Abstract：
Disseminated intravascular coagulation (DIC) is a pathologic state that follows systemic injury and other diseases. Often a complication of sepsis or trauma, DIC causes coagulopathy associated with paradoxical thrombosis and hemorrhage. DIC upregulates the thrombotic pathways while simultaneously downregulating the fibrinolytic pathways that cause excessive fibrin deposition, microcirculatory thrombosis, multiorgan dysfunction, and consumptive coagulopathy with excessive bleeding. Given these opposing disease phenotypes, DIC management is challenging and includes treating the underlying disease and managing the coagulopathy. Currently, no therapies are approved for DIC. We have developed clot-targeted therapeutics that inhibit clot polymerization and activate clot fibrinolysis to manage DIC. We hypothesize that delivering both an anticoagulant and a fibrinolytic agent directly to clots will inhibit active clot polymerization while also breaking up pre-existing clots; therefore, reversing consumptive coagulopathy and restoring hemostatic balance. To test this hypothesis, we single- and dual-loaded fibrin-specific nanogels (FSNs) with antithrombinIII (ATIII) and/or tissue plasminogen activator (tPA) and evaluated their clot preventing and clot lysing abilities in vitro and in a rodent model of DIC. In vivo, single-loaded ATIII-FSNs decreased fibrin deposits in DIC organs and reduced blood loss when DIC rodents were injured. We also observed that the addition of tPA in dual-loaded ATIII-tPA-FSNs intensified the antithrombotic and fibrinolytic mechanisms, which proved advantageous for clot lysis and restoring platelet counts. However, the addition of tPA may have hindered wound healing capabilities when an injury was introduced. Our data supports the benefits of delivering both anticoagulants and fibrinolytic agents directly to clots to reduce the fibrin load and restore hemostatic balance in DIC.
摘要：
弥散性血管内凝血(DIC)是伴随全身损伤和其他疾病的病理状态。通常是败血症或创伤的并发症，DIC引起与矛盾的血栓形成和出血相关的凝血病。DIC上调血栓形成途径，同时下调导致过度纤维蛋白沉积的纤溶途径。微循环血栓形成，多器官功能障碍,和过度出血的消耗性凝血病。鉴于这些相反的疾病表型，DIC管理具有挑战性，包括治疗基础疾病和管理凝血病。目前,没有批准治疗DIC。我们已经开发了抑制凝块聚合并激活凝块纤维蛋白溶解以管理DIC的凝块靶向治疗剂。我们假设，将抗凝剂和纤维蛋白溶解剂直接递送到凝块将抑制活性凝块聚合，同时也打破预先存在的凝块;因此，逆转消耗性凝血障碍和恢复止血平衡。为了检验这个假设，我们使用抗凝血酶III(ATIII)和/或组织纤溶酶原激活剂(tPA)进行了单负载和双负载纤维蛋白特异性纳米凝胶(FSNs),并在体外和啮齿动物DIC模型中评估了它们的凝块预防和凝块溶解能力.在体内,单负载ATIII-FSNs减少了DIC器官中的纤维蛋白沉积，并减少了DIC啮齿动物受伤时的失血量。我们还观察到，在双负载ATIII-tPA-FSNs中添加tPA增强了抗血栓形成和纤溶机制，这证明有利于凝块溶解和恢复血小板计数。然而,当引入损伤时,添加tPA可能阻碍伤口愈合能力。我们的数据支持将抗凝剂和纤维蛋白溶解剂直接递送到凝块以减少DIC中的纤维蛋白负荷并恢复止血平衡的益处。
