Expansion of intracranial hemorrhage by tPA after traumatic brain injury

tPA对脑外伤后颅内出血的扩张作用

• 批准号: 8508346
• 负责人: Abd Alroof HIGAZI
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508346
• 关键词: Adopted; Alteplase; Antifibrinolytic Agents; Aprotinin; Attenuated; Binding; Blood Circulation; Blood Clot; Blood Coagulation Disorders; Blood coagulation; Brain; Brain Injuries; Brain imaging; Cause of Death; Cerebral hemisphere hemorrhage; Clinical; Coagulation Process; Cytolysis; Data; Deterioration; Development; Dose; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Evolution; Factor VIIa; Family suidae; Fibrin; Fibrin fragment D; Fibrinolysis; Figs - dietary; Functional disorder; Generations; Genetic; Hemorrhage; Hemostatic function; Histocompatibility Testing; Hour; Intervention; Intracranial Hemorrhages; Ischemia; Knowledge; Lead; Maps; Mediating; Medical; Modeling; Morbidity - disease rate; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nervous System Physiology; Neuraxis; Neurological outcome; Neurons; Outcome; Pathogenesis; Pathway interactions; Plasminogen; Plasminogen Activator; Platelet Activation; Prevention; Proteins; Reagent; Recombinants; Resistance; Signal Transduction; Specificity; Testing; Thrombin; Thrombocytopenia; Thromboplastin; Thrombosis; Thrombus; Time; Tissues; Tranexamic Acid; Trauma; Traumatic Brain Injury; Urokinase; Variant; base; cell injury; cerebrovascular; disability; hexanoic acid; improved; inhibitor/antagonist; injured; insight; lysine analog; meetings; mortality; neuroprotection; neurotoxic; neurotoxicity; novel; novel strategies; novel therapeutic intervention; premature; prevent; public health relevance; success

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.

描述（由申请人提供）：颅内出血（ICH）是脑外伤（TBI）的常见后遗症，也是死亡和残疾的主要原因。对于那些在最初的创伤中幸存下来的人，在创伤后的第一个小时内ICH的扩大是发病率和死亡率的一个强有力的预测因素。然而，目前预防ICH进展的方法取得的成功有限。损伤的脑是高度促凝的，并且TBI释放丰富的组织因子（TF），其导致局部血小板和凝血蛋白的活化。其次是全身性凝血酶介导的凝血病，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凝血因子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ICH扩张的病理生理学和一种新的预防方法。我们推测，纤维蛋白溶解引发剂，组织型纤溶酶原激活剂（tPA）和尿激酶纤溶酶原激活剂，从受伤的大脑中显着释放导致：1）过早凝块溶解和ICH扩张;和2）神经毒性的N-甲基-D-天冬氨酸受体（NMDA-Rs）的过度激活tPA，这是不减弱TA或rVIIa。为了支持这一假设，我们表明， 无活性tPA变体（tPAS 481 A），其特异性地和以靶向方式抑制脑中新形成的血凝块的溶解：a）减弱ICH的扩展，B）减少D-二聚体，c）减轻血小板减少症，d）降低tPA介导的神经毒性，和e）改善TBI后的神经学结果。tPAS481A在所有结局方面均显著优于TA。我们还开发了tPA变体，其通过阻断过度的NMDA-R介导的信号转导来选择性地抑制tPA介导的神经毒性，防止纤维蛋白溶解或阻断两种途径。我们将测试这些tPA变体，并使用tPA基因缺失的小鼠来深入了解TBI后进行性ICH的发病机制，并开发新的治疗干预措施。