Expansion of intracranial hemorrhage by tPA after traumatic brain injury

描述（由申请人提供）：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，在创伤后的第一个小时内脑出血的扩大是发病率和死亡率的一个强有力的预测指标。然而，目前预防非物质脑炎进展的方法收效甚微。脑损伤具有高度的促凝作用，脑外伤释放大量的组织因子（TF），导致血小板和凝血蛋白的局部活化。随后是全身性凝血酶介导的凝血功能障碍，这限制了非特异性抗纤溶氨甲环酸（TA）的疗效，这可能有助于解释使用重组因子VIIa （rVIIa）后死亡率增加的原因。我们提出了一个新的假说来解释脑出血扩大的病理生理和预防脑出血的新方法。我们推测，纤维蛋白溶解启动剂，组织型纤溶酶原激活剂（tPA）和尿激酶纤溶酶原激活剂，从损伤的大脑中显著释放导致：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）的神经毒性，而TA或rVIIa不会减弱这种活性。为了支持这一假设，我们证明了催化

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.