神经毒性，e)改善脑损伤后的神经预后。对于所有结果，tPAS481a明显比TA更有效。我们还开发了tPA变异体，通过阻断过度的NMDA-R介导的信号转导，选择性地抑制tPA介导的神经毒性，防止纤溶或阻断这两条途径。我们将测试这些tPA变异体，并使用tPA基因缺失的小鼠来深入了解脑外伤后进行性脑出血的发病机制，并开发新的治疗干预措施。

DESCRIPTION (provided by applicant): Intracranial hemorrhage (ICH) is a common sequel to traumatic brain injury (TBI) and a major cause of death and disability. For those who survive the initial insult, expansion of ICH within the first hours after trauma is a strong predictor of morbiity and mortality. However, current approaches to prevent progression of ICH have met with limited success. Injured brain is highly procoagulant and TBI releases abundant tissue factor (TF), which leads locally to the activation of platelets and coagulation proteins. This is followed by a systemic thrombin-mediated coagulopathy that constrains the efficacy of the unspecific anti-fibrinolytic tranexamic acid (TA) and may help explain the increased mortality that follows use of recombinant factor VIIa (rVIIa). We present a new hypothesis to explain the pathophysiology of ICH expansion and a new approach to its prevention. We postulate that marked release of the fibrinolysis initiators, tissue type plasminogen activator (tPA) and urokinase plasminogen activator, from the injured brain leads to both: 1) premature clot lysis and ICH expansion; and 2) neurotoxicity by excessive activation of N-methyl-D-aspartate receptors (NMDA-Rs) by tPA, which is not attenuated by TA or rVIIa. In support of this hypothesis, we show that a catalytically inactive tPA variant (tPAS481A) that specifically and in targeted fashion inhibits lysis of newly formed blood clots in the brain: a) attenuates expansion of ICH, b) reduces D-Dimers, c) lessens thrombocytopenia, d) decreases tPA mediated neurotoxicity, and e) improves neurological outcome post TBI. tPAS481A is significantly more effective than TA for all outcomes. We also developed tPA variants that selectively inhibit tPA-mediated neurotoxicity by blocking excessive NMDA-R mediated signal transduction, prevent fibrinolysis or block both pathways. We will test these tPA variants and use mice with genetic deletion of tPA to provide insight into the pathogenesis of progressive ICH post TBI and to develop novel therapeutic interventions.